21 U.S.C. § 356a — Manufacturing changes

Page 281 TITLE 21—FOOD AND DRUGS § 356a FF of Pub. L. 117–328, set out as a note under section 350a–1 of this title. § 356a. Manufacturing changes (a) In general With respect to a drug for which there is in ef- fect an approved application under section 355 or 360b of this title or a license under section 262 of title 42, a change from the manufacturing proc- ess approved pursuant to such application or li- cense may be made, and the drug as made with the change may be distributed, if— (1) the holder of the approved application or license (referred to in this section as a ‘‘hold- er’’) has validated the effects of the change in accordance with subsection (b); and (2)(A) in the case of a major manufacturing change, the holder has complied with the re- quirements of subsection (c); or (B) in the case of a change that is not a major manufacturing change, the holder com- plies with the applicable requirements of sub- section (d). (b) Validation of effects of changes For purposes of subsection (a)(1), a drug made with a manufacturing change (whether a major manufacturing change or otherwise) may be dis- tributed only if, before distribution of the drug as so made, the holder involved validates the ef- fects of the change on the identity, strength, quality, purity, and potency of the drug as the identity, strength, quality, purity, and potency may relate to the safety or effectiveness of the drug. (c) Major manufacturing changes (1) Requirement of supplemental application For purposes of subsection (a)(2)(A), a drug made with a major manufacturing change may be distributed only if, before the distribution of the drug as so made, the holder involved submits to the Secretary a supplemental ap- plication for such change and the Secretary approves the application. The application shall contain such information as the Sec- retary determines to be appropriate, and shall include the information developed under sub- section (b) by the holder in validating the ef- fects of the change. (2) Changes qualifying as major changes For purposes of subsection (a)(2)(A), a major manufacturing change is a manufacturing change that is determined by the Secretary to have substantial potential to adversely affect the identity, strength, quality, purity, or po- tency of the drug as they may relate to the safety or effectiveness of a drug. Such a change includes a change that— (A) is made in the qualitative or quan- titative formulation of the drug involved or in the specifications in the approved applica- tion or license referred to in subsection (a) for the drug (unless exempted by the Sec- retary by regulation or guidance from the requirements of this subsection); (B) is determined by the Secretary by reg- ulation or guidance to require completion of an appropriate clinical study demonstrating equivalence of the drug to the drug as manu- factured without the change; or (C) is another type of change determined by the Secretary by regulation or guidance to have a substantial potential to adversely affect the safety or effectiveness of the drug. (d) Other manufacturing changes (1) In general For purposes of subsection (a)(2)(B), the Sec- retary may regulate drugs made with manu- facturing changes that are not major manu- facturing changes as follows: (A) The Secretary may in accordance with paragraph (2) authorize holders to distribute such drugs without submitting a supple- mental application for such changes. (B) The Secretary may in accordance with paragraph (3) require that, prior to the dis- tribution of such drugs, holders submit to the Secretary supplemental applications for such changes. (C) The Secretary may establish categories of such changes and designate categories to which subparagraph (A) applies and cat- egories to which subparagraph (B) applies. (2) Changes not requiring supplemental appli- cation (A) Submission of report A holder making a manufacturing change to which paragraph (1)(A) applies shall sub- mit to the Secretary a report on the change, which shall contain such information as the Secretary determines to be appropriate, and which shall include the information devel- oped under subsection (b) by the holder in validating the effects of the change. The re- port shall be submitted by such date as the Secretary may specify. (B) Authority regarding annual reports In the case of a holder that during a single year makes more than one manufacturing change to which paragraph (1)(A) applies, the Secretary may in carrying out subpara- graph (A) authorize the holder to comply with such subparagraph by submitting a sin- gle report for the year that provides the in- formation required in such subparagraph for all the changes made by the holder during the year. (3) Changes requiring supplemental applica- tion (A) Submission of supplemental application The supplemental application required under paragraph (1)(B) for a manufacturing change shall contain such information as the Secretary determines to be appropriate, which shall include the information devel- oped under subsection (b) by the holder in validating the effects of the change. (B) Authority for distribution In the case of a manufacturing change to which paragraph (1)(B) applies: (i) The holder involved may commence distribution of the drug involved 30 days after the Secretary receives the supple- mental application under such paragraph, unless the Secretary notifies the holder within such 30-day period that prior ap- proval of the application is required before distribution may be commenced. Page 282 TITLE 21—FOOD AND DRUGS § 356b (ii) The Secretary may designate a cat- egory of such changes for the purpose of providing that, in the case of a change that is in such category, the holder in- volved may commence distribution of the drug involved upon the receipt by the Sec- retary of a supplemental application for the change. (iii) If the Secretary disapproves the sup- plemental application, the Secretary may order the manufacturer to cease the dis- tribution of the drugs that have been made with the manufacturing change. (June 25, 1938, ch. 675, § 506A, as added Pub. L. 105–115, title I, § 116(a), Nov. 21, 1997, 111 Stat. 2313.) Statutory Notes and Related Subsidiaries EFFECTIVE DATE Pub. L. 105–115, title I, § 116(b), Nov. 21, 1997, 111 Stat. 2315, provided that: ‘‘The amendment made by sub- section (a) [enacting this section] takes effect upon the effective date of regulations promulgated by the Sec- retary of Health and Human Services to implement such amendment, or upon the expiration of the 24- month period beginning on the date of the enactment of this Act [Nov. 21, 1997], whichever occurs first.’’ § 356b. Reports of postmarketing studies (a) Submission (1) In general A sponsor of a drug that has entered into an agreement with the Secretary to conduct a postmarketing study of a drug shall submit to the Secretary, within 1 year after the approval of such drug and annually thereafter until the study is completed or terminated, a report of the progress of the study or the reasons for the failure of the sponsor to conduct the study. The report shall be submitted in such form as is prescribed by the Secretary in regulations issued by the Secretary. (2) Accelerated approval Notwithstanding paragraph (1), a sponsor of a drug approved pursuant to accelerated ap- proval shall submit to the Secretary a report of the progress of any study required under section 356(c) of this title, including progress toward enrollment targets, milestones, and other information as required by the Sec- retary, not later than 180 days after the ap- proval of such drug and not less frequently than every 180 days thereafter, until the study is completed or terminated. The Secretary shall promptly publish on the website of the Food and Drug Administration, in an easily searchable format, the information reported under this paragraph. (3) Agreements prior to effective date Any agreement entered into between the Secretary and a sponsor of a drug, prior to No- vember 21, 1997, to conduct a postmarketing study of a drug shall be subject to the require- ments of paragraph (1). An initial report for such an agreement shall be submitted within 6 months after the date of the issuance of the regulations under paragraph (1). (b) Consideration of information as public infor- mation Any information pertaining to a report de- scribed in subsection (a) shall be considered to be public information to the extent that the in- formation is necessary— (1) to identify the sponsor; and (2) to establish the status of a study de- scribed in subsection (a) and the reasons, if any, for any failure to carry out the study. (c) Status of studies and reports The Secretary shall annually develop and pub- lish in the Federal Register a report that pro- vides information on the status of the post- marketing studies— (1) that sponsors have entered into agree- ments to conduct; and (2) for which reports have been submitted under subsection (a)(1). (d) Disclosure If a sponsor fails to complete an agreed upon study required by this section by its original or otherwise negotiated deadline, the Secretary shall publish a statement on the Internet site of the Food and Drug Administration stating that the study was not completed and, if the reasons for such failure to complete the study were not satisfactory to the Secretary, a statement that such reasons were not satisfactory to the Sec- retary. (e) Notification With respect to studies of the type required under section 356(c)(2)(A) of this title or under section 314.510 or 601.41 of title 21, Code of Fed- eral Regulations, as each of such sections was in effect on the day before the effective date of this subsection, the Secretary may require that a sponsor who, for reasons not satisfactory to the Secretary, fails to complete by its deadline a study under any of such sections of such type for a drug or biological product (including such a study conducted after such effective date) notify practitioners who prescribe such drug or biologi- cal product of the failure to complete such study and the questions of clinical benefit, and, where appropriate, questions of safety, that remain un- answered as a result of the failure to complete such study. Nothing in this subsection shall be construed as altering the requirements of the types of studies required under section 356(c)(2)(A) of this title or under section 314.510 or 601.41 of title 21, Code of Federal Regulations, as so in effect, or as prohibiting the Secretary from modifying such sections of title 21 of such Code to provide for studies in addition to those of such type. (June 25, 1938, ch. 675, § 506B, as added Pub. L. 105–115, title I, § 130(a), Nov. 21, 1997, 111 Stat. 2331; amended Pub. L. 107–188, title V, § 506, June 12, 2002, 116 Stat. 693; Pub. L. 112–144, title IX, § 902(c), July 9, 2012, 126 Stat. 1088; Pub. L. 117–328, div. FF, title III, § 3210(b), Dec. 29, 2022, 136 Stat. 5823.) Editorial Notes REFERENCES IN TEXT The effective date of this subsection, referred to in subsec. (e), is Oct. 1, 2002, see Effective Date of 2002 Amendment note set out below.