21 U.S.C. § 360ee — Grants and contracts for development of

Page 396 TITLE 21—FOOD AND DRUGS § 360dd 2017—Subsec. (a). Pub. L. 115–52, § 607(a)(1), sub- stituted ‘‘the same drug for the same disease or condi- tion’’ for ‘‘such drug for such disease or condition’’ in concluding provisions. Subsec. (b). Pub. L. 115–52, § 607(a)(2)(A), in introduc- tory provisions, substituted ‘‘During the 7-year period described in subsection (a) for an approved application under section 355 of this title or license under section 262 of title 42, the Secretary may approve an applica- tion or issue a license for a drug that is otherwise the same, as determined by the Secretary, as the already approved drug for the same rare disease or condition if’’ for ‘‘If an application filed pursuant to section 355 of this title is approved for a drug designated under sec- tion 360bb of this title for a rare disease or condition or if a license is issued under section 262 of title 42 for such a drug, the Secretary may, during the seven-year period beginning on the date of the application ap- proval or of the issuance of the license, approve an- other application under section 355 of this title or issue a license under section 262 of title 42, for such drug for such disease or condition for a person who is not the holder of such approved application or of such license if’’. Subsec. (b)(1). Pub. L. 115–52, § 607(a)(2)(B), substituted ‘‘of exclusive approval or licensure notice and oppor- tunity for the submission of views, that during such pe- riod the holder of the exclusive approval or licensure cannot ensure’’ for ‘‘notice and opportunity for the sub- mission of views, that in such period the holder of the approved application or of the license cannot assure’’. Subsec. (b)(2). Pub. L. 115–52, § 607(a)(2)(C), substituted ‘‘the holder provides’’ for ‘‘such holder provides’’. Subsecs. (c) to (e). Pub. L. 115–52, § 607(a)(3), added subsecs. (c) to (e). 2002—Subsec. (a). Pub. L. 107–281, in concluding provi- sions, struck out ‘‘, of such certification,’’ after ‘‘such approved application’’ and ‘‘, the issuance of the cer- tification,’’ after ‘‘approval of the approved applica- tion’’. 1997—Subsec. (a). Pub. L. 105–115, § 125(b)(2)(J), struck out ‘‘, issue another certification under section 357 of this title,’’ before ‘‘or issue another license’’ in closing provisions, inserted ‘‘or’’ at end of par. (1), redesignated par. (3) as (2), and struck out former par. (2) which read as follows: ‘‘issues a certification under section 357 of this title, or’’. Subsec. (b). Pub. L. 105–115, § 125(b)(2)(K), in introduc- tory provisions, struck out ‘‘, if a certification is issued under section 357 of this title for such a drug,’’ after ‘‘rare disease or condition’’, ‘‘, of the issuance of the certification under section 357 of this title,’’ after ‘‘application approval’’, ‘‘, issue another certification under section 357 of this title,’’ after ‘‘application under section 355 of this title’’, and ‘‘, of such certifi- cation,’’ after ‘‘approved application’’. Subsec. (b)(1). Pub. L. 105–115, § 125(b)(2)(K), struck out ‘‘, of the certification,’’ after ‘‘holder of the ap- proved application’’. Subsec. (b)(2). Pub. L. 105–115, § 125(b)(2)(K), struck out ‘‘, issuance of other certifications,’’ after ‘‘approval of other applications’’. 1993—Subsec. (b). Pub. L. 103–80 struck out extraneous comma before ‘‘or issue a license under section 262’’ in introductory provisions and substituted ‘‘the’’ for ‘‘The’’ at beginning of par. (1). 1985—Pub. L. 99–91, § 2(3), struck out ‘‘unpatented’’ be- fore ‘‘drugs’’ in section catchline. Subsec. (a). Pub. L. 99–91, §§ 2(1), 3(a)(3)(A)–(D), struck out ‘‘or’’ at end of par. (1), added par. (2), redesignated former par. (2) as (3), struck out ‘‘and for which a United States Letter of Patent may not be issued’’ after ‘‘rare disease or condition’’, inserted in first sen- tence ‘‘, issue another certification under section 357 of this title,’’ after ‘‘section 355 of this title’’ the second time it appeared, inserted ‘‘, of such certification,’’ after ‘‘holder of such approved application’’, and in- serted ‘‘, the issuance of the certification,’’ after ‘‘ap- proval of the approved application’’. Subsec. (b). Pub. L. 99–91, §§ 2(2), 3(a)(3)(E)–(K), struck out ‘‘and if a United States Letter of Patent may not be issued for the drug’’ after ‘‘such a drug’’, substituted ‘‘, if a certification is issued under section 357 of this title for such a drug, or if a license’’ for ‘‘or a license’’, inserted ‘‘, of the issuance of the certification under section 357 of this title,’’ after ‘‘application approval’’, struck out ‘‘, if the drug is a biological product,’’ be- fore ‘‘issue a license’’, inserted ‘‘, issue another certifi- cation under section 357 of this title,’’ after ‘‘section 355 of this title’’, inserted ‘‘, of such certification,’’ after ‘‘holder of such approved application’’, inserted ‘‘, of such certification,’’ after ‘‘application’’ in par. (1), and inserted ‘‘, issuance of other certifications,’’ after ‘‘other applications’’ in par. (2). 1984—Subsecs. (a), (b). Pub. L. 98–417 substituted ‘‘sec- tion 355’’ for ‘‘section 355(b)’’ wherever appearing. Statutory Notes and Related Subsidiaries EFFECTIVE DATE OF 1985 AMENDMENT Amendment by Pub. L. 99–91 effective Aug. 15, 1985, see section 8(b) of Pub. L. 99–91, set out as a note under section 360aa of this title. CONSTRUCTION Pub. L. 115–52, title VI, § 607(b), Aug. 18, 2017, 131 Stat. 1050, provided that: ‘‘Nothing in the amendments made by subsection (a) [amending this section] shall affect any determination under sections 526 and 527 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360bb, 360cc) made prior to the date of enactment of the FDA Reauthorization Act of 2017 [Aug. 18, 2017].’’ § 360dd. Open protocols for investigations of drugs for rare diseases or conditions If a drug is designated under section 360bb of this title as a drug for a rare disease or condi- tion and if notice of a claimed exemption under section 355(i) of this title or regulations issued thereunder is filed for such drug, the Secretary shall encourage the sponsor of such drug to de- sign protocols for clinical investigations of the drug which may be conducted under the exemp- tion to permit the addition to the investigations of persons with the disease or condition who need the drug to treat the disease or condition and who cannot be satisfactorily treated by available alternative drugs. (June 25, 1938, ch. 675, § 528, as added Pub. L. 97–414, § 2(a), Jan. 4, 1983, 96 Stat. 2051.) § 360ee. Grants and contracts for development of drugs for rare diseases and conditions (a) Authority of Secretary The Secretary may make grants to and enter into contracts with public and private entities and individuals to assist in (1) defraying the costs of developing drugs for rare diseases or conditions, including qualified testing expenses, (2) defraying the costs of developing medical de- vices for rare diseases or conditions, (3) defray- ing the costs of developing medical foods for rare diseases or conditions, and (4) developing regulatory science pertaining to the chemistry, manufacturing, and controls of individualized medical products to treat individuals with rare diseases or conditions. (b) Definitions For purposes of subsection (a): (1) The term ‘‘qualified testing’’ means— (A) human clinical testing— (i) which is carried out under an exemp- tion for a drug for a rare disease or condi- Page 397 TITLE 21—FOOD AND DRUGS § 360ee 1 See 2022 Amendment notes below. tion under section 355(i) of this title (or regulations issued under such section); and (ii) which occurs before the date on which an application with respect to such drug is submitted under section 355(b) of this title or under section 262 of title 42; (B) preclinical testing involving a drug for a rare disease or condition which occurs after the date such drug is designated under section 360bb of this title and before the date on which an application with respect to such drug is submitted under section 355(b) of this title or under section 262 of title 42; and (C) prospectively planned and designed ob- servational studies and other analyses con- ducted to assist in the understanding of the natural history of a rare disease or condition and in the development of a therapy, includ- ing studies and analyses to— (i) develop or validate a drug develop- ment tool related to a rare disease or con- dition; or (ii) understand the full spectrum of the disease manifestations, including describ- ing genotypic and phenotypic variability and identifying and defining distinct sub- populations affected by a rare disease or condition. (2) The term ‘‘rare disease or condition’’ means (1) in the case of a drug, any disease or condition which (A) affects less than 200,000 persons in the United States, or (B) affects more than 200,000 in the United States and for which there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will be recovered from sales in the United States of such drug, (2) in the case of a medical device, any disease or condition that occurs so infrequently in the United States that there is no reasonable expectation that a medical device for such disease or condition will be developed without assistance under subsection (a), and (3) in the case of a medical food, any disease or condition that occurs so infrequently in the United States that there is no reasonable expectation that a medical food for such disease or condition will be developed without assistance under subsection (a). De- terminations under the preceding sentence with respect to any drug shall be made on the basis of the facts and circumstances as of the date the request for designation of the drug under section 360bb of this title is made. (3) The term ‘‘medical food’’ means a food which is formulated to be consumed or admin- istered enterally under the supervision of a physician and which is intended for the spe- cific dietary management of a disease or con- dition for which distinctive nutritional re- quirements, based on recognized scientific principles, are established by medical evalua- tion. (c) Authorization of appropriations For grants and contracts under subsection (a), there is authorized to be appropriated $6,904,110 for the period beginning on October 1, 2022 and ending on December 23, 2022.1 (Pub. L. 97–414, § 5, Jan. 4, 1983, 96 Stat. 2056; Pub. L. 98–551, § 4(b), Oct. 30, 1984, 98 Stat. 2817; Pub. L. 99–91, § 5, Aug. 15, 1985, 99 Stat. 391; Pub. L. 100–290, § 3(a)–(c), Apr. 18, 1988, 102 Stat. 90, 91; Pub. L. 105–115, title I, § 125(b)(2)(N), Nov. 21, 1997, 111 Stat. 2326; Pub. L. 107–281, § 3, Nov. 6, 2002, 116 Stat. 1993; Pub. L. 110–85, title XI, § 1112(b), Sept. 27, 2007, 121 Stat. 976; Pub. L. 112–144, title IX, § 906, July 9, 2012, 126 Stat. 1092; Pub. L. 114–255, div. A, title III, § 3015, Dec. 13, 2016, 130 Stat. 1094; Pub. L. 115–52, title VI, § 603, Aug. 18, 2017, 131 Stat. 1048; Pub. L. 117–180, div. F, title V, § 5006, Sept. 30, 2022, 136 Stat. 2167; Pub. L. 117–229, div. C, title III, § 307, Dec. 16, 2022, 136 Stat. 2312; Pub. L. 117–328, div. FF, title III, § 3107, Dec. 29, 2022, 136 Stat. 5808.) Editorial Notes CODIFICATION Section was enacted as part of the Orphan Drug Act, and not as part of the Federal Food, Drug, and Cos- metic Act which comprises this chapter. AMENDMENTS 2022—Subsec. (a)(4). Pub. L. 117–328, § 3107(1), added par. (4). Subsec. (c). Pub. L. 117–328, § 3107(2), which directed the substitution of ‘‘$30,000,000 for each of fiscal years 2023 through 2027’’ for ‘‘$6,328,767 for the period begin- ning on October 1, 2022, and ending on December 23, 2022’’, could not be executed because ‘‘$6,328,767’’ did not appear after the intervening amendment by Pub. L. 117–229. See below. Pub. L. 117–229 substituted ‘‘$6,904,110 for the period beginning on October 1, 2022 and ending on December 23, 2022’’ for ‘‘$6,328,767 for the period beginning on Oc- tober 1, 2022, and ending on December 16, 2022’’. Pub. L. 117–180 substituted ‘‘$6,328,767 for the period beginning on October 1, 2022, and ending on December 16, 2022’’ for ‘‘$30,000,000 for each of fiscal years 2018 through 2022’’. 2017—Subsec. (c). Pub. L. 115–52 substituted ‘‘2018 through 2022’’ for ‘‘2013 through 2017’’. 2016—Subsec. (a)(1). Pub. L. 114–255, § 3015(1), added par. (1) and struck out former par. (1) which read as fol- lows: ‘‘defraying the costs of qualified testing expenses incurred in connection with the development of drugs for rare diseases and conditions,’’. Subsec. (b)(1)(C). Pub. L. 114–255, § 3015(2), added sub- par. (C). 2012—Subsec. (b)(1)(A)(ii). Pub. L. 112–144, § 906(a), struck out ‘‘after the date such drug is designated under section 360bb of this title and’’ after ‘‘which oc- curs’’. Subsec. (c). Pub. L. 112–144, § 906(b), amended subsec. (c) generally. Prior to amendment, text read as follows: ‘‘For grants and contracts under subsection (a), there is authorized to be appropriated $30,000,000 for each of fis- cal years 2008 through 2012.’’ 2007—Subsec. (c). Pub. L. 110–85 amended subsec. (c) generally. Prior to amendment, subsec. (c) read as fol- lows: ‘‘For grants and contracts under subsection (a) of this section, there are authorized to be appropriated such sums as already have been appropriated for fiscal year 2002, and $25,000,000 for each of the fiscal years 2003 through 2006.’’ 2002—Subsec. (c). Pub. L. 107–281 amended subsec. (c) generally. Prior to amendment, subsec. (c) read as fol- lows: ‘‘For grants and contracts under subsection (a) of this section there are authorized to be appropriated $10,000,000 for fiscal year 1988, $12,000,000 for fiscal year 1989, $14,000,000 for fiscal year 1990.’’ 1997—Subsec. (b)(1)(A)(ii), (B). Pub. L. 105–115 struck out ‘‘or 357’’ after ‘‘355(b)’’. 1988—Subsec. (a). Pub. L. 100–290, § 3(a)(1), (b)(1), in- serted ‘‘(1)’’ after ‘‘assist in’’ and added pars. (2) and (3). Page 398 TITLE 21—FOOD AND DRUGS § 360ee Subsec. (b)(2). Pub. L. 100–290, § 3(a)(2), (b)(2), inserted ‘‘(1) in the case of a drug,’’ after ‘‘means’’, added cls. (2) and (3), and substituted ‘‘under section 360bb of this title’’ for ‘‘under this subsection’’ in last sentence. Subsec. (b)(3). Pub. L. 100–290, § 3(b)(3), added par. (3). Subsec. (c). Pub. L. 100–290, § 3(c), amended subsec. (c) generally. Prior to amendment, subsec. (c) read as fol- lows: ‘‘For grants and contracts under subsection (a) of this section there are authorized to be appropriated $4,000,000 for fiscal year 1986, $4,000,000 for fiscal year 1987, and $4,000,000 for fiscal year 1988.’’ 1985—Subsec. (a). Pub. L. 99–91, § 5(a)(1), struck out ‘‘clinical’’ before ‘‘testing’’. Subsec. (b)(1). Pub. L. 99–91, § 5(a)(2), substituted pro- visions defining ‘‘qualified testing’’ for provisions de- fining ‘‘qualified clinical testing’’. Subsec. (c). Pub. L. 99–91, § 5(b), substituted provi- sions authorizing appropriations for fiscal years 1986 to 1988, for provisions authorizing appropriations for fiscal years 1983 and the two succeeding fiscal years. 1984—Subsec. (b)(2). Pub. L. 98–551 substituted ‘‘which (A) affects less than 200,000 persons in the United States, or (B) affects more than 200,000 in the United States and for which’’ for ‘‘which occurs so infre- quently in the United States that’’. Statutory Notes and Related Subsidiaries EFFECTIVE DATE OF 1985 AMENDMENT Amendment by Pub. L. 99–91 effective Oct. 1, 1985, see section 8(a) of Pub. L. 99–91, set out as a note under sec- tion 360aa of this title. GRANTS FOR RESEARCH ON THERAPIES FOR ALS Pub. L. 117–79, § 2, Dec. 23, 2021, 135 Stat. 1533, provided that: ‘‘(a) IN GENERAL.—The Secretary of Health and Human Services (referred to in this section as the ‘Sec- retary’) shall award grants to participating entities for purposes of scientific research utilizing data from ex- panded access to investigational drugs for individuals who are not otherwise eligible for clinical trials for the prevention, diagnosis, mitigation, treatment, or cure of amyotrophic lateral sclerosis. In the case of a partici- pating entity seeking such a grant, an expanded access request must be submitted, and allowed to proceed by the Secretary, under section 561 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360bbb) and part 312 of title 21, Code of Federal Regulations (or any suc- cessor regulations), before the application for such grant is submitted. ‘‘(b) APPLICATION.— ‘‘(1) IN GENERAL.—A participating entity seeking a grant under this section shall submit to the Sec- retary an application at such time, in such manner, and containing such information as the Secretary shall specify. ‘‘(2) USE OF DATA.—An application submitted under paragraph (1) shall include a description of how data generated through an expanded access request under section 561 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360bbb) with respect to the investiga- tional drug involved will be used to support research or development related to the prevention, diagnosis, mitigation, treatment, or cure of amyotrophic lateral sclerosis. ‘‘(3) NONINTERFERENCE WITH CLINICAL TRIALS.—An application submitted under paragraph (1) shall in- clude a description of how the proposed expanded ac- cess program will be designed so as not to interfere with patient enrollment in ongoing clinical trials for investigational therapies for the prevention, diag- nosis, mitigation, treatment, or cure of amyotrophic lateral sclerosis. ‘‘(c) SELECTION.—Consistent with sections 406 and 492 of the Public Health Service Act (42 U.S.C. 284a, 289a), the Secretary shall, in determining whether to award a grant under this section, confirm that— ‘‘(1) such grant will be used to support a scientific research objective relating to the prevention, diag- nosis, mitigation, treatment, or cure of amyotrophic lateral sclerosis (as described in subsection (a)); ‘‘(2) such grant shall not have the effect of dimin- ishing eligibility for, or impeding enrollment of, on- going clinical trials for the prevention, diagnosis, mitigation, treatment, or cure of amyotrophic lateral sclerosis by determining that individuals who receive expanded access to investigational drugs through such a grant are not eligible for enrollment in— ‘‘(A) ongoing clinical trials that are registered on ClinicalTrials.gov (or successor website), with re- spect to a drug for the prevention, diagnosis, miti- gation, treatment, or cure of amyotrophic lateral sclerosis; or ‘‘(B) clinical trials for the prevention, diagnosis, mitigation, treatment, or cure of amyotrophic lat- eral sclerosis for which an exemption under section 505(i) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(i)) has been granted by the Food and Drug Administration and which are expected to begin enrollment within one year; and ‘‘(3) the resulting project funded by such grant will allow for equitable access to investigational drugs by minority and underserved populations. ‘‘(d) USE OF FUNDS.—A participating entity shall use funds received through the grant— ‘‘(1) to pay the manufacturer or sponsor for the di- rect costs of the investigational drug, as authorized under section 312.8(d) of title 21, Code of Federal Reg- ulations (or successor regulations), to prevent, diag- nose, mitigate, treat, or cure amyotrophic lateral sclerosis that is the subject of an expanded access re- quest described in subsection (a), if such costs are justified as part of peer review of the grant; ‘‘(2) for the entity’s direct costs incurred in pro- viding such drug consistent with the research mission of the grant; or ‘‘(3) for the direct and indirect costs of the entity in conducting research with respect to such drug. ‘‘(e) DEFINITIONS.—In this section: ‘‘(1) The term ‘participating entity’ means a par- ticipating clinical trial site or sites sponsored by a small business concern (as defined in section 3(a) of the Small Business Act (15 U.S.C. 632(a))) that is the sponsor of a drug that is the subject of an investiga- tional new drug application under section 505(i) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(i)) to prevent, diagnose, mitigate, treat, or cure amyotrophic lateral sclerosis. ‘‘(2) The term ‘participating clinical trial’ means a phase 3 clinical trial conducted pursuant to an ex- emption under section 505(i) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(i)) or section 351(a) of the Public Health Service Act (42 U.S.C. 262(a)) to investigate a drug intended to prevent, di- agnose, mitigate, treat, or cure amyotrophic lateral sclerosis. ‘‘(3) The term ‘participating clinical trial site’ means a health care facility, or network of facilities, at which patients participating in a participating clinical trial receive an investigational drug through such trial. ‘‘(f) SUNSET.—The Secretary may not award grants under this section on or after September 30, 2026.’’ FINDINGS AND PURPOSES Pub. L. 107–281, § 2, Nov. 6, 2002, 116 Stat. 1992, pro- vided that: ‘‘(a) FINDINGS.—Congress makes the following find- ings: ‘‘(1) Rare diseases and disorders are those which af- fect small patient populations, typically populations smaller than 200,000 individuals in the United States. Such diseases and conditions include Huntington’s disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease), Tourette syndrome, Crohn’s disease, cystic fibrosis, cystinosis, and Duchenne muscular dys- trophy. ‘‘(2) For many years, the 25,000,000 Americans suf- fering from the over 6,000 rare diseases and disorders Page 399 TITLE 21—FOOD AND DRUGS § 360ff were denied access to effective medicines because prescription drug manufacturers could rarely make a profit from marketing drugs for such small groups of patients. The prescription drug industry did not ade- quately fund research into such treatments. Despite the urgent health need for these medicines, they came to be known as ‘orphan drugs’ because no com- panies would commercialize them. ‘‘(3) During the 1970s, an organization called the Na- tional Organization for Rare Disorders (NORD) was founded to provide services and to lobby on behalf of patients with rare diseases and disorders. NORD was instrumental in pressing Congress for legislation to encourage the development of orphan drugs. ‘‘(4) The Orphan Drug Act [see Short Title of 1983 Amendments note set out under section 301 of this title] created financial incentives for the research and production of such orphan drugs. New Federal programs at the National Institutes of Health and the Food and Drug Administration encouraged clinical research and commercial product development for products that target rare diseases. An Orphan Prod- ucts Board was established to promote the develop- ment of drugs and devices for rare diseases or dis- orders. ‘‘(5) Before 1983, some 38 orphan drugs had been de- veloped. Since the enactment of the Orphan Drug Act [Jan. 4, 1983], more than 220 new orphan drugs have been approved and marketed in the United States and more than 800 additional drugs are in the research pipeline. ‘‘(6) Despite the tremendous success of the Orphan Drug Act, rare diseases and disorders deserve greater emphasis in the national biomedical research enter- prise. ‘‘(7) The Food and Drug Administration supports small clinical trials through Orphan Products Re- search Grants. Such grants embody successful part- nerships of government and industry, and have led to the development of at least 23 drugs and four medical devices for rare diseases and disorders. Yet the appro- priations in fiscal year 2001 for such grants were less than in fiscal year 1995. ‘‘(b) PURPOSES.—The purpose of this Act [see Short Title of 2002 Amendments note set out under section 301 of this title] is to increase the national investment in the development of diagnostics and treatments for pa- tients with rare diseases and disorders.’’ § 360ee–1. FDA rare neurodegenerative disease grant program The Secretary of Health and Human Services, acting through the Commissioner of Food and Drugs, shall award grants and contracts to pub- lic and private entities to cover the costs of re- search on, and development of interventions in- tended to prevent, diagnose, mitigate, treat, or cure, amyotrophic lateral sclerosis and other rare neurodegenerative diseases in adults and children, including costs incurred with respect to the development and critical evaluation of tools, methods, and processes— (1) to characterize such neurodegenerative diseases and their natural history; (2) to identify molecular targets for such neurodegenerative diseases; and (3) to increase efficiency and productivity of clinical development of therapies, including through— (A) the use of master protocols and adapt- ive and add-on clinical trial designs; and (B) efforts to establish new or leverage ex- isting clinical trial networks. (Pub. L. 117–79, § 5, Dec. 23, 2021, 135 Stat. 1537.) Editorial Notes CODIFICATION Section was enacted as part of the Accelerating Ac- cess to Critical Therapies for ALS Act, and not as part of the Federal Food, Drug, and Cosmetic Act which comprises this chapter. § 360ff. Priority review to encourage treatments for rare pediatric diseases (a) Definitions In this section: (1) Priority review The term ‘‘priority review’’, with respect to a human drug application as defined in section 379g(1) of this title, means review and action by the Secretary on such application not later than 6 months after receipt by the Secretary of such application, as described in the Manual of Policies and Procedures of the Food and Drug Administration and goals identified in the letters described in section 101(b) of the Prescription Drug User Fee Amendments of 2012. (2) Priority review voucher The term ‘‘priority review voucher’’ means a voucher issued by the Secretary to the sponsor of a rare pediatric disease product application that entitles the holder of such voucher to pri- ority review of a single human drug applica- tion submitted under section 355(b)(1) of this title or section 351(a) of the Public Health Service Act [42 U.S.C. 262(a)] after the date of approval of the rare pediatric disease product application. (3) Rare pediatric disease The term ‘‘rare pediatric disease’’ means a disease that meets each of the following cri- teria: (A) The disease is a serious or life-threat- ening disease in which the serious or life- threatening manifestations primarily affect individuals aged from birth to 18 years, in- cluding age groups often called neonates, in- fants, children, and adolescents. (B) The disease is a rare disease or condi- tion, within the meaning of section 360bb of this title. (4) Rare pediatric disease product application The term ‘‘rare pediatric disease product ap- plication’’ means a human drug application, as defined in section 379g(1) of this title, that— (A) is for a drug or biological product that is for the prevention or treatment of a rare pediatric disease; (B)(i) is for such a drug— (I) that contains no active moiety (as de- fined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) that has been previously approved in any other applica- tion under subsection (b)(1), (b)(2), or (j) of section 355 of this title; and (II) that is the subject of an application submitted under section 355(b)(1) of this title; or (ii) is for such a biological product— (I) that contains no active ingredient that has been previously approved in any