SUBCHAPTER V—DRUGS AND DEVICES
Part A—Drugs and Devices
§351. Adulterated drugs and devices
A drug or device shall be deemed to be adulterated—
(a) Poisonous, insanitary, etc., ingredients; adequate controls in manufacture
(1) If it consists in whole or in part of any filthy, putrid, or decomposed substance; or (2)(A) if it has been prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth, or whereby it may have been rendered injurious to health; or (B) if it is a drug and the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this chapter as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess; or (C) if it is a compounded positron emission tomography drug and the methods used in, or the facilities and controls used for, its compounding, processing, packing, or holding do not conform to or are not operated or administered in conformity with the positron emission tomography compounding standards and the official monographs of the United States Pharmacopoeia to assure that such drug meets the requirements of this chapter as to safety and has the identity and strength, and meets the quality and purity characteristics, that it purports or is represented to possess; or (3) if its container is composed, in whole or in part, of any poisonous or deleterious substance which may render the contents injurious to health; or (4) if (A) it bears or contains, for purposes of coloring only, a color additive which is unsafe within the meaning of
(b) Strength, quality, or purity differing from official compendium
If it purports to be or is represented as a drug the name of which is recognized in an official compendium, and its strength differs from, or its quality or purity falls below, the standard set forth in such compendium. Such determination as to strength, quality, or purity shall be made in accordance with the tests or methods of assay set forth in such compendium, except that whenever tests or methods of assay have not been prescribed in such compendium, or such tests or methods of assay as are prescribed are, in the judgment of the Secretary, insufficient for the making of such determination, the Secretary shall bring such fact to the attention of the appropriate body charged with the revision of such compendium, and if such body fails within a reasonable time to prescribe tests or methods of assay which, in the judgment of the Secretary, are sufficient for purposes of this paragraph, then the Secretary shall promulgate regulations prescribing appropriate tests or methods of assay in accordance with which such determination as to strength, quality, or purity shall be made. No drug defined in an official compendium shall be deemed to be adulterated under this paragraph because it differs from the standard of strength, quality, or purity therefor set forth in such compendium, if its difference in strength, quality, or purity from such standard is plainly stated on its label. Whenever a drug is recognized in both the United States Pharmacopoeia and the Homoeopathic Pharmacopoeia of the United States it shall be subject to the requirements of the United States Pharmacopoeia unless it is labeled and offered for sale as a homoeopathic drug, in which case it shall be subject to the provisions of the Homoeopathic Pharmacopoeia of the United States and not to those of the United States Pharmacopoeia.
(c) Misrepresentation of strength, etc., where drug is unrecognized in compendium
If it is not subject to the provisions of paragraph (b) of this section and its strength differs from, or its purity or quality falls below, that which it purports or is represented to possess.
(d) Mixture with or substitution of another substance
If it is a drug and any substance has been (1) mixed or packed therewith so as to reduce its quality or strength or (2) substituted wholly or in part therefor.
(e) Devices not in conformity with performance standards
(1) If it is, or purports to be or is represented as, a device which is subject to a performance standard established under
(2) If it is declared to be, purports to be, or is represented as, a device that is in conformity with any standard recognized under
(f) Certain class III devices
(1) If it is a class III device—
(A)(i) which is required by an order issued under subsection (b) of
(ii)(I) for which an application for premarket approval or a notice of completion of a product development protocol was not filed with the Secretary within the ninety-day period beginning on the date of the issuance of such order, or
(II) for which such an application was filed and approval of the application has been denied, suspended, or withdrawn, or such a notice was filed and has been declared not completed or the approval of the device under the protocol has been withdrawn;
(B)(i) which was classified under
(ii) which has an application which has been suspended or is otherwise not in effect; or
(C) which was classified under
(2)(A) In the case of a device classified under
(B) In the case of a device subject to an order issued under subsection (b) of
(i) on the last day of the thirtieth calendar month beginning after the month in which the classification of the device in class III became effective under
(ii) on the ninetieth day after the date of the issuance of such order,
whichever occurs later.
(3) In the case of a device with respect to which a regulation was promulgated under
(g) Banned devices
If it is a banned device.
(h) Manufacture, packing, storage, or installation of device not in conformity with applicable requirements or conditions
If it is a device and the methods used in, or the facilities or controls used for, its manufacture, packing, storage, or installation are not in conformity with applicable requirements under
(i) Failure to comply with requirements under which device was exempted for investigational use
If it is a device for which an exemption has been granted under
(j) Delayed, denied, or limited inspection; refusal to permit entry or inspection
If it is a drug or device and it has been manufactured, processed, packed, or held in any factory, warehouse, or establishment and the owner, operator, or agent of such factory, warehouse, or establishment delays, denies, or limits an inspection, or refuses to permit entry or inspection.
For purposes of paragraph (a)(2)(B), the term "current good manufacturing practice" includes the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.
(June 25, 1938, ch. 675, §501,
Editorial Notes
Amendments
2017—Par. (j).
2012—
Par. (f)(1)(A)(i).
Par. (f)(1)(A)(ii)(I).
Par. (f)(2)(B).
Par. (f)(3).
Par. (j).
1997—Par. (a)(2)(C).
Par. (e).
1992—Par. (a)(4).
1990—Par. (f)(1).
1976—Par. (a).
Pars. (e) to (i).
1968—Par. (a).
1962—Par. (a).
1960—Par. (a).
Statutory Notes and Related Subsidiaries
Effective and Termination Dates of 1997 Amendment
Amendment by
Effective Date of 1968 Amendment
Amendment by
Effective Date of 1962 Amendment; Exceptions
Amendment by
Effective Date of 1960 Amendment
Amendment by
Effective Date; Postponement
Par. (a)(4) effective Jan. 1, 1940, see act June 23, 1939, ch. 242,
Approval by Regulation Prior to July 9, 2012
Guidance
Executive Documents
Transfer of Functions
For transfer of functions of Federal Security Administrator to Secretary of Health, Education, and Welfare [now Health and Human Services], and of Food and Drug Administration in the Department of Agriculture to Federal Security Agency, see notes set out under
1 So in original. Probably should be "subparagraph".
§352. Misbranded drugs and devices
A drug or device shall be deemed to be misbranded—
(a) False or misleading label
(1) If its labeling is false or misleading in any particular. Health care economic information provided to a payor, formulary committee, or other similar entity with knowledge and expertise in the area of health care economic analysis, carrying out its responsibilities for the selection of drugs or devices for coverage or reimbursement, shall not be considered to be false or misleading under this paragraph if the health care economic information relates to an indication approved under
(2)(A) For purposes of this paragraph,1 the term "health care economic information" means any analysis (including the clinical data, inputs, clinical or other assumptions, methods, results, and other components underlying or comprising the analysis) that identifies, measures, or describes the economic consequences, which may be based on the separate or aggregated clinical consequences of the represented health outcomes, of the use of a drug or device. Such analysis may be comparative to the use of another drug or device, to another health care intervention, or to no intervention.
(B) Such term does not include any analysis that relates only to an indication that is not approved under
(b) Package form; contents of label
If in package form unless it bears a label containing (1) the name and place of business of the manufacturer, packer, or distributor; and (2) an accurate statement of the quantity of the contents in terms of weight, measure, or numerical count: Provided, That under clause (2) of this paragraph reasonable variations shall be permitted, and exemptions as to small packages shall be established, by regulations prescribed by the Secretary.
(c) Prominence of information on label
If any word, statement, or other information required by or under authority of this chapter to appear on the label or labeling is not prominently placed thereon with such conspicuousness (as compared with other words, statements, designs, or devices, in the labeling) and in such terms as to render it likely to be read and understood by the ordinary individual under customary conditions of purchase and use.
(d) Repealed. Pub. L. 105–115, title I, §126(b), Nov. 21, 1997, 111 Stat. 2327
(e) Designation of drugs or devices by established names
(1)(A) If it is a drug, unless its label bears, to the exclusion of any other nonproprietary name (except the applicable systematic chemical name or the chemical formula)—
(i) the established name (as defined in subparagraph (3)) of the drug, if there is such a name;
(ii) the established name and quantity or, if determined to be appropriate by the Secretary, the proportion of each active ingredient, including the quantity, kind, and proportion of any alcohol, and also including whether active or not the established name and quantity or if determined to be appropriate by the Secretary, the proportion of any bromides, ether, chloroform, acetanilide, acetophenetidin, amidopyrine, antipyrine, atropine, hyoscine, hyoscyamine, arsenic, digitalis, digitalis glucosides, mercury, ouabain, strophanthin, strychnine, thyroid, or any derivative or preparation of any such substances, contained therein, except that the requirement for stating the quantity of the active ingredients, other than the quantity of those specifically named in this subclause, shall not apply to nonprescription drugs not intended for human use; and
(iii) the established name of each inactive ingredient listed in alphabetical order on the outside container of the retail package and, if determined to be appropriate by the Secretary, on the immediate container, as prescribed in regulation promulgated by the Secretary, except that nothing in this subclause shall be deemed to require that any trade secret be divulged, and except that the requirements of this subclause with respect to alphabetical order shall apply only to nonprescription drugs that are not also cosmetics and that this subclause shall not apply to nonprescription drugs not intended for human use.
(B) For any prescription drug the established name of such drug or ingredient, as the case may be, on such label (and on any labeling on which a name for such drug or ingredient is used) shall be printed prominently and in type at least half as large as that used thereon for any proprietary name or designation for such drug or ingredient, except that to the extent that compliance with the requirements of subclause (ii) or (iii) of clause (A) or this clause is impracticable, exemptions shall be established by regulations promulgated by the Secretary.
(2) If it is a device and it has an established name, unless its label bears, to the exclusion of any other nonproprietary name, its established name (as defined in subparagraph (4)) prominently printed in type at least half as large as that used thereon for any proprietary name or designation for such device, except that to the extent compliance with the requirements of this subparagraph is impracticable, exemptions shall be established by regulations promulgated by the Secretary.
(3) As used in subparagraph (1), the term "established name", with respect to a drug or ingredient thereof, means (A) the applicable official name designated pursuant to
(4) As used in subparagraph (2), the term "established name" with respect to a device means (A) the applicable official name of the device designated pursuant to
(f) Directions for use and warnings on label
Unless its labeling bears (1) adequate directions for use; and (2) such adequate warnings against use in those pathological conditions or by children where its use may be dangerous to health, or against unsafe dosage or methods or duration of administration or application, in such manner and form, as are necessary for the protection of users, except that where any requirement of clause (1) of this paragraph, as applied to any drug or device, is not necessary for the protection of the public health, the Secretary shall promulgate regulations exempting such drug or device from such requirement. Required labeling for prescription devices intended for use in health care facilities or by a health care professional and required labeling for in vitro diagnostic devices intended for use by health care professionals or in blood establishments may be made available solely by electronic means, provided that the labeling complies with all applicable requirements of law, and that the manufacturer affords such users the opportunity to request the labeling in paper form, and after such request, promptly provides the requested information without additional cost.
(g) Representations as recognized drug; packing and labeling; inconsistent requirements for designation of drug
If it purports to be a drug the name of which is recognized in an official compendium, unless it is packaged and labeled as prescribed therein. The method of packing may be modified with the consent of the Secretary. Whenever a drug is recognized in both the United States Pharmacopoeia and the Homoeopathic Pharmacopoeia of the United States, it shall be subject to the requirements of the United States Pharmacopoeia with respect to packaging and labeling unless it is labeled and offered for sale as a homoeopathic drug, in which case it shall be subject to the provisions of the Homoeopathic Pharmacopoeia of the United States, and not those of the United States Pharmacopoeia, except that in the event of inconsistency between the requirements of this paragraph and those of paragraph (e) as to the name by which the drug or its ingredients shall be designated, the requirements of paragraph (e) shall prevail.
(h) Deteriorative drugs; packing and labeling
If it has been found by the Secretary to be a drug liable to deterioration, unless it is packaged in such form and manner, and its label bears a statement of such precautions, as the Secretary shall by regulations require as necessary for the protection of the public health. No such regulation shall be established for any drug recognized in an official compendium until the Secretary shall have informed the appropriate body charged with the revision of such compendium of the need for such packaging or labeling requirements and such body shall have failed within a reasonable time to prescribe such requirements.
(i) Drug; misleading container; imitation; offer for sale under another name
(1) If it is a drug and its container is so made, formed, or filled as to be misleading; or (2) if it is an imitation of another drug; or (3) if it is offered for sale under the name of another drug.
(j) Health-endangering when used as prescribed
If it is dangerous to health when used in the dosage or manner, or with the frequency or duration prescribed, recommended, or suggested in the labeling thereof.
(k), (l) Repealed. Pub. L. 105–115, title I, §125(a)(2)(B), (b)(2)(D), Nov. 21, 1997, 111 Stat. 2325
(m) Color additives; packing and labeling
If it is a color additive the intended use of which is for the purpose of coloring only, unless its packaging and labeling are in conformity with such packaging and labeling requirements applicable to such color additive, as may be contained in regulations issued under
(n) Prescription drug advertisements: established name; quantitative formula; side effects, contraindications, and effectiveness; prior approval; false advertising; labeling; construction of the Convention on Psychotropic Substances
In the case of any prescription drug distributed or offered for sale in any State, unless the manufacturer, packer, or distributor thereof includes in all advertisements and other descriptive printed matter issued or caused to be issued by the manufacturer, packer, or distributor with respect to that drug a true statement of (1) the established name as defined in paragraph (e), printed prominently and in type at least half as large as that used for any trade or brand name thereof, (2) the formula showing quantitatively each ingredient of such drug to the extent required for labels under paragraph (e), and (3) such other information in brief summary relating to side effects, contraindications, and effectiveness as shall be required in regulations which shall be issued by the Secretary in accordance with
(o) Drugs or devices from nonregistered establishments
If it was manufactured, prepared, propagated, compounded, or processed in an establishment not duly registered under
(p) Packaging or labeling of drugs in violation of regulations
If it is a drug and its packaging or labeling is in violation of an applicable regulation issued pursuant to
(q) Restricted devices using false or misleading advertising or used in violation of regulations
In the case of any restricted device distributed or offered for sale in any State, if (1) its advertising is false or misleading in any particular, or (2) it is sold, distributed, or used in violation of regulations prescribed under
(r) Restricted devices not carrying requisite accompanying statements in advertisements and other descriptive printed matter
In the case of any restricted device distributed or offered for sale in any State, unless the manufacturer, packer, or distributor thereof includes in all advertisements and other descriptive printed matter issued or caused to be issued by the manufacturer, packer, or distributor with respect to that device (1) a true statement of the device's established name as defined in subsection (e), printed prominently and in type at least half as large as that used for any trade or brand name thereof, and (2) a brief statement of the intended uses of the device and relevant warnings, precautions, side effects, and contraindications and, in the case of specific devices made subject to a finding by the Secretary after notice and opportunity for comment that such action is necessary to protect the public health, a full description of the components of such device or the formula showing quantitatively each ingredient of such device to the extent required in regulations which shall be issued by the Secretary after an opportunity for a hearing. Except in extraordinary circumstances, no regulation issued under this paragraph shall require prior approval by the Secretary of the content of any advertisement and no advertisement of a restricted device, published after the effective date of this paragraph shall, with respect to the matters specified in this paragraph or covered by regulations issued hereunder, be subject to the provisions of
(s) Devices subject to performance standards not bearing requisite labeling
If it is a device subject to a performance standard established under
(t) Devices for which there has been a failure or refusal to give required notification or to furnish required material or information
If it is a device and there was a failure or refusal (1) to comply with any requirement prescribed under
(u) Identification of manufacturer
(1) Subject to paragraph (2), if it is a reprocessed single-use device, unless it, or an attachment thereto, prominently and conspicuously bears the name of the manufacturer of the reprocessed device, a generally recognized abbreviation of such name, or a unique and generally recognized symbol identifying such manufacturer.
(2) If the original device or an attachment thereto does not prominently and conspicuously bear the name of the manufacturer of the original device, a generally recognized abbreviation of such name, or a unique and generally recognized symbol identifying such manufacturer, a reprocessed device may satisfy the requirements of paragraph (1) through the use of a detachable label on the packaging that identifies the manufacturer and is intended to be affixed to the medical record of a patient.
(v) Reprocessed single-use devices
If it is a reprocessed single-use device, unless all labeling of the device prominently and conspicuously bears the statement "Reprocessed device for single use. Reprocessed by ____." The name of the manufacturer of the reprocessed device shall be placed in the space identifying the person responsible for reprocessing.
(w) New animal drugs
If it is a new animal drug—
(1) that is conditionally approved under
(2) that is indexed under
(3) for which an application has been approved under
(x) Nonprescription drugs
If it is a nonprescription drug (as defined in
(y) Drugs subject to approved risk evaluation and mitigation strategy
If it is a drug subject to an approved risk evaluation and mitigation strategy pursuant to
(z) Postmarket studies and clinical trials; new safety information in labeling
If it is a drug, and the responsible person (as such term is used in
(aa) Unpaid fees; failure to submit identifying information
If it is a drug, or an active pharmaceutical ingredient, and it was manufactured, prepared, propagated, compounded, or processed in a facility for which fees have not been paid as required by
(bb) False or misleading advertisement or promotion of compounded drug
If the advertising or promotion of a compounded drug is false or misleading in any particular.
(cc) Failure to bear product identifier
If it is a drug and it fails to bear the product identifier as required by
(dd) Improper labeling of antimicrobial drugs
If it is an antimicrobial drug, as defined in
(ee) Nonprescription drug subject to regulation
If it is a nonprescription drug that is subject to
(ff) Drugs manufactured, prepared, propagated, compounded, or processed in facilities for which fees have not been paid
If it is a drug and it was manufactured, prepared, propagated, compounded, or processed in a facility for which fees have not been paid as required by
(gg) Product information prior to approval
(1) Unless its labeling bears adequate directions for use in accordance with paragraph (f), except that (in addition to drugs or devices that conform with exemptions pursuant to such paragraph) no drug or device shall be deemed to be misbranded under such paragraph through the provision of truthful and not misleading product information to a payor, formulary committee, or other similar entity with knowledge and expertise in the area of health care economic analysis carrying out its responsibilities for the selection of drugs or devices for coverage or reimbursement if the product information relates to an investigational drug or device or investigational use of a drug or device that is approved, cleared, granted marketing authorization, or licensed under
(A) the product information includes—
(i) a clear statement that the investigational drug or device or investigational use of a drug or device has not been approved, cleared, granted marketing authorization, or licensed under
(ii) information related to the stage of development of the drug or device involved, such as—
(I) the status of any study or studies in which the investigational drug or device or investigational use is being investigated;
(II) how the study or studies relate to the overall plan for the development of the drug or device; and
(III) whether an application, premarket notification, or request for classification for the investigational drug or device or investigational use has been submitted to the Secretary and when such a submission is planned;
(iii) in the case of information that includes factual presentations of results from studies, which shall not be selectively presented, a description of—
(I) all material aspects of study design, methodology, and results; and
(II) all material limitations related to the study design, methodology, and results;
(iv) where applicable, a prominent statement disclosing the indication or indications for which the Secretary has approved, granted marketing authorization, cleared, or licensed the product pursuant to
(v) updated information, if previously communicated information becomes materially outdated as a result of significant changes or as a result of new information regarding the product or its review status; and
(B) the product information does not include—
(i) information that represents that an unapproved product—
(I) has been approved, cleared, granted marketing authorization, or licensed under
(II) has otherwise been determined to be safe or effective for the purpose or purposes for which the drug or device is being studied; or
(ii) information that represents that an unapproved use of a drug or device that has been so approved, granted marketing authorization, cleared, or licensed—
(I) is so approved, granted marketing authorization, cleared, or licensed; or
(II) that the product is safe or effective for the use or uses for which the drug or device is being studied.
(2) For purposes of this paragraph, the term "product information" includes—
(A) information describing the drug or device (such as drug class, device description, and features);
(B) information about the indication or indications being investigated;
(C) the anticipated timeline for a possible approval, clearance, marketing authorization, or licensure pursuant to
(D) drug or device pricing information;
(E) patient utilization projections;
(F) product-related programs or services; and
(G) factual presentations of results from studies that do not characterize or make conclusions regarding safety or efficacy.
(June 25, 1938, ch. 675, §502,
Editorial Notes
Amendments
2022—Subsec. (a)(1).
Subsec. (a)(2)(A).
Subsec. (a)(2)(B).
Subsec. (gg).
2020—Subsecs. (ee), (ff).
2018—Subsec. (w)(3).
2016—Subsec. (a).
Subsec. (dd).
2013—Par. (bb).
Par. (cc).
2012—Par. (o).
Par. (aa).
2007—Par. (n).
Pars. (y), (z).
2006—Par. (x).
2005—Par. (u).
2004—Par. (f).
Par. (w).
2002—Par. (f).
Par. (u).
Par. (v).
1997—Par. (a).
Par. (d).
Par. (e)(1).
Par. (k).
Par. (l).
1993—Par. (e)(3).
Par. (f).
Par. (g).
Par. (n).
1992—Par. (m).
Par. (t)(3).
1978—Par. (n).
1976—Par. (e).
Par. (j).
Par. (m).
Par. (o).
Pars. (q) to (t).
1970—Par. (p).
1968—Par. (l).
1962—Par. (e).
Par. (g).
Par. (l).
Par. (n).
Par. (o).
1960—Par. (m).
1953—Par. (l). Act Aug. 5, 1953, substituted "chlortetracycline" for "aureomycin".
1949—Par. (l). Act July 13, 1949, inserted ", aureomycin, chloramphenicol, or bacitracin" after "streptomycin".
1947—Par. (l). Act Mar. 10, 1947, inserted "or streptomycin" after "penicillin".
1945—Par. (l). Act July 6, 1945, added par. (l).
1941—Par. (k). Act Dec. 22, 1941, added par. (k).
1939—Par. (d). Act June 29, 1939, substituted "name, and quality or proportion" for "name, quantity, and percentage".
Statutory Notes and Related Subsidiaries
Effective Date of 2018 Amendment
Effective Date of 2012 Amendment
Amendment by section 306 of
Effective Date of 2007 Amendment
Amendment by
Effective Date of 2006 Amendment
"(1)
"(2)
Effective Date of 2002 Amendment
"(1) shall be effective—
"(A) with respect to devices described under paragraph (1) of such section, 12 months after the date of enactment of the Medical Device User Fee Stabilization Act of 2005 [Aug. 1, 2005], or the date on which the original device first bears the name of the manufacturer of the original device, a generally recognized abbreviation of such name, or a unique and generally recognized symbol identifying such manufacturer, whichever is later; and
"(B) with respect to devices described under paragraph (2) of such section 502(u), 12 months after such date of enactment; and
"(2) shall apply only to devices reprocessed and introduced or delivered for introduction in interstate commerce after such applicable effective date."
Effective Date of 1997 Amendment
Amendment by sections 114(a), 126(b), and 412(c) of
Effective Date of 1978 Amendment
Amendment by
Effective Date of 1970 Amendment
Amendment by
Effective Date of 1968 Amendment
Amendment by
Effective Date of 1962 Amendment
Amendment by
Effective Date of 1960 Amendment
Amendment by
Effective Date; Postponement
Pars. (b) and (d) to (h) effective Jan. 1, 1940, and such paragraphs effective July 1, 1940, as provided by regulations for certain lithographed labeling and containers bearing certain labeling, see act June 23, 1939, ch. 242,
Regulations
Construction of 2016 Amendment
Nothing in amendment by section 3044(b)(2) of
Presentation of Prescription Drug Benefit and Risk Information
"(a)
"(b)
"(c)
"(1) the determination by the Secretary under subsection (a); and
"(2) the reasoning and analysis underlying that determination.
"(d)
"(e)
Guidance; Misbranded Devices
Studies
"(1)
"(2)
Counterfeiting of Drugs; Congressional Findings and Declaration of Policy
Provisions as effective Feb. 1, 1966, see section 11 of
Executive Documents
Transfer of Functions
For transfer of functions of Federal Security Administrator to Secretary of Health, Education, and Welfare [now Health and Human Services], and of Food and Drug Administration in the Department of Agriculture to Federal Security Agency, see notes set out under
1 So in original. The term "health care economic information" appears only in par. (1).
§353. Exemptions and consideration for certain drugs, devices, and biological products
(a) Regulations for goods to be processed, labeled, or repacked elsewhere
The Secretary is directed to promulgate regulations exempting from any labeling or packaging requirement of this chapter drugs and devices which are, in accordance with the practice of the trade, to be processed, labeled, or repacked in substantial quantities at establishments other than those where originally processed or packed, on condition that such drugs and devices are not adulterated or misbranded under the provisions of this chapter upon removal from such processing, labeling, or repacking establishment.
(b) Prescription by physician; exemption from labeling and prescription requirements; misbranded drugs; compliance with narcotic and marihuana laws
(1) A drug intended for use by man which—
(A) because of its toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, is not safe for use except under the supervision of a practitioner licensed by law to administer such drug; or
(B) is limited by an approved application under
shall be dispensed only (i) upon a written prescription of a practitioner licensed by law to administer such drug, or (ii) upon an oral prescription of such practitioner which is reduced promptly to writing and filed by the pharmacist, or (iii) by refilling any such written or oral prescription if such refilling is authorized by the prescriber either in the original prescription or by oral order which is reduced promptly to writing and filed by the pharmacist. The act of dispensing a drug contrary to the provisions of this paragraph shall be deemed to be an act which results in the drug being misbranded while held for sale.
(2) Any drug dispensed by filling or refilling a written or oral prescription of a practitioner licensed by law to administer such drug shall be exempt from the requirements of
(3) The Secretary may by regulation remove drugs subject to
(4)(A) A drug that is subject to paragraph (1) shall be deemed to be misbranded if at any time prior to dispensing the label of the drug fails to bear, at a minimum, the symbol "Rx only".
(B) A drug to which paragraph (1) does not apply shall be deemed to be misbranded if at any time prior to dispensing the label of the drug bears the symbol described in subparagraph (A).
(5) Nothing in this subsection shall be construed to relieve any person from any requirement prescribed by or under authority of law with respect to drugs now included or which may hereafter be included within the classifications stated in
(c) Sales restrictions
(1) No person may sell, purchase, or trade or offer to sell, purchase, or trade any drug sample. For purposes of this paragraph and subsection (d), the term "drug sample" means a unit of a drug, subject to subsection (b), which is not intended to be sold and is intended to promote the sale of the drug. Nothing in this paragraph shall subject an officer or executive of a drug manufacturer or distributor to criminal liability solely because of a sale, purchase, trade, or offer to sell, purchase, or trade in violation of this paragraph by other employees of the manufacturer or distributor.
(2) No person may sell, purchase, or trade, offer to sell, purchase, or trade, or counterfeit any coupon. For purposes of this paragraph, the term "coupon" means a form which may be redeemed, at no cost or at a reduced cost, for a drug which is prescribed in accordance with subsection (b).
(3)(A) No person may sell, purchase, or trade, or offer to sell, purchase, or trade, any drug—
(i) which is subject to subsection (b), and
(ii)(I) which was purchased by a public or private hospital or other health care entity, or
(II) which was donated or supplied at a reduced price to a charitable organization described in
(B) Subparagraph (A) does not apply to—
(i) the purchase or other acquisition by a hospital or other health care entity which is a member of a group purchasing organization of a drug for its own use from the group purchasing organization or from other hospitals or health care entities which are members of such organization,
(ii) the sale, purchase, or trade of a drug or an offer to sell, purchase, or trade a drug by an organization described in subparagraph (A)(ii)(II) to a nonprofit affiliate of the organization to the extent otherwise permitted by law,
(iii) a sale, purchase, or trade of a drug or an offer to sell, purchase, or trade a drug among hospitals or other health care entities which are under common control,
(iv) a sale, purchase, or trade of a drug or an offer to sell, purchase, or trade a drug for emergency medical reasons, or
(v) a sale, purchase, or trade of a drug, an offer to sell, purchase, or trade a drug, or the dispensing of a drug pursuant to a prescription executed in accordance with subsection (b).
For purposes of this paragraph, the term "entity" does not include a wholesale distributor of drugs or a retail pharmacy licensed under State law and the term "emergency medical reasons" includes transfers of a drug between health care entities or from a health care entity to a retail pharmacy undertaken to alleviate temporary shortages of the drug arising from delays in or interruptions of regular distribution schedules.
(d) Distribution of drug samples
(1) Except as provided in paragraphs (2) and (3), no person may distribute any drug sample. For purposes of this subsection, the term "distribute" does not include the providing of a drug sample to a patient by a—
(A) practitioner licensed to prescribe such drug,
(B) health care professional acting at the direction and under the supervision of such a practitioner, or
(C) pharmacy of a hospital or of another health care entity that is acting at the direction of such a practitioner and that received such sample pursuant to paragraph (2) or (3).
(2)(A) The manufacturer or authorized distributor of record of a drug subject to subsection (b) may, in accordance with this paragraph, distribute drug samples by mail or common carrier to practitioners licensed to prescribe such drugs or, at the request of a licensed practitioner, to pharmacies of hospitals or other health care entities. Such a distribution of drug samples may only be made—
(i) in response to a written request for drug samples made on a form which meets the requirements of subparagraph (B), and
(ii) under a system which requires the recipient of the drug sample to execute a written receipt for the drug sample upon its delivery and the return of the receipt to the manufacturer or authorized distributor of record.
(B) A written request for a drug sample required by subparagraph (A)(i) shall contain—
(i) the name, address, professional designation, and signature of the practitioner making the request,
(ii) the identity of the drug sample requested and the quantity requested,
(iii) the name of the manufacturer of the drug sample requested, and
(iv) the date of the request.
(C) Each drug manufacturer or authorized distributor of record which makes distributions by mail or common carrier under this paragraph shall maintain, for a period of 3 years, the request forms submitted for such distributions and the receipts submitted for such distributions and shall maintain a record of distributions of drug samples which identifies the drugs distributed and the recipients of the distributions. Forms, receipts, and records required to be maintained under this subparagraph shall be made available by the drug manufacturer or authorized distributor of record to Federal and State officials engaged in the regulation of drugs and in the enforcement of laws applicable to drugs.
(3) The manufacturer or authorized distributor of record of a drug subject to subsection (b) may, by means other than mail or common carrier, distribute drug samples only if the manufacturer or authorized distributor of record makes the distributions in accordance with subparagraph (A) and carries out the activities described in subparagraphs (B) through (F) as follows:
(A) Drug samples may only be distributed—
(i) to practitioners licensed to prescribe such drugs if they make a written request for the drug samples, or
(ii) at the written request of such a licensed practitioner, to pharmacies of hospitals or other health care entities.
A written request for drug samples shall be made on a form which contains the practitioner's name, address, and professional designation, the identity of the drug sample requested, the quantity of drug samples requested, the name of the manufacturer or authorized distributor of record of the drug sample, the date of the request and signature of the practitioner making the request.
(B) Drug manufacturers or authorized distributors of record shall store drug samples under conditions that will maintain their stability, integrity, and effectiveness and will assure that the drug samples will be free of contamination, deterioration, and adulteration.
(C) Drug manufacturers or authorized distributors of record shall conduct, at least annually, a complete and accurate inventory of all drug samples in the possession of representatives of the manufacturer or authorized distributor of record. Drug manufacturers or authorized distributors of record shall maintain lists of the names and address of each of their representatives who distribute drug samples and of the sites where drug samples are stored. Drug manufacturers or authorized distributors of record shall maintain records for at least 3 years of all drug samples distributed, destroyed, or returned to the manufacturer or authorized distributor of record, of all inventories maintained under this subparagraph, of all thefts or significant losses of drug samples, and of all requests made under subparagraph (A) for drug samples. Records and lists maintained under this subparagraph shall be made available by the drug manufacturer or authorized distributor of record to the Secretary upon request.
(D) Drug manufacturers or authorized distributors of record shall notify the Secretary of any significant loss of drug samples and any known theft of drug samples.
(E) Drug manufacturers or authorized distributors of record shall report to the Secretary any conviction of their representatives for violations of subsection (c)(1) or a State law because of the sale, purchase, or trade of a drug sample or the offer to sell, purchase, or trade a drug sample.
(F) Drug manufacturers or authorized distributors of record shall provide to the Secretary the name and telephone number of the individual responsible for responding to a request for information respecting drug samples.
(4) In this subsection, the term "authorized distributors of record" means those distributors with whom a manufacturer has established an ongoing relationship to distribute such manufacturer's products.
(e) Licensing and reporting requirements for wholesale distributors; fees; definitions
(1)
(A)
(i)(I) is licensed by the State from which the drug is distributed; or
(II) if the State from which the drug is distributed has not established a licensure requirement, is licensed by the Secretary; and
(ii) if the drug is distributed interstate, is licensed by the State into which the drug is distributed if the State into which the drug is distributed requires the licensure of a person that distributes drugs into the State.
(B)
(2)
(A)
(i) report to the Secretary, on an annual basis pursuant to a schedule determined by the Secretary—
(I) each State by which the person is licensed and the appropriate identification number of each such license; and
(II) the name, address, and contact information of each facility at which, and all trade names under which, the person conducts business; and
(ii) report to the Secretary within a reasonable period of time and in a reasonable manner, as determined by the Secretary, any significant disciplinary actions, such as the revocation or suspension of a wholesale distributor license, taken by a State or the Federal Government during the reporting period against the wholesale distributor.
(B)
(i) identify each authorized wholesale distributor by name, contact information, and each State where such wholesale distributor is appropriately licensed to engage in wholesale distribution;
(ii) be available to the public on the Internet Web site of the Food and Drug Administration; and
(iii) be regularly updated on a schedule determined by the Secretary.
(C)
(D)
(3)
(A)
(B)
(4) For the purposes of this subsection and subsection (d), the term "wholesale distribution" means the distribution of a drug subject to subsection (b) to a person other than a consumer or patient, or receipt of a drug subject to subsection (b) by a person other than the consumer or patient, but does not include—
(A) intracompany distribution of any drug between members of an affiliate or within a manufacturer;
(B) the distribution of a drug, or an offer to distribute a drug among hospitals or other health care entities which are under common control;
(C) the distribution of a drug or an offer to distribute a drug for emergency medical reasons, including a public health emergency declaration pursuant to section 319 of the Public Health Service Act [
(D) the dispensing of a drug pursuant to a prescription executed in accordance with subsection (b)(1);
(E) the distribution of minimal quantities of drug by a licensed retail pharmacy to a licensed practitioner for office use;
(F) the distribution of a drug or an offer to distribute a drug by a charitable organization to a nonprofit affiliate of the organization to the extent otherwise permitted by law;
(G) the purchase or other acquisition by a dispenser, hospital, or other health care entity of a drug for use by such dispenser, hospital, or other health care entity;
(H) the distribution of a drug by the manufacturer of such drug;
(I) the receipt or transfer of a drug by an authorized third-party logistics provider provided that such third-party logistics provider does not take ownership of the drug;
(J) a common carrier that transports a drug, provided that the common carrier does not take ownership of the drug;
(K) the distribution of a drug, or an offer to distribute a drug by an authorized repackager that has taken ownership or possession of the drug and repacks it in accordance with
(L) salable drug returns when conducted by a dispenser;
(M) the distribution of a collection of finished medical devices, which may include a product or biological product, assembled in kit form strictly for the convenience of the purchaser or user (referred to in this subparagraph as a "medical convenience kit") if—
(i) the medical convenience kit is assembled in an establishment that is registered with the Food and Drug Administration as a device manufacturer in accordance with
(ii) the medical convenience kit does not contain a controlled substance that appears in a schedule contained in the Comprehensive Drug Abuse Prevention and Control Act of 1970 [
(iii) in the case of a medical convenience kit that includes a product, the person that manufacturers the kit—
(I) purchased such product directly from the pharmaceutical manufacturer or from a wholesale distributor that purchased the product directly from the pharmaceutical manufacturer; and
(II) does not alter the primary container or label of the product as purchased from the manufacturer or wholesale distributor; and
(iv) in the case of a medical convenience kit that includes a product, the product is—
(I) an intravenous solution intended for the replenishment of fluids and electrolytes;
(II) a product intended to maintain the equilibrium of water and minerals in the body;
(III) a product intended for irrigation or reconstitution;
(IV) an anesthetic;
(V) an anticoagulant;
(VI) a vasopressor; or
(VII) a sympathomimetic;
(N) the distribution of an intravenous drug that, by its formulation, is intended for the replenishment of fluids and electrolytes (such as sodium, chloride, and potassium) or calories (such as dextrose and amino acids);
(O) the distribution of an intravenous drug used to maintain the equilibrium of water and minerals in the body, such as dialysis solutions;
(P) the distribution of a drug that is intended for irrigation, or sterile water, whether intended for such purposes or for injection;
(Q) the distribution of medical gas, as defined in
(R) facilitating the distribution of a product by providing solely administrative services, including processing of orders and payments; or
(S) the transfer of a product by a hospital or other health care entity, or by a wholesale distributor or manufacturer operating at the direction of the hospital or other health care entity, to a repackager described in
(5)
(6)
(A) one business entity controls, or has the power to control, the other business entity; or
(B) a third party controls, or has the power to control, both of the business entities.
(f) Veterinary prescription drugs
(1)(A) A drug intended for use by animals other than man, other than a veterinary feed directive drug intended for use in animal feed or an animal feed bearing or containing a veterinary feed directive drug, which—
(i) because of its toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary for its use, is not safe for animal use except under the professional supervision of a licensed veterinarian, or
(ii) is limited by an approved application under subsection (b) of
shall be dispensed only by or upon the lawful written or oral order of a licensed veterinarian in the course of the veterinarian's professional practice.
(B) For purposes of subparagraph (A), an order is lawful if the order—
(i) is a prescription or other order authorized by law,
(ii) is, if an oral order, promptly reduced to writing by the person lawfully filling the order, and filed by that person, and
(iii) is refilled only if authorized in the original order or in a subsequent oral order promptly reduced to writing by the person lawfully filling the order, and filed by that person.
(C) The act of dispensing a drug contrary to the provisions of this paragraph shall be deemed to be an act which results in the drug being misbranded while held for sale.
(2) Any drug when dispensed in accordance with paragraph (1) of this subsection—
(A) shall be exempt from the requirements of
(B) shall be exempt from the packaging requirements of subsections (g), (h), and (p) of such section, if—
(i) when dispensed by a licensed veterinarian, the drug bears a label containing the name and address of the practitioner and any directions for use and cautionary statements specified by the practitioner, or
(ii) when dispensed by filling the lawful order of a licensed veterinarian, the drug bears a label containing the name and address of the dispenser, the serial number and date of the order or of its filling, the name of the licensed veterinarian, and the directions for use and cautionary statements, if any, contained in such order.
The preceding sentence shall not apply to any drug dispensed in the course of the conduct of a business of dispensing drugs pursuant to diagnosis by mail.
(3) The Secretary may by regulation exempt drugs for animals other than man subject to
(4) A drug which is subject to paragraph (1) shall be deemed to be misbranded if at any time prior to dispensing its label fails to bear the statement "Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian.". A drug to which paragraph (1) does not apply shall be deemed to be misbranded if at any time prior to dispensing its label bears the statement specified in the preceding sentence.
(g) Regulation of combination products
(1)(A) The Secretary shall, in accordance with this subsection, assign a primary agency center to regulate products that constitute a combination of a drug, device, or biological product.
(B) The Secretary shall conduct the premarket review of any combination product under a single application, whenever appropriate.
(C) For purposes of this subsection, the term "primary mode of action" means the single mode of action of a combination product expected to make the greatest contribution to the overall intended therapeutic effects of the combination product.
(D) The Secretary shall determine the primary mode of action of the combination product. If the Secretary determines that the primary mode of action is that of—
(i) a drug (other than a biological product), the agency center charged with premarket review of drugs shall have primary jurisdiction;
(ii) a device, the agency center charged with premarket review of devices shall have primary jurisdiction; or
(iii) a biological product, the agency center charged with premarket review of biological products shall have primary jurisdiction.
(E) In determining the primary mode of action of a combination product, the Secretary shall not determine that the primary mode of action is that of a drug or biological product solely because the combination product has any chemical action within or on the human body.
(F) If a sponsor of a combination product disagrees with the determination under subparagraph (D)—
(i) such sponsor may request, and the Secretary shall provide, a substantive rationale to such sponsor that references scientific evidence provided by the sponsor and any other scientific evidence relied upon by the Secretary to support such determination; and
(ii)(I) the sponsor of the combination product may propose one or more studies (which may be nonclinical, clinical, or both) to establish the relevance, if any, of the chemical action in achieving the primary mode of action of such product;
(II) if the sponsor proposes any such studies, the Secretary and the sponsor of such product shall collaborate and seek to reach agreement, within a reasonable time of such proposal, not to exceed 90 calendar days, on the design of such studies; and
(III) if an agreement is reached under subclause (II) and the sponsor conducts one or more of such studies, the Secretary shall consider the data resulting from any such study when reevaluating the determination of the primary mode of action of such product, and unless and until such reevaluation has occurred and the Secretary issues a new determination, the determination of the Secretary under subparagraph (D) shall remain in effect.
(2)(A) 1 (i) To establish clarity and certainty for the sponsor, the sponsor of a combination product may request a meeting on such combination product. If the Secretary concludes that a determination of the primary mode of action pursuant to paragraph (1)(D) is necessary, the sponsor may request such meeting only after the Secretary makes such determination. If the sponsor submits a written meeting request, the Secretary shall, not later than 75 calendar days after receiving such request, meet with the sponsor of such combination product.
(ii) A meeting under clause (i) may—
(I) address the standards and requirements for market approval or clearance of the combination product;
(II) address other issues relevant to such combination product, such as requirements related to postmarket modification of such combination product and good manufacturing practices applicable to such combination product; and
(III) identify elements under subclauses (I) and (II) that may be more appropriate for discussion and agreement with the Secretary at a later date given that scientific or other information is not available, or agreement is otherwise not feasible regarding such elements, at the time a request for such meeting is made.
(iii) Any agreement under this subparagraph shall be in writing and made part of the administrative record by the Secretary.
(iv) Any such agreement shall remain in effect, except—
(I) upon the written agreement of the Secretary and the sponsor or applicant; or
(II) pursuant to a decision by the director of the reviewing division of the primary agency center, or a person more senior than such director, in consultation with consulting centers and the Office, as appropriate, that an issue essential to determining whether the standard for market clearance or other applicable standard under this chapter or the Public Health Service Act [
(3) For purposes of conducting the premarket review of a combination product that contains an approved constituent part described in paragraph (4), the Secretary may require that the sponsor of such combination product submit to the Secretary only data or information that the Secretary determines is necessary to meet the standard for clearance or approval, as applicable, under this chapter or the Public Health Service Act, including any incremental risks and benefits posed by such combination product, using a risk-based approach and taking into account any prior finding of safety and effectiveness or substantial equivalence for the approved constituent part relied upon by the applicant in accordance with paragraph (5).
(4) For purposes of paragraph (3), an approved constituent part is—
(A) a drug constituent part of a combination product being reviewed in a single application or request under
(B) a device constituent part approved under
(C) any constituent part that was previously approved, cleared, or classified under
(5)(A) If an application is submitted under
(i) the application or request shall include the certification or statement described in
(ii) the applicant or requester shall provide notice as described in
(B) For purposes of this paragraph and paragraph (4), the term "approved drug" means an active ingredient—
(i) that was in an application previously approved under
(ii) where such application is relied upon by the applicant submitting the application or request described in subparagraph (A);
(iii) for which full reports of investigations that have been made to show whether such drug is safe for use and whether such drug is effective in use were not conducted by or for the applicant submitting the application or request described in subparagraph (A); and
(iv) for which the applicant submitting the application or request described in subparagraph (A) has not obtained a right of reference or use from the person by or for whom the investigations described in clause (iii) were conducted.
(C) The following provisions shall apply with respect to an application or request described in subparagraph (A) to the same extent and in the same manner as if such application or request were an application described in
(i) Subparagraphs (A), (B), (C), and (D) of
(ii) Clauses (ii), (iii), and (iv) of
(iii) Subsections (b) and (c) of
(iv)
(v)
(D) Notwithstanding any other provision of this subsection, an application or request for classification for a combination product described in subparagraph (A) shall be considered an application submitted under
(6) Nothing in this subsection shall be construed as prohibiting a sponsor from submitting separate applications for the constituent parts of a combination product, unless the Secretary determines that a single application is necessary.
(7) Nothing in this subsection shall prevent the Secretary from using any agency resources of the Food and Drug Administration necessary to ensure adequate review of the safety, effectiveness, or substantial equivalence of an article.
(8)(A) Not later than 60 days after October 26, 2002, the Secretary shall establish within the Office of the Commissioner of Food and Drugs an office to ensure the prompt assignment of combination products to agency centers, the timely and effective premarket review of such products, and consistent and appropriate postmarket regulation of like products subject to the same statutory requirements to the extent permitted by law. Additionally, the office shall, in determining whether a product is to be designated a combination product, consult with the component within the Office of the Commissioner of Food and Drugs that is responsible for such determinations. Such office (referred to in this paragraph as the "Office") shall have appropriate scientific and medical expertise, and shall be headed by a director.
(B) In carrying out this subsection, the Office shall, for each combination product, promptly assign an agency center with primary jurisdiction in accordance with paragraph (1) for the premarket review of such product.
(C)(i) In carrying out this subsection, the Office shall help to ensure timely and effective premarket review that involves more than one agency center by coordinating such reviews, overseeing the timeliness of such reviews, and overseeing the alignment of feedback regarding such reviews.
(ii) In order to ensure the timeliness and alignment of the premarket review of a combination product, the agency center with primary jurisdiction for the product, and the consulting agency center, shall be responsible to the Office with respect to the timeliness and alignment of the premarket review.
(iii) The Office shall ensure that, with respect to a combination product, a designated person or persons in the primary agency center is the primary point or points of contact for the sponsor of such combination product. The Office shall also coordinate communications to and from any consulting center involved in such premarket review, if requested by such primary agency center or any such consulting center. Agency communications and commitments, to the extent consistent with other provisions of law and the requirements of all affected agency centers, from the primary agency center shall be considered as communication from the Secretary on behalf of all agency centers involved in the review.
(iv) The Office shall, with respect to the premarket review of a combination product—
(I) ensure that any meeting between the Secretary and the sponsor of such product is attended by each agency center involved in the review, as appropriate;
(II) ensure that each consulting agency center has completed its premarket review and provided the results of such review to the primary agency center in a timely manner; and
(III) ensure that each consulting center follows the guidance described in clause (vi) and advises, as appropriate, on other relevant regulations, guidances, and policies.
(v) In seeking agency action with respect to a combination product, the sponsor of such product—
(I) shall identify the product as a combination product; and
(II) may request in writing the participation of representatives of the Office in meetings related to such combination product, or to have the Office otherwise engage on such regulatory matters concerning the combination product.
(vi) Not later than 4 years after December 13, 2016, and after a public comment period of not less than 60 calendar days, the Secretary shall issue a final guidance that describes—
(I) the structured process for managing pre-submission interactions with sponsors developing combination products;
(II) the best practices for ensuring that the feedback in such pre-submission interactions represents the Agency's best advice based on the information provided during such pre-submission interactions; 2
(III) the information that is required to be submitted with a meeting request under paragraph (2), how such meetings relate to other types of meetings in the Food and Drug Administration, and the form and content of any agreement reached through a meeting under such paragraph (2); 3
(D) In carrying out this subsection, the Office shall ensure the consistency and appropriateness of postmarket regulation of like products subject to the same statutory requirements to the extent permitted by law.
(E)(i) Any dispute regarding the timeliness of the premarket review of a combination product may be presented to the Office for resolution, unless the dispute is clearly premature.
(ii) During the review process, any dispute regarding the substance of the premarket review may be presented to the Commissioner of Food and Drugs after first being considered by the agency center with primary jurisdiction of the premarket review, under the scientific dispute resolution procedures for such center. The Commissioner of Food and Drugs shall consult with the Director of the Office in resolving the substantive dispute.
(F) The Secretary, acting through the Office, shall review each agreement, guidance, or practice of the Secretary that is specific to the assignment of combination products to agency centers and shall determine whether the agreement, guidance, or practice is consistent with the requirements of this subsection. In carrying out such review, the Secretary shall consult with stakeholders and the directors of the agency centers. After such consultation, the Secretary shall determine whether to continue in effect, modify, revise, or eliminate such agreement, guidance, or practice, and shall publish in the Federal Register a notice of the availability of such modified or revised agreement, guidance or practice. Nothing in this paragraph shall be construed as preventing the Secretary from following each agreement, guidance, or practice until continued, modified, revised, or eliminated.
(G) Not later than one year after October 26, 2002 (except with respect to clause (iv), beginning not later than one year after December 13, 2016), and annually thereafter, the Secretary shall report to the appropriate committees of Congress on the activities and impact of the Office. The report shall include provisions—
(i) describing the numbers and types of combination products under review and the timeliness in days of such assignments, reviews, and dispute resolutions;
(ii) identifying the number of premarket reviews of such products that involved a consulting agency center;
(iii) describing improvements in the consistency of postmarket regulation of combination products; and
(iv) identifying the percentage of combination products for which a dispute resolution, with respect to premarket review, was requested by the combination product's sponsor.
(H) Nothing in this paragraph shall be construed to limit the regulatory authority of any agency center.
(9) As used in this subsection:
(A) The term "agency center" means a center or alternative organizational component of the Food and Drug Administration.
(B) The term "biological product" has the meaning given the term in section 351(i) of the Public Health Service Act (
(C) The term "market clearance" includes—
(i) approval of an application under section 355, 357,4 360e, or 360j(g) of this title;
(ii) a finding of substantial equivalence under this part;
(iii) approval of a biologics license application under subsection (a) of section 351 of the Public Health Service Act (
(iv) de novo classification under
(D) The terms "premarket review" and "reviews" include all activities of the Food and Drug Administration conducted prior to approval or clearance of an application, notification, or request for classification submitted under
(h) Regulation of certain products as drugs
(1) Any contrast agent, radioactive drug, or OTC monograph drug shall be deemed to be a drug under
(2) For purposes of this subsection:
(A) The term "contrast agent" means an article that is intended for use in conjunction with a medical imaging device, and—
(i) is a diagnostic radiopharmaceutical, as defined in sections 315.2 and 601.31 of title 21, Code of Federal Regulations (or any successor regulations); or
(ii) is a diagnostic agent that improves the visualization of structure or function within the body by increasing the relative difference in signal intensity within the target tissue, structure, or fluid.
(B) The term "radioactive drug" has the meaning given such term in section 310.3(n) of title 21, Code of Federal Regulations (or any successor regulations), except that such term does not include—
(i) an implant or article similar to an implant;
(ii) an article that applies radiation from outside of the body; or
(iii) the radiation source of an article described in clause (i) or (ii).
(C) The term "OTC monograph drug" has the meaning given such term in
(3) Nothing in this subsection shall be construed as allowing for the classification of a product as a drug (as defined in
(A) is not described in paragraph (1); and
(B) meets the definition of a device under
unless another provision of this chapter otherwise indicates a different classification.
(4) The Secretary shall waive the application fee under
(A) on September 30, 2022, legally marketed as devices; and
(B) deemed drugs pursuant to paragraph (1) 5
(June 25, 1938, ch. 675, §503,
Editorial Notes
References in Text
The Comprehensive Drug Abuse Prevention and Control Act of 1970, referred to in subsec. (e)(4)(M)(ii), is
The Public Health Service Act, referred to in subsec. (g)(2)(A)(iv)(II), (3), is act July 1, 1944, ch. 373,
Codification
In subsec. (b)(5), "
Amendments
2022—Subsec. (h).
2016—Subsec. (g)(1).
"(A) a drug (other than a biological product), the agency center charged with premarket review of drugs shall have primary jurisdiction,
"(B) a device, the agency center charged with premarket review of devices shall have primary jurisdiction, or
"(C) a biological product, the agency center charged with premarket review of biological products shall have primary jurisdiction."
Subsec. (g)(2).
Subsec. (g)(3).
Subsec. (g)(4) to (6).
Subsec. (g)(7).
Subsec. (g)(8).
Subsec. (g)(8)(C)(i).
Subsec. (g)(8)(C)(ii).
Subsec. (g)(8)(C)(iii) to (vi).
Subsec. (g)(8)(G).
Subsec. (g)(8)(G)(iv).
Subsec. (g)(9).
Subsec. (g)(9)(C).
Subsec. (g)(9)(D).
2013—Subsec. (d)(4).
Subsec. (e).
2004—Subsec. (f)(1)(A)(ii).
Subsec. (f)(3).
2002—Subsec. (g)(1).
Subsec. (g)(1)(A) to (C).
Subsec. (g)(4).
Subsec. (g)(5).
1997—Subsec. (b)(1)(A) to (C).
Subsec. (b)(3).
Subsec. (b)(4).
Subsec. (g)(4)(A).
Subsec. (g)(4)(B)(iii).
1996—Subsec. (f)(1)(A).
1992—Subsec. (d)(1).
Subsec. (d)(2).
Subsec. (d)(3).
Subsec. (e)(1).
Subsec. (e)(2)(A).
Subsec. (e)(3).
Subsec. (e)(4).
Subsec. (f)(1)(B).
Subsec. (g)(3).
1991—Subsec. (c).
Subsec. (c)(2), (3)(B)(v).
Subsec. (d)(3)(E).
Subsec. (f).
Subsec. (g).
1990—
Subsec. (f).
1988—Subsec. (c).
Subsec. (d).
Subsec. (e).
1970—Subsec. (b)(2).
1962—Subsec. (b)(1)(C).
1951—Subsec. (b). Act Oct. 26, 1951, amended subsec. (b) generally to protect the public from abuses in the sale of potent prescription drugs, and to relieve retail pharmacists and the public from unnecessary restrictions on the dispensation of drugs that are safe to use without supervision of a doctor.
Statutory Notes and Related Subsidiaries
Effective Date of 2013 Amendment
Effective Date of 1997 Amendment
Amendment by
Termination Date of 1992 Amendment
Effective Date of 1988 Amendment
"(a)
"(b)
"(1) Section 503(d) of the Federal Food, Drug, and Cosmetic Act [
"(2) The Secretary of Health and Human Services shall by regulation issue the guidelines required by section 503(e)(2)(B) of the Federal Food, Drug, and Cosmetic Act [
Effective Date of 1970 Amendment
Amendment by
Effective Date of 1962 Amendment
Amendment by
Effective Date of 1951 Amendment
Amendment by act Oct. 26, 1951, effective six months after Oct. 26, 1951, see section 3 of act Oct. 26, 1951, set out as a note under
Effective Medication Guides
"(a)
"(b)
"(c)
"(1) identify the plan goals;
"(2) assess the effectiveness of the current private-sector approaches used to provide oral and written prescription information to consumers;
"(3) develop guidelines for providing effective oral and written prescription information consistent with the findings of any such assessment;
"(4) contain elements necessary to ensure the transmittal of useful information to the consuming public, including being scientifically accurate, non-promotional in tone and content, sufficiently specific and comprehensive as to adequately inform consumers about the use of the product, and in an understandable, legible format that is readily comprehensible and not confusing to consumers expected to use the product.[;]
"(5) develop a mechanism to assess periodically the quality of the oral and written prescription information and the frequency with which the information is provided to consumers; and
"(6) provide for compliance with relevant State board regulations.
"(d)
"(e)
Congressional Findings
"(1) American consumers cannot purchase prescription drugs with the certainty that the products are safe and effective.
"(2) The integrity of the distribution system for prescription drugs is insufficient to prevent the introduction and eventual retail sale of substandard, ineffective, or even counterfeit drugs.
"(3) The existence and operation of a wholesale submarket, commonly known as the 'diversion market', prevents effective control over or even routine knowledge of the true sources of prescription drugs in a significant number of cases.
"(4) Large amounts of drugs are being reimported to the United States as American goods returned. These imports are a health and safety risk to American consumers because they may have become subpotent or adulterated during foreign handling and shipping.
"(5) The ready market for prescription drug reimports has been the catalyst for a continuing series of frauds against American manufacturers and has provided the cover for the importation of foreign counterfeit drugs.
"(6) The existing system of providing drug samples to physicians through manufacturer's representatives has been abused for decades and has resulted in the sale to consumers of misbranded, expired, and adulterated pharmaceuticals.
"(7) The bulk resale of below wholesale priced prescription drugs by health care entities, for ultimate sale at retail, helps fuel the diversion market and is an unfair form of competition to wholesalers and retailers that must pay otherwise prevailing market prices.
"(8) The effect of these several practices and conditions is to create an unacceptable risk that counterfeit, adulterated, misbranded, subpotent, or expired drugs will be sold to American consumers."
Executive Documents
Transfer of Functions
For transfer of functions of Federal Security Administrator to Secretary of Health, Education, and Welfare [now Health and Human Services], and of Food and Drug Administration in the Department of Agriculture to Federal Security Agency, see notes set out under
1 So in original. No subpar. (B) has been enacted.
2 So in original. The word "and" probably should appear.
3 So in original. The semicolon probably should be a period.
4 See References in Text note below.
5 So in original. Probably should be followed by a period.
§353a. Pharmacy compounding
(a) In general
(1) is by—
(A) a licensed pharmacist in a State licensed pharmacy or a Federal facility, or
(B) a licensed physician,
on the prescription order for such individual patient made by a licensed physician or other licensed practitioner authorized by State law to prescribe drugs; or
(2)(A) is by a licensed pharmacist or licensed physician in limited quantities before the receipt of a valid prescription order for such individual patient; and
(B) is based on a history of the licensed pharmacist or licensed physician receiving valid prescription orders for the compounding of the drug product, which orders have been generated solely within an established relationship between—
(i) the licensed pharmacist or licensed physician; and
(ii)(I) such individual patient for whom the prescription order will be provided; or
(II) the physician or other licensed practitioner who will write such prescription order.
(b) Compounded drug
(1) Licensed pharmacist and licensed physician
A drug product may be compounded under subsection (a) if the licensed pharmacist or licensed physician—
(A) compounds the drug product using bulk drug substances, as defined in regulations of the Secretary published at section 207.3(a)(4) of title 21 of the Code of Federal Regulations—
(i) that—
(I) comply with the standards of an applicable United States Pharmacopoeia or National Formulary monograph, if a monograph exists, and the United States Pharmacopoeia chapter on pharmacy compounding;
(II) if such a monograph does not exist, are drug substances that are components of drugs approved by the Secretary; or
(III) if such a monograph does not exist and the drug substance is not a component of a drug approved by the Secretary, that appear on a list developed by the Secretary through regulations issued by the Secretary under subsection (c);
(ii) that are manufactured by an establishment that is registered under
(iii) that are accompanied by valid certificates of analysis for each bulk drug substance;
(B) compounds the drug product using ingredients (other than bulk drug substances) that comply with the standards of an applicable United States Pharmacopoeia or National Formulary monograph, if a monograph exists, and the United States Pharmacopoeia chapter on pharmacy compounding;
(C) does not compound a drug product that appears on a list published by the Secretary in the Federal Register of drug products that have been withdrawn or removed from the market because such drug products or components of such drug products have been found to be unsafe or not effective; and
(D) does not compound regularly or in inordinate amounts (as defined by the Secretary) any drug products that are essentially copies of a commercially available drug product.
(2) Definition
For purposes of paragraph (1)(D), the term "essentially a copy of a commercially available drug product" does not include a drug product in which there is a change, made for an identified individual patient, which produces for that patient a significant difference, as determined by the prescribing practitioner, between the compounded drug and the comparable commercially available drug product.
(3) Drug product
A drug product may be compounded under subsection (a) only if—
(A) such drug product is not a drug product identified by the Secretary by regulation as a drug product that presents demonstrable difficulties for compounding that reasonably demonstrate an adverse effect on the safety or effectiveness of that drug product; and
(B) such drug product is compounded in a State—
(i) that has entered into a memorandum of understanding with the Secretary which addresses the distribution of inordinate amounts of compounded drug products interstate and provides for appropriate investigation by a State agency of complaints relating to compounded drug products distributed outside such State; or
(ii) that has not entered into the memorandum of understanding described in clause (i) and the licensed pharmacist, licensed pharmacy, or licensed physician distributes (or causes to be distributed) compounded drug products out of the State in which they are compounded in quantities that do not exceed 5 percent of the total prescription orders dispensed or distributed by such pharmacy or physician.
The Secretary shall, in consultation with the National Association of Boards of Pharmacy, develop a standard memorandum of understanding for use by the States in complying with subparagraph (B)(i).
(c) Regulations
(1) In general
The Secretary shall issue regulations to implement this section. Before issuing regulations to implement subsections (b)(1)(A)(i)(III), (b)(1)(C), or (b)(3)(A), the Secretary shall convene and consult an advisory committee on compounding unless the Secretary determines that the issuance of such regulations before consultation is necessary to protect the public health. The advisory committee shall include representatives from the National Association of Boards of Pharmacy, the United States Pharmacopoeia, pharmacy, physician, and consumer organizations, and other experts selected by the Secretary.
(2) Limiting compounding
The Secretary, in consultation with the United States Pharmacopoeia Convention, Incorporated, shall promulgate regulations identifying drug substances that may be used in compounding under subsection (b)(1)(A)(i)(III) for which a monograph does not exist or which are not components of drug products approved by the Secretary. The Secretary shall include in the regulation the criteria for such substances, which shall include historical use, reports in peer reviewed medical literature, or other criteria the Secretary may identify.
(d) Application
This section shall not apply to—
(1) compounded positron emission tomography drugs as defined in
(2) radiopharmaceuticals.
(e) "Compounding" defined
As used in this section, the term "compounding" does not include mixing, reconstituting, or other such acts that are performed in accordance with directions contained in approved labeling provided by the product's manufacturer and other manufacturer directions consistent with that labeling.
(June 25, 1938, ch. 675, §503A, as added
Editorial Notes
Amendments
2013—Subsec. (a).
Subsec. (b)(1)(A)(i)(III).
Subsecs. (c) to (f).
Statutory Notes and Related Subsidiaries
Effective Date
§353a–1. Enhanced communication
(a) Submissions from State boards of pharmacy
In a manner specified by the Secretary of Health and Human Services (referred to in this section as the "Secretary"), the Secretary shall receive submissions from State boards of pharmacy—
(1) describing actions taken against compounding pharmacies, as described in subsection (b); or
(2) expressing concerns that a compounding pharmacy may be acting contrary to
(b) Content of submissions from State boards of pharmacy
An action referred to in subsection (a)(1) is, with respect to a pharmacy that compounds drugs, any of the following:
(1) The issuance of a warning letter, or the imposition of sanctions or penalties, by a State for violations of a State's pharmacy regulations pertaining to compounding.
(2) The suspension or revocation of a State-issued pharmacy license or registration for violations of a State's pharmacy regulations pertaining to compounding.
(3) The recall of a compounded drug due to concerns relating to the quality or purity of such drug.
(c) Consultation
The Secretary shall implement subsection (a) in consultation with the National Association of Boards of Pharmacy.
(d) Notifying State boards of pharmacy
The Secretary shall immediately notify State boards of pharmacy when—
(1) the Secretary receives a submission under subsection (a)(1); or
(2) the Secretary makes a determination that a pharmacy is acting contrary to
(
Editorial Notes
Codification
Section was enacted as part of the Compounding Quality Act and also as part of the Drug Quality and Security Act, and not as part of the Federal Food, Drug, and Cosmetic Act which comprises this chapter.
§353b. Outsourcing facilities
(a) In general
(1) Registration and reporting
The drug is compounded in an outsourcing facility that is in compliance with the requirements of subsection (b).
(2) Bulk drug substances
The drug is compounded in an outsourcing facility that does not compound using bulk drug substances (as defined in section 207.3(a)(4) of title 21, Code of Federal Regulations (or any successor regulation)), unless—
(A)(i) the bulk drug substance appears on a list established by the Secretary identifying bulk drug substances for which there is a clinical need, by—
(I) publishing a notice in the Federal Register proposing bulk drug substances to be included on the list, including the rationale for such proposal;
(II) providing a period of not less than 60 calendar days for comment on the notice; and
(III) publishing a notice in the Federal Register designating bulk drug substances for inclusion on the list; or
(ii) the drug compounded from such bulk drug substance appears on the drug shortage list in effect under
(B) if an applicable monograph exists under the United States Pharmacopeia, the National Formulary, or another compendium or pharmacopeia recognized by the Secretary for purposes of this paragraph, the bulk drug substances each comply with the monograph;
(C) the bulk drug substances are each manufactured by an establishment that is registered under
(D) the bulk drug substances are each accompanied by a valid certificate of analysis.
(3) Ingredients (other than bulk drug substances)
If any ingredients (other than bulk drug substances) are used in compounding the drug, such ingredients comply with the standards of the applicable United States Pharmacopeia or National Formulary monograph, if such monograph exists, or of another compendium or pharmacopeia recognized by the Secretary for purposes of this paragraph if any.
(4) Drugs withdrawn or removed because unsafe or not effective
The drug does not appear on a list published by the Secretary of drugs that have been withdrawn or removed from the market because such drugs or components of such drugs have been found to be unsafe or not effective.
(5) Essentially a copy of an approved drug
The drug is not essentially a copy of one or more approved drugs.
(6) Drugs presenting demonstrable difficulties for compounding
The drug—
(A) is not identified (directly or as part of a category of drugs) on a list published by the Secretary, through the process described in subsection (c), of drugs or categories of drugs that present demonstrable difficulties for compounding that are reasonably likely to lead to an adverse effect on the safety or effectiveness of the drug or category of drugs, taking into account the risks and benefits to patients; or
(B) is compounded in accordance with all applicable conditions identified on the list described in subparagraph (A) as conditions that are necessary to prevent the drug or category of drugs from presenting the demonstrable difficulties described in subparagraph (A).
(7) Elements to assure safe use
In the case of a drug that is compounded from a drug that is the subject of a risk evaluation and mitigation strategy approved with elements to assure safe use pursuant to
(8) Prohibition on wholesaling
The drug will not be sold or transferred by an entity other than the outsourcing facility that compounded such drug. This paragraph does not prohibit administration of a drug in a health care setting or dispensing a drug pursuant to a prescription executed in accordance with
(9) Fees
The drug is compounded in an outsourcing facility that has paid all fees owed by such facility pursuant to
(10) Labeling of drugs
(A) Label
The label of the drug includes—
(i) the statement "This is a compounded drug." or a reasonable comparable alternative statement (as specified by the Secretary) that prominently identifies the drug as a compounded drug;
(ii) the name, address, and phone number of the applicable outsourcing facility; and
(iii) with respect to the drug—
(I) the lot or batch number;
(II) the established name of the drug;
(III) the dosage form and strength;
(IV) the statement of quantity or volume, as appropriate;
(V) the date that the drug was compounded;
(VI) the expiration date;
(VII) storage and handling instructions;
(VIII) the National Drug Code number, if available;
(IX) the statement "Not for resale", and, if the drug is dispensed or distributed other than pursuant to a prescription for an individual identified patient, the statement "Office Use Only"; and
(X) subject to subparagraph (B)(i), a list of active and inactive ingredients, identified by established name and the quantity or proportion of each ingredient.
(B) Container
The container from which the individual units of the drug are removed for dispensing or for administration (such as a plastic bag containing individual product syringes) shall include—
(i) the information described under subparagraph (A)(iii)(X), if there is not space on the label for such information;
(ii) the following information to facilitate adverse event reporting: www.fda.gov/medwatch and 1–800–FDA–1088 (or any successor Internet Web site or phone number); and
(iii) directions for use, including, as appropriate, dosage and administration.
(C) Additional information
The label and labeling of the drug shall include any other information as determined necessary and specified in regulations promulgated by the Secretary.
(11) Outsourcing facility requirement
The drug is compounded in an outsourcing facility in which the compounding of drugs occurs only in accordance with this section.
(b) Registration of outsourcing facilities and reporting of drugs
(1) Registration of outsourcing facilities
(A) Annual registration
Upon electing and in order to become an outsourcing facility, and during the period beginning on October 1 and ending on December 31 of each year thereafter, a facility—
(i) shall register with the Secretary its name, place of business, and unique facility identifier (which shall conform to the requirements for the unique facility identifier established under
(ii) shall indicate whether the outsourcing facility intends to compound a drug that appears on the list in effect under
(B) Availability of registration for inspection; list
(i) Registrations
The Secretary shall make available for inspection, to any person so requesting, any registration filed pursuant to this paragraph.
(ii) List
The Secretary shall make available on the public Internet Web site of the Food and Drug Administration a list of the name of each facility registered under this subsection as an outsourcing facility, the State in which each such facility is located, whether the facility compounds from bulk drug substances, and whether any such compounding from bulk drug substances is for sterile or nonsterile drugs.
(2) Drug reporting by outsourcing facilities
(A) In general
Upon initially registering as an outsourcing facility, once during the month of June of each year, and once during the month of December of each year, each outsourcing facility that registers with the Secretary under paragraph (1) shall submit to the Secretary a report—
(i) identifying the drugs compounded by such outsourcing facility during the previous 6-month period; and
(ii) with respect to each drug identified under clause (i), providing the active ingredient, the source of such active ingredient, the National Drug Code number of the source drug or bulk active ingredient, if available, the strength of the active ingredient per unit, the dosage form and route of administration, the package description, the number of individual units produced, and the National Drug Code number of the final product, if assigned.
(B) Form
Each report under subparagraph (A) shall be prepared in such form and manner as the Secretary may prescribe by regulation or guidance.
(C) Confidentiality
Reports submitted under this paragraph shall be exempt from inspection under paragraph (1)(B)(i), unless the Secretary finds that such an exemption would be inconsistent with the protection of the public health.
(3) Electronic registration and reporting
Registrations and drug reporting under this subsection (including the submission of updated information) shall be submitted to the Secretary by electronic means unless the Secretary grants a request for waiver of such requirement because use of electronic means is not reasonable for the person requesting waiver.
(4) Risk-based inspection frequency
(A) In general
Outsourcing facilities—
(i) shall be subject to inspection pursuant to
(ii) shall not be eligible for the exemption under
(B) Risk-based schedule
The Secretary, acting through one or more officers or employees duly designated by the Secretary, shall inspect outsourcing facilities in accordance with a risk-based schedule established by the Secretary.
(C) Risk factors
In establishing the risk-based schedule, the Secretary shall inspect outsourcing facilities according to the known safety risks of such outsourcing facilities, which shall be based on the following factors:
(i) The compliance history of the outsourcing facility.
(ii) The record, history, and nature of recalls linked to the outsourcing facility.
(iii) The inherent risk of the drugs compounded at the outsourcing facility.
(iv) The inspection frequency and history of the outsourcing facility, including whether the outsourcing facility has been inspected pursuant to
(v) Whether the outsourcing facility has registered under this paragraph as an entity that intends to compound a drug that appears on the list in effect under
(vi) Any other criteria deemed necessary and appropriate by the Secretary for purposes of allocating inspection resources.
(5) Adverse event reporting
Outsourcing facilities shall submit adverse event reports to the Secretary in accordance with the content and format requirements established through guidance or regulation under section 310.305 of title 21, Code of Federal Regulations (or any successor regulations).
(c) Regulations
(1) In general
The Secretary shall implement the list described in subsection (a)(6) through regulations.
(2) Advisory committee on compounding
Before issuing regulations to implement subsection (a)(6), the Secretary shall convene and consult an advisory committee on compounding. The advisory committee shall include representatives from the National Association of Boards of Pharmacy, the United States Pharmacopeia, pharmacists with current experience and expertise in compounding, physicians with background and knowledge in compounding, and patient and public health advocacy organizations.
(3) Interim list
(A) In general
Before the effective date of the regulations finalized to implement subsection (a)(6), the Secretary may designate drugs, categories of drugs, or conditions as described such 1 subsection by—
(i) publishing a notice of such substances, drugs, categories of drugs, or conditions proposed for designation, including the rationale for such designation, in the Federal Register;
(ii) providing a period of not less than 60 calendar days for comment on the notice; and
(iii) publishing a notice in the Federal Register designating such drugs, categories of drugs, or conditions.
(B) Sunset of notice
Any notice provided under subparagraph (A) shall not be effective after the earlier of—
(i) the date that is 5 years after November 27, 2013; or
(ii) the effective date of the final regulations issued to implement subsection (a)(6).
(4) Updates
The Secretary shall review, and update as necessary, the regulations containing the lists of drugs, categories of drugs, or conditions described in subsection (a)(6) regularly, but not less than once every 4 years. Nothing in the previous sentence prohibits submissions to the Secretary, before or during any 4-year period described in such sentence, requesting updates to such lists.
(d) 2 Definitions
In this section:
(1) The term "compounding" includes the combining, admixing, mixing, diluting, pooling, reconstituting, or otherwise altering of a drug or bulk drug substance to create a drug.
(2) The term "essentially a copy of an approved drug" means—
(A) a drug that is identical or nearly identical to an approved drug, or a marketed drug not subject to
(B) a drug, a component of which is a bulk drug substance that is a component of an approved drug or a marketed drug that is not subject to
(3) The term "approved drug" means a drug that is approved under
(4)(A) The term "outsourcing facility" means a facility at one geographic location or address that—
(i) is engaged in the compounding of sterile drugs;
(ii) has elected to register as an outsourcing facility; and
(iii) complies with all of the requirements of this section.
(B) An outsourcing facility is not required to be a licensed pharmacy.
(C) An outsourcing facility may or may not obtain prescriptions for identified individual patients.
(5) The term "sterile drug" means a drug that is intended for parenteral administration, an ophthalmic or oral inhalation drug in aqueous format, or a drug that is required to be sterile under Federal or State law.
(d) 2 Obligation to pay fees
Payment of the fee under
(June 25, 1938, ch. 675, §503B, as added
Editorial Notes
Prior Provisions
A prior section 503B of act June 25, 1938, ch. 675, was renumbered section 503C by
2 So in original. Two subsecs. (d) have been enacted.
§353c. Prereview of television advertisements
(a) In general
The Secretary may require the submission of any television advertisement for a drug (including any script, story board, rough, or a completed video production of the television advertisement) to the Secretary for review under this section not later than 45 days before dissemination of the television advertisement.
(b) Review
In conducting a review of a television advertisement under this section, the Secretary may make recommendations with respect to information included in the label of the drug—
(1) on changes that are—
(A) necessary to protect the consumer good and well-being; or
(B) consistent with prescribing information for the product under review; and
(2) if appropriate and if information exists, on statements for inclusion in the advertisement to address the specific efficacy of the drug as it relates to specific population groups, including elderly populations, children, and racial and ethnic minorities.
(c) No authority to require changes
Except as provided by subsection (e), this section does not authorize the Secretary to make or direct changes in any material submitted pursuant to subsection (a).
(d) Elderly populations, children, racially and ethnically diverse communities
In formulating recommendations under subsection (b), the Secretary shall take into consideration the impact of the advertised drug on elderly populations, children, and racially and ethnically diverse communities.
(e) Specific disclosures
(1) Serious risk; safety protocol
In conducting a review of a television advertisement under this section, if the Secretary determines that the advertisement would be false or misleading without a specific disclosure about a serious risk listed in the labeling of the drug involved, the Secretary may require inclusion of such disclosure in the advertisement.
(2) Date of approval
In conducting a review of a television advertisement under this section, the Secretary may require the advertisement to include, for a period not to exceed 2 years from the date of the approval of the drug under
(f) Rule of construction
Nothing in this section may be construed as having any effect on requirements under
(June 25, 1938, ch. 675, §503C, formerly §503B, as added
Editorial Notes
Codification
Section was formerly classified to
Statutory Notes and Related Subsidiaries
Effective Date
Section effective 180 days after Sept. 27, 2007, see section 909 of
§353d. Process to update labeling for certain generic drugs
(a) Definitions
For purposes of this section:
(1) The term "covered drug" means a drug approved under
(A) for which there are no unexpired patents included in the list under
(B) for which the approval of the application has been withdrawn for reasons other than safety or effectiveness; and
(C) for which—
(i)(I) there is new scientific evidence available pertaining to new or existing conditions of use that is not reflected in the approved labeling;
(II) the approved labeling does not reflect current legal and regulatory requirements for content or format; or
(III) there is a relevant accepted use in clinical practice that is not reflected in the approved labeling; and
(ii) updating the approved labeling would benefit the public health.
(2) The term "period of exclusivity", with respect to a drug approved under
(3) The term "generic version" means a drug approved under
(4) The term "relevant accepted use" means a use for a drug in clinical practice that is supported by scientific evidence that appears to the Secretary to meet the standards for approval under
(5) The term "selected drug" means a covered drug for which the Secretary has determined through the process under subsection (c) that the labeling should be changed.
(b) Identification of covered drugs
The Secretary may identify covered drugs for which labeling updates would provide a public health benefit. To assist in identifying covered drugs, the Secretary may do one or both of the following:
(1) Enter into cooperative agreements or contracts with public or private entities to review the available scientific evidence concerning such drugs.
(2) Seek public input concerning such drugs, including input on whether there is a relevant accepted use in clinical practice that is not reflected in the approved labeling of such drugs or whether new scientific evidence is available regarding the conditions of use for such drug, by—
(A) holding one or more public meetings;
(B) opening a public docket for the submission of public comments; or
(C) other means, as the Secretary determines appropriate.
(c) Selection of drugs for updating
If the Secretary determines, with respect to a covered drug, that the available scientific evidence meets the standards under
(d) Initiation of the process of updating
If the Secretary determines that labeling changes are appropriate for a selected drug pursuant to subsection (c), the Secretary shall provide notice to the holders of approved applications for a generic version of such drug that—
(1) summarizes the findings supporting the determination of the Secretary that the available scientific evidence meets the standards under
(2) provides a clear statement regarding the additional, modified, or supplemental information for such labeling, according to the determination by the Secretary (including, as applicable, modifications to add the relevant accepted use to the labeling of the drug as an additional indication for the drug); and
(3) states whether the statement under paragraph (2) applies to the selected drug as a class of covered drugs or only to a specific drug product.
(e) Response to notification
Within 30 days of receipt of notification provided by the Secretary pursuant to subsection (d), the holder of an approved application for a generic version of the selected drug shall—
(1) agree to change the approved labeling to reflect the additional, modified, or supplemental information the Secretary has determined to be appropriate; or
(2) notify the Secretary that the holder of the approved application does not believe that the requested labeling changes are warranted and submit a statement detailing the reasons why such changes are not warranted.
(f) Review of application holder's response
(1) In general
Upon receipt of the application holder's response, the Secretary shall promptly review each statement received under subsection (e)(2) and determine which labeling changes pursuant to the Secretary's notice under subsection (d) are appropriate, if any. If the Secretary disagrees with the reasons why such labeling changes are not warranted, the Secretary shall provide opportunity for discussions with the application holders to reach agreement on whether the labeling for the covered drug should be updated to reflect available scientific evidence, and if so, the content of such labeling changes.
(2) Changes to labeling
After considering all responses from the holder of an approved application under paragraph (1) or (2) of subsection (e), and any discussion under paragraph (1), the Secretary may order such holder to make the labeling changes the Secretary determines are appropriate. Such holder of an approved application shall—
(A) update its paper labeling for the drug at the next printing of that labeling;
(B) update any electronic labeling for the drug within 30 days of such order; and
(C) submit the revised labeling through the form, "Supplement—Changes Being Effected".
(g) Violation
If the holder of an approved application for the generic version of the selected drug does not comply with the requirements of subsection (f)(2), such generic version of the selected drug shall be deemed to be misbranded under
(h) Limitations; generic drugs
(1) In general
With respect to any labeling change required under this section, the generic version shall be deemed to have the same conditions of use and the same labeling as its reference listed drug for purposes of clauses (i) and (v) of
(2) Supplemental applications
Changes to labeling made in accordance with this section shall not be eligible for an exclusivity period under this chapter.
(3) Selection of drugs
The Secretary shall not identify a drug as a covered drug or select a drug label for updating under subsection (b) or (c) solely based on the availability of new safety information. Upon identification of a drug as a covered drug under subsection (b), the Secretary may then consider the availability of new safety information (as defined in
(i) Rules of construction
(1) Approval standards
This section shall not be construed as altering the applicability of the standards for approval of an application under
(2) Removal of information
Nothing in this section shall be construed to give the Secretary additional authority to remove approved indications for drugs, other than the authority described in this section.
(3) Secretary authority
Nothing in this section shall be construed to limit the authority of the Secretary to require labeling changes under
(4) Maintenance of labeling
Nothing in this section shall be construed to affect the responsibility of the holder of an approved application under
(j) Reports
Not later than 4 years after December 27, 2020, and every 4 years thereafter, the Secretary shall prepare and submit to the Committee on Energy and Commerce of the House of Representatives and the Committee on Health, Education, Labor, and Pensions of the Senate, a report that—
(1) describes the actions of the Secretary under this section, including—
(A) the number of covered drugs and description of the types of drugs the Secretary has selected for labeling changes and the rationale for such recommended changes; and
(B) the number of times the Secretary entered into discussions concerning a disagreement with an application holder or holders and a summary of the decision regarding a labeling change, if any; and
(2) includes any recommendations of the Secretary for modifying the program under this section.
(June 25, 1938, ch. 675, §503D, as added
§354. Veterinary feed directive drugs
(a) Lawful veterinary feed directive requirement
(1) A drug intended for use in or on animal feed which is limited by an approved application filed pursuant to
(2) A veterinary feed directive is lawful if it—
(A) contains such information as the Secretary may by general regulation or by order require; and
(B) is in compliance with the conditions and indications for use of the drug set forth in the notice published pursuant to
(3)(A) Any persons involved in the distribution or use of animal feed bearing or containing a veterinary feed directive drug and the licensed veterinarian issuing the veterinary feed directive shall maintain a copy of the veterinary feed directive applicable to each such feed, except in the case of a person distributing such feed to another person for further distribution. Such person distributing the feed shall maintain a written acknowledgment from the person to whom the feed is shipped stating that that person shall not ship or move such feed to an animal production facility without a veterinary feed directive or ship such feed to another person for further distribution unless that person has provided the same written acknowledgment to its immediate supplier.
(B) Every person required under subparagraph (A) to maintain records, and every person in charge or custody thereof, shall, upon request of an officer or employee designated by the Secretary, permit such officer or employee at all reasonable times to have access to and copy and verify such records.
(C) Any person who distributes animal feed bearing or containing a veterinary feed directive drug shall upon first engaging in such distribution notify the Secretary of that person's name and place of business. The failure to provide such notification shall be deemed to be an act which results in the drug being misbranded.
(b) Labeling and advertising
A veterinary feed directive drug and any feed bearing or containing a veterinary feed directive drug shall be deemed to be misbranded if their labeling fails to bear such cautionary statement and such other information as the Secretary may by general regulation or by order prescribe, or their advertising fails to conform to the conditions and indications for use published pursuant to
(c) Nonprescription status
Neither a drug subject to this section, nor animal feed bearing or containing such a drug, shall be deemed to be a prescription article under any Federal or State law.
(June 25, 1938, ch. 675, §504, as added
Editorial Notes
Prior Provisions
A prior section 354, act June 25, 1938, ch. 675, §504,
Amendments
2004—Subsec. (a)(1).
Subsecs. (a)(2)(B), (b).
§355. New drugs
(a) Necessity of effective approval of application
No person shall introduce or deliver for introduction into interstate commerce any new drug, unless an approval of an application filed pursuant to subsection (b) or (j) is effective with respect to such drug.
(b) Filing application; contents
(1)(A) Any person may file with the Secretary an application with respect to any drug subject to the provisions of subsection (a). Such persons shall submit to the Secretary as part of the application—
(i) full reports of investigations which have been made to show whether such drug is safe for use and whether such drug is effective in use;
(ii) a full list of the articles used as components of such drug;
(iii) a full statement of the composition of such drug;
(iv) a full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug;
(v) such samples of such drug and of the articles used as components thereof as the Secretary may require;
(vi) specimens of the labeling proposed to be used for such drug;
(vii) any assessments required under
(viii) the patent number and expiration date of each patent for which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug, and that—
(I) claims the drug for which the applicant submitted the application and is a drug substance (active ingredient) patent or a drug product (formulation or composition) patent; or
(II) claims a method of using such drug for which approval is sought or has been granted in the application.
(B) If an application is filed under this subsection for a drug, and a patent of the type described in subparagraph (A)(viii) is issued after the filing date but before approval of the application, the applicant shall amend the application to include the patent number and expiration date.
(2) An application submitted under paragraph (1) for a drug for which the investigations described in clause (A) of such paragraph and relied upon by the applicant for approval of the application were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted shall also include—
(A) a certification, in the opinion of the applicant and to the best of his knowledge, with respect to each patent which claims the drug for which such investigations were conducted or which claims a use for such drug for which the applicant is seeking approval under this subsection and for which information is required to be filed under paragraph (1) or subsection (c)—
(i) that such patent information has not been filed,
(ii) that such patent has expired,
(iii) of the date on which such patent will expire, or
(iv) that such patent is invalid or will not be infringed by the manufacture, use, or sale of the new drug for which the application is submitted; and
(B) if with respect to the drug for which investigations described in paragraph (1)(A) were conducted information was filed under paragraph (1) or subsection (c) for a method of use patent which does not claim a use for which the applicant is seeking approval under this subsection, a statement that the method of use patent does not claim such a use.
(3)
(A)
(B)
(i) if the certification is in the application, not later than 20 days after the date of the postmark on the notice with which the Secretary informs the applicant that the application has been filed; or
(ii) if the certification is in an amendment or supplement to the application, at the time at which the applicant submits the amendment or supplement, regardless of whether the applicant has already given notice with respect to another such certification contained in the application or in an amendment or supplement to the application.
(C)
(i) each owner of the patent that is the subject of the certification (or a representative of the owner designated to receive such a notice); and
(ii) the holder of the approved application under this subsection for the drug that is claimed by the patent or a use of which is claimed by the patent (or a representative of the holder designated to receive such a notice).
(D)
(i) state that an application that contains data from bioavailability or bioequivalence studies has been submitted under this subsection for the drug with respect to which the certification is made to obtain approval to engage in the commercial manufacture, use, or sale of the drug before the expiration of the patent referred to in the certification; and
(ii) include a detailed statement of the factual and legal basis of the opinion of the applicant that the patent is invalid or will not be infringed.
(4)(A) An applicant may not amend or supplement an application referred to in paragraph (2) to seek approval of a drug that is a different drug than the drug identified in the application as submitted to the Secretary.
(B) With respect to the drug for which such an application is submitted, nothing in this subsection or subsection (c)(3) prohibits an applicant from amending or supplementing the application to seek approval of a different strength.
(5)(A) The Secretary shall issue guidance for the individuals who review applications submitted under paragraph (1) or under
(B) The Secretary shall meet with a sponsor of an investigation or an applicant for approval for a drug under this subsection or
(i)(I) of clinical trials intended to form the primary basis of an effectiveness claim; or
(II) in the case where human efficacy studies are not ethical or feasible, of animal and any associated clinical trials which, in combination, are intended to form the primary basis of an effectiveness claim; or
(ii) with respect to an application for approval of a biological product under
The sponsor or applicant shall provide information necessary for discussion and agreement on the design and size of the clinical trials. Minutes of any such meeting shall be prepared by the Secretary and made available to the sponsor or applicant upon request.
(C) Any agreement regarding the parameters of the design and size of clinical trials of a new drug under this paragraph that is reached between the Secretary and a sponsor or applicant shall be reduced to writing and made part of the administrative record by the Secretary. Such agreement shall not be changed after the testing begins, except—
(i) with the written agreement of the sponsor or applicant; or
(ii) pursuant to a decision, made in accordance with subparagraph (D) by the director of the reviewing division, that a substantial scientific issue essential to determining the safety or effectiveness of the drug has been identified after the testing has begun.
(D) A decision under subparagraph (C)(ii) by the director shall be in writing and the Secretary shall provide to the sponsor or applicant an opportunity for a meeting at which the director and the sponsor or applicant will be present and at which the director will document the scientific issue involved.
(E) The written decisions of the reviewing division shall be binding upon, and may not directly or indirectly be changed by, the field or compliance division personnel unless such field or compliance division personnel demonstrate to the reviewing division why such decision should be modified.
(F) No action by the reviewing division may be delayed because of the unavailability of information from or action by field personnel unless the reviewing division determines that a delay is necessary to assure the marketing of a safe and effective drug.
(G) For purposes of this paragraph, the reviewing division is the division responsible for the review of an application for approval of a drug under this subsection or
(6) An application submitted under this subsection shall be accompanied by the certification required under
(c) Period for approval of application; period for, notice, and expedition of hearing; period for issuance of order
(1) Within one hundred and eighty days after the filing of an application under subsection (b), or such additional period as may be agreed upon by the Secretary and the applicant, the Secretary shall either—
(A) approve the application if he then finds that none of the grounds for denying approval specified in subsection (d) applies, or
(B) give the applicant notice of an opportunity for a hearing before the Secretary under subsection (d) on the question whether such application is approvable. If the applicant elects to accept the opportunity for hearing by written request within thirty days after such notice, such hearing shall commence not more than ninety days after the expiration of such thirty days unless the Secretary and the applicant otherwise agree. Any such hearing shall thereafter be conducted on an expedited basis and the Secretary's order thereon shall be issued within ninety days after the date fixed by the Secretary for filing final briefs.
(2) Not later than 30 days after the date of approval of an application submitted under subsection (b), the holder of the approved application shall file with the Secretary the patent number and the expiration date of any patent described in subsection (b)(1)(A)(viii), except that a patent that is identified as claiming a method of using such drug shall be filed only if the patent claims a method of use approved in the application. If a patent described in subsection (b)(1)(A)(viii) is issued after the date of approval of an application submitted under subsection (b), the holder of the approved application shall, not later than 30 days after the date of issuance of the patent, file the patent number and the expiration date of the patent, except that a patent that claims a method of using such drug shall be filed only if approval for such use has been granted in the application. If the patent information described in subsection (b) could not be filed with the submission of an application under subsection (b) because the application was filed before the patent information was required under subsection (b) or a patent was issued after the application was approved under such subsection, the holder of an approved application shall file with the Secretary the patent number and the expiration date of any patent described in subsection (b)(1)(A)(viii). If the holder of an approved application could not file patent information under subsection (b) because it was not required at the time the application was approved, the holder shall file such information under this subsection not later than thirty days after September 24, 1984, and if the holder of an approved application could not file patent information under subsection (b) because no patent of the type for which information is required to be submitted in subsection (b)(1)(A)(viii) had been issued when an application was filed or approved, the holder shall file such information under this subsection not later than thirty days after the date the patent involved is issued. Upon the submission of patent information under this subsection, the Secretary shall publish it. Patent information that is not the type of patent information required by subsection (b)(1)(A)(viii) shall not be submitted under this paragraph.
(3) The approval of an application filed under subsection (b) which contains a certification required by paragraph (2) of such subsection shall be made effective on the last applicable date determined by applying the following to each certification made under subsection (b)(2)(A):
(A) If the applicant only made a certification described in clause (i) or (ii) of subsection (b)(2)(A) or in both such clauses, the approval may be made effective immediately.
(B) If the applicant made a certification described in clause (iii) of subsection (b)(2)(A), the approval may be made effective on the date certified under clause (iii).
(C) If the applicant made a certification described in clause (iv) of subsection (b)(2)(A), the approval shall be made effective immediately unless, before the expiration of 45 days after the date on which the notice described in subsection (b)(3) is received, an action is brought for infringement of the patent that is the subject of the certification and for which information was submitted to the Secretary under paragraph (2) or subsection (b)(1) before the date on which the application (excluding an amendment or supplement to the application) was submitted. If such an action is brought before the expiration of such days, the approval may be made effective upon the expiration of the thirty-month period beginning on the date of the receipt of the notice provided under subsection (b)(3) or such shorter or longer period as the court may order because either party to the action failed to reasonably cooperate in expediting the action, except that—
(i) if before the expiration of such period the district court decides that the patent is invalid or not infringed (including any substantive determination that there is no cause of action for patent infringement or invalidity), the approval shall be made effective on—
(I) the date on which the court enters judgment reflecting the decision; or
(II) the date of a settlement order or consent decree signed and entered by the court stating that the patent that is the subject of the certification is invalid or not infringed;
(ii) if before the expiration of such period the district court decides that the patent has been infringed—
(I) if the judgment of the district court is appealed, the approval shall be made effective on—
(aa) the date on which the court of appeals decides that the patent is invalid or not infringed (including any substantive determination that there is no cause of action for patent infringement or invalidity); or
(bb) the date of a settlement order or consent decree signed and entered by the court of appeals stating that the patent that is the subject of the certification is invalid or not infringed; or
(II) if the judgment of the district court is not appealed or is affirmed, the approval shall be made effective on the date specified by the district court in a court order under
(iii) if before the expiration of such period the court grants a preliminary injunction prohibiting the applicant from engaging in the commercial manufacture or sale of the drug until the court decides the issues of patent validity and infringement and if the court decides that such patent is invalid or not infringed, the approval shall be made effective as provided in clause (i); or
(iv) if before the expiration of such period the court grants a preliminary injunction prohibiting the applicant from engaging in the commercial manufacture or sale of the drug until the court decides the issues of patent validity and infringement and if the court decides that such patent has been infringed, the approval shall be made effective as provided in clause (ii).
In such an action, each of the parties shall reasonably cooperate in expediting the action.
(D)
(i)
(I)
(aa) the 45-day period referred to in such subparagraph has expired;
(bb) neither the owner of such patent nor the holder of the approved application under subsection (b) for the drug that is claimed by the patent or a use of which is claimed by the patent brought a civil action against the applicant for infringement of the patent before the expiration of such period; and
(cc) in any case in which the notice provided under paragraph (2)(B) relates to noninfringement, the notice was accompanied by a document described in subclause (III).
(II)
(III)
(ii)
(I)
(aa) the drug for which the application was approved; or
(bb) an approved method of using the drug.
(II)
(iii)
(E)(i) Repealed.
(ii) If an application submitted under subsection (b) for a drug, no active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) of which has been approved in any other application under subsection (b), is approved after September 24, 1984, no application which refers to the drug for which the subsection (b) application was submitted and for which the investigations described in subsection (b)(1)(A)(i) and relied upon by the applicant for approval of the application were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted may be submitted under subsection (b) before the expiration of five years from the date of the approval of the application under subsection (b), except that such an application may be submitted under subsection (b) after the expiration of four years from the date of the approval of the subsection (b) application if it contains a certification of patent invalidity or noninfringement described in clause (iv) of subsection (b)(2)(A). The approval of such an application shall be made effective in accordance with this paragraph except that, if an action for patent infringement is commenced during the one-year period beginning forty-eight months after the date of the approval of the subsection (b) application, the thirty-month period referred to in subparagraph (C) shall be extended by such amount of time (if any) which is required for seven and one-half years to have elapsed from the date of approval of the subsection (b) application.
(iii) If an application submitted under subsection (b) for a drug, which includes an active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) that has been approved in another application approved under subsection (b), is approved after September 24, 1984, and if such application contains reports of new clinical investigations (other than bioavailability studies) essential to the approval of the application and conducted or sponsored by the applicant, the Secretary may not make the approval of an application submitted under subsection (b) for the conditions of approval of such drug in the approved subsection (b) application effective before the expiration of three years from the date of the approval of the application under subsection (b) if the investigations described in subsection (b)(1)(A)(i) and relied upon by the applicant for approval of the application were not conducted by or for the applicant and if the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted.
(iv) If a supplement to an application approved under subsection (b) is approved after September 24, 1984, and the supplement contains reports of new clinical investigations (other than bioavailabilty 1 studies) essential to the approval of the supplement and conducted or sponsored by the person submitting the supplement, the Secretary may not make the approval of an application submitted under subsection (b) for a change approved in the supplement effective before the expiration of three years from the date of the approval of the supplement under subsection (b) if the investigations described in subsection (b)(1)(A)(i) and relied upon by the applicant for approval of the application were not conducted by or for the applicant and if the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted.
(v) If an application (or supplement to an application) submitted under subsection (b) for a drug, which includes an active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) that has been approved in another application under subsection (b), was approved during the period beginning January 1, 1982, and ending on September 24, 1984, the Secretary may not make the approval of an application submitted under this subsection and for which the investigations described in subsection (b)(1)(A)(i) and relied upon by the applicant for approval of the application were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted and which refers to the drug for which the subsection (b) application was submitted effective before the expiration of two years from September 24, 1984.
(4) A drug manufactured in a pilot or other small facility may be used to demonstrate the safety and effectiveness of the drug and to obtain approval for the drug prior to manufacture of the drug in a larger facility, unless the Secretary makes a determination that a full scale production facility is necessary to ensure the safety or effectiveness of the drug.
(5)(A) The Secretary may rely upon qualified data summaries to support the approval of a supplemental application, with respect to a qualified indication for a drug, submitted under subsection (b), if such supplemental application complies with subparagraph (B).
(B) A supplemental application is eligible for review as described in subparagraph (A) only if—
(i) there is existing data available and acceptable to the Secretary demonstrating the safety of the drug; and
(ii) all data used to develop the qualified data summaries are submitted to the Secretary as part of the supplemental application.
(C) The Secretary shall post on the Internet website of the Food and Drug Administration and update annually—
(i) the number of applications reviewed solely under subparagraph (A) or
(ii) the average time for completion of review under subparagraph (A) or
(iii) the average time for review of supplemental applications where the Secretary did not use review flexibility under subparagraph (A) or
(iv) the number of applications reviewed under subparagraph (A) or
(D) In this paragraph—
(i) the term "qualified indication" means an indication for a drug that the Secretary determines to be appropriate for summary level review under this paragraph; and
(ii) the term "qualified data summary" means a summary of clinical data that demonstrates the safety and effectiveness of a drug with respect to a qualified indication.
(d) Grounds for refusing application; approval of application; "substantial evidence" defined
If the Secretary finds, after due notice to the applicant in accordance with subsection (c) and giving him an opportunity for a hearing, in accordance with said subsection, that (1) the investigations, reports of which are required to be submitted to the Secretary pursuant to subsection (b), do not include adequate tests by all methods reasonably applicable to show whether or not such drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof; (2) the results of such tests show that such drug is unsafe for use under such conditions or do not show that such drug is safe for use under such conditions; (3) the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug are inadequate to preserve its identity, strength, quality, and purity; (4) upon the basis of the information submitted to him as part of the application, or upon the basis of any other information before him with respect to such drug, he has insufficient information to determine whether such drug is safe for use under such conditions; or (5) evaluated on the basis of the information submitted to him as part of the application and any other information before him with respect to such drug, there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof; or (6) the application failed to contain the patent information prescribed by subsection (b); or (7) based on a fair evaluation of all material facts, such labeling is false or misleading in any particular; he shall issue an order refusing to approve the application. If, after such notice and opportunity for hearing, the Secretary finds that clauses (1) through (6) do not apply, he shall issue an order approving the application. As used in this subsection and subsection (e), the term "substantial evidence" means evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. If the Secretary determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness, the Secretary may consider such data and evidence to constitute substantial evidence for purposes of the preceding sentence. The Secretary shall implement a structured risk-benefit assessment framework in the new drug approval process to facilitate the balanced consideration of benefits and risks, a consistent and systematic approach to the discussion and regulatory decisionmaking, and the communication of the benefits and risks of new drugs. Nothing in the preceding sentence shall alter the criteria for evaluating an application for marketing approval of a drug.
(e) Withdrawal of approval; grounds; immediate suspension upon finding imminent hazard to public health
The Secretary shall, after due notice and opportunity for hearing to the applicant, withdraw approval of an application with respect to any drug under this section if the Secretary finds (1) that clinical or other experience, tests, or other scientific data show that such drug is unsafe for use under the conditions of use upon the basis of which the application was approved; (2) that new evidence of clinical experience, not contained in such application or not available to the Secretary until after such application was approved, or tests by new methods, or tests by methods not deemed reasonably applicable when such application was approved, evaluated together with the evidence available to the Secretary when the application was approved, shows that such drug is not shown to be safe for use under the conditions of use upon the basis of which the application was approved; or (3) on the basis of new information before him with respect to such drug, evaluated together with the evidence available to him when the application was approved, that there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling thereof; or (4) the patent information prescribed by subsection (c) was not filed within thirty days after the receipt of written notice from the Secretary specifying the failure to file such information; or (5) that the application contains any untrue statement of a material fact: Provided, That if the Secretary (or in his absence the officer acting as Secretary) finds that there is an imminent hazard to the public health, he may suspend the approval of such application immediately, and give the applicant prompt notice of his action and afford the applicant the opportunity for an expedited hearing under this subsection; but the authority conferred by this proviso to suspend the approval of an application shall not be delegated. The Secretary may also, after due notice and opportunity for hearing to the applicant, withdraw the approval of an application submitted under subsection (b) or (j) with respect to any drug under this section if the Secretary finds (1) that the applicant has failed to establish a system for maintaining required records, or has repeatedly or deliberately failed to maintain such records or to make required reports, in accordance with a regulation or order under subsection (k) or to comply with the notice requirements of
(f) Revocation of order refusing, withdrawing or suspending approval of application
Whenever the Secretary finds that the facts so require, he shall revoke any previous order under subsection (d) or (e) refusing, withdrawing, or suspending approval of an application and shall approve such application or reinstate such approval, as may be appropriate.
(g) Service of orders
Orders of the Secretary issued under this section shall be served (1) in person by any officer or employee of the department designated by the Secretary or (2) by mailing the order by registered mail or by certified mail addressed to the applicant or respondent at his last-known address in the records of the Secretary.
(h) Appeal from order
An appeal may be taken by the applicant from an order of the Secretary refusing or withdrawing approval of an application under this section. Such appeal shall be taken by filing in the United States court of appeals for the circuit wherein such applicant resides or has his principal place of business, or in the United States Court of Appeals for the District of Columbia Circuit, within sixty days after the entry of such order, a written petition praying that the order of the Secretary be set aside. A copy of such petition shall be forthwith transmitted by the clerk of the court to the Secretary, or any officer designated by him for that purpose, and thereupon the Secretary shall certify and file in the court the record upon which the order complained of was entered, as provided in
(i) Exemptions of drugs for research; discretionary and mandatory conditions; direct reports to Secretary
(1) The Secretary shall promulgate regulations for exempting from the operation of the foregoing subsections of this section drugs intended solely for investigational use by experts qualified by scientific training and experience to investigate the safety and effectiveness of drugs. Such regulations may, within the discretion of the Secretary, among other conditions relating to the protection of the public health, provide for conditioning such exemption upon—
(A) the submission to the Secretary, before any clinical testing of a new drug is undertaken, of reports, by the manufacturer or the sponsor of the investigation of such drug, of nonclinical tests of such drug adequate to justify the proposed clinical testing;
(B) the manufacturer or the sponsor of the investigation of a new drug proposed to be distributed to investigators for clinical testing obtaining a signed agreement from each of such investigators that patients to whom the drug is administered will be under his personal supervision, or under the supervision of investigators responsible to him, and that he will not supply such drug to any other investigator, or to clinics, for administration to human beings;
(C) the establishment and maintenance of such records, and the making of such reports to the Secretary, by the manufacturer or the sponsor of the investigation of such drug, of data (including but not limited to analytical reports by investigators) obtained as the result of such investigational use of such drug, as the Secretary finds will enable him to evaluate the safety and effectiveness of such drug in the event of the filing of an application pursuant to subsection (b); and
(D) the submission to the Secretary by the manufacturer or the sponsor of the investigation of a new drug of a statement of intent regarding whether the manufacturer or sponsor has plans for assessing pediatric safety and efficacy.
(2) Subject to paragraph (3), a clinical investigation of a new drug may begin 30 days after the Secretary has received from the manufacturer or sponsor of the investigation a submission containing such information about the drug and the clinical investigation, including—
(A) information on design of the investigation and adequate reports of basic information, certified by the applicant to be accurate reports, necessary to assess the safety of the drug for use in clinical investigation; and
(B) adequate information on the chemistry and manufacturing of the drug, controls available for the drug, and primary data tabulations from nonclinical tests or human studies.
(3)(A) At any time, the Secretary may prohibit the sponsor of an investigation from conducting the investigation (referred to in this paragraph as a "clinical hold") if the Secretary makes a determination described in subparagraph (B). The Secretary shall specify the basis for the clinical hold, including the specific information available to the Secretary which served as the basis for such clinical hold, and confirm such determination in writing.
(B) For purposes of subparagraph (A), a determination described in this subparagraph with respect to a clinical hold is that—
(i) the drug involved represents an unreasonable risk to the safety of the persons who are the subjects of the clinical investigation, taking into account the qualifications of the clinical investigators, information about the drug, the design of the clinical investigation, the condition for which the drug is to be investigated, and the health status of the subjects involved; or
(ii) the clinical hold should be issued for such other reasons as the Secretary may by regulation establish (including reasons established by regulation before November 21, 1997).
(C) Any written request to the Secretary from the sponsor of an investigation that a clinical hold be removed shall receive a decision, in writing and specifying the reasons therefor, within 30 days after receipt of such request. Any such request shall include sufficient information to support the removal of such clinical hold.
(4) Regulations under paragraph (1) shall provide that such exemption shall be conditioned upon the manufacturer, or the sponsor of the investigation, requiring that experts using such drugs for investigational purposes certify to such manufacturer or sponsor that they will inform any human beings to whom such drugs, or any controls used in connection therewith, are being administered, or their representatives, that such drugs are being used for investigational purposes and will obtain the consent of such human beings or their representatives, except where it is not feasible, it is contrary to the best interests of such human beings, or the proposed clinical testing poses no more than minimal risk to such human beings and includes appropriate safeguards as prescribed to protect the rights, safety, and welfare of such human beings. Nothing in this subsection shall be construed to require any clinical investigator to submit directly to the Secretary reports on the investigational use of drugs. The Secretary shall update such regulations to require inclusion in the informed consent documents and process a statement that clinical trial information for such clinical investigation has been or will be submitted for inclusion in the registry data bank pursuant to subsection (j) of
(j) Abbreviated new drug applications
(1) Any person may file with the Secretary an abbreviated application for the approval of a new drug.
(2)(A) An abbreviated application for a new drug shall contain—
(i) information to show that the conditions of use prescribed, recommended, or suggested in the labeling proposed for the new drug have been previously approved for a drug listed under paragraph (7) (hereinafter in this subsection referred to as a "listed drug");
(ii)(I) if the listed drug referred to in clause (i) has only one active ingredient, information to show that the active ingredient of the new drug is the same as that of the listed drug;
(II) if the listed drug referred to in clause (i) has more than one active ingredient, information to show that the active ingredients of the new drug are the same as those of the listed drug, or
(III) if the listed drug referred to in clause (i) has more than one active ingredient and if one of the active ingredients of the new drug is different and the application is filed pursuant to the approval of a petition filed under subparagraph (C), information to show that the other active ingredients of the new drug are the same as the active ingredients of the listed drug, information to show that the different active ingredient is an active ingredient of a listed drug or of a drug which does not meet the requirements of
(iii) information to show that the route of administration, the dosage form, and the strength of the new drug are the same as those of the listed drug referred to in clause (i) or, if the route of administration, the dosage form, or the strength of the new drug is different and the application is filed pursuant to the approval of a petition filed under subparagraph (C), such information respecting the route of administration, dosage form, or strength with respect to which the petition was filed as the Secretary may require;
(iv) information to show that the new drug is bioequivalent to the listed drug referred to in clause (i), except that if the application is filed pursuant to the approval of a petition filed under subparagraph (C), information to show that the active ingredients of the new drug are of the same pharmacological or therapeutic class as those of the listed drug referred to in clause (i) and the new drug can be expected to have the same therapeutic effect as the listed drug when administered to patients for a condition of use referred to in clause (i);
(v) information to show that the labeling proposed for the new drug is the same as the labeling approved for the listed drug referred to in clause (i) except for changes required because of differences approved under a petition filed under subparagraph (C) or because the new drug and the listed drug are produced or distributed by different manufacturers;
(vi) the items specified in clauses (ii) through (vi) of subsection (b)(1)(A);
(vii) a certification, in the opinion of the applicant and to the best of his knowledge, with respect to each patent which claims the listed drug referred to in clause (i) or which claims a use for such listed drug for which the applicant is seeking approval under this subsection and for which information is required to be filed under subsection (b) or (c)—
(I) that such patent information has not been filed,
(II) that such patent has expired,
(III) of the date on which such patent will expire, or
(IV) that such patent is invalid or will not be infringed by the manufacture, use, or sale of the new drug for which the application is submitted; and
(viii) if with respect to the listed drug referred to in clause (i) information was filed under subsection (b) or (c) for a method of use patent which does not claim a use for which the applicant is seeking approval under this subsection, a statement that the method of use patent does not claim such a use.
The Secretary may not require that an abbreviated application contain information in addition to that required by clauses (i) through (viii).
(B)
(i)
(ii)
(I) if the certification is in the application, not later than 20 days after the date of the postmark on the notice with which the Secretary informs the applicant that the application has been filed; or
(II) if the certification is in an amendment or supplement to the application, at the time at which the applicant submits the amendment or supplement, regardless of whether the applicant has already given notice with respect to another such certification contained in the application or in an amendment or supplement to the application.
(iii)
(I) each owner of the patent that is the subject of the certification (or a representative of the owner designated to receive such a notice); and
(II) the holder of the approved application under subsection (b) for the drug that is claimed by the patent or a use of which is claimed by the patent (or a representative of the holder designated to receive such a notice).
(iv)
(I) state that an application that contains data from bioavailability or bioequivalence studies has been submitted under this subsection for the drug with respect to which the certification is made to obtain approval to engage in the commercial manufacture, use, or sale of the drug before the expiration of the patent referred to in the certification; and
(II) include a detailed statement of the factual and legal basis of the opinion of the applicant that the patent is invalid or will not be infringed.
(C) If a person wants to submit an abbreviated application for a new drug which has a different active ingredient or whose route of administration, dosage form, or strength differ from that of a listed drug, such person shall submit a petition to the Secretary seeking permission to file such an application. The Secretary shall approve or disapprove a petition submitted under this subparagraph within ninety days of the date the petition is submitted. The Secretary shall approve such a petition unless the Secretary finds—
(i) that investigations must be conducted to show the safety and effectiveness of the drug or of any of its active ingredients, the route of administration, the dosage form, or strength which differ from the listed drug; or
(ii) that any drug with a different active ingredient may not be adequately evaluated for approval as safe and effective on the basis of the information required to be submitted in an abbreviated application.
(D)(i) An applicant may not amend or supplement an application to seek approval of a drug referring to a different listed drug from the listed drug identified in the application as submitted to the Secretary.
(ii) With respect to the drug for which an application is submitted, nothing in this subsection prohibits an applicant from amending or supplementing the application to seek approval of a different strength.
(iii) Within 60 days after December 8, 2003, the Secretary shall issue guidance defining the term "listed drug" for purposes of this subparagraph.
(3)(A) The Secretary shall issue guidance for the individuals who review applications submitted under paragraph (1), which shall relate to promptness in conducting the review, technical excellence, lack of bias and conflict of interest, and knowledge of regulatory and scientific standards, and which shall apply equally to all individuals who review such applications.
(B) The Secretary shall meet with a sponsor of an investigation or an applicant for approval for a drug under this subsection if the sponsor or applicant makes a reasonable written request for a meeting for the purpose of reaching agreement on the design and size of bioavailability and bioequivalence studies needed for approval of such application. The sponsor or applicant shall provide information necessary for discussion and agreement on the design and size of such studies. Minutes of any such meeting shall be prepared by the Secretary and made available to the sponsor or applicant.
(C) Any agreement regarding the parameters of design and size of bioavailability and bioequivalence studies of a drug under this paragraph that is reached between the Secretary and a sponsor or applicant shall be reduced to writing and made part of the administrative record by the Secretary. Such agreement shall not be changed after the testing begins, except—
(i) with the written agreement of the sponsor or applicant; or
(ii) pursuant to a decision, made in accordance with subparagraph (D) by the director of the reviewing division, that a substantial scientific issue essential to determining the safety or effectiveness of the drug has been identified after the testing has begun.
(D) A decision under subparagraph (C)(ii) by the director shall be in writing and the Secretary shall provide to the sponsor or applicant an opportunity for a meeting at which the director and the sponsor or applicant will be present and at which the director will document the scientific issue involved.
(E) The written decisions of the reviewing division shall be binding upon, and may not directly or indirectly be changed by, the field or compliance office personnel unless such field or compliance office personnel demonstrate to the reviewing division why such decision should be modified.
(F) No action by the reviewing division may be delayed because of the unavailability of information from or action by field personnel unless the reviewing division determines that a delay is necessary to assure the marketing of a safe and effective drug.
(G) For purposes of this paragraph, the reviewing division is the division responsible for the review of an application for approval of a drug under this subsection (including scientific matters, chemistry, manufacturing, and controls).
(4) Subject to paragraph (5), the Secretary shall approve an application for a drug unless the Secretary finds—
(A) the methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the drug are inadequate to assure and preserve its identity, strength, quality, and purity;
(B) information submitted with the application is insufficient to show that each of the proposed conditions of use have been previously approved for the listed drug referred to in the application;
(C)(i) if the listed drug has only one active ingredient, information submitted with the application is insufficient to show that the active ingredient is the same as that of the listed drug;
(ii) if the listed drug has more than one active ingredient, information submitted with the application is insufficient to show that the active ingredients are the same as the active ingredients of the listed drug, or
(iii) if the listed drug has more than one active ingredient and if the application is for a drug which has an active ingredient different from the listed drug, information submitted with the application is insufficient to show—
(I) that the other active ingredients are the same as the active ingredients of the listed drug, or
(II) that the different active ingredient is an active ingredient of a listed drug or a drug which does not meet the requirements of
or no petition to file an application for the drug with the different ingredient was approved under paragraph (2)(C);
(D)(i) if the application is for a drug whose route of administration, dosage form, or strength of the drug is the same as the route of administration, dosage form, or strength of the listed drug referred to in the application, information submitted in the application is insufficient to show that the route of administration, dosage form, or strength is the same as that of the listed drug, or
(ii) if the application is for a drug whose route of administration, dosage form, or strength of the drug is different from that of the listed drug referred to in the application, no petition to file an application for the drug with the different route of administration, dosage form, or strength was approved under paragraph (2)(C);
(E) if the application was filed pursuant to the approval of a petition under paragraph (2)(C), the application did not contain the information required by the Secretary respecting the active ingredient, route of administration, dosage form, or strength which is not the same;
(F) information submitted in the application is insufficient to show that the drug is bioequivalent to the listed drug referred to in the application or, if the application was filed pursuant to a petition approved under paragraph (2)(C), information submitted in the application is insufficient to show that the active ingredients of the new drug are of the same pharmacological or therapeutic class as those of the listed drug referred to in paragraph (2)(A)(i) and that the new drug can be expected to have the same therapeutic effect as the listed drug when administered to patients for a condition of use referred to in such paragraph;
(G) information submitted in the application is insufficient to show that the labeling proposed for the drug is the same as the labeling approved for the listed drug referred to in the application except for changes required because of differences approved under a petition filed under paragraph (2)(C) or because the drug and the listed drug are produced or distributed by different manufacturers;
(H) information submitted in the application or any other information available to the Secretary shows that (i) the inactive ingredients of the drug are unsafe for use under the conditions prescribed, recommended, or suggested in the labeling proposed for the drug, or (ii) the composition of the drug is unsafe under such conditions because of the type or quantity of inactive ingredients included or the manner in which the inactive ingredients are included;
(I) the approval under subsection (c) of the listed drug referred to in the application under this subsection has been withdrawn or suspended for grounds described in the first sentence of subsection (e), the Secretary has published a notice of opportunity for hearing to withdraw approval of the listed drug under subsection (c) for grounds described in the first sentence of subsection (e), the approval under this subsection of the listed drug referred to in the application under this subsection has been withdrawn or suspended under paragraph (6), or the Secretary has determined that the listed drug has been withdrawn from sale for safety or effectiveness reasons;
(J) the application does not meet any other requirement of paragraph (2)(A); or
(K) the application contains an untrue statement of material fact.
(5)(A) Within one hundred and eighty days of the initial receipt of an application under paragraph (2) or within such additional period as may be agreed upon by the Secretary and the applicant, the Secretary shall approve or disapprove the application.
(B) The approval of an application submitted under paragraph (2) shall be made effective on the last applicable date determined by applying the following to each certification made under paragraph (2)(A)(vii):
(i) If the applicant only made a certification described in subclause (I) or (II) of paragraph (2)(A)(vii) or in both such subclauses, the approval may be made effective immediately.
(ii) If the applicant made a certification described in subclause (III) of paragraph (2)(A)(vii), the approval may be made effective on the date certified under subclause (III).
(iii) If the applicant made a certification described in subclause (IV) of paragraph (2)(A)(vii), the approval shall be made effective immediately unless, before the expiration of 45 days after the date on which the notice described in paragraph (2)(B) is received, an action is brought for infringement of the patent that is the subject of the certification and for which information was submitted to the Secretary under subsection (b)(1) or (c)(2) before the date on which the application (excluding an amendment or supplement to the application), which the Secretary later determines to be substantially complete, was submitted. If such an action is brought before the expiration of such days, the approval shall be made effective upon the expiration of the thirty-month period beginning on the date of the receipt of the notice provided under paragraph (2)(B)(i) or such shorter or longer period as the court may order because either party to the action failed to reasonably cooperate in expediting the action, except that—
(I) if before the expiration of such period the district court decides that the patent is invalid or not infringed (including any substantive determination that there is no cause of action for patent infringement or invalidity), the approval shall be made effective on—
(aa) the date on which the court enters judgment reflecting the decision; or
(bb) the date of a settlement order or consent decree signed and entered by the court stating that the patent that is the subject of the certification is invalid or not infringed;
(II) if before the expiration of such period the district court decides that the patent has been infringed—
(aa) if the judgment of the district court is appealed, the approval shall be made effective on—
(AA) the date on which the court of appeals decides that the patent is invalid or not infringed (including any substantive determination that there is no cause of action for patent infringement or invalidity); or
(BB) the date of a settlement order or consent decree signed and entered by the court of appeals stating that the patent that is the subject of the certification is invalid or not infringed; or
(bb) if the judgment of the district court is not appealed or is affirmed, the approval shall be made effective on the date specified by the district court in a court order under
(III) if before the expiration of such period the court grants a preliminary injunction prohibiting the applicant from engaging in the commercial manufacture or sale of the drug until the court decides the issues of patent validity and infringement and if the court decides that such patent is invalid or not infringed, the approval shall be made effective as provided in subclause (I); or
(IV) if before the expiration of such period the court grants a preliminary injunction prohibiting the applicant from engaging in the commercial manufacture or sale of the drug until the court decides the issues of patent validity and infringement and if the court decides that such patent has been infringed, the approval shall be made effective as provided in subclause (II).
In such an action, each of the parties shall reasonably cooperate in expediting the action.
(iv) 180-
(I)
(II)
(aa) 180-
(bb)
(cc)
(dd)
(AA)
(BB)
(v) 180-
(I)
(II)
(III)
(aa) The term "competitive generic therapy" means a drug—
(AA) that is designated as a competitive generic therapy under
(BB) for which there are no unexpired patents or exclusivities on the list of products described in
(bb) The term "first approved applicant" means any applicant that has submitted an application that—
(AA) is for a competitive generic therapy that is approved on the first day on which any application for such competitive generic therapy is approved;
(BB) is not eligible for a 180-day exclusivity period under clause (iv) for the drug that is the subject of the application for the competitive generic therapy; and
(CC) is not for a drug for which all drug versions have forfeited eligibility for a 180-day exclusivity period under clause (iv) pursuant to subparagraph (D).
(C)
(i)
(I)
(aa) the 45-day period referred to in such subparagraph has expired;
(bb) neither the owner of such patent nor the holder of the approved application under subsection (b) for the drug that is claimed by the patent or a use of which is claimed by the patent brought a civil action against the applicant for infringement of the patent before the expiration of such period; and
(cc) in any case in which the notice provided under paragraph (2)(B) relates to noninfringement, the notice was accompanied by a document described in subclause (III).
(II)
(III)
(ii)
(I)
(aa) the drug for which the application was approved; or
(bb) an approved method of using the drug.
(II)
(iii)
(D)
(i)
(I)
(aa) the earlier of the date that is—
(AA) 75 days after the date on which the approval of the application of the first applicant is made effective under subparagraph (B)(iii); or
(BB) 30 months after the date of submission of the application of the first applicant; or
(bb) with respect to the first applicant or any other applicant (which other applicant has received tentative approval), the date that is 75 days after the date as of which, as to each of the patents with respect to which the first applicant submitted and lawfully maintained a certification qualifying the first applicant for the 180-day exclusivity period under subparagraph (B)(iv), at least 1 of the following has occurred:
(AA) In an infringement action brought against that applicant with respect to the patent or in a declaratory judgment action brought by that applicant with respect to the patent, a court enters a final decision from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has been or can be taken that the patent is invalid or not infringed.
(BB) In an infringement action or a declaratory judgment action described in subitem (AA), a court signs a settlement order or consent decree that enters a final judgment that includes a finding that the patent is invalid or not infringed.
(CC) The patent information submitted under subsection (b) or (c) is withdrawn by the holder of the application approved under subsection (b).
(II)
(III)
(IV)
(V)
(VI)
(ii)
(iii)
(I) approval of any application containing a certification described in paragraph (2)(A)(vii)(IV) shall be made effective in accordance with subparagraph (B)(iii); and
(II) no applicant shall be eligible for a 180-day exclusivity period.
(iv)
(E) If the Secretary decides to disapprove an application, the Secretary shall give the applicant notice of an opportunity for a hearing before the Secretary on the question of whether such application is approvable. If the applicant elects to accept the opportunity for hearing by written request within thirty days after such notice, such hearing shall commence not more than ninety days after the expiration of such thirty days unless the Secretary and the applicant otherwise agree. Any such hearing shall thereafter be conducted on an expedited basis and the Secretary's order thereon shall be issued within ninety days after the date fixed by the Secretary for filing final briefs.
(F)(i) Repealed.
(ii) If an application submitted under subsection (b) for a drug, no active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) of which has been approved in any other application under subsection (b), is approved after September 24, 1984, no application may be submitted under this subsection which refers to the drug for which the subsection (b) application was submitted before the expiration of five years from the date of the approval of the application under subsection (b), except that such an application may be submitted under this subsection after the expiration of four years from the date of the approval of the subsection (b) application if it contains a certification of patent invalidity or noninfringement described in subclause (IV) of paragraph (2)(A)(vii). The approval of such an application shall be made effective in accordance with subparagraph (B) except that, if an action for patent infringement is commenced during the one-year period beginning forty-eight months after the date of the approval of the subsection (b) application, the thirty-month period referred to in subparagraph (B)(iii) shall be extended by such amount of time (if any) which is required for seven and one-half years to have elapsed from the date of approval of the subsection (b) application.
(iii) If an application submitted under subsection (b) for a drug, which includes an active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) that has been approved in another application approved under subsection (b), is approved after September 24, 1984, and if such application contains reports of new clinical investigations (other than bioavailability studies) essential to the approval of the application and conducted or sponsored by the applicant, the Secretary may not make the approval of an application submitted under this subsection for the conditions of approval of such drug in the subsection (b) application effective before the expiration of three years from the date of the approval of the application under subsection (b) for such drug.
(iv) If a supplement to an application approved under subsection (b) is approved after September 24, 1984, and the supplement contains reports of new clinical investigations (other than bioavailability studies) essential to the approval of the supplement and conducted or sponsored by the person submitting the supplement, the Secretary may not make the approval of an application submitted under this subsection for a change approved in the supplement effective before the expiration of three years from the date of the approval of the supplement under subsection (b).
(v) If an application (or supplement to an application) submitted under subsection (b) for a drug, which includes an active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) that has been approved in another application under subsection (b), was approved during the period beginning January 1, 1982, and ending on September 24, 1984, the Secretary may not make the approval of an application submitted under this subsection which refers to the drug for which the subsection (b) application was submitted or which refers to a change approved in a supplement to the subsection (b) application effective before the expiration of two years from September 24, 1984.
(6) If a drug approved under this subsection refers in its approved application to a drug the approval of which was withdrawn or suspended for grounds described in the first sentence of subsection (e) or was withdrawn or suspended under this paragraph or which, as determined by the Secretary, has been withdrawn from sale for safety or effectiveness reasons, the approval of the drug under this subsection shall be withdrawn or suspended—
(A) for the same period as the withdrawal or suspension under subsection (e) or this paragraph, or
(B) if the listed drug has been withdrawn from sale, for the period of withdrawal from sale or, if earlier, the period ending on the date the Secretary determines that the withdrawal from sale is not for safety or effectiveness reasons.
(7)(A)(i) Within sixty days of September 24, 1984, the Secretary shall publish and make available to the public—
(I) a list in alphabetical order of the official and proprietary name of each drug which has been approved for safety and effectiveness under subsection (c) before September 24, 1984;
(II) the date of approval if the drug is approved after 1981 and the number of the application which was approved; and
(III) whether in vitro or in vivo bioequivalence studies, or both such studies, are required for applications filed under this subsection which will refer to the drug published.
(ii) Every thirty days after the publication of the first list under clause (i) the Secretary shall revise the list to include each drug which has been approved for safety and effectiveness under subsection (c) or approved under this subsection during the thirty-day period.
(iii) When patent information submitted under subsection (c) respecting a drug included on the list is to be published by the Secretary, the Secretary shall, in revisions made under clause (ii), include such information for such drug.
(iv) For each drug included on the list, the Secretary shall specify any exclusivity period that is applicable, for which the Secretary has determined the expiration date, and for which such period has not yet expired, under—
(I) clause (ii), (iii), or (iv) of subsection (c)(3)(E);
(II) clause (iv) or (v) of paragraph (5)(B);
(III) clause (ii), (iii), or (iv) of paragraph (5)(F);
(IV)
(V)
(VI)
(VII) subsection (u).
(v)(I) With respect to an application submitted pursuant to subsection (b)(2) for a drug that is subject to
(aa) With respect to such an application submitted after December 29, 2022, the evaluation shall be made with respect to a listed drug relied upon in the application pursuant to subsection (b)(2) that is a pharmaceutical equivalent (as defined in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) to the drug in the application pursuant to subsection (b)(2) at the time of approval of such application or not later than 180 days after the date of such approval, provided that the request for such an evaluation is made in the original application (or in a resubmission to a complete response letter), and all necessary data and information are submitted in the original application (or in a resubmission in response to a complete response letter) for the therapeutic equivalence evaluation, including information to demonstrate bioequivalence, in a form and manner prescribed by the Secretary.
(bb) With respect to such an application approved prior to or on December 29, 2022, the evaluation shall be made not later than 180 days after receipt of a request for a therapeutic equivalence evaluation submitted as part of a supplement to such application; or with respect to an application that was submitted prior to December 29, 2022, but not approved as of December 29, 2022, the evaluation shall be made not later than 180 days after the date of approval of such application if a request for such evaluation is submitted as an amendment to the application, provided that—
(AA) such request for a therapeutic equivalence evaluation is being sought with respect to a listed drug relied upon in the application, and the relied upon listed drug is in the prescription drug product section of the list under this paragraph and is a pharmaceutical equivalent (as defined in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) to the drug for which a therapeutic equivalence evaluation is sought; and
(BB) the amendment or supplement, as applicable, containing such request, or the relevant application, includes all necessary data and information for the therapeutic equivalence evaluation, including information to demonstrate bioequivalence, in a form and manner prescribed by the Secretary.
(II) When the Secretary makes an evaluation under subclause (I), the Secretary shall, in revisions made to the list pursuant to clause (ii), include such information for such drug.
(B) A drug approved for safety and effectiveness under subsection (c) or approved under this subsection shall, for purposes of this subsection, be considered to have been published under subparagraph (A) on the date of its approval or September 24, 1984, whichever is later.
(C) If the approval of a drug was withdrawn or suspended for grounds described in the first sentence of subsection (e) or was withdrawn or suspended under paragraph (6) or if the Secretary determines that a drug has been withdrawn from sale for safety or effectiveness reasons, it may not be published in the list under subparagraph (A) or, if the withdrawal or suspension occurred after its publication in such list, it shall be immediately removed from such list—
(i) for the same period as the withdrawal or suspension under subsection (e) or paragraph (6), or
(ii) if the listed drug has been withdrawn from sale, for the period of withdrawal from sale or, if earlier, the period ending on the date the Secretary determines that the withdrawal from sale is not for safety or effectiveness reasons.
A notice of the removal shall be published in the Federal Register.
(D) In the case of a listed drug for which the list under subparagraph (A)(i) includes a patent for such drug, and any claim of the patent has been cancelled or invalidated pursuant to a final decision issued by the Patent Trial and Appeal Board of the United States Patent and Trademark Office or by a court, from which no appeal has been, or can be, taken, if the holder of the applicable application approved under subsection (c) determines that a patent for such drug, or any patent information for such drug, no longer meets the listing requirements under this section—
(i) the holder of such approved application shall notify the Secretary, in writing, within 14 days of such decision of such cancellation or invalidation and request that such patent or patent information, as applicable, be amended or withdrawn in accordance with the decision issued by the Patent Trial and Appeal Board or a court;
(ii) the holder of such approved application shall include in any notification under clause (i) information related to such patent cancellation or invalidation decision and submit such information, including a copy of such decision, to the Secretary; and
(iii) the Secretary shall, in response to a notification under clause (i), amend or remove patent or patent information in accordance with the relevant decision from the Patent Trial and Appeals Board or court, as applicable, except that the Secretary shall not remove from the list any patent or patent information before the expiration of any 180-day exclusivity period under paragraph (5)(B)(iv) that relies on a certification described in paragraph (2)(A)(vii)(IV).
(8) For purposes of this subsection:
(A)(i) The term "bioavailability" means the rate and extent to which the active ingredient or therapeutic ingredient is absorbed from a drug and becomes available at the site of drug action.
(ii) For a drug that is not intended to be absorbed into the bloodstream, the Secretary may assess bioavailability by scientifically valid measurements intended to reflect the rate and extent to which the active ingredient or therapeutic ingredient becomes available at the site of drug action.
(B) A drug shall be considered to be bioequivalent to a listed drug if—
(i) the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses; or
(ii) the extent of absorption of the drug does not show a significant difference from the extent of absorption of the listed drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses and the difference from the listed drug in the rate of absorption of the drug is intentional, is reflected in its proposed labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug.
(C) For a drug that is not intended to be absorbed into the bloodstream, the Secretary may establish alternative, scientifically valid methods to show bioequivalence if the alternative methods are expected to detect a significant difference between the drug and the listed drug in safety and therapeutic effect.
(9) The Secretary shall, with respect to each application submitted under this subsection, maintain a record of—
(A) the name of the applicant,
(B) the name of the drug covered by the application,
(C) the name of each person to whom the review of the chemistry of the application was assigned and the date of such assignment, and
(D) the name of each person to whom the bioequivalence review for such application was assigned and the date of such assignment.
The information the Secretary is required to maintain under this paragraph with respect to an application submitted under this subsection shall be made available to the public after the approval of such application.
(10)(A) If the proposed labeling of a drug that is the subject of an application under this subsection differs from the listed drug due to a labeling revision described under clause (i), the drug that is the subject of such application shall, notwithstanding any other provision of this chapter, be eligible for approval and shall not be considered misbranded under
(i) a revision to the labeling of the listed drug has been approved by the Secretary within 90 days of when the application is otherwise eligible for approval under this subsection;
(ii) the sponsor of the application agrees to submit revised labeling for the drug that is the subject of the application not later than 60 days after approval under this subsection of the application;
(iii) the labeling revision described under clause (i) does not include a change to the "Warnings" section of the labeling; and
(iv) such application otherwise meets the applicable requirements for approval under this subsection.
(B) If, after a labeling revision described in subparagraph (A)(i), the Secretary determines that the continued presence in interstate commerce of the labeling of the listed drug (as in effect before the revision described in subparagraph (A)(i)) adversely impacts the safe use of the drug, no application under this subsection shall be eligible for approval with such labeling.
(11)(A) Subject to subparagraph (B), the Secretary shall prioritize the review of, and act within 8 months of the date of the submission of, an original abbreviated new drug application submitted for review under this subsection that is for a drug—
(i) for which there are not more than 3 approved drug products listed under paragraph (7) and for which there are no blocking patents and exclusivities; or
(ii) that has been included on the list under
(B) To qualify for priority review under this paragraph, not later than 60 days prior to the submission of an application described in subparagraph (A) or that the Secretary may prioritize pursuant to subparagraph (D), the applicant shall provide complete, accurate information regarding facilities involved in manufacturing processes and testing of the drug that is the subject of the application, including facilities in corresponding Type II active pharmaceutical ingredients drug master files referenced in an application and sites or organizations involved in bioequivalence and clinical studies used to support the application, to enable the Secretary to make a determination regarding whether an inspection of a facility is necessary. Such information shall include the relevant (as determined by the Secretary) sections of such application, which shall be unchanged relative to the date of the submission of such application, except to the extent that a change is made to such information to exclude a facility that was not used to generate data to meet any application requirements for such submission and that is not the only facility intended to conduct one or more unit operations in commercial production. Information provided by an applicant under this subparagraph shall not be considered the submission of an application under this subsection.
(C) The Secretary may expedite an inspection or reinspection under
(D) Nothing in this paragraph shall prevent the Secretary from prioritizing the review of other applications as the Secretary determines appropriate.
(12) The Secretary shall publish on the internet website of the Food and Drug Administration, and update at least once every 6 months, a list of all drugs approved under subsection (c) for which all patents and periods of exclusivity under this chapter have expired and for which no application has been approved under this subsection.
(13) Upon the request of an applicant regarding one or more specified pending applications under this subsection, the Secretary shall, as appropriate, provide review status updates indicating the categorical status of the applications by each relevant review discipline.
(k) Records and reports; required information; regulations and orders; access to records
(1) In the case of any drug for which an approval of an application filed under subsection (b) or (j) is in effect, the applicant shall establish and maintain such records, and make such reports to the Secretary, of data relating to clinical experience and other data or information, received or otherwise obtained by such applicant with respect to such drug, as the Secretary may by general regulation, or by order with respect to such application, prescribe on the basis of a finding that such records and reports are necessary in order to enable the Secretary to determine, or facilitate a determination, whether there is or may be ground for invoking subsection (e). Regulations and orders issued under this subsection and under subsection (i) shall have due regard for the professional ethics of the medical profession and the interests of patients and shall provide, where the Secretary deems it to be appropriate, for the examination, upon request, by the persons to whom such regulations or orders are applicable, of similar information received or otherwise obtained by the Secretary.
(2) Every person required under this section to maintain records, and every person in charge or custody thereof, shall, upon request of an officer or employee designated by the Secretary, permit such officer or employee at all reasonable times to have access to and copy and verify such records.
(3)
(A)
(B)
(i) develop methods to obtain access to disparate data sources including the data sources specified in subparagraph (C);
(ii) develop validated methods for the establishment of a postmarket risk identification and analysis system to link and analyze safety data from multiple sources, with the goals of including, in aggregate—
(I) at least 25,000,000 patients by July 1, 2010; and
(II) at least 100,000,000 patients by July 1, 2012; and
(iii) convene a committee of experts, including individuals who are recognized in the field of protecting data privacy and security, to make recommendations to the Secretary on the development of tools and methods for the ethical and scientific uses for, and communication of, postmarketing data specified under subparagraph (C), including recommendations on the development of effective research methods for the study of drug safety questions.
(C)
(i)
(I) for risk identification and analysis based on electronic health data, in compliance with the regulations promulgated under section 264(c) of the Health Insurance Portability and Accountability Act of 1996, and in a manner that does not disclose individually identifiable health information in violation of paragraph (4)(B);
(II) for the reporting (in a standardized form) of data on all serious adverse drug experiences (as defined in
(III) to provide for active adverse event surveillance using the following data sources, as available:
(aa) Federal health-related electronic data (such as data from the Medicare program and the health systems of the Department of Veterans Affairs);
(bb) private sector health-related electronic data (such as pharmaceutical purchase data and health insurance claims data); and
(cc) other data as the Secretary deems necessary to create a robust system to identify adverse events and potential drug safety signals;
(IV) to identify certain trends and patterns with respect to data accessed by the system;
(V) to provide regular reports to the Secretary concerning adverse event trends, adverse event patterns, incidence and prevalence of adverse events, and other information the Secretary determines appropriate, which may include data on comparative national adverse event trends; and
(VI) to enable the program to export data in a form appropriate for further aggregation, statistical analysis, and reporting.
(ii)
(iii)
(iv)
(I) approaches that are complementary with respect to assessing the safety of use of a drug in domestic populations not included, or underrepresented, in the trials used to approve the drug (such as older people, people with comorbidities, pregnant women, or children); and
(II) existing approaches such as the Vaccine Adverse Event Reporting System and the Vaccine Safety Datalink or successor databases.
(v)
(4)
(A)
(i) improve the quality and efficiency of postmarket drug safety risk-benefit analysis;
(ii) provide the Secretary with routine access to outside expertise to study advanced drug safety questions; and
(iii) enhance the ability of the Secretary to make timely assessments based on drug safety data.
(B)
(C)
(i) priority drug safety questions; and
(ii) mechanisms for answering such questions, including through—
(I) active risk identification under paragraph (3); and
(II) when such risk identification is not sufficient, postapproval studies and clinical trials under subsection (o)(3).
(D)
(i)
(I) classify, analyze, or aggregate data described in paragraph (3)(C) and information that is publicly available or is provided by the Secretary;
(II) allow for prompt investigation of priority drug safety questions, including—
(aa) unresolved safety questions for drugs or classes of drugs; and
(bb) for a newly-approved drugs,2 safety signals from clinical trials used to approve the drug and other preapproval trials; rare, serious drug side effects; and the safety of use in domestic populations not included, or underrepresented, in the trials used to approve the drug (such as older people, people with comorbidities, pregnant women, or children);
(III) perform advanced research and analysis on identified drug safety risks;
(IV) focus postapproval studies and clinical trials under subsection (o)(3) more effectively on cases for which reports under paragraph (1) and other safety signal detection is not sufficient to resolve whether there is an elevated risk of a serious adverse event associated with the use of a drug; and
(V) carry out other activities as the Secretary deems necessary to carry out the purposes of this paragraph.
(ii)
(E)
(F)
(i)
(ii)
(I) The research, statistical, epidemiologic, or clinical capability and expertise to conduct and complete the activities under this paragraph, including the capability and expertise to provide the Secretary de-identified data consistent with the requirements of this subsection.
(II) An information technology infrastructure in place to support electronic data and operational standards to provide security for such data.
(III) Experience with, and expertise on, the development of drug safety and effectiveness research using electronic population data.
(IV) An understanding of drug development or risk/benefit balancing in a clinical setting.
(V) Other expertise which the Secretary deems necessary to fulfill the activities under this paragraph.
(G)
(i)
(I) violates the regulations promulgated under section 264(c) of the Health Insurance Portability and Accountability Act of 1996;
(II) violates
(III) discloses individually identifiable health information when presenting drug safety signals and trends or when responding to inquiries regarding drug safety signals and trends.
Nothing in this clause prohibits lawful disclosure for other purposes.
(ii)
(I) the qualified entity shall establish appropriate security measures to maintain the confidentiality and privacy of such data; and
(II) the entity shall not make an unauthorized disclosure of such data to the other components of the organization in breach of such confidentiality and privacy requirement.
(iii)
(I)
(II)
(H)
(I)
(J)
(5) The Secretary shall—
(A) conduct regular screenings of the Adverse Event Reporting System database and post a quarterly report on the Adverse Event Reporting System Web site of any new safety information or potential signal of a serious risk identified by Adverse 3 Event Reporting System within the last quarter; and 4
(B) on an annual basis, review the entire backlog of postmarket safety commitments to determine which commitments require revision or should be eliminated, report to the Congress on these determinations, and assign start dates and estimated completion dates for such commitments; and
(C) make available on the Internet website of the Food and Drug Administration—
(i) guidelines, developed with input from experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, that detail best practices for drug safety surveillance using the Adverse Event Reporting System; and
(ii) criteria for public posting of adverse event signals.
(l) Public disclosure of safety and effectiveness data and action package
(1) Safety and effectiveness data and information which has been submitted in an application under subsection (b) for a drug and which has not previously been disclosed to the public shall be made available to the public, upon request, unless extraordinary circumstances are shown—
(A) if no work is being or will be undertaken to have the application approved,
(B) if the Secretary has determined that the application is not approvable and all legal appeals have been exhausted,
(C) if approval of the application under subsection (c) is withdrawn and all legal appeals have been exhausted,
(D) if the Secretary has determined that such drug is not a new drug, or
(E) upon the effective date of the approval of the first application under subsection (j) which refers to such drug or upon the date upon which the approval of an application under subsection (j) which refers to such drug could be made effective if such an application had been submitted.
(2)
(A)
(i) not later than 30 days after the date of approval of such applications—
(I) for a drug, no active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) of which has been approved in any other application under this section; or
(II) for a biological product, no active ingredient of which has been approved in any other application under
(ii) not later than 30 days after the third request for such action package for approval received under
(B)
(C)
(i) Documents generated by the Food and Drug Administration related to review of the application.
(ii) Documents pertaining to the format and content of the application generated during drug development.
(iii) Labeling submitted by the applicant.
(iv) A summary review that documents conclusions from all reviewing disciplines about the drug, noting any critical issues and disagreements with the applicant and within the review team and how they were resolved, recommendations for action, and an explanation of any nonconcurrence with review conclusions.
(v) The Division Director and Office Director's decision document which includes—
(I) a brief statement of concurrence with the summary review;
(II) a separate review or addendum to the review if disagreeing with the summary review; and
(III) a separate review or addendum to the review to add further analysis.
(vi) Identification by name of each officer or employee of the Food and Drug Administration who—
(I) participated in the decision to approve the application; and
(II) consents to have his or her name included in the package.
(D)
(E)
(m) "Patent" defined
For purposes of this section, the term "patent" means a patent issued by the United States Patent and Trademark Office.
(n) Scientific advisory panels
(1) For the purpose of providing expert scientific advice and recommendations to the Secretary regarding a clinical investigation of a drug or the approval for marketing of a drug under this section or
(2) The Secretary may delegate the appointment and oversight authority granted under
(3) The Secretary shall make appointments to each panel established under paragraph (1) so that each panel shall consist of—
(A) members who are qualified by training and experience to evaluate the safety and effectiveness of the drugs to be referred to the panel and who, to the extent feasible, possess skill and experience in the development, manufacture, or utilization of such drugs;
(B) members with diverse expertise in such fields as clinical and administrative medicine, pharmacy, pharmacology, pharmacoeconomics, biological and physical sciences, and other related professions;
(C) a representative of consumer interests, and a representative of interests of the drug manufacturing industry not directly affected by the matter to be brought before the panel; and
(D) two or more members who are specialists or have other expertise in the particular disease or condition for which the drug under review is proposed to be indicated.
Scientific, trade, and consumer organizations shall be afforded an opportunity to nominate individuals for appointment to the panels. No individual who is in the regular full-time employ of the United States and engaged in the administration of this chapter may be a voting member of any panel. The Secretary shall designate one of the members of each panel to serve as chairman thereof.
(4) The Secretary shall, as appropriate, provide education and training to each new panel member before such member participates in a panel's activities, including education regarding requirements under this chapter and related regulations of the Secretary, and the administrative processes and procedures related to panel meetings.
(5) Panel members (other than officers or employees of the United States), while attending meetings or conferences of a panel or otherwise engaged in its business, shall be entitled to receive compensation for each day so engaged, including traveltime, at rates to be fixed by the Secretary, but not to exceed the daily equivalent of the rate in effect for positions classified above grade GS–15 of the General Schedule. While serving away from their homes or regular places of business, panel members may be allowed travel expenses (including per diem in lieu of subsistence) as authorized by
(6) The Secretary shall ensure that scientific advisory panels meet regularly and at appropriate intervals so that any matter to be reviewed by such a panel can be presented to the panel not more than 60 days after the matter is ready for such review. Meetings of the panel may be held using electronic communication to convene the meetings.
(7) Within 90 days after a scientific advisory panel makes recommendations on any matter under its review, the Food and Drug Administration official responsible for the matter shall review the conclusions and recommendations of the panel, and notify the affected persons of the final decision on the matter, or of the reasons that no such decision has been reached. Each such final decision shall be documented including the rationale for the decision.
(o) Postmarket studies and clinical trials; labeling
(1) In general
A responsible person may not introduce or deliver for introduction into interstate commerce the new drug involved if the person is in violation of a requirement established under paragraph (3) or (4) with respect to the drug.
(2) Definitions
For purposes of this subsection:
(A) Responsible person
The term "responsible person" means a person who—
(i) has submitted to the Secretary a covered application that is pending; or
(ii) is the holder of an approved covered application.
(B) Covered application
The term "covered application" means—
(i) an application under subsection (b) for a drug that is subject to
(ii) an application under
(C) New safety information; serious risk
The terms "new safety information", "serious risk", and "signal of a serious risk" have the meanings given such terms in
(3) Studies and clinical trials
(A) In general
For any or all of the purposes specified in subparagraph (B), the Secretary may, subject to subparagraph (D), require a responsible person for a drug to conduct a postapproval study or studies of the drug, or a postapproval clinical trial or trials of the drug, on the basis of scientific data deemed appropriate by the Secretary, including information regarding chemically-related or pharmacologically-related drugs.
(B) Purposes of study or clinical trial
The purposes referred to in this subparagraph with respect to a postapproval study or postapproval clinical trial are the following:
(i) To assess a known serious risk related to the use of the drug involved.
(ii) To assess signals of serious risk related to the use of the drug.
(iii) To identify an unexpected serious risk when available data indicates the potential for a serious risk.
(C) Establishment of requirement after approval of covered application
The Secretary may require a postapproval study or studies or postapproval clinical trial or trials for a drug for which an approved covered application is in effect as of the date on which the Secretary seeks to establish such requirement only if the Secretary becomes aware of new safety information.
(D) Determination by Secretary
(i) Postapproval studies
The Secretary may not require the responsible person to conduct a study under this paragraph, unless the Secretary makes a determination that the reports under subsection (k)(1) and the active postmarket risk identification and analysis system as available under subsection (k)(3) will not be sufficient to meet the purposes set forth in subparagraph (B).
(ii) Postapproval clinical trials
The Secretary may not require the responsible person to conduct a clinical trial under this paragraph, unless the Secretary makes a determination that a postapproval study or studies will not be sufficient to meet the purposes set forth in subparagraph (B).
(E) Notification; timetables; periodic reports
(i) Notification
The Secretary shall notify the responsible person regarding a requirement under this paragraph to conduct a postapproval study or clinical trial by the target dates for communication of feedback from the review team to the responsible person regarding proposed labeling and postmarketing study commitments as set forth in the letters described in section 101(c) of the Food and Drug Administration Amendments Act of 2007.
(ii) Timetable; periodic reports
For each study or clinical trial required to be conducted under this paragraph, the Secretary shall require that the responsible person submit a timetable for completion of the study or clinical trial. With respect to each study required to be conducted under this paragraph or otherwise undertaken by the responsible person to investigate a safety issue, the Secretary shall require the responsible person to periodically report to the Secretary on the status of such study including whether any difficulties in completing the study have been encountered. With respect to each clinical trial required to be conducted under this paragraph or otherwise undertaken by the responsible person to investigate a safety issue, the Secretary shall require the responsible person to periodically report to the Secretary on the status of such clinical trial including whether enrollment has begun, the number of participants enrolled, the expected completion date, whether any difficulties completing the clinical trial have been encountered, and registration information with respect to the requirements under
(F) Dispute resolution
The responsible person may appeal a requirement to conduct a study or clinical trial under this paragraph using dispute resolution procedures established by the Secretary in regulation and guidance.
(4) Safety labeling changes requested by Secretary
(A) New safety or new effectiveness information
If the Secretary becomes aware of new information, including any new safety information or information related to reduced effectiveness, that the Secretary determines should be included in the labeling of the drug, the Secretary shall promptly notify the responsible person or, if the same drug approved under subsection (b) is not currently marketed, the holder of an approved application under subsection (j).
(B) Response to notification
Following notification pursuant to subparagraph (A), the responsible person or the holder of the approved application under subsection (j) shall within 30 days—
(i) submit a supplement proposing changes to the approved labeling to reflect the new safety information, including changes to boxed warnings, contraindications, warnings, precautions, or adverse reactions, or new effectiveness information; or
(ii) notify the Secretary that the responsible person or the holder of the approved application under subsection (j) does not believe a labeling change is warranted and submit a statement detailing the reasons why such a change is not warranted.
(C) Review
Upon receipt of such supplement, the Secretary shall promptly review and act upon such supplement. If the Secretary disagrees with the proposed changes in the supplement or with the statement setting forth the reasons why no labeling change is necessary, the Secretary shall initiate discussions to reach agreement on whether the labeling for the drug should be modified to reflect the new safety or new effectiveness information, and if so, the contents of such labeling changes.
(D) Discussions
Such discussions shall not extend for more than 30 days after the response to the notification under subparagraph (B), unless the Secretary determines an extension of such discussion period is warranted.
(E) Order
Within 15 days of the conclusion of the discussions under subparagraph (D), the Secretary may issue an order directing the responsible person or the holder of the approved application under subsection (j) to make such a labeling change as the Secretary deems appropriate to address the new safety or new effectiveness information. Within 15 days of such an order, the responsible person or the holder of the approved application under subsection (j) shall submit a supplement containing the labeling change.
(F) Dispute resolution
Within 5 days of receiving an order under subparagraph (E), the responsible person or the holder of the approved application under subsection (j) may appeal using dispute resolution procedures established by the Secretary in regulation and guidance.
(G) Violation
If the responsible person or the holder of the approved application under subsection (j) has not submitted a supplement within 15 days of the date of such order under subparagraph (E), and there is no appeal or dispute resolution proceeding pending, the responsible person or holder shall be considered to be in violation of this subsection. If at the conclusion of any dispute resolution procedures the Secretary determines that a supplement must be submitted and such a supplement is not submitted within 15 days of the date of that determination, the responsible person or holder shall be in violation of this subsection.
(H) Public health threat
Notwithstanding subparagraphs (A) through (F), if the Secretary concludes that such a labeling change is necessary to protect the public health, the Secretary may accelerate the timelines in such subparagraphs.
(I) Rule of construction
This paragraph shall not be construed to affect the responsibility of the responsible person or the holder of the approved application under subsection (j) to maintain its label in accordance with existing requirements, including subpart B of part 201 and sections 314.70 and 601.12 of title 21, Code of Federal Regulations (or any successor regulations).
(5) Non-delegation
Determinations by the Secretary under this subsection for a drug shall be made by individuals at or above the level of individuals empowered to approve a drug (such as division directors within the Center for Drug Evaluation and Research).
(p) Risk evaluation and mitigation strategy
(1) In general
A person may not introduce or deliver for introduction into interstate commerce a new drug if—
(A)(i) the application for such drug is approved under subsection (b) or (j) and is subject to
(ii) the application for such drug is approved under
(B) a risk evaluation and mitigation strategy is required under
(2) Certain postmarket studies
The failure to conduct a postmarket study under
(q) Petitions and civil actions regarding approval of certain applications
(1) In general
(A) Determination
The Secretary shall not delay approval of a pending application submitted under subsection (b)(2) or (j) of this section or
(i) the request is in writing and is a petition submitted to the Secretary pursuant to section 10.30 or 10.35 of title 21, Code of Federal Regulations (or any successor regulations); and
(ii) the Secretary determines, upon reviewing the petition, that a delay is necessary to protect the public health.
Consideration of the petition shall be separate and apart from review and approval of any application.
(B) Notification
If the Secretary determines under subparagraph (A) that a delay is necessary with respect to an application, the Secretary shall provide to the applicant, not later than 30 days after making such determination, the following information:
(i) Notification of the fact that a determination under subparagraph (A) has been made.
(ii) If applicable, any clarification or additional data that the applicant should submit to the docket on the petition to allow the Secretary to review the petition promptly.
(iii) A brief summary of the specific substantive issues raised in the petition which form the basis of the determination.
(C) Format
The information described in subparagraph (B) shall be conveyed via either, at the discretion of the Secretary—
(i) a document; or
(ii) a meeting with the applicant involved.
(D) Public disclosure
Any information conveyed by the Secretary under subparagraph (C) shall be considered part of the application and shall be subject to the disclosure requirements applicable to information in such application.
(E) Denial based on intent to delay
If the Secretary determines that a petition or a supplement to the petition was submitted with the primary purpose of delaying the approval of an application and the petition does not on its face raise valid scientific or regulatory issues, the Secretary may deny the petition at any point based on such determination. The Secretary may issue guidance to describe the factors that will be used to determine under this subparagraph whether a petition is submitted with the primary purpose of delaying the approval of an application.
(F) Final agency action
The Secretary shall take final agency action on a petition not later than 150 days after the date on which the petition is submitted. The Secretary shall not extend such period for any reason, including—
(i) any determination made under subparagraph (A);
(ii) the submission of comments relating to the petition or supplemental information supplied by the petitioner; or
(iii) the consent of the petitioner.
(G) Extension of 30-month period
If the filing of an application resulted in first-applicant status under subsection (j)(5)(D)(i)(IV) and approval of the application was delayed because of a petition, the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final agency action on the petition (inclusive of such beginning and ending dates), without regard to whether the Secretary grants, in whole or in part, or denies, in whole or in part, the petition.
(H) Certification
The Secretary shall not consider a petition for review unless the party submitting such petition does so in written form and the subject document is signed and contains the following certification: "I certify that, to my best knowledge and belief: (a) this petition includes all information and views upon which the petition relies; (b) this petition includes representative data and/or information known to the petitioner which are unfavorable to the petition; and (c) I have taken reasonable steps to ensure that any representative data and/or information which are unfavorable to the petition were disclosed to me. I further certify that the information upon which I have based the action requested herein first became known to the party on whose behalf this petition is submitted on or about the following date: ____________________. If I received or expect to receive payments, including cash and other forms of consideration, to file this information or its contents, I received or expect to receive those payments from the following persons or organizations: __________________________. I verify under penalty of perjury that the foregoing is true and correct as of the date of the submission of this petition.", with the date on which such information first became known to such party and the names of such persons or organizations inserted in the first and second blank space, respectively.
(I) Verification
The Secretary shall not accept for review any supplemental information or comments on a petition unless the party submitting such information or comments does so in written form and the subject document is signed and contains the following verification: "I certify that, to my best knowledge and belief: (a) I have not intentionally delayed submission of this document or its contents; and (b) the information upon which I have based the action requested herein first became known to me on or about ____________________. If I received or expect to receive payments, including cash and other forms of consideration, to file this information or its contents, I received or expect to receive those payments from the following persons or organizations: __________. I verify under penalty of perjury that the foregoing is true and correct as of the date of the submission of this petition.", with the date on which such information first became known to the party and the names of such persons or organizations inserted in the first and second blank space, respectively.
(2) Exhaustion of administrative remedies
(A) Final agency action within 150 days
The Secretary shall be considered to have taken final agency action on a petition if—
(i) during the 150-day period referred to in paragraph (1)(F), the Secretary makes a final decision within the meaning of section 10.45(d) of title 21, Code of Federal Regulations (or any successor regulation); or
(ii) such period expires without the Secretary having made such a final decision.
(B) Dismissal of certain civil actions
If a civil action is filed against the Secretary with respect to any issue raised in the petition before the Secretary has taken final agency action on the petition within the meaning of subparagraph (A), the court shall dismiss without prejudice the action for failure to exhaust administrative remedies.
(C) Administrative record
For purposes of judicial review related to the approval of an application for which a petition under paragraph (1) was submitted, the administrative record regarding any issue raised by the petition shall include—
(i) the petition filed under paragraph (1) and any supplements and comments thereto;
(ii) the Secretary's response to such petition, if issued; and
(iii) other information, as designated by the Secretary, related to the Secretary's determinations regarding the issues raised in such petition, as long as the information was considered by the agency no later than the date of final agency action as defined under subparagraph (2)(A), and regardless of whether the Secretary responded to the petition at or before the approval of the application at issue in the petition.
(3) Annual report on delays in approvals per petitions
The Secretary shall annually submit to the Congress a report that specifies—
(A) the number of applications that were approved during the preceding 12-month period;
(B) the number of such applications whose effective dates were delayed by petitions referred to in paragraph (1) during such period;
(C) the number of days by which such applications were so delayed; and
(D) the number of such petitions that were submitted during such period.
(4) Exceptions
(A) This subsection does not apply to—
(i) a petition that relates solely to the timing of the approval of an application pursuant to subsection (j)(5)(B)(iv); or
(ii) a petition that is made by the sponsor of an application and that seeks only to have the Secretary take or refrain from taking any form of action with respect to that application.
(B) Paragraph (2) does not apply to a petition addressing issues concerning an application submitted pursuant to
(5) Definitions
(A) Application
For purposes of this subsection, the term "application" means an application submitted under subsection (b)(2) or (j) of this section or
(B) Petition
For purposes of this subsection, other than paragraph (1)(A)(i), the term "petition" means a request described in paragraph (1)(A)(i).
(r) Postmarket drug safety information for patients and providers
(1) Establishment
Not later than 1 year after September 27, 2007, the Secretary shall improve the transparency of information about drugs and allow patients and health care providers better access to information about drugs by developing and maintaining an Internet Web site that—
(A) provides links to drug safety information listed in paragraph (2) for prescription drugs that are approved under this section or licensed under
(B) improves communication of drug safety information to patients and providers.
(2) Internet Web site
The Secretary shall carry out paragraph (1) by—
(A) developing and maintaining an accessible, consolidated Internet Web site with easily searchable drug safety information, including the information found on United States Government Internet Web sites, such as the United States National Library of Medicine's Daily Med and Medline Plus Web sites, in addition to other such Web sites maintained by the Secretary;
(B) ensuring that the information provided on the Internet Web site is comprehensive and includes, when available and appropriate—
(i) patient labeling and patient packaging inserts;
(ii) a link to a list of each drug, whether approved under this section or licensed under such section 262, for which a Medication Guide, as provided for under part 208 of title 21, Code of Federal Regulations (or any successor regulations), is required;
(iii) a link to the registry and results data bank provided for under subsections (i) and (j) of
(iv) the most recent safety information and alerts issued by the Food and Drug Administration for drugs approved by the Secretary under this section, such as product recalls, warning letters, and import alerts;
(v) publicly available information about implemented RiskMAPs and risk evaluation and mitigation strategies under subsection (o);
(vi) guidance documents and regulations related to drug safety; and
(vii) other material determined appropriate by the Secretary;
(C) providing access to summaries of the assessed and aggregated data collected from the active surveillance infrastructure under subsection (k)(3) to provide information of known and serious side-effects for drugs approved under this section or licensed under such section 262;
(D) preparing and making publicly available on the Internet website established under paragraph (1) best practices for drug safety surveillance activities for drugs approved under this section or
(E) enabling patients, providers, and drug sponsors to submit adverse event reports through the Internet Web site;
(F) providing educational materials for patients and providers about the appropriate means of disposing of expired, damaged, or unusable medications; and
(G) supporting initiatives that the Secretary determines to be useful to fulfill the purposes of the Internet Web site.
(3) Posting of drug labeling
The Secretary shall post on the Internet Web site established under paragraph (1) the approved professional labeling and any required patient labeling of a drug approved under this section or licensed under such section 262 not later than 21 days after the date the drug is approved or licensed, including in a supplemental application with respect to a labeling change.
(4) Private sector resources
To ensure development of the Internet Web site by the date described in paragraph (1), the Secretary may, on a temporary or permanent basis, implement systems or products developed by private entities.
(5) Authority for contracts
The Secretary may enter into contracts with public and private entities to fulfill the requirements of this subsection.
(6) Review
The Advisory Committee on Risk Communication under
(s) Referral to advisory committee
The Secretary shall—
(1) refer a drug or biological product to a Food and Drug Administration advisory committee for review at a meeting of such advisory committee prior to the approval of such drug or biological if it is—
(A) a drug, no active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) of which has been approved in any other application under this section; or
(B) a biological product, no active ingredient of which has been approved in any other application under
(2) if the Secretary does not refer a drug or biological product described in paragraph (1) to a Food and Drug Administration advisory committee prior to such approval, provide in the action letter on the application for the drug or biological product a summary of the reasons why the Secretary did not refer the drug or biological product to an advisory committee prior to approval.
(t) Database for authorized generic drugs
(1) In general
(A) Publication
The Commissioner shall—
(i) not later than 9 months after September 27, 2007, publish a complete list on the Internet Web site of the Food and Drug Administration of all authorized generic drugs (including drug trade name, brand company manufacturer, and the date the authorized generic drug entered the market); and
(ii) update the list quarterly to include each authorized generic drug included in an annual report submitted to the Secretary by the sponsor of a listed drug during the preceding 3-month period.
(B) Notification
The Commissioner shall notify relevant Federal agencies, including the Centers for Medicare & Medicaid Services and the Federal Trade Commission, when the Commissioner first publishes the information described in subparagraph (A) that the information has been published and that the information will be updated quarterly.
(2) Inclusion
The Commissioner shall include in the list described in paragraph (1) each authorized generic drug included in an annual report submitted to the Secretary by the sponsor of a listed drug after January 1, 1999.
(3) Authorized generic drug
In this section, the term "authorized generic drug" means a listed drug (as that term is used in subsection (j)) that—
(A) has been approved under subsection (c); and
(B) is marketed, sold, or distributed directly or indirectly to retail class of trade under a different labeling, packaging (other than repackaging as the listed drug in blister packs, unit doses, or similar packaging for use in institutions), product code, labeler code, trade name, or trade mark than the listed drug.
(u) Certain drugs containing single enantiomers
(1) In general
For purposes of subsections (c)(3)(E)(ii) and (j)(5)(F)(ii), if an application is submitted under subsection (b) for a non-racemic drug containing as an active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) a single enantiomer that is contained in a racemic drug approved in another application under subsection (b), the applicant may, in the application for such non-racemic drug, elect to have the single enantiomer not be considered the same active moiety as that contained in the approved racemic drug, if—
(A)(i) the single enantiomer has not been previously approved except in the approved racemic drug; and
(ii) the application submitted under subsection (b) for such non-racemic drug—
(I) includes full reports of new clinical investigations (other than bioavailability studies)—
(aa) necessary for the approval of the application under subsections (c) and (d); and
(bb) conducted or sponsored by the applicant; and
(II) does not rely on any clinical investigations (other than bioavailability studies) that are part of an application submitted under subsection (b) for approval of the approved racemic drug; and
(B) the application submitted under subsection (b) for such non-racemic drug is not submitted for approval of a condition of use—
(i) in a therapeutic category in which the approved racemic drug has been approved; or
(ii) for which any other enantiomer of the racemic drug has been approved.
(2) Limitation
(A) No approval in certain therapeutic categories
Until the date that is 10 years after the date of approval of a non-racemic drug described in paragraph (1) and with respect to which the applicant has made the election provided for by such paragraph, the Secretary shall not approve such non-racemic drug for any condition of use in the therapeutic category in which the racemic drug has been approved.
(B) Labeling
If applicable, the labeling of a non-racemic drug described in paragraph (1) and with respect to which the applicant has made the election provided for by such paragraph shall include a statement that the non-racemic drug is not approved, and has not been shown to be safe and effective, for any condition of use of the racemic drug.
(3) Definition
(A) In general
For purposes of this subsection, the term "therapeutic category" means a therapeutic category identified in the list developed by the United States Pharmacopeia pursuant to
(B) Publication by Secretary
The Secretary shall publish the list described in subparagraph (A) and may amend such list by regulation.
(4) Availability
The election referred to in paragraph (1) may be made only in an application that is submitted to the Secretary after September 27, 2007, and before October 1, 2027.
(v) Antibiotic drugs submitted before November 21, 1997
(1) Antibiotic drugs approved before November 21, 1997
(A) In general
Notwithstanding any provision of the Food and Drug Administration Modernization Act of 1997 or any other provision of law, a sponsor of a drug that is the subject of an application described in subparagraph (B)(i) shall be eligible for, with respect to the drug, the 3-year exclusivity period referred to under clauses (iii) and (iv) of subsection (c)(3)(E) and under clauses (iii) and (iv) of subsection (j)(5)(F), subject to the requirements of such clauses, as applicable.
(B) Application; antibiotic drug described
(i) Application
An application described in this clause is an application for marketing submitted under this section after October 8, 2008, in which the drug that is the subject of the application contains an antibiotic drug described in clause (ii).
(ii) Antibiotic drug
An antibiotic drug described in this clause is an antibiotic drug that was the subject of an application approved by the Secretary under
(2) Antibiotic drugs submitted before November 21, 1997, but not approved
(A) In general
Notwithstanding any provision of the Food and Drug Administration Modernization Act of 1997 or any other provision of law, a sponsor of a drug that is the subject of an application described in subparagraph (B)(i) may elect to be eligible for, with respect to the drug—
(i)(I) the 3-year exclusivity period referred to under clauses (iii) and (iv) of subsection (c)(3)(E) and under clauses (iii) and (iv) of subsection (j)(5)(F), subject to the requirements of such clauses, as applicable; and
(II) the 5-year exclusivity period referred to under clause (ii) of subsection (c)(3)(E) and under clause (ii) of subsection (j)(5)(F), subject to the requirements of such clauses, as applicable; or
(ii) a patent term extension under
(B) Application; antibiotic drug described
(i) Application
An application described in this clause is an application for marketing submitted under this section after October 8, 2008, in which the drug that is the subject of the application contains an antibiotic drug described in clause (ii).
(ii) Antibiotic drug
An antibiotic drug described in this clause is an antibiotic drug that was the subject of 1 or more applications received by the Secretary under
(3) Limitations
(A) Exclusivities and extensions
Paragraphs (1)(A) and (2)(A) shall not be construed to entitle a drug that is the subject of an approved application described in subparagraphs 5 (1)(B)(i) or (2)(B)(i), as applicable, to any market exclusivities or patent extensions other than those exclusivities or extensions described in paragraph (1)(A) or (2)(A).
(B) Conditions of use
Paragraphs (1)(A) and (2)(A)(i) shall not apply to any condition of use for which the drug referred to in subparagraph (1)(B)(i) or (2)(B)(i), as applicable, was approved before October 8, 2008.
(4) Application of certain provisions
Notwithstanding section 125, or any other provision, of the Food and Drug Administration Modernization Act of 1997, or any other provision of law, and subject to the limitations in paragraphs (1), (2), and (3), the provisions of the Drug Price Competition and Patent Term Restoration Act of 1984 shall apply to any drug subject to paragraph (1) or any drug with respect to which an election is made under paragraph (2)(A).
(w) Deadline for determination on certain petitions
The Secretary shall issue a final, substantive determination on a petition submitted pursuant to subsection (b) of section 314.161 of title 21, Code of Federal Regulations (or any successor regulations), no later than 270 days after the date the petition is submitted.
(x) Date of approval in the case of recommended controls under the CSA
(1) In general
In the case of an application under subsection (b) with respect to a drug for which the Secretary provides notice to the sponsor that the Secretary intends to issue a scientific and medical evaluation and recommend controls under the Controlled Substances Act [
(2) Date of approval
For purposes of this section, with respect to an application described in paragraph (1), the term "date of approval" shall mean the later of—
(A) the date an application under subsection (b) is approved under subsection (c); or
(B) the date of issuance of the interim final rule controlling the drug.
(y) Contrast agents intended for use with applicable medical imaging devices
(1) In general
The sponsor of a contrast agent for which an application has been approved under this section may submit a supplement to the application seeking approval for a new use following the authorization of a premarket submission for an applicable medical imaging device for that use with the contrast agent pursuant to
(2) Review of supplement
In reviewing a supplement submitted under this subsection, the agency center charged with the premarket review of drugs may—
(A) consult with the center charged with the premarket review of devices; and
(B) review information and data submitted to the Secretary by the sponsor of an applicable medical imaging device pursuant to
(3) Definitions
For purposes of this subsection—
(A) the term "new use" means a use of a contrast agent that is described in the approved labeling of an applicable medical imaging device described in
(B) the terms "applicable medical imaging device" and "contrast agent" have the meanings given such terms in
(z) 6 Nonclinical test defined
For purposes of this section, the term "nonclinical test" means a test conducted in vitro, in silico, or in chemico, or a nonhuman in vivo test, that occurs before or during the clinical trial phase of the investigation of the safety and effectiveness of a drug. Such test may include the following:
(1) Cell-based assays.
(2) Organ chips and microphysiological systems.
(3) Computer modeling.
(4) Other nonhuman or human biology-based test methods, such as bioprinting.
(5) Animal tests.
(z) 6 Diversity action plan for clinical studies 7
(1) With respect to a clinical investigation of a new drug that is a phase 3 study, as defined in section 312.21(c) of title 21, Code of Federal Regulations (or successor regulations), or, as appropriate, another pivotal study of a new drug (other than bioavailability or bioequivalence studies), the sponsor of such drug shall submit to the Secretary a diversity action plan.
(2) Such diversity action plan shall include—
(A) the sponsor's goals for enrollment in such clinical study;
(B) the sponsor's rationale for such goals; and
(C) an explanation of how the sponsor intends to meet such goals.
(3) The sponsor shall submit to the Secretary such diversity action plan, in the form and manner specified by the Secretary in guidance, as soon as practicable but not later than the date on which the sponsor submits the protocol to the Secretary for such a phase 3 study or other pivotal study of the drug. The sponsor may submit modifications to the diversity action plan. Any such modifications shall be in the form and manner specified by the Secretary in guidance.
(4)(A) On the initiative of the Secretary or at the request of a sponsor, the Secretary may waive any requirement in paragraph (1), (2), or (3) if the Secretary determines that a waiver is necessary based on what is known or what can be determined about the prevalence or incidence of the disease or condition for which the new drug is under investigation (including in terms of the patient population that may use the drug), if conducting a clinical investigation in accordance with a diversity action plan would otherwise be impracticable, or if such waiver is necessary to protect public health during a public health emergency.
(B) The Secretary shall issue a written response granting or denying a request from a sponsor for a waiver within 60 days of receiving such request.
(5) No diversity action plan shall be required for a submission described in
(June 25, 1938, ch. 675, §505,
Delayed Applicability of Amendment
For delayed applicability of subsection (z) of this section as added by section 3601(a) of
Editorial Notes
References in Text
Section 264(c) of the Health Insurance Portability and Accountability Act of 1996, referred to in subsec. (k)(3)(C)(i)(I), (4)(G)(i)(I), is section 264(c) of
The General Schedule, referred to in subsec. (n)(5), is set out under
Section 101(c) of the Food and Drug Administration Amendments Act of 2007, referred to in subsec. (o)(3)(E)(i), is section 101(c) of
The Food and Drug Administration Modernization Act of 1997, referred to in subsec. (v)(1)(A), (2)(A), (4), is
The Drug Price Competition and Patent Term Restoration Act of 1984, referred to in subsec. (v)(4), is
The Controlled Substances Act, referred to in subsec. (x)(1), is title II of
Codification
In subsec. (k)(4)(H), "
Amendments
2022—Subsec. (i)(1)(A).
Subsec. (i)(2)(B).
Subsec. (j)(7)(A)(v).
Subsec. (j)(10)(A)(i) to (iii).
"(i) the application is otherwise eligible for approval under this subsection but for expiration of patent, an exclusivity period, or of a delay in approval described in paragraph (5)(B)(iii), and a revision to the labeling of the listed drug has been approved by the Secretary within 60 days of such expiration;
"(ii) the labeling revision described under clause (i) does not include a change to the 'Warnings' section of the labeling;
"(iii) the sponsor of the application under this subsection agrees to submit revised labeling of the drug that is the subject of such application not later than 60 days after the notification of any changes to such labeling required by the Secretary; and".
Subsec. (u)(1)(A)(ii)(II).
Subsec. (u)(4).
Subsec. (z).
2021—Subsec. (b)(1).
Subsec. (c)(2).
Subsec. (c)(3)(E).
Subsec. (c)(3)(E)(i).
Subsec. (j)(2)(A)(vi).
Subsec. (j)(5)(F).
Subsec. (j)(5)(F)(i).
Subsec. (j)(7)(A)(iii).
Subsec. (j)(7)(A)(iv).
Subsec. (j)(7)(D).
Subsec. (l)(2)(A)(i).
Subsec. (l)(2)(A)(ii).
Subsec. (s).
"(1) refer such drug to a Food and Drug Administration advisory committee for review at a meeting of such advisory committee; or
"(2) if the Secretary does not refer such a drug to a Food and Drug Administration advisory committee prior to the approval of the drug, provide in the action letter on the application for the drug a summary of the reasons why the Secretary did not refer the drug to an advisory committee prior to approval."
Subsec. (u)(1).
2018—Subsec. (o)(4)(A).
Subsec. (o)(4)(B)(i).
Subsec. (o)(4)(C).
Subsec. (o)(4)(E).
2017—Subsec. (j)(5)(B)(v).
Subsec. (j)(5)(D)(iv).
Subsec. (j)(11), (12).
Subsec. (j)(13).
Subsec. (k)(5).
Subsec. (u)(4).
Subsec. (y).
2016—Subsec. (c)(5).
Subsec. (d).
Subsec. (i)(4).
Subsec. (k)(5)(A).
Subsec. (k)(5)(B).
Subsec. (k)(5)(C).
Subsec. (q)(5)(A).
Subsec. (r)(2)(D).
2015—Subsec. (x).
2013—Subsec. (b)(5)(B).
2012—Subsec. (d).
Subsec. (q)(1)(A).
Subsec. (q)(1)(F).
Subsec. (q)(2)(A).
Subsec. (q)(2)(A)(i).
Subsec. (q)(4).
Subsec. (q)(5)(A).
Subsec. (u)(1)(A)(ii)(II).
Subsec. (u)(4).
Subsec. (w).
2010—Subsec. (b)(5)(B).
Subsec. (j)(10).
2009—Subsec. (n)(2).
2008—Subsec. (q)(1)(A).
Subsec. (v).
2007—Subsec. (b)(6).
Subsec. (e).
Subsec. (i)(4).
Subsec. (k)(3), (4).
Subsec. (k)(5).
Subsec. (l).
Subsec. (n)(4) to (8).
Subsecs. (o), (p).
Subsec. (q).
Subsec. (r).
Subsec. (s).
Subsec. (t).
Subsec. (u).
2003—Subsec. (b)(1).
Subsec. (b)(3).
Subsec. (b)(4), (5).
Subsec. (c)(3).
Subsec. (c)(3)(C).
Subsec. (c)(3)(C)(i).
Subsec. (c)(3)(C)(ii).
Subsec. (c)(3)(C)(iii).
Subsec. (c)(3)(C)(iv).
Subsec. (c)(3)(D), (E).
Subsec. (j)(2)(B).
Subsec. (j)(2)(D).
Subsec. (j)(5)(B).
Subsec. (j)(5)(B)(iii).
Subsec. (j)(5)(B)(iii)(I).
Subsec. (j)(5)(B)(iii)(II).
Subsec. (j)(5)(B)(iii)(III).
Subsec. (j)(5)(B)(iii)(IV).
Subsec. (j)(5)(B)(iv).
"(I) the date the Secretary receives notice from the applicant under the previous application of the first commercial marketing of the drug under the previous application, or
"(II) the date of a decision of a court in an action described in clause (iii) holding the patent which is the subject of the certification to be invalid or not infringed,
whichever is earlier."
Subsec. (j)(5)(C).
Subsec. (j)(5)(D).
Subsec. (j)(5)(E), (F).
Subsec. (j)(8)(A).
Subsec. (j)(8)(C).
2002—Subsec. (i)(1)(D).
1999—Subsec. (m).
1997—Subsec. (b)(1).
Subsec. (b)(4).
Subsec. (c)(4).
Subsec. (d).
Subsec. (i).
Subsec. (j)(2)(A)(i).
Subsec. (j)(3).
Subsec. (j)(4).
Subsec. (j)(4)(I).
Subsec. (j)(5), (6).
Subsec. (j)(7).
Subsec. (j)(8), (9).
Subsec. (n).
1993—Subsec. (j)(6)(A)(ii).
Subsec. (j)(6)(A)(iii).
Subsec. (k)(1).
1992—Subsec. (j)(8).
1984—Subsec. (a).
Subsec. (b).
Subsec. (c).
Subsec. (d)(6), (7).
Subsec. (e).
Subsecs. (j), (k).
Subsec. (k)(1).
Subsecs. (l), (m).
1972—Subsec. (e).
1962—Subsec. (a).
Subsec. (b).
Subsec. (c).
Subsec. (d).
Subsec. (e).
Subsec. (f).
Subsec. (h).
Subsec. (i).
Subsec. (j).
1960—Subsec. (g).
Statutory Notes and Related Subsidiaries
Effective Date of 2022 Amendment
Effective Date of 2021 Amendment
Effective Date of 2012 Amendment
Effective Date of 2007 Amendment
Amendment by sections 901(a), 903, and 905(a) of
Effective Date of 2003 Amendments
"(1)
"(2)
"(3)
"(1)
"(2)
"(3)
Amendment by
Effective Date of 1999 Amendment
Amendment by
Effective Date of 1997 Amendment
Amendment by
Effective Date of 1984 Amendment
"(a) The Secretary of Health and Human Services shall promulgate, in accordance with the notice and comment requirements of
"(b) During the period beginning sixty days after the date of the enactment of this Act [Sept. 24, 1984], and ending on the date regulations promulgated under subsection (a) take effect, abbreviated new drug applications may be submitted in accordance with the provisions of section 314.2 of title 21 of the Code of Federal Regulations and shall be considered as suitable for any drug which has been approved for safety and effectiveness under section 505(c) of the Federal Food, Drug, and Cosmetic Act [subsec. (c) of this section] before the date of the enactment of this Act. If any such provision is inconsistent with the requirements of section 505(j) of the Federal Food, Drug, and Cosmetic Act, the Secretary shall consider the application under the applicable requirements of such section. The Secretary of Health and Human Services may not approve such an abbreviated new drug application which is filed for a drug which is described in sections 505(c)(3)(D) and 505(j)(4)(D) of the Federal Food, Drug, and Cosmetic Act, except in accordance with such section."
Effective Date of 1972 Amendment
Amendment by
Effective Date of 1962 Amendment
Amendment by
Construction of Amendment by Pub. L. 110–85
Construction of Amendments by Pub. L. 102–282
Amendment by
Extending Expiration Dates for Certain Drugs
"(1) the submission of stability testing data in such applications, including considerations for data requirements that could be streamlined or reduced to facilitate faster review of longer proposed expiration dates;
"(2) establishing in the labeling of drugs the longest feasible expiration date scientifically supported by such data, taking into consideration how extended expiration dates may—
"(A) help prevent or mitigate drug shortages; and
"(B) affect product quality; and
"(3) the use of innovative approaches for drug and combination product stability modeling to support initial product expiration dates and expiration date extensions."
Antifungal Research and Development
"(a)
"(b)
"(c)
Guidance on Diversity Action Plans for Clinical Studies
"(a)
"(1) the format and content of the diversity action plans required by sections 505(z) and 520(g)(9) of the Federal Food, Drug, and Cosmetic Act (
"(A) the rationale for the sponsor's enrollment goals, which may include—
"(i) the estimated prevalence or incidence in the United States of the disease or condition for which the drug or device is being investigated in the relevant clinical trial, if such estimated prevalence or incidence is known or can be determined based on available data;
"(ii) what is known about the disease or condition for which the drug or device is being investigated;
"(iii) any relevant pharmacokinetic or pharmacogenomic data;
"(iv) what is known about the patient population for such disease or condition, including, to the extent data is available—
"(I) demographic information, which may include age group, sex, race, geographic location, socioeconomic status, and ethnicity;
"(II) non-demographic factors, including co-morbidities affecting the patient population; and
"(III) potential barriers to enrolling diverse participants, such as patient population size, geographic location, and socioeconomic status; and
"(v) any other data or information relevant to selecting appropriate enrollment goals, disaggregated by demographic subgroup, such as the inclusion of pregnant and lactating women; and
"(B) an explanation for how the sponsor intends to meet such goals, including demographic-specific outreach and enrollment strategies, study-site selection, clinical study inclusion and exclusion practices, and any diversity training for study personnel;
"(2) submission of any modifications to the diversity action plan;
"(3) considerations for the public posting by a sponsor of key information from the diversity action plan that would be useful to patients and providers on the sponsor's website, as appropriate;
"(4) criteria that the Secretary will consider in assessing whether to grant a sponsor's request to waive the requirement to submit a diversity action plan under section 505(z)(4) or 520(g)(9)(C) of the Federal Food, Drug, and Cosmetic Act [
"(5) how sponsors may include in regular reports otherwise required by the Secretary—
"(A) the sponsor's progress in meeting the goals referred to in paragraph (1)(A); and
"(B) any updates needed to be made to a diversity action plan referred to in paragraph (1) to help meet goals referred to in paragraph (1)(A); and
"(C) if the sponsor does not expect to meet goals referred to in paragraph (1)(A), the sponsor's reasons for why the sponsor does not expect to meet such goals.
"(b)
"(1) not later than 12 months after the date of enactment of this Act [Dec. 29, 2022], issue new draft guidance or update existing draft guidance described in subsection (a); and
"(2) not later than 9 months after closing the comment period on such draft guidance, finalize such guidance."
Annual Summary Report on Progress To Increase Diversity in Clinical Studies
"(a)
"(1) summarizes, in aggregate, the diversity action plans received pursuant to section 505(z) or 520(g)(9) of the Federal Food, Drug, and Cosmetic Act [
"(2) contains information, in the aggregate, on—
"(A) for drugs, biological products, and devices approved, licensed, cleared, or classified under section 505, 515, 510(k), or 513(f)(2) of the Federal Food, Drug, and Cosmetic Act (
"(B) the reasons provided, if any, for why enrollment goals from submitted diversity action plans were not met.
"(b)
Facilitating the Use of Real World Evidence
"(a)
"(1) With respect to drugs, such guidance shall address the use of such data and evidence to support the approval of a drug application under section 505 of the Federal Food, Drug, and Cosmetic Act (
"(2) With respect to devices, such guidance shall address the use of such data and evidence to support the approval, clearance, or classification of a device pursuant to an application or submission submitted under section 510(k), 513(f)(2), or 515 of the Federal Food, Drug, and Cosmetic Act (
"(b)
"(1) the number of applications, submissions, or requests submitted for clearance, approval, or authorization under section 505, 510(k), 513(f)(2), or 515 of the Federal Food, Drug, and Cosmetic Act (
"(2) of the number of applications so submitted, the number of such applications—
"(A) for which real world evidence was submitted and used to support a regulatory decision; and
"(B) for which real world evidence was submitted and determined to be insufficient to support a regulatory decision; and
"(3) a summary explanation of why, in the case of applications described in paragraph (2)(B), real world evidence could not be used to support regulatory decisions.
"(c)
Clarifying FDA Regulation of Non-Addictive Pain Products
"(a)
"(1) the manner by which the Secretary may incorporate the risks of misuse and abuse of a controlled substance (as defined in section 102 of the Controlled Substances Act (
"(2) the application of novel clinical trial designs (consistent with section 3021 of the 21st Century Cures Act (
"(3) the evidentiary standards and the development of opioid-sparing data for inclusion in the labeling of medical products intended to treat acute or chronic pain; and
"(4) the application of eligibility criteria under sections 506 and 515B of the Federal Food, Drug, and Cosmetic Act (
"(b)
"(1) how the Food and Drug Administration may apply sections 506 and 515B of the Federal Food, Drug, and Cosmetic Act (
"(A) may apply the eligibility criteria under such sections 506 and 515B to non-addictive medical products intended to treat pain or addiction;
"(B) considers the risk of addiction of controlled substances approved to treat pain when establishing unmet medical need; and
"(C) considers pain, pain control, or pain management in assessing whether a disease or condition is a serious or life-threatening disease or condition;
"(2) the methods by which sponsors may evaluate acute and chronic pain, endpoints for non-addictive medical products intended to treat pain, the manner in which endpoints and evaluations of efficacy will be applied across and within review divisions, taking into consideration the etiology of the underlying disease, and the manner in which sponsors may use surrogate endpoints, intermediate endpoints, and real world evidence;
"(3) the manner in which the Food and Drug Administration will assess evidence to support the inclusion of opioid-sparing data in the labeling of non-addictive medical products intended to treat acute or chronic pain, including—
"(A) alternative data collection methodologies, including the use of novel clinical trial designs (consistent with section 3021 of the 21st Century Cures Act (
"(B) ethical considerations of exposing subjects to controlled substances in clinical trials to develop opioid-sparing data and considerations on data collection methods that reduce harm, which may include the reduction of opioid use as a clinical benefit;
"(C) endpoints, including primary, secondary, and surrogate endpoints, to evaluate the reduction of opioid use;
"(D) best practices for communication between sponsors and the agency on the development of data collection methods, including the initiation of data collection; and
"(E) the appropriate format in which to submit such data results to the Secretary; and
"(4) the circumstances under which the Food and Drug Administration considers misuse and abuse of a controlled substance (as defined in section 102 of the Controlled Substances Act (
"(c)
"(1) the term 'medical product' means a drug (as defined in section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act (
"(2) the term 'opioid-sparing' means reducing, replacing, or avoiding the use of opioids or other controlled substances intended to treat acute or chronic pain."
Guidance Regarding Reduction in Drug Effectiveness
Annual Report on Inspections
"(1) The median time following a request from staff of the Food and Drug Administration reviewing an application or report to the beginning of the inspection, including—
"(A) the median time for drugs described in 505(j)(11)(A)(i) of the Federal Food, Drug, and Cosmetic Act (
"(B) the median time for drugs for which a notification has been submitted in accordance with section 506C(a) of such Act (
"(C) the median time for drugs on the drug shortage list in effect under section 506E of such Act (
"(2) The median time from the issuance of a report pursuant to section 704(b) of the Federal Food, Drug, and Cosmetic Act (
"(3) The median time from the sending of a warning letter, issuance of an import alert, or holding of a regulatory meeting related to conditions observed by the Secretary during an inspection, to the time at which the Secretary concludes that corrective actions to resolve such conditions have been taken.
"(4) The number of facilities that failed to implement adequate corrective or preventive actions following a report issued pursuant to such section 704(b), resulting in a withhold recommendation for an application under review, including the number of such facilities manufacturing each category of drugs listed in subparagraphs (A) through (C) of paragraph (1)."
Report on Patient Experience Drug Development
Novel Clinical Trial Designs
"(a)
"(b)
"(1)
"(2)
"(A) the use of complex adaptive and other novel trial designs, including how such clinical trials proposed or submitted help to satisfy the substantial evidence standard under section 505(d) of the Federal Food, Drug, and Cosmetic Act (
"(B) how sponsors may obtain feedback from the Secretary on technical issues related to modeling and simulations prior to—
"(i) completion of such modeling or simulations; or
"(ii) the submission of resulting information to the Secretary;
"(C) the types of quantitative and qualitative information that should be submitted for review; and
"(D) recommended analysis methodologies.
"(3)
"(4)
Variations From CGMP Streamlined Approach
FDA Opioid Action Plan
"(1)
"(A)
"(B)
"(i) finds that such a referral is not in the interest of protecting and promoting public health;
"(ii) finds that such a referral is not necessary based on a review of the relevant scientific information; and
"(iii) submits a notice containing the rationale for such findings to the Committee on Health, Education, Labor, and Pensions of the Senate and the Committee on Energy and Commerce of the House of Representatives.
"(2)
"(3)
Guidance on Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products
Guidance on Pathogen-Focused Antibacterial Drug Development
"(a)
"(1) specifies how preclinical and clinical data can be utilized to inform an efficient and streamlined pathogen-focused antibacterial drug development program that meets the approval standards of the Food and Drug Administration; and
"(2) provides advice on approaches for the development of antibacterial drugs that target a more limited spectrum of pathogens.
"(b)
Guidance on Abuse-Deterrent Products
Extension of Period for First Applicant To Obtain Tentative Approval Without Forfeiting 180-Day-Exclusivity Period
"(a)
"(1)
"(A) during the period beginning on the date of enactment of this Act, and ending on September 30, 2015, '40 months'; and
"(B) during the period beginning on October 1, 2015, and ending on September 30, 2016, '36 months'.
"(2)
"(b)
"(c)
Effect of Amendments by Pub. L. 110–85 on Veterinary Medicine
Effect of Amendment by Pub. L. 108–173 on Abbreviated New Drug Applications
Federal Trade Commission Review
"SEC. 1111. DEFINITIONS.
"In this subtitle:
"(1) ANDA.—The term 'ANDA' means an abbreviated drug application, as defined under section 201(aa) of the Federal Food, Drug, and Cosmetic Act [
"(2)
"(3)
"(4)
"(5)
"(6)
"(7)
"(8)
"(9)
"(10)
"(11)
"(12)
"SEC. 1112. NOTIFICATION OF AGREEMENTS.
"(a)
"(1)
"(2)
"(A) the manufacture, marketing, or sale of the brand name drug that is the listed drug in the ANDA or the reference product in the biosimilar biological product application involved;
"(B) the manufacture, marketing, or sale of the generic drug for which the ANDA was submitted or of the biosimilar biological product for which the biosimilar biological product application was submitted; or
"(C) as applicable—
"(i) the 180-day period referred to in section 505(j)(5)(B)(iv) of the Federal Food, Drug, and Cosmetic Act [
"(ii) any of the time periods referred to in section 351(k)(6) of the Public Health Service Act [
"(b)
"(1)
"(A)
"(B)
"(2)
"(c)
"(1)
"(A) purchase orders for raw material supplies;
"(B) equipment and facility contracts;
"(C) employment or consulting contracts; or
"(D) packaging and labeling contracts.
"(2)
"(3)
"SEC. 1113. FILING DEADLINES.
"Any filing required under section 1112 shall be filed with the Assistant Attorney General and the Commission not later than 10 business days after the date the agreements are executed.
"SEC. 1114. DISCLOSURE EXEMPTION.
"Any information or documentary material filed with the Assistant Attorney General or the Commission pursuant to this subtitle shall be exempt from disclosure under
"SEC. 1115. ENFORCEMENT.
"(a)
"(b)
"SEC. 1116. RULEMAKING.
"The Commission, with the concurrence of the Assistant Attorney General and by rule in accordance with
"(1) may define the terms used in this subtitle;
"(2) may exempt classes of persons or agreements from the requirements of this subtitle; and
"(3) may prescribe such other rules as may be necessary and appropriate to carry out the purposes of this subtitle.
"SEC. 1117. SAVINGS CLAUSE.
"Any action taken by the Assistant Attorney General or the Commission, or any failure of the Assistant Attorney General or the Commission to take action, under this subtitle shall not at any time bar any proceeding or any action with respect to any agreement between a brand name drug company and a generic drug applicant or a biosimilar biological product applicant, any agreement between generic drug applicants, or any agreement between biosimilar biological product applicants, under any other provision of law, nor shall any filing under this subtitle constitute or create a presumption of any violation of any competition laws.
"SEC. 1118. EFFECTIVE DATE.
"This subtitle shall—
"(1) take effect 30 days after the date of the enactment of this Act [Dec. 8, 2003]; and
"(2) shall apply to agreements described in section 1112 that are entered into 30 days after the date of the enactment of this Act."
Report on Patient Access to New Therapeutic Agents for Pediatric Cancer
Data Requirements for Drugs and Biologics
Requirements for Review of Approval Procedures and Current Good Manufacturing Practices for Positron Emission Technology
"(1)
"(A)
"(i) appropriate procedures for the approval of positron emission tomography drugs pursuant to section 505 of the Federal Food, Drug, and Cosmetic Act (
"(ii) appropriate current good manufacturing practice requirements for such drugs.
"(B)
"(2)
"(A)
"(B)
"Compounded Positron Emission Topography Drug" Defined
Requirements for Radiopharmaceuticals
"(a)
"(1)
"(A)
"(B)
"(2)
"(b)
"(1) an article—
"(A) that is intended for use in the diagnosis or monitoring of a disease or a manifestation of a disease in humans; and
"(B) that exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons; or
"(2) any nonradioactive reagent kit or nuclide generator that is intended to be used in the preparation of any such article."
Special Rule
Transition
"(1) With respect to a patent issued on or before the date of the enactment of this Act [Oct. 8, 2008], any patent information required to be filed with the Secretary of Health and Human Services under subsection (b)(1) or (c)(2) of section 505 of the Federal Food, Drug, and Cosmetic Act (
"(2) With respect to any patent information referred to in paragraph (1) of this subsection that is filed with the Secretary within the 60-day period after the date of the enactment of this Act [Oct. 8, 2008], the Secretary shall publish such information in the electronic version of the list referred to at section 505(j)(7) of the Federal Food, Drug, and Cosmetic Act (
"(3) With respect to any patent information referred to in paragraph (1) that is filed with the Secretary within the 60-day period after the date of enactment of this Act [Oct. 8, 2008], each applicant that, not later than 120 days after the date of the enactment of this Act, amends an application that is, on or before the date of the enactment of this Act, a substantially complete application (as defined in paragraph (5)(B)(iv) of section 505(j) of the Federal Food, Drug, and Cosmetic Act (
"(1)
"(2)
"(A)(i) Subsections (c)(2), (d)(6), (e)(4), (j)(2)(A)(vii), (j)(2)(A)(viii), (j)(2)(B), (j)(4)(B), and (j)(4)(D); and
"(ii) The third and fourth sentences of subsection (b)(1) (regarding the filing and publication of patent information); and
"(B) Subsections (b)(2)(A), (b)(2)(B), (b)(3), and (c)(3) if the investigations relied upon by the applicant for approval of the application were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted.
"(3)
Termination of Advisory Panels
Advisory panels established after Jan. 5, 1973, to terminate not later than the expiration of the 2-year period beginning on the date of their establishment, unless, in the case of a panel established by the President or an officer of the Federal Government, such panel is renewed by appropriate action prior to the expiration of such 2-year period, or in the case of a panel established by Congress, its duration is otherwise provided for by law. See
Appeals Taken Prior to October 10, 1962
Executive Documents
Transfer of Functions
For transfer of functions of Federal Security Administrator to Secretary of Health, Education, and Welfare [now Health and Human Services], and of Food and Drug Administration in the Department of Agriculture to Federal Security Agency, see notes set out under
1 So in original. Probably should be "bioavailability".
2 So in original. Probably should be "drug,".
3 So in original. Probably should be preceded by "the".
4 So in original. The word "and" probably should not appear.
5 So in original. Probably should be "subparagraph".
6 So in original. Two subsecs. (z) have been enacted.
7 See Delayed Applicability of Amendment note below.
§355–1. Risk evaluation and mitigation strategies
(a) Submission of proposed strategy
(1) Initial approval
If the Secretary, in consultation with the office responsible for reviewing the drug and the office responsible for postapproval safety with respect to the drug, determines that a risk evaluation and mitigation strategy is necessary to ensure that the benefits of the drug outweigh the risks of the drug, and informs the person who submits such application of such determination, then such person shall submit to the Secretary as part of such application a proposed risk evaluation and mitigation strategy. In making such a determination, the Secretary shall consider the following factors:
(A) The estimated size of the population likely to use the drug involved.
(B) The seriousness of the disease or condition that is to be treated with the drug.
(C) The expected benefit of the drug with respect to such disease or condition.
(D) The expected or actual duration of treatment with the drug.
(E) The seriousness of any known or potential adverse events that may be related to the drug and the background incidence of such events in the population likely to use the drug.
(F) Whether the drug is a new molecular entity.
(2) Postapproval requirement
(A) In general
If the Secretary has approved a covered application (including an application approved before the effective date of this section) and did not when approving the application require a risk evaluation and mitigation strategy under paragraph (1), the Secretary, in consultation with the offices described in paragraph (1), may subsequently require such a strategy for the drug involved (including when acting on a supplemental application seeking approval of a new indication for use of the drug) if the Secretary becomes aware of new safety information and makes a determination that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks of the drug.
(B) Submission of proposed strategy
Not later than 120 days after the Secretary notifies the holder of an approved covered application that the Secretary has made a determination under subparagraph (A) with respect to the drug involved, or within such other reasonable time as the Secretary requires to protect the public health, the holder shall submit to the Secretary a proposed risk evaluation and mitigation strategy.
(3) Abbreviated new drug applications
The applicability of this section to an application under
(4) Non-delegation
Determinations by the Secretary under this subsection for a drug shall be made by individuals at or above the level of individuals empowered to approve a drug (such as division directors within the Center for Drug Evaluation and Research).
(b) Definitions
For purposes of this section:
(1) Adverse drug experience
The term "adverse drug experience" means any adverse event associated with the use of a drug in humans, whether or not considered drug related, including—
(A) an adverse event occurring in the course of the use of the drug in professional practice;
(B) an adverse event occurring from an overdose of the drug, whether accidental or intentional;
(C) an adverse event occurring from abuse of the drug;
(D) an adverse event occurring from withdrawal of the drug; and
(E) any failure of expected pharmacological action of the drug, which may include reduced effectiveness under the conditions of use prescribed in the labeling of such drug, but which may not include reduced effectiveness that is in accordance with such labeling.
(2) Covered application
The term "covered application" means an application referred to in
(3) New safety information
The term "new safety information", with respect to a drug, means information derived from a clinical trial, an adverse event report, a postapproval study (including a study under
(A) a serious risk or an unexpected serious risk associated with use of the drug that the Secretary has become aware of (that may be based on a new analysis of existing information) since the drug was approved, since the risk evaluation and mitigation strategy was required, or since the last assessment of the approved risk evaluation and mitigation strategy for the drug; or
(B) the effectiveness of the approved risk evaluation and mitigation strategy for the drug obtained since the last assessment of such strategy.
(4) Serious adverse drug experience
The term "serious adverse drug experience" is an adverse drug experience that—
(A) results in—
(i) death;
(ii) an adverse drug experience that places the patient at immediate risk of death from the adverse drug experience as it occurred (not including an adverse drug experience that might have caused death had it occurred in a more severe form);
(iii) inpatient hospitalization or prolongation of existing hospitalization;
(iv) a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; or
(v) a congenital anomaly or birth defect; or
(B) based on appropriate medical judgment, may jeopardize the patient and may require a medical or surgical intervention to prevent an outcome described under subparagraph (A).
(5) Serious risk
The term "serious risk" means a risk of a serious adverse drug experience.
(6) Signal of a serious risk
The term "signal of a serious risk" means information related to a serious adverse drug experience associated with use of a drug and derived from—
(A) a clinical trial;
(B) adverse event reports;
(C) a postapproval study, including a study under
(D) peer-reviewed biomedical literature;
(E) data derived from the postmarket risk identification and analysis system under
(F) other scientific data deemed appropriate by the Secretary.
(7) Responsible person
The term "responsible person" means the person submitting a covered application or the holder of the approved such application.
(8) Unexpected serious risk
The term "unexpected serious risk" means a serious adverse drug experience that is not listed in the labeling of a drug, or that may be symptomatically and pathophysiologically related to an adverse drug experience identified in the labeling, but differs from such adverse drug experience because of greater severity, specificity, or prevalence.
(c) Contents
A proposed risk evaluation and mitigation strategy under subsection (a) shall—
(1) include the timetable required under subsection (d); and
(2) to the extent required by the Secretary, in consultation with the office responsible for reviewing the drug and the office responsible for postapproval safety with respect to the drug, include additional elements described in subsections (e) and (f).
(d) Minimal strategy
For purposes of subsection (c)(1), the risk evaluation and mitigation strategy for a drug shall require a timetable for submission of assessments of the strategy that—
(1) includes an assessment, by the date that is 18 months after the strategy is initially approved;
(2) includes an assessment by the date that is 3 years after the strategy is initially approved;
(3) includes an assessment in the seventh year after the strategy is so approved; and
(4) subject to paragraphs (1), (2), and (3)—
(A) is at a frequency specified in the strategy;
(B) is increased or reduced in frequency as necessary as provided for in subsection (g)(4)(A); and
(C) is eliminated after the 3-year period described in paragraph (1) if the Secretary determines that serious risks of the drug have been adequately identified and assessed and are being adequately managed.
(e) Additional potential elements of strategy
(1) In general
The Secretary, in consultation with the offices described in subsection (c)(2), may under such subsection require that the risk evaluation and mitigation strategy for a drug include 1 or more of the additional elements described in this subsection if the Secretary makes the determination required with respect to each element involved.
(2) Medication Guide; patient package insert
The risk evaluation and mitigation strategy for a drug may require that, as applicable, the responsible person develop for distribution to each patient when the drug is dispensed—
(A) a Medication Guide, as provided for under part 208 of title 21, Code of Federal Regulations (or any successor regulations); and
(B) a patient package insert, if the Secretary determines that such insert may help mitigate a serious risk of the drug.
(3) Communication plan
The risk evaluation and mitigation strategy for a drug may require that the responsible person conduct a communication plan to health care providers, if, with respect to such drug, the Secretary determines that such plan may support implementation of an element of the strategy (including under this paragraph). Such plan may include—
(A) sending letters to health care providers;
(B) disseminating information about the elements of the risk evaluation and mitigation strategy to encourage implementation by health care providers of components that apply to such health care providers, or to explain certain safety protocols (such as medical monitoring by periodic laboratory tests) 1
(C) disseminating information to health care providers through professional societies about any serious risks of the drug and any protocol to assure safe use; or
(D) disseminating information to health care providers about drug formulations or properties, including information about the limitations or patient care implications of such formulations or properties, and how such formulations or properties may be related to serious adverse drug events associated with use of the drug.
(4) Packaging and disposal
The Secretary may require a risk evaluation mitigation strategy for a drug for which there is a serious risk of an adverse drug experience described in subparagraph (B) or (C) of subsection (b)(1), taking into consideration the factors described in subparagraphs (C) and (D) of subsection (f)(2) and in consultation with other relevant Federal agencies with authorities over drug disposal packaging, which may include requiring that—
(A) the drug be made available for dispensing to certain patients in unit dose packaging, packaging that provides a set duration, or another packaging system that the Secretary determines may mitigate such serious risk; or
(B) the drug be dispensed to certain patients with a safe disposal packaging or safe disposal system if the Secretary determines that such safe disposal packaging or system may mitigate such serious risk and is sufficiently available.
(f) Providing safe access for patients to drugs with known serious risks that would otherwise be unavailable
(1) Allowing safe access to drugs with known serious risks
The Secretary, in consultation with the offices described in subsection (c)(2), may require that the risk evaluation and mitigation strategy for a drug include such elements as are necessary to assure safe use of the drug, because of its inherent toxicity or potential harmfulness, if the Secretary determines that—
(A) the drug, which has been shown to be effective, but is associated with a serious adverse drug experience, can be approved only if, or would be withdrawn unless, such elements are required as part of such strategy to mitigate a specific serious risk listed in the labeling of the drug; and
(B) for a drug initially approved without elements to assure safe use, other elements under subsections (c), (d), and (e) are not sufficient to mitigate such serious risk.
(2) Assuring access and minimizing burden
Such elements to assure safe use under paragraph (1) shall—
(A) be commensurate with the specific serious risk listed in the labeling of the drug;
(B) within 30 days of the date on which any element under paragraph (1) is imposed, be posted publicly by the Secretary with an explanation of how such elements will mitigate the observed safety risk;
(C) considering such risk, not be unduly burdensome on patient access to the drug, considering in particular—
(i) patients with serious or life-threatening diseases or conditions;
(ii) patients who have difficulty accessing health care (such as patients in rural or medically underserved areas); and
(iii) patients with functional limitations; and
(D) to the extent practicable, so as to minimize the burden on the health care delivery system—
(i) conform with elements to assure safe use for other drugs with similar, serious risks; and
(ii) be designed to be compatible with established distribution, procurement, and dispensing systems for drugs.
(3) Elements to assure safe use
The elements to assure safe use under paragraph (1) shall include 1 or more goals to mitigate a specific serious risk listed in the labeling of the drug and, to mitigate such risk, may require that—
(A) health care providers who prescribe the drug have particular training or experience, or are specially certified (the opportunity to obtain such training or certification with respect to the drug shall be available to any willing provider from a frontier area in a widely available training or certification method (including an on-line course or via mail) as approved by the Secretary at reasonable cost to the provider);
(B) pharmacies, practitioners, or health care settings that dispense the drug are specially certified (the opportunity to obtain such certification shall be available to any willing provider from a frontier area);
(C) the drug be dispensed to patients only in certain health care settings, such as hospitals;
(D) the drug be dispensed to patients with evidence or other documentation of safe-use conditions, such as laboratory test results;
(E) each patient using the drug be subject to certain monitoring; or
(F) each patient using the drug be enrolled in a registry.
(4) Implementation system
The elements to assure safe use under paragraph (1) that are described in subparagraphs (B), (C), and (D) of paragraph (3) may include a system through which the applicant is able to take reasonable steps to—
(A) monitor and evaluate implementation of such elements by health care providers, pharmacists, and other parties in the health care system who are responsible for implementing such elements; and
(B) work to improve implementation of such elements by such persons.
(5) Evaluation of elements to assure safe use
The Secretary, through the Drug Safety and Risk Management Advisory Committee (or successor committee) or other advisory committee of the Food and Drug Administration, shall—
(A) seek input from patients, physicians, pharmacists, and other health care providers about how elements to assure safe use under this subsection for 1 or more drugs may be standardized so as not to be—
(i) unduly burdensome on patient access to the drug; and
(ii) to the extent practicable, minimize 2 the burden on the health care delivery system;
(B) periodically evaluate, for 1 or more drugs, the elements to assure safe use of such drug to assess whether the elements—
(i) assure safe use of the drug;
(ii) are not unduly burdensome on patient access to the drug; and
(iii) to the extent practicable, minimize the burden on the health care delivery system; and
(C) considering such input and evaluations—
(i) issue or modify agency guidance about how to implement the requirements of this subsection; and
(ii) modify elements under this subsection for 1 or more drugs as appropriate.
(6) Additional mechanisms to assure access
The mechanisms under
(7) Repealed. Pub. L. 113–5, title III, §302(c)(1), Mar. 13, 2013, 127 Stat. 185
(8) Limitation
No holder of an approved covered application shall use any element to assure safe use required by the Secretary under this subsection to block or delay approval of an application under section 355(b)(2) or (j) of this title or to prevent application of such element under subsection (i)(1)(B) to a drug that is the subject of an abbreviated new drug application.
(g) Assessment and modification of approved strategy
(1) Voluntary assessments
After the approval of a risk evaluation and mitigation strategy under subsection (a), the responsible person involved may, subject to paragraph (2), submit to the Secretary an assessment of the approved strategy for the drug involved at any time.
(2) Required assessments
A responsible person shall submit an assessment of the approved risk evaluation and mitigation strategy for a drug—
(A) when submitting a supplemental application for a new indication for use under
(B) when required by the strategy, as provided for in such timetable under subsection (d);
(C) within a time period to be determined by the Secretary, if the Secretary, in consultation with the offices described in subsection (c)(2), determines that an assessment is needed to evaluate whether the approved strategy should be modified to—
(i) ensure the benefits of the drug outweigh the risks of the drug; or
(ii) minimize the burden on the health care delivery system of complying with the strategy.
(3) Requirements for assessments
An assessment under paragraph (1) or (2) of an approved risk evaluation and mitigation strategy for a drug shall include, with respect to each goal included in the strategy, an assessment of the extent to which the approved strategy, including each element of the strategy, is meeting the goal or whether 1 or more such goals or such elements should be modified.
(4) Modification
(A) On initiative of responsible person
After the approval of a risk evaluation and mitigation strategy by the Secretary, the responsible person may, at any time, submit to the Secretary a proposal to modify the approved strategy. Such proposal may propose the addition, modification, or removal of any goal or element of the approved strategy and shall include an adequate rationale to support such proposed addition, modification, or removal of any goal or element of the strategy.
(B) On initiative of Secretary
After the approval of a risk evaluation and mitigation strategy by the Secretary, the Secretary may, at any time, require a responsible person to submit a proposed modification to the strategy within 120 days or within such reasonable time as the Secretary specifies, if the Secretary, in consultation with the offices described in subsection (c)(2), determines that 1 or more goals or elements should be added, modified, or removed from the approved strategy to—
(i) ensure the benefits of the drug outweigh the risks of the drug;
(ii) minimize the burden on the health care delivery system of complying with the strategy; or
(iii) accommodate different, comparable aspects of the elements to assure safe use for a drug that is the subject of an application under
(h) Review of proposed strategies; review of assessments and modifications of approved strategies
(1) In general
The Secretary, in consultation with the offices described in subsection (c)(2), shall promptly review each proposed risk evaluation and mitigation strategy for a drug submitted under subsection (a) and each assessment of and proposed modification to an approved risk evaluation and mitigation strategy for a drug submitted under subsection (g), and, if necessary, promptly initiate discussions with the responsible person about such proposed strategy, assessment, or modification.
(2) Action
(A) In general
(i) Timeframe
Unless the dispute resolution process described under paragraph (3) or (4) applies, and, except as provided in clause (ii) or clause (iii) below, the Secretary, in consultation with the offices described in subsection (c)(2), shall review and act on the proposed risk evaluation and mitigation strategy for a drug or any proposed modification to any required strategy within 180 days of receipt of the proposed strategy or modification.
(ii) Minor modifications
The Secretary shall review and act on a proposed minor modification, as defined by the Secretary in guidance, within 60 days of receipt of such modification.
(iii) REMS modification due to safety labeling changes
Not later than 60 days after the Secretary receives a proposed modification to an approved risk evaluation and mitigation strategy to conform the strategy to approved safety labeling changes, including safety labeling changes initiated by the responsible person in accordance with FDA regulatory requirements, or to a safety labeling change that the Secretary has directed the holder of the application to make pursuant to
(iv) Guidance
The Secretary shall establish, through guidance, that responsible persons may implement certain modifications to an approved risk evaluation and mitigation strategy following notification to the Secretary.
(B) Inaction
An approved risk evaluation and mitigation strategy shall remain in effect until the Secretary acts, if the Secretary fails to act as provided under subparagraph (A).
(C) Public availability
Upon acting on a proposed risk evaluation and mitigation strategy or proposed modification to a risk evaluation and mitigation strategy under subparagraph (A), the Secretary shall make publicly available an action letter describing the actions taken by the Secretary under such subparagraph (A).
(3) Dispute resolution at initial approval
If a proposed risk evaluation and mitigation strategy is submitted under subsection (a)(1) in an application for initial approval of a drug and there is a dispute about the strategy, the responsible person shall use the major dispute resolution procedures as set forth in the letters described in section 101(c) of the Food and Drug Administration Amendments Act of 2007.
(4) Dispute resolution in all other cases
(A) Request for review
(i) In general
The responsible person may, after the sponsor is required to make a submission under subsection (a)(2) or (g), request in writing that a dispute about the strategy be reviewed by the Drug Safety Oversight Board under subsection (j), except that the determination of the Secretary to require a risk evaluation and mitigation strategy is not subject to review under this paragraph. The preceding sentence does not prohibit review under this paragraph of the particular elements of such a strategy.
(ii) Scheduling
Upon receipt of a request under clause (i), the Secretary shall schedule the dispute involved for review under subparagraph (B) and, not later than 5 business days of 3 scheduling the dispute for review, shall publish by posting on the Internet or otherwise a notice that the dispute will be reviewed by the Drug Safety Oversight Board.
(B) Scheduling review
If a responsible person requests review under subparagraph (A), the Secretary—
(i) shall schedule the dispute for review at 1 of the next 2 regular meetings of the Drug Safety Oversight Board, whichever meeting date is more practicable; or
(ii) may convene a special meeting of the Drug Safety Oversight Board to review the matter more promptly, including to meet an action deadline on an application (including a supplemental application).
(C) Agreement after discussion or administrative appeals
(i) Further discussion or administrative appeals
A request for review under subparagraph (A) shall not preclude further discussions to reach agreement on the risk evaluation and mitigation strategy, and such a request shall not preclude the use of administrative appeals within the Food and Drug Administration to reach agreement on the strategy, including appeals as described in the letters described in section 101(c) of the Food and Drug Administration Amendments Act of 2007 for procedural or scientific matters involving the review of human drug applications and supplemental applications that cannot be resolved at the divisional level. At the time a review has been scheduled under subparagraph (B) and notice of such review has been posted, the responsible person shall either withdraw the request under subparagraph (A) or terminate the use of such administrative appeals.
(ii) Agreement terminates dispute resolution
At any time before a decision and order is issued under subparagraph (G), the Secretary (in consultation with the offices described in subsection (c)(2)) and the responsible person may reach an agreement on the risk evaluation and mitigation strategy through further discussion or administrative appeals, terminating the dispute resolution process, and the Secretary shall issue an action letter or order, as appropriate, that describes the strategy.
(D) Meeting of the Board
At a meeting of the Drug Safety Oversight Board described in subparagraph (B), the Board shall—
(i) hear from both parties via written or oral presentation; and
(ii) review the dispute.
(E) Record of proceedings
The Secretary shall ensure that the proceedings of any such meeting are recorded, transcribed, and made public within 90 days of the meeting. The Secretary shall redact the transcript to protect any trade secrets and other information that is exempted from disclosure under
(F) Recommendation of the Board
Not later than 5 days after any such meeting, the Drug Safety Oversight Board shall provide a written recommendation on resolving the dispute to the Secretary. Not later than 5 days after the Board provides such written recommendation to the Secretary, the Secretary shall make the recommendation available to the public.
(G) Action by the Secretary
(i) Action letter
With respect to a proposal or assessment referred to in paragraph (1), the Secretary shall issue an action letter that resolves the dispute not later than the later of—
(I) the action deadline for the action letter on the application; or
(II) 7 days after receiving the recommendation of the Drug Safety Oversight Board.
(ii) Order
With respect to an assessment of an approved risk evaluation and mitigation strategy under subsection (g)(1) or under any of subparagraphs (B) through (D) of subsection (g)(2), the Secretary shall issue an order, which shall be made public, that resolves the dispute not later than 7 days after receiving the recommendation of the Drug Safety Oversight Board.
(H) Inaction
An approved risk evaluation and mitigation strategy shall remain in effect until the Secretary acts, if the Secretary fails to act as provided for under subparagraph (G).
(I) Effect on action deadline
With respect to a proposal or assessment referred to in paragraph (1), the Secretary shall be considered to have met the action deadline for the action letter on the application if the responsible person requests the dispute resolution process described in this paragraph and if the Secretary has complied with the timing requirements of scheduling review by the Drug Safety Oversight Board, providing a written recommendation, and issuing an action letter under subparagraphs (B), (F), and (G), respectively.
(J) Disqualification
No individual who is an employee of the Food and Drug Administration and who reviews a drug or who participated in an administrative appeal under subparagraph (C)(i) with respect to such drug may serve on the Drug Safety Oversight Board at a meeting under subparagraph (D) to review a dispute about the risk evaluation and mitigation strategy for such drug.
(K) Additional expertise
The Drug Safety Oversight Board may add members with relevant expertise from the Food and Drug Administration, including the Office of Pediatrics, the Office of Women's Health, or the Office of Rare Diseases, or from other Federal public health or health care agencies, for a meeting under subparagraph (D) of the Drug Safety Oversight Board.
(5) Use of advisory committees
The Secretary may convene a meeting of 1 or more advisory committees of the Food and Drug Administration to—
(A) review a concern about the safety of a drug or class of drugs, including before an assessment of the risk evaluation and mitigation strategy or strategies of such drug or drugs is required to be submitted under subparagraph (B) or (C) of subsection (g)(2);
(B) review the risk evaluation and mitigation strategy or strategies of a drug or group of drugs; or
(C) review a dispute under paragraph (3) or (4).
(6) Process for addressing drug class effects
(A) In general
When a concern about a serious risk of a drug may be related to the pharmacological class of the drug, the Secretary, in consultation with the offices described in subsection (c)(2), may defer assessments of the approved risk evaluation and mitigation strategies for such drugs until the Secretary has convened 1 or more public meetings to consider possible responses to such concern.
(B) Notice
If the Secretary defers an assessment under subparagraph (A), the Secretary shall—
(i) give notice of the deferral to the holder of the approved covered application not later than 5 days after the deferral;
(ii) publish the deferral in the Federal Register; and
(iii) give notice to the public of any public meetings to be convened under subparagraph (A), including a description of the deferral.
(C) Public meetings
Such public meetings may include—
(i) 1 or more meetings of the responsible person for such drugs;
(ii) 1 or more meetings of 1 or more advisory committees of the Food and Drug Administration, as provided for under paragraph (6); 4 or
(iii) 1 or more workshops of scientific experts and other stakeholders.
(D) Action
After considering the discussions from any meetings under subparagraph (A), the Secretary may—
(i) announce in the Federal Register a planned regulatory action, including a modification to each risk evaluation and mitigation strategy, for drugs in the pharmacological class;
(ii) seek public comment about such action; and
(iii) after seeking such comment, issue an order addressing such regulatory action.
(7) International coordination
The Secretary, in consultation with the offices described in subsection (c)(2), may coordinate the timetable for submission of assessments under subsection (d), or a study or clinical trial under
(8) Effect
Use of the processes described in paragraphs (6) and (7) shall not be the sole source of delay of action on an application or a supplement to an application for a drug.
(i) Abbreviated new drug applications
(1) In general
A drug that is the subject of an abbreviated new drug application under
(A) A Medication Guide or patient package insert, if required under subsection (e) for the applicable listed drug.
(B) A packaging or disposal requirement, if required under subsection (e)(4) for the applicable listed drug.
(C)(i) Elements to assure safe use, if required under subsection (f) for the listed drug, which, subject to clause (ii), for a drug that is the subject of an application under
(I) a single, shared system with the listed drug under subsection (f); or
(II) a different, comparable aspect of the elements to assure safe use under subsection (f).
(ii) The Secretary may require a drug that is the subject of an application under
(2) Action by Secretary
For an applicable listed drug for which a drug is approved under
(A) shall undertake any communication plan to health care providers required under subsection (e)(3) for the applicable listed drug;
(B) shall permit packaging systems and safe disposal packaging or safe disposal systems that are different from those required for the applicable listed drug under subsection (e)(4); and
(C) shall inform the responsible person for the drug that is so approved if the risk evaluation and mitigation strategy for the applicable listed drug is modified.
(3) Shared REMS
If the Secretary approves, in accordance with paragraph (1)(C)(i)(II), a different, comparable aspect of the elements to assure safe use under subsection (f) for a drug that is the subject of an abbreviated new drug application under
(j) Drug Safety Oversight Board
(1) In general
There is established a Drug Safety Oversight Board.
(2) Composition; meetings
The Drug Safety Oversight Board shall—
(A) be composed of scientists and health care practitioners appointed by the Secretary, each of whom is an employee of the Federal Government;
(B) include representatives from offices throughout the Food and Drug Administration, including the offices responsible for postapproval safety of drugs;
(C) include at least 1 representative each from the National Institutes of Health and the Department of Health and Human Services (other than the Food and Drug Administration);
(D) include such representatives as the Secretary shall designate from other appropriate agencies that wish to provide representatives; and
(E) meet at least monthly to provide oversight and advice to the Secretary on the management of important drug safety issues.
(k) Waiver in public health emergencies
The Secretary may waive any requirement of this section with respect to a qualified countermeasure (as defined in
(1) a determination described in subparagraph (A), (B), or (C) of
(2) the identification of a material threat described in subparagraph (D) of
(l) Provision of samples not a violation of strategy
The provision of samples of a covered product to an eligible product developer (as those terms are defined in
(m) Separate REMS
When used in this section, the term "different, comparable aspect of the elements to assure safe use" means a risk evaluation and mitigation strategy for a drug that is the subject of an application under
(June 25, 1938, ch. 675, §505–1, as added
Editorial Notes
References in Text
For the effective date of this section, referred to in subsec. (a)(2)(A), see Effective Date note below.
Section 101(c) of the Food and Drug Administration Amendments Act of 2007, referred to in subsec. (h)(3), (4)(C)(i), is section 101(c) of
Paragraph (6), referred to in subsec. (h)(6)(C)(ii), was redesignated par. (5) of subsec. (h) of this section by
Amendments
2022—Subsec. (e)(4)(B).
2019—Subsec. (g)(4)(B)(iii).
Subsec. (i)(1)(C).
"(i) the burden of creating a single, shared system outweighs the benefit of a single, system, taking into consideration the impact on health care providers, patients, the applicant for the abbreviated new drug application, and the holder of the reference drug product; or
"(ii) an aspect of the elements to assure safe use for the applicable listed drug is claimed by a patent that has not expired or is a method or process that, as a trade secret, is entitled to protection, and the applicant for the abbreviated new drug application certifies that it has sought a license for use of an aspect of the elements to assure safe use for the applicable listed drug and that it was unable to obtain a license.
A certification under clause (ii) shall include a description of the efforts made by the applicant for the abbreviated new drug application to obtain a license. In a case described in clause (ii), the Secretary may seek to negotiate a voluntary agreement with the owner of the patent, method, or process for a license under which the applicant for such abbreviated new drug application may use an aspect of the elements to assure safe use, if required under subsection (f) for the applicable listed drug, that is claimed by a patent that has not expired or is a method or process that as a trade secret is entitled to protection."
Subsec. (i)(3).
Subsec. (l).
Subsec. (m).
2018—Subsec. (b)(1)(E).
Subsec. (e)(4).
Subsec. (f)(2)(C)(iii).
Subsec. (i)(1)(B), (C).
Subsec. (i)(2)(B), (C).
2017—Subsec. (e)(3)(B).
Subsec. (e)(3)(D).
2016—Subsec. (f)(5).
Subsec. (f)(5)(B).
Subsec. (h)(2)(A)(iii).
Subsec. (h)(8).
2013—Subsec. (f)(7).
Subsec. (k).
2012—Subsec. (g)(1).
Subsec. (g)(2).
Subsec. (g)(2)(C).
"(i) an element under subsection (d) or (e) should be modified or included in the strategy; or
"(ii) an element under subsection (f) should be modified or included in the strategy; or".
Subsec. (g)(2)(D).
Subsec. (g)(3).
Subsec. (g)(4).
"(A) modifying the timetable for assessments of the strategy as provided in subsection (d)(3), including to eliminate assessments; or
"(B) adding, modifying, or removing an element to assure safe use under subsection (f)."
Subsec. (h).
Subsec. (h)(1).
Subsec. (h)(2).
Subsec. (h)(2)(A).
Subsec. (h)(2)(C).
Subsec. (h)(3), (4).
Subsec. (h)(4)(A)(i).
Subsec. (h)(4)(I).
"(i) has initiated the discussions described under paragraph (2) not less than 60 days before such action deadline; and
"(ii) has complied with the timing requirements of scheduling review by the Drug Safety Oversight Board, providing a written recommendation, and issuing an action letter under subparagraphs (B), (F), and (G), respectively."
Subsec. (h)(5).
Subsec. (h)(6), (7).
Subsec. (h)(8), (9).
Statutory Notes and Related Subsidiaries
Effective Date
Section effective 180 days after Sept. 27, 2007, see section 909 of
Evidence-Based Opioid Analgesic Prescribing Guidelines and Report
"(a)
"(b)
"(1) consult with stakeholders, which may include conducting a public meeting of medical professional societies (including any State-based societies), health care providers, State medical boards, medical specialties including pain medicine specialty societies, patient groups, pharmacists, academic or medical research entities, and other entities with experience in health care, as appropriate;
"(2) collaborate with the Director of the Centers for Disease Control and Prevention, as applicable and appropriate, and other Federal agencies with relevant expertise as appropriate; and
"(3) provide for a notice and comment period consistent with section 701(h) of the Federal Food, Drug, and Cosmetic Act (
"(c)
"(d)
"(1) update the guidelines under subsection (a), informed by public input described in subsection (b); and
"(2) submit to the committees specified in subsection (c) and post on the public website of the Food and Drug Administration an updated report under such subsection.
"(e)
"(1) are intended to help inform clinical decisionmaking by prescribers and patients; and
"(2) are not intended to be used for the purposes of restricting, limiting, delaying, or denying coverage for, or access to, a prescription issued for a legitimate medical purpose by an individual practitioner acting in the usual course of professional practice."
Prescriber Education
"(1) which prescribers should participate in such programs; and
"(2) how often participation in such programs is necessary."
Guidance
1 So in original. Probably should be followed by a semicolon.
2 So in original. Does not follow from introductory provisions.
4 See References in Text note below.
§355–2. Actions for delays of generic drugs and biosimilar biological products
(a) Definitions
In this section—
(1) the term "commercially reasonable, market-based terms" means—
(A) a nondiscriminatory price for the sale of the covered product at or below, but not greater than, the most recent wholesale acquisition cost for the drug, as defined in
(B) a schedule for delivery that results in the transfer of the covered product to the eligible product developer consistent with the timing under subsection (b)(2)(A)(iv); and
(C) no additional conditions are imposed on the sale of the covered product;
(2) the term "covered product"—
(A) means—
(i) any drug approved under subsection (c) or (j) of
(ii) any combination of a drug or biological product described in clause (i); or
(iii) when reasonably necessary to support approval of an application under
(B) does not include any drug or biological product that appears on the drug shortage list in effect under
(i) the drug or biological product has been on the drug shortage list in effect under such
(ii) the Secretary determines that inclusion of the drug or biological product as a covered product is likely to contribute to alleviating or preventing a shortage.
(3) the term "device" has the meaning given the term in
(4) the term "eligible product developer" means a person that seeks to develop a product for approval pursuant to an application for approval under subsection (b)(2) or (j) of
(5) the term "license holder" means the holder of an application approved under subsection (c) or (j) of
(6) the term "REMS" means a risk evaluation and mitigation strategy under
(7) the term "REMS with ETASU" means a REMS that contains elements to assure safe use under
(8) the term "Secretary" means the Secretary of Health and Human Services;
(9) the term "single, shared system of elements to assure safe use" means a single, shared system of elements to assure safe use under
(10) the term "sufficient quantities" means an amount of a covered product that the eligible product developer determines allows it to—
(A) conduct testing to support an application under—
(i) subsection (b)(2) or (j) of
(ii)
(B) fulfill any regulatory requirements relating to approval of such an application.
(b) Civil action for failure to provide sufficient quantities of a covered product
(1) In general
An eligible product developer may bring a civil action against the license holder for a covered product seeking relief under this subsection in an appropriate district court of the United States alleging that the license holder has declined to provide sufficient quantities of the covered product to the eligible product developer on commercially reasonable, market-based terms.
(2) Elements
(A) In general
To prevail in a civil action brought under paragraph (1), an eligible product developer shall prove, by a preponderance of the evidence—
(i) that—
(I) the covered product is not subject to a REMS with ETASU; or
(II) if the covered product is subject to a REMS with ETASU—
(aa) the eligible product developer has obtained a covered product authorization from the Secretary in accordance with subparagraph (B); and
(bb) the eligible product developer has provided a copy of the covered product authorization to the license holder;
(ii) that, as of the date on which the civil action is filed, the eligible product developer has not obtained sufficient quantities of the covered product on commercially reasonable, market-based terms;
(iii) that the eligible product developer has submitted a written request to purchase sufficient quantities of the covered product to the license holder, and such request—
(I) was sent to a named corporate officer of the license holder;
(II) was made by certified or registered mail with return receipt requested;
(III) specified an individual as the point of contact for the license holder to direct communications related to the sale of the covered product to the eligible product developer and a means for electronic and written communications with that individual; and
(IV) specified an address to which the covered product was to be shipped upon reaching an agreement to transfer the covered product; and
(iv) that the license holder has not delivered to the eligible product developer sufficient quantities of the covered product on commercially reasonable, market-based terms—
(I) for a covered product that is not subject to a REMS with ETASU, by the date that is 31 days after the date on which the license holder received the request for the covered product; and
(II) for a covered product that is subject to a REMS with ETASU, by 31 days after the later of—
(aa) the date on which the license holder received the request for the covered product; or
(bb) the date on which the license holder received a copy of the covered product authorization issued by the Secretary in accordance with subparagraph (B).
(B) Authorization for covered product subject to a REMS with ETASU
(i) Request
An eligible product developer may submit to the Secretary a written request for the eligible product developer to be authorized to obtain sufficient quantities of an individual covered product subject to a REMS with ETASU.
(ii) Authorization
Not later than 120 days after the date on which a request under clause (i) is received, the Secretary shall, by written notice, authorize the eligible product developer to obtain sufficient quantities of an individual covered product subject to a REMS with ETASU for purposes of—
(I) development and testing that does not involve human clinical trials, if the eligible product developer has agreed to comply with any conditions the Secretary determines necessary; or
(II) development and testing that involves human clinical trials, if the eligible product developer has—
(aa)(AA) submitted protocols, informed consent documents, and informational materials for testing that include protections that provide safety protections comparable to those provided by the REMS for the covered product; or
(BB) otherwise satisfied the Secretary that such protections will be provided; and
(bb) met any other requirements the Secretary may establish.
(iii) Notice
A covered product authorization issued under this subparagraph shall state that the provision of the covered product by the license holder under the terms of the authorization will not be a violation of the REMS for the covered product.
(3) Affirmative defense
In a civil action brought under paragraph (1), it shall be an affirmative defense, on which the defendant has the burden of persuasion by a preponderance of the evidence—
(A) that, on the date on which the eligible product developer requested to purchase sufficient quantities of the covered product from the license holder—
(i) neither the license holder nor any of its agents, wholesalers, or distributors was engaged in the manufacturing or commercial marketing of the covered product; and
(ii) neither the license holder nor any of its agents, wholesalers, or distributors otherwise had access to inventory of the covered product to supply to the eligible product developer on commercially reasonable, market-based terms;
(B) that—
(i) the license holder sells the covered product through agents, distributors, or wholesalers;
(ii) the license holder has placed no restrictions, explicit or implicit, on its agents, distributors, or wholesalers to sell covered products to eligible product developers; and
(iii) the covered product can be purchased by the eligible product developer in sufficient quantities on commercially reasonable, market-based terms from the agents, distributors, or wholesalers of the license holder; or
(C) that the license holder made an offer to the individual specified pursuant to paragraph (2)(A)(iii)(III), by a means of communication (electronic, written, or both) specified pursuant to such paragraph, to sell sufficient quantities of the covered product to the eligible product developer at commercially reasonable market-based terms—
(i) for a covered product that is not subject to a REMS with ETASU, by the date that is 14 days after the date on which the license holder received the request for the covered product, and the eligible product developer did not accept such offer by the date that is 7 days after the date on which the eligible product developer received such offer from the license holder; or
(ii) for a covered product that is subject to a REMS with ETASU, by the date that is 20 days after the date on which the license holder received the request for the covered product, and the eligible product developer did not accept such offer by the date that is 10 days after the date on which the eligible product developer received such offer from the license holder.
(4) Remedies
(A) In general
If an eligible product developer prevails in a civil action brought under paragraph (1), the court shall—
(i) order the license holder to provide to the eligible product developer without delay sufficient quantities of the covered product on commercially reasonable, market-based terms;
(ii) award to the eligible product developer reasonable attorney's fees and costs of the civil action; and
(iii) award to the eligible product developer a monetary amount sufficient to deter the license holder from failing to provide eligible product developers with sufficient quantities of a covered product on commercially reasonable, market-based terms, if the court finds, by a preponderance of the evidence—
(I) that the license holder delayed providing sufficient quantities of the covered product to the eligible product developer without a legitimate business justification; or
(II) that the license holder failed to comply with an order issued under clause (i).
(B) Maximum monetary amount
A monetary amount awarded under subparagraph (A)(iii) shall not be greater than the revenue that the license holder earned on the covered product during the period—
(i) beginning on—
(I) for a covered product that is not subject to a REMS with ETASU, the date that is 31 days after the date on which the license holder received the request; or
(II) for a covered product that is subject to a REMS with ETASU, the date that is 31 days after the later of—
(aa) the date on which the license holder received the request; or
(bb) the date on which the license holder received a copy of the covered product authorization issued by the Secretary in accordance with paragraph (2)(B); and
(ii) ending on the date on which the eligible product developer received sufficient quantities of the covered product.
(C) Avoidance of delay
The court may issue an order under subparagraph (A)(i) before conducting further proceedings that may be necessary to determine whether the eligible product developer is entitled to an award under clause (ii) or (iii) of subparagraph (A), or the amount of any such award.
(c) Limitation of liability
A license holder for a covered product shall not be liable for any claim under Federal, State, or local law arising out of the failure of an eligible product developer to follow adequate safeguards to assure safe use of the covered product during development or testing activities described in this section, including transportation, handling, use, or disposal of the covered product by the eligible product developer.
(d) Omitted
(e) Rule of construction
(1) Definition
In this subsection, the term "antitrust laws"—
(A) has the meaning given the term in subsection (a) of
(B) includes
(2) Antitrust laws
Nothing in this section shall be construed to limit the operation of any provision of the antitrust laws.
(f) Omitted
(g) Rule of construction
Nothing in this section, the amendments made by this section, or in
(1) prohibiting a license holder from providing an eligible product developer access to a covered product in the absence of an authorization under this section; or
(2) in any way negating the applicability of a REMS with ETASU, as otherwise required under such
(
Editorial Notes
Codification
Section was enacted as part of the Further Consolidated Appropriations Act, 2020, and not as part of the Federal Food, Drug, and Cosmetic Act which comprises this chapter.
Section is comprised of section 610 of
§355a. Pediatric studies of drugs
(a) Definitions
As used in this section, the term "pediatric studies" or "studies" means at least one clinical investigation (that, at the Secretary's discretion, may include pharmacokinetic studies) in pediatric age groups (including neonates in appropriate cases) in which a drug is anticipated to be used, and, at the discretion of the Secretary, may include preclinical studies.
(b) Market exclusivity for new drugs
(1) In general
Except as provided in paragraph (2), if, prior to approval of an application that is submitted under
(A)(i)(I) the period referred to in subsection (c)(3)(E)(ii) of
(II) the period referred to in clauses (iii) and (iv) of subsection (c)(3)(E) of such section, and in clauses (iii) and (iv) of subsection (j)(5)(F) of such section, is deemed to be three years and six months rather than three years; and
(ii) if the drug is designated under
(B)(i) if the drug is the subject of—
(I) a listed patent for which a certification has been submitted under subsection (b)(2)(A)(ii) or (j)(2)(A)(vii)(II) of
(II) a listed patent for which a certification has been submitted under subsections (b)(2)(A)(iii) or (j)(2)(A)(vii)(III) of
the period during which an application may not be approved under
(ii) if the drug is the subject of a listed patent for which a certification has been submitted under subsection (b)(2)(A)(iv) or (j)(2)(A)(vii)(IV) of
(2) Exception
The Secretary shall not extend the period referred to in paragraph (1)(A) or (1)(B) if the determination made under subsection (d)(4) is made later than 9 months prior to the expiration of such period.
(c) Market exclusivity for already-marketed drugs
(1) In general
Except as provided in paragraph (2), if the Secretary determines that information relating to the use of an approved drug in the pediatric population may produce health benefits in that population and makes a written request to the holder of an approved application under
(A)(i)(I) the period referred to in subsection (c)(3)(E)(ii) of
(II) the period referred to in clauses (iii) and (iv) of subsection (c)(3)(E) of such section, and in clauses (iii) and (iv) of subsection (j)(5)(F) of such section, is deemed to be three years and six months rather than three years; and
(ii) if the drug is designated under
(B)(i) if the drug is the subject of—
(I) a listed patent for which a certification has been submitted under subsection (b)(2)(A)(ii) or (j)(2)(A)(vii)(II) of
(II) a listed patent for which a certification has been submitted under subsection (b)(2)(A)(iii) or (j)(2)(A)(vii)(III) of
the period during which an application may not be approved under
(ii) if the drug is the subject of a listed patent for which a certification has been submitted under subsection (b)(2)(A)(iv) or (j)(2)(A)(vii)(IV) of
(2) Exception
The Secretary shall not extend the period referred to in paragraph (1)(A) or (1)(B) if the determination made under subsection (d)(4) is made later than 9 months prior to the expiration of such period.
(d) Conduct of pediatric studies
(1) Request for studies
(A) In general
The Secretary may, after consultation with the sponsor of an application for an investigational new drug under
(B) Single written request
A single written request—
(i) may relate to more than one use of a drug; and
(ii) may include uses that are both approved and unapproved.
(2) Written request for pediatric studies
(A) Request and response
(i) In general
If the Secretary makes a written request for pediatric studies (including neonates, as appropriate) under subsection (b) or (c), the applicant or holder, not later than 180 days after receiving the written request, shall respond to the Secretary as to the intention of the applicant or holder to act on the request by—
(I) indicating when the pediatric studies will be initiated, if the applicant or holder agrees to the request; or
(II) indicating that the applicant or holder does not agree to the request and stating the reasons for declining the request.
(ii) Disagree with request
If, on or after September 27, 2007, the applicant or holder does not agree to the request on the grounds that it is not possible to develop the appropriate pediatric formulation, the applicant or holder shall submit to the Secretary the reasons such pediatric formulation cannot be developed.
(B) Adverse event reports
An applicant or holder that, on or after September 27, 2007, agrees to the request for such studies shall provide the Secretary, at the same time as the submission of the reports of such studies, with all postmarket adverse event reports regarding the drug that is the subject of such studies and are available prior to submission of such reports.
(3) Action on submissions
The Secretary shall review and act upon a submission by a sponsor or holder of a proposed pediatric study request or a proposed amendment to a written request for pediatric studies within 120 calendar days of the submission.
(4) Meeting the studies requirement
Not later than 180 days after the submission of the reports of the studies, the Secretary shall accept or reject such reports and so notify the sponsor or holder. The Secretary's only responsibility in accepting or rejecting the reports shall be to determine, within the 180-day period, whether the studies fairly respond to the written request, have been conducted in accordance with commonly accepted scientific principles and protocols, and have been reported in accordance with the requirements of the Secretary for filing.
(5) Effect of subsection
Nothing in this subsection alters or amends
(6) Consultation
With respect to a drug that is a qualified countermeasure (as defined in
(e) Notice of determinations on studies requirement
(1) In general
The Secretary shall publish a notice of any determination, made on or after September 27, 2007, that the requirements of subsection (d) have been met and that submissions and approvals under subsection (b)(2) or (j) of
(2) Identification of certain drugs
The Secretary shall publish a notice identifying any drug for which, on or after September 27, 2007, a pediatric formulation was developed, studied, and found to be safe and effective in the pediatric population (or specified subpopulation) if the pediatric formulation for such drug is not introduced onto the market within one year after the date that the Secretary publishes the notice described in paragraph (1). Such notice identifying such drug shall be published not later than 30 days after the date of the expiration of such one year period.
(f) Internal review of written requests and pediatric studies
(1) Internal review
The Secretary shall utilize the internal review committee established under
(2) Review of written requests
The committee referred to in paragraph (1) shall review all written requests issued pursuant to this section prior to being issued.
(3) Review of pediatric studies
The committee referred to in paragraph (1) may review studies conducted pursuant to this section to make a recommendation to the Secretary whether to accept or reject such reports under subsection (d)(4).
(4) Activity by committee
The committee referred to in paragraph (1) may operate using appropriate members of such committee and need not convene all members of the committee.
(5) Documentation of committee action
For each drug, the committee referred to in paragraph (1) shall document, for each activity described in paragraph (2) or (3), which members of the committee participated in such activity.
(6) Tracking pediatric studies and labeling changes
The Secretary, in consultation with the committee referred to in paragraph (1), shall track and make available to the public, in an easily accessible manner, including through posting on the Web site of the Food and Drug Administration—
(A) the number of studies conducted under this section and under
(B) the specific drugs and drug uses, including labeled and off-labeled indications, studied under such sections;
(C) the types of studies conducted under such sections, including trial design, the number of pediatric patients studied, and the number of centers and countries involved;
(D) the number of pediatric formulations developed and the number of pediatric formulations not developed and the reasons such formulations were not developed;
(E) the labeling changes made as a result of studies conducted under such sections;
(F) an annual summary of labeling changes made as a result of studies conducted under such sections for distribution pursuant to subsection (k)(2); and
(G) information regarding reports submitted on or after September 27, 2007.
(7) Informing internal review committee
The Secretary shall provide to the committee referred to in paragraph (1) any response issued to an applicant or holder with respect to a proposed pediatric study request.
(g) Limitations
Notwithstanding subsection (c)(2), a drug to which the six-month period under subsection (b) or (c) has already been applied—
(1) may receive an additional six-month period under subsection (c)(1)(A)(i)(II) for a supplemental application if all other requirements under this section are satisfied, except that such drug may not receive any additional such period under subsection (c)(1)(B); and
(2) may not receive any additional such period under subsection (c)(1)(A)(ii).
(h) Relationship to pediatric research requirements
Exclusivity under this section shall only be granted for the completion of a study or studies that are the subject of a written request and for which reports are submitted and accepted in accordance with subsection (d)(4). Written requests under this section may consist of a study or studies required under
(i) Labeling changes
(1) Priority status for pediatric applications and supplements
Any application or supplement to an application under
(A) shall be considered to be a priority application or supplement; and
(B) shall be subject to the performance goals established by the Commissioner for priority drugs.
(2) Dispute resolution
(A) Request for labeling change and failure to agree
If, on or after September 27, 2007, the Commissioner determines that the sponsor and the Commissioner have been unable to reach agreement on appropriate changes to the labeling for the drug that is the subject of the application, not later than 180 days after the date of submission of the application—
(i) the Commissioner shall request that the sponsor of the application make any labeling change that the Commissioner determines to be appropriate; and
(ii) if the sponsor of the application does not agree within 30 days after the Commissioner's request to make a labeling change requested by the Commissioner, the Commissioner shall refer the matter to the Pediatric Advisory Committee.
(B) Action by the Pediatric Advisory Committee
Not later than 90 days after receiving a referral under subparagraph (A)(ii), the Pediatric Advisory Committee shall—
(i) review the pediatric study reports; and
(ii) make a recommendation to the Commissioner concerning appropriate labeling changes, if any.
(C) Consideration of recommendations
The Commissioner shall consider the recommendations of the Pediatric Advisory Committee and, if appropriate, not later than 30 days after receiving the recommendation, make a request to the sponsor of the application to make any labeling change that the Commissioner determines to be appropriate.
(D) Misbranding
If the sponsor of the application, within 30 days after receiving a request under subparagraph (C), does not agree to make a labeling change requested by the Commissioner, the Commissioner may deem the drug that is the subject of the application to be misbranded.
(E) No effect on authority
Nothing in this subsection limits the authority of the United States to bring an enforcement action under this chapter when a drug lacks appropriate pediatric labeling. Neither course of action (the Pediatric Advisory Committee process or an enforcement action referred to in the preceding sentence) shall preclude, delay, or serve as the basis to stay the other course of action.
(j) Other labeling changes
If, on or after September 27, 2007, the Secretary determines that a pediatric study conducted under this section does or does not demonstrate that the drug that is the subject of the study is safe and effective, including whether such study results are inconclusive, in pediatric populations or subpopulations, the Secretary shall order the labeling of such product to include information about the results of the study and a statement of the Secretary's determination.
(k) Dissemination of pediatric information
(1) In general
Not later than 210 days after the date of submission of a report on a pediatric study under this section, the Secretary shall make available to the public the medical, statistical, and clinical pharmacology reviews of pediatric studies conducted under subsection (b) or (c).
(2) Dissemination of information regarding labeling changes
Beginning on September 27, 2007, the Secretary shall include as a requirement of a written request that the sponsors of the studies that result in labeling changes that are reflected in the annual summary developed pursuant to subsection (f)(6)(F) distribute, at least annually (or more frequently if the Secretary determines that it would be beneficial to the public health), such information to physicians and other health care providers.
(3) Effect of subsection
Nothing in this subsection alters or amends
(l) Adverse event reporting
(1) Reporting in first 18-month period
Beginning on September 27, 2007, during the 18-month period beginning on the date a labeling change is approved pursuant to subsection (i), the Secretary shall ensure that all adverse event reports that have been received for such drug (regardless of when such report was received) are referred to the Office of Pediatric Therapeutics established under
(2) Reporting in subsequent periods
Following the 18-month period described in paragraph (1), the Secretary shall, as appropriate, refer to the Office of Pediatric Therapeutics all pediatric adverse event reports for a drug for which a pediatric study was conducted under this section. In considering such reports, the Director of such Office may provide for the review of such reports by the Pediatric Advisory Committee, including obtaining any recommendation of such Committee regarding whether the Secretary should take action in response to such reports.
(3) Preservation of authority
Nothing in this subsection shall prohibit the Office of Pediatric Therapeutics from providing for the review of adverse event reports by the Pediatric Advisory Committee prior to the 18-month period referred to in paragraph (1), if such review is necessary to ensure safe use of a drug in a pediatric population.
(4) Effect
The requirements of this subsection shall supplement, not supplant, other review of such adverse event reports by the Secretary.
(m) Clarification of interaction of market exclusivity under this section and market exclusivity awarded to an applicant for approval of a drug under section 355(j) of this title
If a 180-day period under
(1) the date on which the 180-day period would have expired by the number of days of the overlap, if the 180-day period would, but for the application of this subsection, expire after the 6-month exclusivity period; or
(2) the date on which the 6-month exclusivity period expires, by the number of days of the overlap if the 180-day period would, but for the application of this subsection, expire during the six-month exclusivity period.
(n) Referral if pediatric studies not submitted
(1) In general
Beginning on September 27, 2007, if pediatric studies of a drug have not been submitted by the date specified in the written request issued or if the applicant or holder does not agree to the request under subsection (d) and if the Secretary, through the committee established under
(A) For a drug for which a listed patent has not expired, or for which a period of exclusivity eligible for extension under subsection (b)(1) or (c)(1) of this section or under subsection (m)(2) or (m)(3) of
(B) For a drug that has no unexpired listed patents and for which no unexpired periods of exclusivity eligible for extension under subsection (b)(1) or (c)(1) of this section or under subsection (m)(2) or (m)(3) of
(C) For a drug that is a qualified countermeasure (as defined in
(2) Public notice
The Secretary shall give the public notice of a decision under paragraph (1)(A) not to require an assessment under
(3) Effect of subsection
Nothing in this subsection alters or amends
(o) Prompt approval of drugs when pediatric information is added to labeling
(1) General rule
A drug for which an application has been submitted or approved under subsection (b)(2) or (j) of
(2) Labeling
Notwithstanding clauses (iii) and (iv) of
(A) a statement that, because of marketing exclusivity for a manufacturer—
(i) the drug is not labeled for pediatric use; or
(ii) in the case of a drug for which there is an additional pediatric use not referred to in paragraph (1), the drug is not labeled for the pediatric use under paragraph (1); and
(B) a statement of any appropriate pediatric contraindications, warnings, precautions, or other information that the Secretary considers necessary to assure safe use.
(3) Preservation of pediatric exclusivity and extensions
This subsection does not affect—
(A) the availability or scope of exclusivity under—
(i) this section;
(ii)
(iii)
(B) the availability or scope of an extension to any such exclusivity, including an extension under this section or
(C) the question of the eligibility for approval under
(i) clause (iii) or (iv) of
(ii) clause (iii) or (iv) of
(iii)
(D) except as expressly provided in paragraphs (1) and (2), the operation of
(June 25, 1938, ch. 675, §505A, as added
Editorial Notes
Amendments
2021—Subsec. (c)(1)(A)(i)(II).
2017—Subsecs. (b), (c).
Subsec. (d)(3) to (6).
Subsec. (f)(3).
Subsec. (f)(7).
Subsec. (h).
Subsec. (o).
Subsec. (o)(1).
Subsec. (o)(2).
Subsec. (o)(3).
"(A) the availability or scope of exclusivity under this section;
"(B) the availability or scope of exclusivity under
"(C) the question of the eligibility for approval of any application under
"(D) except as expressly provided in paragraphs (1) and (2), the operation of
2016—Subsec. (p).
2013—Subsec. (d)(5).
Subsec. (n)(1)(C).
2012—Subsec. (d)(1)(A).
Subsec. (h).
Subsec. (k)(2).
Subsec. (l)(1).
Subsec. (l)(2).
Subsec. (l)(3), (4).
Subsec. (n).
Subsec. (n)(1).
Subsec. (n)(1)(A).
Subsec. (n)(1)(B).
Subsec. (o)(2)(B).
Subsec. (q).
"(1) on or before October 1, 2012, the Secretary makes a written request for pediatric studies of the drug;
"(2) on or before October 1, 2012, an application for the drug is accepted for filing under
"(3) all requirements of this section are met."
2010—Subsec. (p)(4) to (6).
"(4) review and assess the pediatric studies of biological products as required under subsections (a) and (b) of
"(5) make recommendations regarding appropriate incentives for encouraging pediatric studies of biologics."
2007—
2003—Subsec. (b)(1)(A)(i).
Subsec. (b)(1)(A)(ii).
Subsec. (b)(2).
Subsec. (c)(1)(A)(i).
Subsec. (c)(1)(A)(ii).
Subsec. (c)(2).
Subsec. (e).
Subsec. (h).
Subsec. (i)(2).
Subsec. (l).
2002—Subsec. (a).
Subsec. (a)(1)(A).
Subsec. (b).
Subsec. (c).
Subsec. (c)(1)(A).
Subsec. (d)(1).
Subsec. (d)(2).
Subsec. (d)(3).
Subsec. (d)(4).
Subsec. (e).
Subsec. (g).
Subsec. (h).
Subsec. (i).
Subsec. (j).
"(1) the drug was in commercial distribution as of November 21, 1997;
"(2) the drug was included by the Secretary on the list under subsection (b) of this section as of January 1, 2002;
"(3) the Secretary determines that there is a continuing need for information relating to the use of the drug in the pediatric population and that the drug may provide health benefits in that population; and
"(4) all requirements of this section are met."
Subsec. (k).
Subsec. (l).
Subsec. (m).
Subsec. (n).
Subsec. (o).
Statutory Notes and Related Subsidiaries
Effective Date of 2012 Amendment
"(1)
"(2)
Effective Date of 2007 Amendment
"(A)
"(B)
Effective Date of 2003 Amendment
Amendment by
Effective Date of 2002 Amendment
Construction of 2007 Amendments on Pediatric Studies
Plan for Earlier Submission of Pediatric Studies
"(1) earlier discussion of proposed pediatric study requests and written requests with sponsors, and if appropriate, discussion of such requests at the meeting required under section 505B(e)(2)(C) of the Federal Food, Drug, and Cosmetic Act (
"(2) earlier issuance of written requests for a pediatric study under such section 505A, including for investigational new drugs prior to the submission of an application under section 505(b)(1) of such Act (
"(3) shorter timelines, when appropriate, for the completion of studies pursuant to a written request under such section 505A or such section 351(m)."
Draft Guidance for Neonatal Studies
Communication With Pediatric Review Committee
Access to Data
Report on Pediatric Exclusivity Program
Study by General Accounting Office
§355b. Adverse-event reporting
(a) Toll-free number in labeling
Not later than one year after January 4, 2002, the Secretary of Health and Human Services shall promulgate a final rule requiring that the labeling of each drug for which an appli