21 U.S.C. § 355c — Research into pediatric uses for drugs

Page 248 TITLE 21—FOOD AND DRUGS § 355b 1 So in original. Probably should be preceded by ‘‘section’’. 2 So in original. Probably should be ‘‘Committee’’. STUDY BY GENERAL ACCOUNTING OFFICE Pub. L. 107–109, § 18(b), Jan. 4, 2002, 115 Stat. 1423, re- quired the Comptroller General, not later than Jan. 10, 2003, to conduct a study relating to the representation of children of ethnic and racial minorities in studies under section 355a of this title and to submit a report to Congress describing the findings of the study. § 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 application is approved under section 505 of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 355] (regard- less of the date on which approved) include the toll-free number maintained by the Secretary for the purpose of receiving reports of adverse events regarding drugs and a statement that such number is to be used for reporting purposes only, not to receive medical advice. With re- spect to the final rule: (1) The rule shall provide for the implemen- tation of such labeling requirement in a man- ner that the Secretary considers to be most likely to reach the broadest consumer audi- ence. (2) In promulgating the rule, the Secretary shall seek to minimize the cost of the rule on the pharmacy profession. (3) The rule shall take effect not later than 60 days after the date on which the rule is pro- mulgated. (b) Drugs with pediatric market exclusivity (1) In general During the one year beginning on the date on which a drug receives a period of market exclusivity under 505A 1 of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 355a], any report of an adverse event regarding the drug that the Secretary of Health and Human Serv- ices receives shall be referred to the Office of Pediatric Therapeutics established under sec- tion 393a of this title. In considering the re- port, the Director of such Office shall provide for the review of the report by the Pediatric Advisory Committee, including obtaining any recommendations of such subcommittee 2 re- garding whether the Secretary should take ac- tion under the Federal Food, Drug, and Cos- metic Act [21 U.S.C. 301 et seq.] in response to the report. (2) Rule of construction Paragraph (1) may not be construed as re- stricting the authority of the Secretary of Health and Human Services to continue car- rying out the activities described in such para- graph regarding a drug after the one-year pe- riod described in such paragraph regarding the drug has expired. (Pub. L. 107–109, § 17, Jan. 4, 2002, 115 Stat. 1422; Pub. L. 108–155, § 3(b)(5), Dec. 3, 2003, 117 Stat. 1942.) Editorial Notes REFERENCES IN TEXT The Federal Food, Drug, and Cosmetic Act, referred to in subsec. (b)(1), is act June 25, 1938, ch. 675, 52 Stat. 1040, which is classified generally to this chapter. For complete classification of this Act to the Code, see sec- tion 301 of this title and Tables. CODIFICATION Section was enacted as part of the Best Pharma- ceuticals for Children Act, and not as part of the Fed- eral Food, Drug, and Cosmetic Act which comprises this chapter. AMENDMENTS 2003—Subsec. (b)(1). Pub. L. 108–155 struck out ‘‘Advi- sory Subcommittee of the Anti-Infective Drugs’’ before ‘‘Advisory Committee’’. Statutory Notes and Related Subsidiaries EFFECTIVE DATE OF 2003 AMENDMENT Amendment by Pub. L. 108–155 effective Dec. 3, 2003, except as otherwise provided, see section 4 of Pub. L. 108–155, set out as an Effective Date note under section 355c of this title. § 355c. Research into pediatric uses for drugs and biological products (a) New drugs and biological products (1) In general (A) General requirements Except with respect to an application for which subparagraph (B) applies, a person that submits, on or after September 27, 2007, an application (or supplement to an applica- tion) for a drug— (i) under section 355 of this title for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration; or (ii) under section 262 of title 42 for a new active ingredient, new indication, new dos- age form, new dosing regimen, or new route of administration, shall submit with the application the assess- ments described in paragraph (2). (B) Certain molecularly targeted cancer indi- cations A person that submits, on or after the date that is 3 years after August 18, 2017, an origi- nal application for a new active ingredient under section 355 of this title or section 262 of title 42, shall submit with the application reports on the investigation described in paragraph (3) if the drug or biological prod- uct that is the subject of the application is— (i) intended for the treatment of an adult cancer; and (ii) directed at a molecular target that the Secretary determines to be substan- tially relevant to the growth or progres- sion of a pediatric cancer. (2) Assessments (A) In general The assessments referred to in paragraph (1)(A) shall contain data, gathered using ap- propriate formulations for each age group Page 249 TITLE 21—FOOD AND DRUGS § 355c for which the assessment is required, that are adequate— (i) to assess the safety and effectiveness of the drug or the biological product for the claimed indications in all relevant pe- diatric subpopulations; and (ii) to support dosing and administration for each pediatric subpopulation for which the drug or the biological product is safe and effective. (B) Similar course of disease or similar effect of drug or biological product (i) In general If the course of the disease and the ef- fects of the drug are sufficiently similar in adults and pediatric patients, the Sec- retary may conclude that pediatric effec- tiveness can be extrapolated from ade- quate and well-controlled studies in adults, usually supplemented with other information obtained in pediatric patients, such as pharmacokinetic studies. (ii) Extrapolation between age groups A study may not be needed in each pedi- atric age group if data from one age group can be extrapolated to another age group. (iii) Information on extrapolation A brief documentation of the scientific data supporting the conclusion under clauses (i) and (ii) shall be included in any pertinent reviews for the application under section 355 of this title or section 262 of title 42. (3) Molecularly targeted pediatric cancer in- vestigation (A) In general With respect to a drug or biological prod- uct described in paragraph (1)(B), the inves- tigation described in this paragraph is a mo- lecularly targeted pediatric cancer inves- tigation, which shall be designed to yield clinically meaningful pediatric study data, gathered using appropriate formulations for each age group for which the study is re- quired, regarding dosing, safety, and pre- liminary efficacy to inform potential pedi- atric labeling. (B) Extrapolation of data Paragraph (2)(B) shall apply to investiga- tions described in this paragraph to the same extent and in the same manner as paragraph (2)(B) applies with respect to the assessments required under paragraph (1)(A). (C) Deferrals and waivers Deferrals and waivers under paragraphs (4) and (5) shall apply to investigations de- scribed in this paragraph to the same extent and in the same manner as such deferrals and waivers apply with respect to the assess- ments under paragraph (2)(B). (4) Deferral (A) In general On the initiative of the Secretary or at the request of the applicant, the Secretary may defer submission of some or all assessments required under paragraph (1)(A) or reports on the investigation required under paragraph (1)(B) until a specified date after approval of the drug or issuance of the license for a bio- logical product if— (i) the Secretary finds that— (I) the drug or biological product is ready for approval for use in adults be- fore pediatric studies are complete; (II) pediatric studies should be delayed until additional safety or effectiveness data have been collected; or (III) there is another appropriate rea- son for deferral; and (ii) the applicant submits to the Sec- retary— (I) certification of the grounds for de- ferring the assessments or reports on the investigation; (II) a pediatric study plan as described in subsection (e); (III) evidence that the studies are being conducted or will be conducted with due diligence and at the earliest possible time; and (IV) a timeline for the completion of such studies. (B) Deferral extension (i) In general On the initiative of the Secretary or at the request of the applicant, the Secretary may grant an extension of a deferral ap- proved under subparagraph (A) for submis- sion of some or all assessments required under paragraph (1)(A) or reports on the investigation required under paragraph (1)(B) if— (I) the Secretary determines that the conditions described in subclause (II) or (III) of subparagraph (A)(i) continue to be met; and (II) the applicant submits a new timeline under subparagraph (A)(ii)(IV) and any significant updates to the infor- mation required under subparagraph (A)(ii). (ii) Timing and information If the deferral extension under this sub- paragraph is requested by the applicant, the applicant shall submit the deferral ex- tension request containing the informa- tion described in this subparagraph not less than 90 days prior to the date that the deferral would expire. The Secretary shall respond to such request not later than 45 days after the receipt of such letter. If the Secretary grants such an extension, the specified date shall be the extended date. The sponsor of the required assessment under paragraph (1)(A) or reports on the investigation under paragraph (1)(B) shall not be issued a letter described in sub- section (d) unless the specified or extended date of submission for such required stud- ies has passed or if the request for an ex- tension is pending. For a deferral that has expired prior to July 9, 2012, or that will expire prior to 270 days after July 9, 2012, a deferral extension shall be requested by Page 250 TITLE 21—FOOD AND DRUGS § 355c an applicant not later than 180 days after July 9, 2012. The Secretary shall respond to any such request as soon as practicable, but not later than 1 year after July 9, 2012. Nothing in this clause shall prevent the Secretary from updating the status of a study or studies publicly if components of such study or studies are late or delayed. (C) Annual review (i) In general On an annual basis following the ap- proval of a deferral under subparagraph (A), the applicant shall submit to the Sec- retary the following information: (I) Information detailing the progress made in conducting pediatric studies. (II) If no progress has been made in conducting such studies, evidence and documentation that such studies will be conducted with due diligence and at the earliest possible time. (III) Projected completion date for pe- diatric studies. (IV) The reason or reasons why a defer- ral or deferral extension continues to be necessary. (ii) Public availability Not later than 90 days after the submis- sion to the Secretary of the information submitted through the annual review under clause (i), the Secretary shall make available to the public in an easily acces- sible manner, including through the Inter- net Web site of the Food and Drug Admin- istration— (I) such information; (II) the name of the applicant for the product subject to the assessment or in- vestigation; (III) the date on which the product was approved; and (IV) the date of each deferral or defer- ral extension under this paragraph for the product. (5) Waivers (A) Full waiver On the initiative of the Secretary or at the request of an applicant, the Secretary shall grant a full waiver, as appropriate, of the re- quirement to submit assessments or reports on the investigation for a drug or biological product under this subsection if the appli- cant certifies and the Secretary finds that— (i) necessary studies are impossible or highly impracticable (because, for exam- ple, the number of patients is so small or the patients are geographically dispersed); (ii) there is evidence strongly suggesting that the drug or biological product would be ineffective or unsafe in all pediatric age groups; or (iii) the drug or biological product— (I) does not represent a meaningful therapeutic benefit over existing thera- pies for pediatric patients; and (II) is not likely to be used in a sub- stantial number of pediatric patients. (B) Partial waiver On the initiative of the Secretary or at the request of an applicant, the Secretary shall grant a partial waiver, as appropriate, of the requirement to submit assessments or re- ports on the investigation for a drug or bio- logical product under this subsection with respect to a specific pediatric age group if the applicant certifies and the Secretary finds that— (i) necessary studies are impossible or highly impracticable (because, for exam- ple, the number of patients in that age group is so small or patients in that age group are geographically dispersed); (ii) there is evidence strongly suggesting that the drug or biological product would be ineffective or unsafe in that age group; (iii) the drug or biological product— (I) does not represent a meaningful therapeutic benefit over existing thera- pies for pediatric patients in that age group; and (II) is not likely to be used by a sub- stantial number of pediatric patients in that age group; or (iv) the applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary for that age group have failed. (C) Pediatric formulation not possible If a partial waiver is granted on the ground that it is not possible to develop a pediatric formulation, the waiver shall cover only the pediatric groups requiring that for- mulation. An applicant seeking such a par- tial waiver shall submit to the Secretary documentation detailing why a pediatric for- mulation cannot be developed and, if the waiver is granted, the applicant’s submis- sion shall promptly be made available to the public in an easily accessible manner, in- cluding through posting on the Web site of the Food and Drug Administration. (D) Labeling requirement If the Secretary grants a full or partial waiver because there is evidence that a drug or biological product would be ineffective or unsafe in pediatric populations, the informa- tion shall be included in the labeling for the drug or biological product. (b) Marketed drugs and biological products (1) In general The Secretary may (by order in the form of a letter) require the sponsor or holder of an approved application for a drug under section 355 of this title or the holder of a license for a biological product under section 262 of title 42 to submit by a specified date the assessments described in subsection (a)(2), if the Secretary finds that— (A)(i) the drug or biological product is used for a substantial number of pediatric patients for the labeled indications; and (ii) adequate pediatric labeling could con- fer a benefit on pediatric patients; (B) there is reason to believe that the drug or biological product would represent a meaningful therapeutic benefit over existing therapies for pediatric patients for 1 or more of the claimed indications; or Page 251 TITLE 21—FOOD AND DRUGS § 355c (C) the absence of adequate pediatric label- ing could pose a risk to pediatric patients. (2) Waivers (A) Full waiver At the request of an applicant, the Sec- retary shall grant a full waiver, as appro- priate, of the requirement to submit assess- ments under this subsection if the applicant certifies and the Secretary finds that— (i) necessary studies are impossible or highly impracticable (because, for exam- ple, the number of patients in that age group is so small or patients in that age group are geographically dispersed); or (ii) there is evidence strongly suggesting that the drug or biological product would be ineffective or unsafe in all pediatric age groups. (B) Partial waiver At the request of an applicant, the Sec- retary shall grant a partial waiver, as appro- priate, of the requirement to submit assess- ments under this subsection with respect to a specific pediatric age group if the appli- cant certifies and the Secretary finds that— (i) necessary studies are impossible or highly impracticable (because, for exam- ple, the number of patients in that age group is so small or patients in that age group are geographically dispersed); (ii) there is evidence strongly suggesting that the drug or biological product would be ineffective or unsafe in that age group; (iii)(I) the drug or biological product— (aa) does not represent a meaningful therapeutic benefit over existing thera- pies for pediatric patients in that age group; and (bb) is not likely to be used in a sub- stantial number of pediatric patients in that age group; and (II) the absence of adequate labeling could not pose significant risks to pedi- atric patients; or (iv) the applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary for that age group have failed. (C) Pediatric formulation not possible If a waiver is granted on the ground that it is not possible to develop a pediatric for- mulation, the waiver shall cover only the pe- diatric groups requiring that formulation. An applicant seeking either a full or partial waiver shall submit to the Secretary docu- mentation detailing why a pediatric formu- lation cannot be developed and, if the waiver is granted, the applicant’s submission shall promptly be made available to the public in an easily accessible manner, including through posting on the Web site of the Food and Drug Administration. (D) Labeling requirement If the Secretary grants a full or partial waiver because there is evidence that a drug or biological product would be ineffective or unsafe in pediatric populations, the informa- tion shall be included in the labeling for the drug or biological product. (3) Effect of subsection Nothing in this subsection alters or amends section 331(j) of this title or section 552 of title 5 or section 1905 of title 18. (c) Meaningful therapeutic benefit For the purposes of paragraph (4)(A)(iii)(I) and (4)(B)(iii)(I) of subsection (a) and paragraphs (1)(B) and (2)(B)(iii)(I)(aa) of subsection (b), a drug or biological product shall be considered to represent a meaningful therapeutic benefit over existing therapies if the Secretary determines that— (1) if approved, the drug or biological prod- uct could represent an improvement in the treatment, diagnosis, or prevention of a dis- ease, compared with marketed products ade- quately labeled for that use in the relevant pe- diatric population; or (2) the drug or biological product is in a class of products or for an indication for which there is a need for additional options. (d) Submission of assessments and reports on the investigation If a person fails to submit a required assess- ment described in subsection (a)(2) or the inves- tigation described in subsection (a)(3), fails to meet the applicable requirements in subsection (a)(4), or fails to submit a request for approval of a pediatric formulation described in subsection (a) or (b), in accordance with applicable provi- sions of subsections (a) and (b), the following shall apply: (1) Beginning 270 days after July 9, 2012, the Secretary shall issue a non-compliance letter to such person informing them of such failure to submit or meet the requirements of the ap- plicable subsection. Such letter shall require the person to respond in writing within 45 cal- endar days of issuance of such letter. Such re- sponse may include the person’s request for a deferral extension if applicable. Such letter and the person’s written response to such let- ter shall be made publicly available on the Internet Web site of the Food and Drug Ad- ministration 60 calendar days after issuance, with redactions for any trade secrets and con- fidential commercial information. If the Sec- retary determines that the letter was issued in error, the requirements of this paragraph shall not apply. The Secretary shall inform the Pe- diatric Advisory Committee of letters issued under this paragraph and responses to such letters. (2) The drug or biological product that is the subject of an assessment described in sub- section (a)(2) or the investigation described in subsection (a)(3), applicable requirements in subsection (a)(4), or request for approval of a pediatric formulation, may be considered mis- branded solely because of that failure and sub- ject to relevant enforcement action (except that the drug or biological product shall not be subject to action under section 333 of this title), but such failure shall not be the basis for a proceeding— (A) to withdraw approval for a drug under section 355(e) of this title; or (B) to revoke the license for a biological product under section 262 of title 42. Page 252 TITLE 21—FOOD AND DRUGS § 355c (e) Pediatric study plans (1) In general An applicant subject to subsection (a) shall submit to the Secretary an initial pediatric study plan prior to the submission of the as- sessments described under subsection (a)(2) or the investigation described in subsection (a)(3). (2) Timing; content; meetings (A) Timing An applicant shall submit the initial pedi- atric study plan under paragraph (1)— (i) before the date on which the appli- cant submits the assessments under sub- section (a)(2) or the investigation de- scribed in subsection (a)(3); and (ii) not later than— (I) 60 calendar days after the date of the end-of-Phase 2 meeting (as such term is used in section 312.47 of title 21, Code of Federal Regulations, or successor reg- ulations); or (II) such other time as may be agreed upon between the Secretary and the ap- plicant. Nothing in this section shall preclude the Secretary from accepting the submission of an initial pediatric study plan earlier than the date otherwise applicable under this sub- paragraph. (B) Content of initial pediatric study plan The initial pediatric study plan shall in- clude— (i) an outline of the pediatric study or studies that the applicant plans to conduct (including, to the extent practicable study objectives and design, age groups, relevant endpoints, and statistical approach); (ii) any request for a deferral, partial waiver, or waiver under this section, if ap- plicable, along with any supporting infor- mation; and (iii) other information specified in the regulations promulgated under paragraph (7). (C) Meetings The Secretary— (i) shall meet with the applicant— (I) if requested by the applicant with respect to a drug or biological product that is intended to treat a serious or life- threatening disease or condition, to dis- cuss preparation of the initial pediatric study plan, not later than the end-of- Phase 1 meeting (as such term is used in section 312.82(b) of title 21, Code of Fed- eral Regulations, or successor regula- tions) or within 30 calendar days of re- ceipt of such request, whichever is later; (II) to discuss the initial pediatric study plan as soon as practicable, but not later than 90 calendar days after the receipt of such plan under subparagraph (A); and (III) to discuss the bases for the defer- ral under subsection (a)(4) or a full or partial waiver under subsection (a)(5); (ii) may determine that a written re- sponse to the initial pediatric study plan is sufficient to communicate comments on the initial pediatric study plan, and that no meeting under clause (i)(II) is nec- essary; and (iii) if the Secretary determines that no meeting under clause (i)(II) is necessary, shall so notify the applicant and provide written comments of the Secretary as soon as practicable, but not later than 90 cal- endar days after the receipt of the initial pediatric study plan. (3) Agreed initial pediatric study plan Not later than 90 calendar days following the meeting under paragraph (2)(C)(i)(II) or the re- ceipt of a written response from the Secretary under paragraph (2)(C)(iii), the applicant shall document agreement on the initial pediatric study plan in a submission to the Secretary marked ‘‘Agreed Initial Pediatric Study Plan’’, and the Secretary shall confirm such agreement to the applicant in writing not later than 30 calendar days of receipt of such agreed initial pediatric study plan. (4) Deferral and waiver If the agreed initial pediatric study plan contains a request from the applicant for a de- ferral, partial waiver, or waiver under this sec- tion, the written confirmation under para- graph (3) shall include a recommendation from the Secretary as to whether such request meets the standards under paragraphs (3) or (4) of subsection (a). (5) Amendments to the agreed initial pediatric study plan At the initiative of the Secretary or the ap- plicant, the agreed initial pediatric study plan may be amended at any time. The require- ments of paragraph (2)(C) shall apply to any such proposed amendment in the same manner and to the same extent as such requirements apply to an initial pediatric study plan under paragraph (1). The requirements of paragraphs (3) and (4) shall apply to any agreement result- ing from such proposed amendment in the same manner and to the same extent as such requirements apply to an agreed initial pedi- atric study plan. (6) Internal committee The Secretary shall consult the internal committee under section 355d of this title on the review of the initial pediatric study plan, agreed initial pediatric study plan, and any significant amendments to such plans. (7) Required rulemaking Not later than 1 year after July 9, 2012, the Secretary shall promulgate proposed regula- tions and issue guidance to implement the provisions of this subsection. (f) Review of pediatric study plans, assessments, deferrals, deferral extensions, and waivers (1) Review Beginning not later than 30 days after Sep- tember 27, 2007, the Secretary shall utilize the internal committee established under section 355d of this title to provide consultation to re- viewing divisions on initial pediatric study plans, agreed initial pediatric study plans, and Page 253 TITLE 21—FOOD AND DRUGS § 355c any significant amendments to such plans, and assessments prior to approval of an appli- cation or supplement for which a pediatric as- sessment is required under this section and all deferral, deferral extension, and waiver re- quests granted pursuant to this section. (2) 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. (3) Documentation of committee action For each drug or biological product, the committee referred to in paragraph (1) shall document, for each activity described in para- graph (4) or (5), which members of the com- mittee participated in such activity. (4) Review of pediatric study plans, assess- ments, deferrals, deferral extensions, and waivers Consultation on initial pediatric study plans, agreed initial pediatric study plans, and assessments by the committee referred to in paragraph (1) pursuant to this section shall occur prior to approval of an application or supplement for which a pediatric assessment is required under this section. The committee shall review all requests for deferrals, deferral extensions, and waivers from the requirement to submit a pediatric assessment granted under this section and shall provide rec- ommendations as needed to reviewing divi- sions, including with respect to whether such a supplement, when submitted, shall be con- sidered for priority review. (5) Retrospective review of pediatric assess- ments, deferrals, and waivers Not later than 1 year after September 27, 2007, the committee referred to in paragraph (1) shall conduct a retrospective review and analysis of a representative sample of assess- ments submitted and deferrals and waivers ap- proved under this section since December 3, 2003. Such review shall include an analysis of the quality and consistency of pediatric infor- mation in pediatric assessments and the ap- propriateness of waivers and deferrals granted. Based on such review, the Secretary shall issue recommendations to the review divisions for improvements and initiate guidance to in- dustry related to the scope of pediatric studies required under this section. (6) Tracking of assessments 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 assessments conducted under this section; (B) the specific drugs and biological prod- ucts and their uses assessed under this sec- tion; (C) the types of assessments conducted under this section, including trial design, the number of pediatric patients studied, and the number of centers and countries in- volved; (D) aggregated on an annual basis— (i) the total number of deferrals and de- ferral extensions requested and granted under this section and, if granted, the rea- sons for each such deferral or deferral ex- tension; (ii) the timeline for completion of the as- sessments; (iii) the number of assessments com- pleted and pending; and (iv) the number of postmarket non-com- pliance letters issued pursuant to sub- section (d), and the recipients of such let- ters; (E) the number of waivers requested and granted under this section and, if granted, the reasons for the waivers; (F) the number of pediatric formulations developed and the number of pediatric for- mulations not developed and the reasons any such formulation was not developed; (G) the labeling changes made as a result of assessments conducted under this section; (H) an annual summary of labeling changes made as a result of assessments con- ducted under this section for distribution pursuant to subsection (h)(2); (I) an annual summary of information sub- mitted pursuant to subsection (a)(4)(C); and (J) the number of times the committee re- ferred to in paragraph (1) made a rec- ommendation to the Secretary under para- graph (4) regarding priority review, the num- ber of times the Secretary followed or did not follow such a recommendation, and, if not followed, the reasons why such a rec- ommendation was not followed. (g) Labeling changes (1) Dispute resolution (A) Request for labeling change and failure to agree If, on or after September 27, 2007, the Com- missioner determines that a sponsor and the Commissioner have been unable to reach agreement on appropriate changes to the la- beling for the drug that is the subject of the application or supplement, not later than 180 days after the date of the submission of the application or supplement that receives a priority review or 330 days after the date of the submission of an application or supple- ment that receives a standard review— (i) the Commissioner shall request that the sponsor of the application make any labeling change that the Commissioner de- termines to be appropriate; and (ii) if the sponsor 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 Com- mittee Not later than 90 days after receiving a re- ferral under subparagraph (A)(ii), the Pedi- atric Advisory Committee shall— Page 254 TITLE 21—FOOD AND DRUGS § 355c (i) review the pediatric study reports; and (ii) make a recommendation to the Com- missioner concerning appropriate labeling changes, if any. (C) Consideration of recommendations The Commissioner shall consider the rec- ommendations of the Pediatric Advisory Committee and, if appropriate, not later than 30 days after receiving the rec- ommendation, make a request to the spon- sor of the application or supplement to make any labeling changes that the Com- missioner determines to be appropriate. (D) Misbranding If the sponsor of the application or supple- ment, within 30 days after receiving a re- quest 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 applica- tion or supplement to be misbranded. (E) No effect on authority Nothing in this subsection limits the au- thority of the United States to bring an en- forcement action under this chapter when a drug lacks appropriate pediatric labeling. Neither course of action (the Pediatric Advi- sory 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. (2) Other labeling changes If, on or after September 27, 2007, the Sec- retary makes a determination that a pediatric assessment conducted under this section does or does not demonstrate that the drug that is the subject of such assessment is safe and ef- fective in pediatric populations or subpopula- tions, including whether such assessment re- sults are inconclusive, the Secretary shall order the labeling of such product to include information about the results of the assess- ment and a statement of the Secretary’s de- termination. (h) Dissemination of pediatric information (1) In general Not later than 210 days after the date of sub- mission of an application (or supplement to an application) that contains a pediatric assess- ment under this section, if the application (or supplement) receives a priority review, or not later than 330 days after the date of submis- sion of an application (or supplement to an ap- plication) that contains a pediatric assess- ment under this section, if the application (or supplement) receives a standard review, the Secretary shall make available to the public in an easily accessible manner the medical, statistical, and clinical pharmacology reviews of such pediatric assessments, and shall post such assessments on the Web site of the Food and Drug Administration. (2) Dissemination of information regarding la- beling changes Beginning on September 27, 2007, the Sec- retary shall require that the sponsors of the assessments that result in labeling changes that are reflected in the annual summary de- veloped pursuant to subsection (f)(6)(H) dis- tribute such information to physicians and other health care providers. (3) Effect of subsection Nothing in this subsection shall alter or amend section 331(j) of this title or section 552 of title 5 or section 1905 of title 18. (i) 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 label- ing change is made pursuant to subsection (g), the Secretary shall ensure that all adverse event reports that have been received for such drug (regardless of when such report was re- ceived) are referred to the Office of Pediatric Therapeutics. In considering such reports, the Director of such Office shall provide for the re- view of such reports by the Pediatric Advisory Committee, including obtaining any rec- ommendations of such committee regarding whether the Secretary should take action under this chapter in response to such reports. (2) Reporting in subsequent periods Following the 18-month period described in paragraph (1), the Secretary shall, as appro- priate, refer to the Office of Pediatric Thera- peutics all pediatric adverse event reports for a drug for which a pediatric study was con- ducted under this section. In considering such reports, the Director of such Office may pro- vide for the review of such reports by the Pedi- atric Advisory Committee, including obtain- ing 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 pro- viding 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. (j) Scope of authority Nothing in this section provides to the Sec- retary any authority to require a pediatric as- sessment of any drug or biological product, or any assessment regarding other populations or uses of a drug or biological product, other than the pediatric assessments described in this sec- tion. (k) Relation to orphan drugs (1) In general; exemption for orphan indica- tions Unless the Secretary requires otherwise by regulation and except as provided in para- graph (2), this section does not apply to any drug or biological product for an indication for which orphan designation has been granted under section 360bb of this title. Page 255 TITLE 21—FOOD AND DRUGS § 355c 1 So in original. Probably should be preceded by ‘‘section’’. (2) Applicability despite orphan designation of certain indications This section shall apply with respect to a drug or biological product for which an indica- tion has been granted orphan designation under 360bb 1 of this title if the investigation described in subsection (a)(3) applies to the drug or biological product as described in sub- section (a)(1)(B). (l) New active ingredient (1) Non-interchangeable biosimilar biological product A biological product that is biosimilar to a reference product under section 262 of title 42, and that the Secretary has not determined to meet the standards described in subsection (k)(4) of such section for interchangeability with the reference product, shall be considered to have a new active ingredient under this sec- tion. (2) Interchangeable biosimilar biological prod- uct A biological product that is interchangeable with a reference product under section 262 of title 42 shall not be considered to have a new active ingredient under this section. (m) List of primary molecular targets (1) In general Within one year of August 18, 2017, the Sec- retary shall establish and update regularly, and shall publish on the internet website of the Food and Drug Administration— (A) a list of molecular targets considered, on the basis of data the Secretary deter- mines to be adequate, to be substantially relevant to the growth and progression of a pediatric cancer, and that may trigger the requirements under this section; and (B) a list of molecular targets of new can- cer drugs and biological products in develop- ment for which pediatric cancer study re- quirements under this section will be auto- matically waived. (2) Consultation In establishing the lists described in para- graph (1), the Secretary shall consult the Na- tional Cancer Institute, members of the inter- nal committee under section 355d of this title, and the Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee, and shall take into account comments from the meeting under subsection (c). (3) Rule of construction Nothing in paragraph (1) shall be con- strued— (A) to require the inclusion of a molecular target on the list published under such para- graph as a condition for triggering the re- quirements under subsection (a)(1)(B) with respect to a drug or biological product di- rected at such molecular target; or (B) to authorize the disclosure of confiden- tial commercial information, as prohibited under section 331(j) of this title or section 1905 of title 18. (June 25, 1938, ch. 675, § 505B, as added Pub. L. 108–155, § 2(a), Dec. 3, 2003, 117 Stat. 1936; amend- ed Pub. L. 110–85, title IV, § 402(a), Sept. 27, 2007, 121 Stat. 866; Pub. L. 111–148, title VII, § 7002(d)(2), Mar. 23, 2010, 124 Stat. 816; Pub. L. 112–144, title V, §§ 501(b), 505–506(b), 509(b), July 9, 2012, 126 Stat. 1040–1044, 1048; Pub. L. 114–255, div. A, title III, §§ 3101(a)(2)(D), 3102(3), Dec. 13, 2016, 130 Stat. 1153, 1156; Pub. L. 115–52, title V, §§ 503–504(b), 505(e), Aug. 18, 2017, 131 Stat. 1038–1041, 1047; Pub. L. 117–328, div. FF, title II, § 2515(c), Dec. 29, 2022, 136 Stat. 5806.) Editorial Notes AMENDMENTS 2022—Subsec. (f)(6)(I). Pub. L. 117–328 substituted ‘‘subsection (a)(4)(C)’’ for ‘‘subsection (a)(3)(B)’’. 2017—Subsec. (a)(1). Pub. L. 115–52, § 504(a)(1)(A), des- ignated existing provisions as subpar. (A) and inserted heading, substituted ‘‘Except with respect to an appli- cation for which subparagraph (B) applies, a person’’ for ‘‘A person’’, redesignated former subpars. (A) and (B) as cls. (i) and (ii), respectively, of subpar. (A) and realigned margins, substituted ‘‘; or’’ for ‘‘, or’’ at end of subpar. (A)(i), and added subpar. (B). Subsec. (a)(2)(A). Pub. L. 115–52, § 504(a)(1)(B), sub- stituted ‘‘paragraph (1)(A)’’ for ‘‘paragraph (1)’’ in in- troductory provisions. Subsec. (a)(3). Pub. L. 115–52, § 504(a)(1)(D), added par. (3). Former par. (3) redesignated (4). Subsec. (a)(4). Pub. L. 115–52, § 504(a)(1)(C), redesig- nated par. (3) as (4). Former par. (4) redesignated (5). Subsec. (a)(4)(A). Pub. L. 115–52, § 504(a)(1)(E)(i), sub- stituted ‘‘assessments required under paragraph (1)(A) or reports on the investigation required under para- graph (1)(B)’’ for ‘‘assessments required under para- graph (1)’’ in introductory provisions. Subsec. (a)(4)(A)(ii)(I). Pub. L. 115–52, § 504(a)(1)(E)(ii), inserted ‘‘or reports on the investigation’’ after ‘‘as- sessments’’. Subsec. (a)(4)(B)(i). Pub. L. 115–52, § 504(a)(1)(E)(i), substituted ‘‘assessments required under paragraph (1)(A) or reports on the investigation required under paragraph (1)(B)’’ for ‘‘assessments required under paragraph (1)’’ in introductory provisions. Subsec. (a)(4)(B)(ii). Pub. L. 115–52, § 504(a)(1)(E)(iii), substituted ‘‘assessment under paragraph (1)(A) or re- ports on the investigation under paragraph (1)(B)’’ for ‘‘assessment under paragraph (1)’’. Subsec. (a)(4)(C)(ii)(II). Pub. L. 115–52, § 504(a)(1)(E)(iv), inserted ‘‘or investigation’’ after ‘‘as- sessment’’. Subsec. (a)(5). Pub. L. 115–52, § 504(a)(1)(C), redesig- nated par. (4) as (5). Subsec. (a)(5)(A), (B). Pub. L. 115–52, § 504(a)(1)(F), in- serted ‘‘or reports on the investigation’’ after ‘‘assess- ments’’ in introductory provisions. Subsec. (d). Pub. L. 115–52, § 504(a)(2), inserted ‘‘and reports on the investigation’’ after ‘‘Submission of as- sessments’’ in heading and, in introductory provisions, inserted ‘‘or the investigation described in subsection (a)(3)’’ after ‘‘assessment described in subsection (a)(2)’’ and substituted ‘‘subsection (a)(4)’’ for ‘‘subsection (a)(3)’’. Subsec. (d)(1). Pub. L. 115–52, § 505(e), inserted at end ‘‘The Secretary shall inform the Pediatric Advisory Committee of letters issued under this paragraph and responses to such letters.’’ Subsec. (d)(2). Pub. L. 115–52, § 504(a)(2)(A), (C), in in- troductory provisions, inserted ‘‘or the investigation described in subsection (a)(3)’’ after ‘‘assessment de- scribed in subsection (a)(2)’’ and substituted ‘‘sub- section (a)(4)’’ for ‘‘subsection (a)(3)’’. Subsec. (e)(1). Pub. L. 115–52, § 504(a)(3)(A), inserted ‘‘or the investigation described in subsection (a)(3)’’ after ‘‘under subsection (a)(2)’’. Subsec. (e)(2). Pub. L. 115–52, § 503(b)(1), substituted ‘‘meetings’’ for ‘‘meeting’’ in heading. Page 256 TITLE 21—FOOD AND DRUGS § 355c Subsec. (e)(2)(A)(i). Pub. L. 115–52, § 504(a)(3)(B), in- serted ‘‘or the investigation described in subsection (a)(3)’’ after ‘‘under subsection (a)(2)’’. Subsec. (e)(2)(C). Pub. L. 115–52, § 503(b)(2), substituted ‘‘Meetings’’ for ‘‘Meeting’’ in heading. Subsec. (e)(2)(C)(i). Pub. L. 115–52, § 503(a), amended cl. (i) generally. Prior to amendment, cl. (i) read as fol- lows: ‘‘shall meet with the applicant to discuss the ini- tial pediatric study plan as soon as practicable, but not later than 90 calendar days after the receipt of such plan under subparagraph (A);’’. Subsec. (e)(2)(C)(ii), (iii). Pub. L. 115–52, § 503(b)(3), substituted ‘‘no meeting under clause (i)(II)’’ for ‘‘no meeting’’. Subsec. (e)(3). Pub. L. 115–52, § 503(b)(4), substituted ‘‘meeting under paragraph (2)(C)(i)(II)’’ for ‘‘meeting under paragraph (2)(C)(i)’’. Subsec. (k). Pub. L. 115–52, § 504(b), amended subsec. (k) generally. Prior to amendment, text read as fol- lows: ‘‘Unless the Secretary requires otherwise by regu- lation, this section does not apply to any drug for an indication for which orphan designation has been granted under section 360bb of this title.’’ Subsec. (m). Pub. L. 115–52, § 504(a)(4), added subsec. (m). 2016—Subsec. (e)(2)(A). Pub. L. 114–255, § 3101(a)(2)(D)(i)(I)(aa), inserted ‘‘study’’ after ‘‘initial pediatric’’ in introductory and concluding provisions. Subsec. (e)(2)(B). Pub. L. 114–255, § 3101(a)(2)(D)(i)(I)(bb), substituted ‘‘Content of initial pediatric study plan’’ for ‘‘Content of initial plan’’ in heading. Subsec. (e)(5). Pub. L. 114–255, § 3101(a)(2)(D)(i)(II), in- serted ‘‘agreed initial pediatric study’’ before ‘‘plan’’ in heading. Subsec. (e)(6). Pub. L. 114–255, § 3101(a)(2)(D)(i)(III), substituted ‘‘agreed initial pediatric study plan’’ for ‘‘agreed initial pediatric plan’’. Subsec. (f)(1). Pub. L. 114–255, § 3101(a)(2)(D)(ii), in- serted ‘‘and any significant amendments to such plans,’’ after ‘‘agreed initial pediatric study plans,’’. Subsecs. (l), (m). Pub. L. 114–255, § 3102(3), redesig- nated subsec. (m) as (l) and struck out former subsec. (l) which related to Institute of Medicine study. 2012—Subsec. (a)(1). Pub. L. 112–144, § 509(b)(1)(A), in- serted ‘‘for a drug’’ after ‘‘(or supplement to an applica- tion)’’ in introductory provisions. Subsec. (a)(3)(A)(ii)(II). Pub. L. 112–144, § 506(b)(1), amended subcl. (II) generally. Prior to amendment, subcl. (II) read as follows: ‘‘a description of the planned or ongoing studies;’’. Subsec. (a)(3)(B), (C). Pub. L. 112–144, § 505(a)(1)(A), (B), added subpar. (B) and redesignated former subpar. (B) as (C). Subsec. (a)(3)(C)(i)(III), (IV). Pub. L. 112–144, § 505(a)(1)(C)(i), added subcls. (III) and (IV). Subsec. (a)(3)(C)(ii). Pub. L. 112–144, § 505(a)(1)(C)(ii), amended cl. (ii) generally. Prior to amendment, text read as follows: ‘‘The information submitted through the annual review under clause (i) shall promptly be made available to the public in an easily accessible manner, including through the Web site of the Food and Drug Administration.’’ Subsec. (a)(4)(C). Pub. L. 112–144, § 509(b)(1)(B), in- serted ‘‘partial’’ after ‘‘If a’’ in first sentence and sub- stituted ‘‘such a’’ for ‘‘either a full or’’ in second sen- tence. Subsec. (b)(1). Pub. L. 112–144, § 509(b)(2), substituted ‘‘The’’ for ‘‘After providing notice in the form of a let- ter (that, for a drug approved under section 355 of this title, references a declined written request under sec- tion 355a of this title for a labeled indication which written request is not referred under section 355a(n)(1)(A) of this title to the Foundation of the Na- tional Institutes of Health for the pediatric studies), the’’ in introductory provisions. Subsec. (d). Pub. L. 112–144, § 505(c)(1), amended sub- sec. (d) generally. Prior to amendment, subsec. (d) re- lated to submission of assessments. Subsec. (e). Pub. L. 112–144, § 506(a), amended subsec. (e) generally. Prior to amendment, text read as follows: ‘‘Before and during the investigational process for a new drug or biological product, the Secretary shall meet at appropriate times with the sponsor of the new drug or biological product to discuss— ‘‘(1) information that the sponsor submits on plans and timelines for pediatric studies; or ‘‘(2) any planned request by the sponsor for waiver or deferral of pediatric studies.’’ Subsec. (f). Pub. L. 112–144, § 506(b)(2)(A), substituted ‘‘pediatric study plans,’’ for ‘‘pediatric plans,’’ in head- ing. Pub. L. 112–144, § 505(a)(2)(A), inserted ‘‘deferral exten- sions,’’ after ‘‘deferrals,’’ in heading. Subsec. (f)(1). Pub. L. 112–144, § 506(b)(2)(B), sub- stituted ‘‘initial pediatric study plans, agreed initial pediatric study plans,’’ for ‘‘all pediatric plans’’. Pub. L. 112–144, § 505(a)(2)(B), inserted ‘‘, deferral ex- tension,’’ after ‘‘deferral’’. Subsec. (f)(4). Pub. L. 112–144, § 506(b)(2)(C), sub- stituted ‘‘pediatric study plans,’’ for ‘‘pediatric plans,’’ in heading and ‘‘initial pediatric study plans, agreed initial pediatric study plans,’’ for ‘‘pediatric plans’’ in text. Pub. L. 112–144, § 505(a)(2)(C), inserted ‘‘deferral exten- sions,’’ after ‘‘deferrals,’’ in heading and ‘‘, deferral ex- tensions,’’ after ‘‘deferrals’’ in text. Subsec. (f)(6)(D). Pub. L. 112–144, § 505(b), amended subpar. (D) generally. Prior to amendment, subpar. (D) read as follows: ‘‘the total number of deferrals re- quested and granted under this section and, if granted, the reasons for such deferrals, the timeline for comple- tion, and the number completed and pending by the specified date, as outlined in subsection (a)(3);’’. Subsec. (f)(6)(D)(iv). Pub. L. 112–144, § 505(c)(2), added cl. (iv). Subsec. (g)(1)(A). Pub. L. 112–144, § 509(b)(3)(A), in- serted ‘‘that receives a priority review or 330 days after the date of the submission of an application or supple- ment that receives a standard review’’ after ‘‘after the date of the submission of the application or supple- ment’’ in introductory provisions. Subsec. (g)(2). Pub. L. 112–144, § 509(b)(3)(B), sub- stituted ‘‘the labeling of such product’’ for ‘‘the label of such product’’. Subsec. (h)(1). Pub. L. 112–144, § 509(b)(4), inserted ‘‘an application (or supplement to an application) that con- tains’’ after ‘‘date of submission of’’ and ‘‘if the appli- cation (or supplement) receives a priority review, or not later than 330 days after the date of submission of an application (or supplement to an application) that contains a pediatric assessment under this section, if the application (or supplement) receives a standard re- view,’’ after ‘‘under this section,’’. Subsec. (i)(1). Pub. L. 112–144, § 509(b)(5)(A), sub- stituted ‘‘first 18-month period’’ for ‘‘year one’’ in heading and ‘‘18-month’’ for ‘‘one-year’’ in text. Subsec. (i)(2). Pub. L. 112–144, § 509(b)(5)(B), sub- stituted ‘‘periods’’ for ‘‘years’’ in heading and ‘‘18- month period’’ for ‘‘one-year period’’ in text. Subsec. (i)(3), (4). Pub. L. 112–144, § 509(b)(5)(C), (D), added par. (3) and redesignated former par. (3) as (4). Subsecs. (m), (n). Pub. L. 112–144, § 501(b), redesig- nated subsec. (n) as (m) and struck out former subsec. (m). Prior to amendment, text of subsec. (m) read as follows: ‘‘The authority under this section shall remain in effect so long as an application subject to this sec- tion may be accepted for filing by the Secretary on or before the date specified in section 355a(q) of this title.’’ 2010—Subsec. (n). Pub. L. 111–148 added subsec. (n). 2007—Pub. L. 110–85 amended section generally. Prior to amendment, section related to required submission of assessments with an application for a new drug or new biological product and by order of the Secretary for certain marketed drugs and biological products used for pediatric patients, a definition of meaningful therapeutic benefit, consequences of failure to submit required assessments, meetings of the Secretary and the sponsor of a new drug or biological product, a limi- tation of the scope of the Secretary’s authority, appli- Page 257 TITLE 21—FOOD AND DRUGS § 355c cation to orphan drugs, and integration with other pe- diatric studies. Statutory Notes and Related Subsidiaries EFFECTIVE DATE OF 2012 AMENDMENT Pub. L. 112–144, title V, § 506(c), July 9, 2012, 126 Stat. 1045, provided that: ‘‘(1) IN GENERAL.—Subject to paragraph (2), the amendments made by this section [amending this sec- tion] shall take effect 180 calendar days after the date of enactment of this Act [July 9, 2012], irrespective of whether the Secretary [of Health and Human Services] has promulgated final regulations to carry out such amendments. ‘‘(2) RULE OF CONSTRUCTION.—Paragraph (1) shall not be construed to affect the deadline for promulgation of proposed regulations under section 505B(e)(7) of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 355c(e)(7)], as added by subsection (a) of this section.’’ Notwithstanding any provision of this section stating that a provision applies beginning on Sept. 27, 2007, any amendment made by Pub. L. 112–144 to such a provision applies beginning on July 9, 2012, subject to a transi- tional rule, see section 509(g) of Pub. L. 112–144, set out as a note under section 355a of this title. EFFECTIVE DATE OF 2007 AMENDMENT Pub. L. 110–85, title IV, § 402(b), Sept. 27, 2007, 121 Stat. 875, provided that: ‘‘(1) IN GENERAL.—Notwithstanding subsection (h) of section 505B of the Federal Food, Drug and Cosmetic Act [21 U.S.C. 355c(h)], as in effect on the day before the date of the enactment of this Act [Sept. 27, 2007], a pending assessment, including a deferred assessment, required under such section 505B shall be deemed to have been required under section 505B of the Federal Food, Drug and Cosmetic Act as in effect on or after the date of the enactment of this Act. ‘‘(2) CERTAIN ASSESSMENTS AND WAIVER REQUESTS.—An assessment pending on or after the date that is 1 year prior to the date of the enactment of this Act shall be subject to the tracking and disclosure requirements es- tablished under such section 505B, as in effect on or after such date of enactment, except that any such as- sessments submitted or waivers of such assessments re- quested before such date of enactment shall not be sub- ject to subsections (a)(4)(C), (b)(2)(C), (f)(6)(F), and (h) of such section 505B.’’ EFFECTIVE DATE Pub. L. 108–155, § 4, Dec. 3, 2003, 117 Stat. 1942, provided that: ‘‘(a) IN GENERAL.—Subject to subsection (b), this Act [enacting this section, amending sections 355, 355a, and 355b of this title and sections 262 and 284m of Title 42, The Public Health and Welfare, enacting provisions set out as a note under section 301 of this title, and amend- ing provisions set out as notes under section 355a of this title and section 284m of Title 42] and the amend- ments made by this Act take effect on the date of en- actment of this Act [Dec. 3, 2003]. ‘‘(b) APPLICABILITY TO NEW DRUGS AND BIOLOGICAL PRODUCTS.— ‘‘(1) IN GENERAL.—Subsection (a) of section 505B of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 355c(a)] (as added by section 2) shall apply to an appli- cation described in paragraph (1) of that subsection submitted to the Secretary of Health and Human Services on or after April 1, 1999. ‘‘(2) WAIVERS AND DEFERRALS.— ‘‘(A) WAIVER OR DEFERRAL GRANTED.—If, with re- spect to an application submitted to the Secretary of Health and Human Services between April 1, 1999, and the date of enactment of this Act [Dec. 3, 2003], a waiver or deferral of pediatric assessments was granted under regulations of the Secretary then in effect, the waiver or deferral shall be a waiver or deferral under subsection (a) of section 505B of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 355c(a)], except that any date specified in such a de- ferral shall be extended by the number of days that is equal to the number of days between October 17, 2002, and the date of enactment of this Act. ‘‘(B) WAIVER AND DEFERRAL NOT GRANTED.—If, with respect to an application submitted to the Secretary of Health and Human Services between April 1, 1999, and the date of enactment of this Act [Dec. 3, 2003], neither a waiver nor deferral of pedi- atric assessments was granted under regulations of the Secretary then in effect, the person that sub- mitted the application shall be required to submit assessments under subsection (a)(2) of section 505B of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 355c(a)(2)] on the date that is the later of— ‘‘(i) the date that is 1 year after the date of en- actment of this Act; or ‘‘(ii) such date as the Secretary may specify under subsection (a)(3) of that section; unless the Secretary grants a waiver under sub- section (a)(4) of that section. ‘‘(c) NO LIMITATION OF AUTHORITY.—Neither the lack of guidance or regulations to implement this Act or the amendments made by this Act nor the pendency of the process for issuing guidance or regulations shall limit the authority of the Secretary of Health and Human Services under, or defer any requirement under, this Act or those amendments.’’ RULE OF CONSTRUCTION Pub. L. 115–52, title V, § 504(e), Aug. 18, 2017, 131 Stat. 1045, provided that: ‘‘Nothing in this section [amending this section and section 355c–1 of this title and enacting provisions set out as a note below], including the amendments made by this section, shall limit the au- thority of the Secretary of Health and Human Services to issue written requests under section 505A of the Fed- eral Food, Drug, and Cosmetic Act (21 U.S.C. 355a) or section 351(m) of the Public Health Service Act (42 U.S.C. 262(m)), or to negotiate or implement amend- ments to such requests proposed by the an [sic] appli- cant.’’ MEETING, CONSULTATION, AND GUIDANCE Pub. L. 115–52, title V, § 504(c), Aug. 18, 2017, 131 Stat. 1041, provided that: ‘‘(1) MEETING.—The Secretary of Health and Human Services (referred to in this subsection as the ‘Sec- retary’), acting through the Commissioner of Food and Drugs and in collaboration with the Director of the Na- tional Cancer Institute, shall convene a public meeting not later than 1 year after the date of enactment of this Act [Aug. 18, 2017] to solicit feedback from physi- cians and researchers (including pediatric oncologists and rare disease specialists), patients, and other stake- holders to provide input on development of the guid- ance under paragraph (2) and the list under subsection (m) of section 505B of the Federal Food, Drug, and Cos- metic Act (21 U.S.C. 355c), as added by subsection (a). The Secretary shall seek input at such meeting on— ‘‘(A) the data necessary to determine that there is scientific evidence that a drug or biological product is directed at a molecular target that is considered to be substantially relevant to the growth or progres- sion of a pediatric cancer; ‘‘(B) the data necessary to determine that there is scientific evidence that a molecular target is consid- ered to be substantially relevant to the growth or progression of a pediatric cancer; ‘‘(C) the data needed to meet the requirement of conducting an investigation described in section 505B(a)(3) of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 355c(a)(3)], as amended by subsection (a); ‘‘(D) considerations when developing the list under section 505B(m) of the Federal Food, Drug, and Cos- metic Act [21 U.S.C. 355c(m)] that contains molecular targets shared between different tumor types; Page 258 TITLE 21—FOOD AND DRUGS § 355c–1 ‘‘(E) the process the Secretary shall utilize to up- date regularly a list of molecular targets that may trigger a pediatric study under section 505B of the Federal Food, Drug, and Cosmetic Act, as so amend- ed, and how often such updates shall occur; ‘‘(F) how to overcome the challenges related to pe- diatric cancer drug and biological product develop- ment, including issues related to the ethical, prac- tical, and other barriers to conducting clinical trials in pediatric cancer with small patient populations; ‘‘(G) scientific or operational challenges associated with performing an investigation described in section 505B(a)(1)(B) of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 355c(a)(1)(B)], including the effect on pediatric studies currently underway in a pediatric patient population, treatment of a pediatric patient population, and the ability to complete adult clinical trials; ‘‘(H) the advantages and disadvantages of innova- tive clinical trial designs in addressing the develop- ment of cancer drugs or biological products directed at molecular targets in pediatric cancer patients; ‘‘(I) the ways in which the Secretary can improve the current process outlined under sections 505A and 505B of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355a, 355c) to encourage additional research and development of pediatric cancer treatments; ‘‘(J) the ways in which the Secretary might stream- line and improve the written request process, includ- ing when studies contained in a request under such section 505A are not feasible due to the ethical, prac- tical, or other barriers to conducting clinical trials in pediatric cancer populations; ‘‘(K) how the Secretary will facilitate collaboration among pediatric networks, academic centers and ex- perts in pediatric cancer to conduct an investigation described in such section 505B(a)(3); ‘‘(L) how the Secretary may facilitate collabora- tion among sponsors of same-in-class drugs and bio- logical products that would be subject to the require- ments for an investigation under such section 505B based on shared molecular targets; and ‘‘(M) the ways in which the Secretary will help to mitigate the risks, if any, of discouraging the re- search and development of orphan drugs when imple- menting such section 505B as amended. ‘‘(2) GUIDANCE.—Not later than 2 years after the date of enactment of this Act [Aug. 18, 2017], the Secretary, acting through the Commissioner of Food and Drugs, shall issue final guidance on implementation of the amendments to section 505B of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355c) regarding molecu- larly targeted cancer drugs made by this section, in- cluding— ‘‘(A) the scientific criteria, types of data, and regu- latory considerations for determining whether a mo- lecular target is substantially relevant to the growth or progression of a pediatric cancer and would trigger an investigation under section 505B of the Federal Food, Drug, and Cosmetic Act, as amended; ‘‘(B) the process by which the Secretary will engage with sponsors to discuss determinations, investiga- tion requirements, deferrals, waivers, and any other issues that need to be resolved to ensure that any re- quired investigation based on a molecular target can be reasonably conducted; ‘‘(C) the scientific or operational challenges for which the Secretary may issue deferrals or waivers for an investigation described in subsection (a)(3) of such section 505B, including adverse impacts on cur- rent pediatric studies underway in a pediatric patient population, studies involving drugs designated as or- phan drugs, treatment of a pediatric patient popu- lation, or the ability to complete adult clinical trials; ‘‘(D) how the Secretary and sponsors will facilitate collaboration among pediatric networks, academic centers, and experts in pediatric cancer to conduct an investigation described in subsection (a)(3) of such section 505B; ‘‘(E) scientific and regulatory considerations for study designs, including the applicability of innova- tive clinical trial designs for pediatric cancer drug and biological product developments under sections 505A and 505B of the Federal Food, Drug, and Cos- metic Act (21 U.S.C. 355a, 355c); ‘‘(F) approaches to streamline and improve the amendment process, including when studies con- tained in a request under such section 505A are not feasible due to the ethical, practical, or other bar- riers to conducting clinical trials in pediatric cancer populations; ‘‘(G) the process for submission of an initial pedi- atric study plan for the investigation described in section 505B(a)(3) of the Federal Food, Drug, and Cos- metic Act (21 U.S.C. 355c(a)(3)), including the process for a sponsor to meet and reach agreement with the Secretary on the initial pediatric study plan; and ‘‘(H) considerations for implementation of such sec- tion 505B, as so amended, and waivers of the require- ments of such section 505B with regard to molecular targets for which several drugs or biological products may be under investigation.’’ § 355c–1. Report (a) In general Not later than four years after July 9, 2012, and every five years thereafter, the Secretary shall prepare and submit to the Committee on Health, Education, Labor, and Pensions of the Senate and the Committee on Energy and Com- merce of the House of Representatives, and make publicly available, including through post- ing on the Internet Web site of the Food and Drug Administration, a report on the implemen- tation of sections 355a and 355c of this title. (b) Contents Each report under subsection (a) shall in- clude— (1) an assessment of the effectiveness of sec- tions 355a and 355c of this title in improving information about pediatric uses for approved drugs and biological products, including the number and type of labeling changes made since July 9, 2012, and the importance of such uses in the improvement of the health of chil- dren; (2) the number of required studies under such section 355c of this title that have not met the initial deadline provided under such section 355c of this title, including— (A) the number of deferrals and deferral extensions granted and the reasons such ex- tensions were granted; (B) the number of waivers and partial waivers granted; and (C) the number of letters issued under sub- section (d) of such section 355c of this title; (3) an assessment of the timeliness and effec- tiveness of pediatric study planning since July 9, 2012, including the number of initial pedi- atric study plans not submitted in accordance with the requirements of subsection (e) of such section 355c of this title and any resulting rulemaking; (4) the number of written requests issued, ac- cepted, and declined under such section 355a of this title since July 9, 2012, and a listing of any important gaps in pediatric information as a result of such declined requests; (5) a description and current status of refer- rals made under subsection (n) of such section 355a of this title; (6) an assessment of the effectiveness of studying biological products in pediatric popu-