美国儿童用药独占权介绍[1]

1、Pediatric ExclusivityPediatric Exclusivity and Drug Development Requirements in the Overall Pediatric PopulationPrepared by Beckloff Associates, Inc.1 INTRODUCTION AND OVERVIEW 简介Although children suffer from many of the same diseases as adults and are often treated with the same drugs, only a small

2、 fraction of the drugs marketed and used as therapies in the UnitedStates have been studied in pediatric patients 016 years of age. Recent data demonstrates thatonly about 25% of approved drugs marketed in the United States have adequate pediatric data tosupport approval of product labeling by FDA f

3、or dosing, safety, or efficacy in children.1 Thislack of appropriate pediatric testing and labeling increases the chances of incorrect dosing,thereby exposing pediatric patients to either an increased risk of adverse reactions or less thanoptimal therapeutic benefits.2 In addition, the failure of ph

4、armaceutical companies tomanufacture drugs in dosage forms that can be easily and properly used in all pediatric agegroups denies pediatric patients access to necessary medications.虽然儿童患有许多与成年人相同的疾病，治疗往往也用同样的药物，只有一小部分在美国销售和治疗使用的药品在儿科病人016岁中进行过研究。近期的数据表明，在美国上市批准的药品中只有约25有足够的儿科数据支持美国FDA批准的剂量，安全性或有效性在儿

5、童中使用的标签1。这缺乏适当的儿科试验和标签的情况剂量使用不当的几率增加，从而使患儿处于不良反应风险加而最佳的治疗效果降低的境地2。此外，制药公司未能提供适用于各年龄层的准确、简便的剂量规格，使得儿童患者获得必要的药物变得更难。Most drugs prescribed for children lack sufficient pharmacokinetic, pharmacodynamic, efficacy,or safety data to support use in the pediatric population. The pharmaceutical industrytradit

6、ionally has had little incentive to undertake pediatric clinical trials, which has resulted inoff-label use in the pediatric population, ranging from 60 to 90% in children and newborns.3Reasons cited for the lack of studies in the pediatric population include smaller targetpopulations, increased rec

7、ruitment challenges, consent and ethical issues, and lower potential formarket return on corporate investment compared with that seen in adult populations.3Legislation has been enacted in the United States over the past 10 years to provide incentives forpharmaceutical industry sponsors to conduct dr

8、ug studies in the pediatric population. Toencourage pharmaceutical sponsors to undertake clinical studies in the development of pediatricindications for drugs and biologics, Congress and FDA have granted marketing exclusivity ifcertain provisions and requirements are met. Sponsors must be aware of t

9、he provisions of theseenactments to allow for appropriate pediatric programs that fulfill FDA requirements and providenecessary and meaningful information regarding the safe and effective use of drugs in children.大多数儿科药物处方儿童缺乏足够的药代动力学，药效学，有效性及安全性数据支持。医药工业对进行儿科临床试验动力不足，导致儿科人群标示外使用药物范围从儿童60%到新生儿90%3。儿

10、科人群缺乏研究的原因，如上所述除了目标人群小众，入组困难，知情同意和伦理问题外还有对企业来讲相对成人较低的市场潜力，企业投资少3。为鼓励企业申办者进行儿科药品及生物制品的临床试验，在过去10年，美国国会和FDA共同颁布了一些法案以示激励，若满足某些条款和要求，将享有市场独占权。申办者必须实施儿科项目，须提供儿童用药有意义有效性和安全性信息以满足FDA条款要求。The central goal of such legislation is to change the labeling of existing drugs to reflect pediatricuse. In an initial

11、 September 1999 guidance document, FDA determined that pediatric exclusivitywill attach to exclusivity and patent protection on a drug as listed in the Orange Book for anydrug product containing the same active moiety as the drug studied and for which the partysubmitting the studies holds the approv

12、ed New Drug Application (NDA) (505A(a) and (c).4 Forstudies conducted with a previously unapproved drug, pediatric exclusivity will also attach toany exclusivity or patent protection that will be listed in the Orange Book upon approval of thedrug.立法的主要目的是改变现有儿童药物的表示。1999年9月发起的一指导性文件，FDA表示将为任何含有相同的活性

13、成分的药物研究和有提交新药申请(505A(a) and (c)批件的研究确定儿科独占权附入的药品专利保护和市场独占权列入橙皮书。 之前未批准的药物，其儿科独占权也将附入药品专利保护和市场独占权列入橙皮书中。2. LEGISLATIVE HISTORY OF PEDIATRIC EXCLUSIVITY 立法历史和儿科独占权In an attempt to encourage drug sponsors to obtain more pediatric drug data, FDA implemented anumber of measures in the early 1990s to enco

14、urage the submission of pediatric labelinginformation. However, because these efforts were largely voluntary and new studies were notrequired, the measures failed to produce significant increases in pediatric labeling.5 In 1997,Congress enacted the Food and Drug Administration Modernization Act (FDA

15、MA), whichestablished economic incentives for conducting pediatric studies.6 Section 505A of the FDAMA,known as the Pediatric Exclusivity Provision, provided an additional 6 months of patentprotection, or marketing exclusivity, to be attached to any existing exclusivity or patentprotection on a drug

16、 in return for the sponsor performing pediatric studies as requested by FDA.This 6 month period of exclusivity included all active moieties of a drug studied in the pediatricpopulation.为鼓励药物申办者取得更多儿童用药数据，90年代初，FDA增加了一系列条款鼓励提交儿科标识信息。然而由于此项工作大多是自愿性质的对于新的研究并非强行要求，这些措施并未取得很好的成效5。1997年国会通过了FDA现代法案，建立了儿科研

17、究的激励机制6。法案第505A条款，即儿科用药市场独占权规定，为按照FDA要求进行儿科临床试验者提供了额外6个月的专利保护和市场独占权，加入其他现有专利保护和市场独占条款中。这6个月的市场独占包括所有儿科人群中进行的活性成分药物研究。In 2002, Congress enacted the Best Pharmaceuticals for Children Act (BPCA), whichreauthorized the financial marketing incentives as established by the pediatric exclusivityprovision o

18、f the FDAMA.7 The 6 month marketing exclusivity was extended to the firstcompany that conducted the clinical studies and obtained FDA approval for the pediatricindication. The 6 months of market exclusivity is in addition to other patent term extensions ormarket exclusivity provisions. In return, dr

19、ug sponsors are required to publicly post study resultsand report adverse events for 1 year after exclusivity is granted. This process includes theissuance of a Written Request (WR), a legal document sent by FDA to sponsors requestingstudies in the pediatric population, which identifies the indicati

20、on, types of studies to beperformed, number of patients per study/arm, safety and efficacy parameters, and the patient agegroups to be studied. Pediatric exclusivity under BPCA attaches whether the study, as specifiedin the WR, produces positive or negative results.2002年，国会实施最佳儿童用药法案（BPCA）重新授予了经济激励机

21、制，如FDAMA（现代法案）所述的儿科独占权规定7。6个月的市场独占权给予第1个开展儿科适应症临床研究并取得FDA批件的公司。6个月市场独占作为专利期限延长或市场独占规定的补充。作为回报，申办者需公开发表其研究结果，并在授予独占权后，提交1年的不良事件报告。这个过程包括发出书面请求（WR），填写FDA给申办方的一些儿科研究的法律文件，需明确其适应症，研究类型，受试者人数，研究设计（几臂），安全性和有效性参数，受试者的年龄组。BPCA下的儿科独占权研究，如书面文件中标明的，可产生阳性或阴性结果。Prior to issuing a WR to a sponsor, FDA requires th

22、at certain criteria be met regarding theproposed pediatric studies: there must be an expectation of a public health benefit and of asubstantial use in the pediatric age group, there must be a threshold of 50,000 pediatric patientsin the United States with the disease or condition, there must be the

23、expectation of a meaningfultherapeutic benefit in the treatment and diagnosis or prevention of the disease compared withalready approved drugs or biologics, and adequate animal and/or human safety data must exist topermit studies in the target pediatric population(s).8在发出书面申请之前，FDA要求申办方满足下列条件方可通过该儿科

24、目标人群的研究开展：此项研究需预期产生公众健康利益和儿科年龄组内大范围使用，至少有50,000患儿患有此疾病或处于此状态，需预期此项研究产生在疾病的治疗、诊断或疾病预防治中与其他以批准药品或生物制品相比有更好的治疗意义，且提供动物和/或人体安全性信息8。The BPCA incorporates a rather involved process by which FDA formally requests that acompany conduct specific pediatric studies.7 Upon FDAs formal WR to the sponsor to condu

25、ctspecific pediatric studies, the sponsor has 180 days to accept or reject the request or to identify toFDA any aspects that need to be discussed. If the sponsor agrees to conduct the study, thesponsor must follow the designated protocol and comply with applicable regulatoryrequirements, submit adve

26、rse events, and submit a final report to FDA. Upon submission toFDA, the study data is reviewed by the Office of Pediatric Therapeutics. This internal FDAcommittee is mandated to publish the results, thus making data available to the public on bothon-label and off-label uses.根据最佳用药法案，FDA正式要求一个公司开展某项

27、儿科研究包含了一个相当复杂的过程7。 FDA给申办者开展某项儿科研究的正式书面申请，申办者需要在180天内接受或者拒绝，并将需要讨论的方面通知FDA，若申办者同意开展研究，需根据指定的方案和适用的管理条款，提交给FDA不良事件，总结报告。儿科治疗学组办公室将根据提交的文件审查研究数据。FDA内部委员将批准公开发表其研究结果，从而向公众提供说明书内或说明书外的药物使用方法。In 2003, Congress enacted the Pediatric Research Equity Act (PREA), which is related to theBPCA.9 The PREA requir

28、es the conduct of pediatric studies for certain drugs and biologicproducts (unless waived or deferred by FDA) and establishes a Pediatric Advisory Committee.For all NDAs, Biologic License Application (BLAs), or supplements to these applications, thesponsor is required to conduct pediatric studies fo

29、r a new active ingredient, new indication, newdosage form, new dosing regimen, or new route of administration unless waived or deferred.The results of the pediatric studies must contain data adequate to both assess the safety andeffectiveness and to support dosing and administration for each relevan

30、t pediatric subpopulation.The PREA applies to studies that are required and is limited to the indication under development.In contrast, pediatric studies conducted under the BPCA are voluntary.2003年， 国会通过了与最佳法案相关（BPCA）的儿童研究公平法案（PREA）9，公平法案要求开展某药物或生物制品的儿科研究（除非FDA放弃或推迟）并建立儿科咨询委员会。对所有新药申请，生物制品生产许可，新活性成

31、分、新适应症、新剂型、新给药方案、新给药途径的补充申请，除非FDA放弃或推迟，均要求申办者开展儿科研究。研究结果需包含足够的有效性和安全性评价信息以支持个年龄组的剂量制定。公平法案要求的研究是必须开展的而且只限于正在开发研究的适应症。作为对比，最佳法案的儿科研究是自愿的。 3.新的法规 4. 儿科独占权给申办者及儿童带来的利益With the enactment of the Food and Drug Amendments Act (FDAAA) of 2007, Congress incorporated updates of 2003 PREA and 2002 BPCA.10 As i

32、ncluded in the 2003 PREA, the current 2007 PREA11 affects NDA and BLA applications and supplements for new active ingredients, indications, dosage forms, regimens, or routes of administration. In addition, pediatric studies of currently marketed drugs and biologics may be required if the product is

33、used by a “substantial” number of children, if adequate pediatric labeling would provide “meaningful” therapeutic benefit compared with existing treatments for children for the claimed indication, or if the lack of “adequate” labeling poses a risk for the pediatric population. FDAs hope is that forc

34、ing such studies and assessments will increase sponsors awareness of pediatric uses and make it more likely that sponsors will seek approval for a pediatric indication. As previously noted, a sponsor may seek a waiver for the obligation to submit a pediatric assessment for reasons such as the lack o

35、f safety, efficacy, or impracticability for a pediatric population. In that event, FDA requires that the waiver be included in the product labeling so that physicians will be informed prior to using the drug for an off-label pediatric purpose.2007年FDA修正法案，升级了2003年的公平法案和2002年的最佳法案10。跟03年公平法案相同，07年的修正

36、公平法案11 针对新药申请，生物制品生产许可申请和新活性成分、新适应症、新剂型、新给药方案、新给药途径的补充申请。另外已上市药品和生物制品在“大规模”儿童中使用，其说明书提供了同该适应症现有疗法相比“有意义”的治疗优势，或未明确其在儿科人群使用的危险者，可能也要做临床研究。FDA的希望是，通过这些研究和评估增加申办者儿科用药的意识，以期将来申办方主动需求批准开展儿童的适应症研究。如前所述，申办者可以下理由放弃提交儿科用药评价信息，如：缺乏安全性、有效性或无法在儿科人群中实施。这样一来FDA要求其放弃应添加到产品说明书上，便于临床医生在说明书外使用该药物时做到心里有数。 The 2007 PRE

37、A explicitly permits the sponsor to extrapolate data from different subpopulations, which may reduce or eliminate the need for age-specific clinical studies.11 The 2007 PREA also addresses the extensive off-label use of drugs in the pediatric population, in that FDA can require not only the assessme

38、nts mandated for newly submitted NDAs but also such assessments for drugs that have been approved and for which there is no pending NDA.11 The 2007 updated PREA also requires FDA to make the “medical, statistical, and clinical pharmacology” information contained in the pediatric assessments publicly

39、 available to provide information to physicians who are considering using the drug for off-label purposes.11 07年的公平法案详细允许申办者预测在不同亚组人群众的数据，这样将减少或消除按特定年龄的临床研究11，还强调了儿科广泛的说明书外使用药物，FDA可要求不仅在新药批准上市时评估，对已批准药物和未等待新药批准药物做评估11。07年更新的公平法案要求FDA公开“医学、统计、临床药理”儿科评估信息，以便临床医生说明书以外用药时参考11。The FDAAA also reauthorized

40、 the pediatric exclusivity incentive as put forth initially in the BPCA of 2002.10 In the updated legislation as found in the BPCA of 200712, a single WR for pediatric studies may include more than one indication, and these indications may be either “on-label” or “off-label”. In addition, the WR may

41、 include nonclinical studies. Other changes in the BPCA of 2007 include the submission of all adverse event reports with the final pediatric study report, the finalization of the exclusivity determination based on new WRs to be made within 180 days of response to the WR, the grant of exclusivity onl

42、y if there are 9 months of exclusivity or patent protection remaining at the time of determination, and the priority review of any application or supplement submitted in response to the WR.12 Of note, a sponsor must submit its application (or supplement) for pediatric exclusivity 15 months prior to

43、expiration of adult exclusivity.修订法案也重申了02年最佳法案的儿科独占激励措施10。0712年更新的最佳法案中，一个书面申请可能包含多个适应症，这些适应症可以是说明书上有的，也可以是说明书以外的。另外，书面申请可能包含非临床研究。07年最佳法案的另一个改变是在提交的总结报告中应报告所有的不良事件，独占权的最终确定将基于新的书面文件，且在对书面文件答复后的180天内执行，授予独占权只在9个月独占权或决定当时在专利保护期间者适用，对WR做出的回复优先审查申请或补充申请12。值得注意的是，申办者必须成人独占权期满15个月前提交儿童用药独占权申请（或补充申请）。4BENEFITS OF PEDIATRIC EXCLUSIVITY TO SPONSORSFDA is required to treat any application submitted as a result of a pediatric study conducted under the BPCA as a “priorit