FDA发布药物诊断共同开发的指南草案_图文

1、FDA在指南草案中写到，“IVD伴随诊断和治疗产品的共同开发对于精准医疗的推进至关重要。FDA试图通过向开发者提供一套准则，帮助他们进行有效的共同开发以及执行FDA的监管要求，进而加速精准医疗方面的创新。”Rx/Dx共同开发方案的监管对FDA来说，理想的Rx/Dx共同开发方案是，在药物研发的最早期确定需要开发的伴随诊断，两者同时开发并同时进入市场。两年前FDA发布伴随诊断的指南时阐述了上述理想方案。但后来FDA意识到，对药物和伴随诊断同时进行评估并不总是可行，因此允许将伴随诊断的评估时间推后，先确定药物是否对某种无药可用的威胁生命的疾病有效。通常情况下，FDA认为伴随诊断属于ClassIII、

2、高风险产品，需要售前批准。但在共同开发指南中，FDA认为，一些Rx/Dx共同开发产品中的伴随诊断可归类为ClassII、中度风险产品，得到510(k许可或de novo request后即可进入市场。药物和检测开发的推进过程是明显不同的，该指南提供了一个图表，告诉开发者如何调整计划以及何时应该向FDA寻求意见。FDA建议，开发者需对治疗和诊断的研发都有一定的了解，并且治疗和诊断研发双方都要出席与FDA药物和诊断部门的会议。FDA对伴随诊断的定义是，一种必需的验证药物安全性和有效性的检测。因此，FDA建议，伴随诊断（CDx）的性能分析需在它应用在药物的临床试验前进行。当没有足够的数据证明一种试验

3、性新药对患者的风险时，FDA会对这项研究下达“clinical hold（临床试验暂停）”通知。但FDA表示，伴随诊断性能分析的不确定性不会导致这种暂停。如果一种药物的伴随诊断之前未得到FDA批准用于这种特定用途，开发者必须提出申请并获得器械临床研究豁免（IDE）。在该指南草案中，FDA概述了IDE申请应该包含的信息类型，以及在什么情况下体外诊断（IVD）可以不需要这个过程。该指南还讨论了检测开发者在利用训练样本集、检测设计变更的影响和IVD桥接试验中应该考虑的一些因素。样本采集近一段时间，FDA一直在告诫开发者，医生越来越多地预筛选病人，以明确他们进行生物标志物临床试验的资格，而这种行为会给

4、Rx/Dx共同开发带来问题。FDA表示，“预筛查会产生具有偏好性的临床试验人群，这个群体不能代表真实世界中使用IVD伴随诊断的群体。因此，FDA强烈地反对挑选测试对象。”FDA建议，开发者应该要求临床试验参与单位提交的样本来自于所有潜在候选检测人群，而不是经过本地检测筛选出来的人群。FDA说，这样才能够评估IVD真实的分析能力，并且能够确保意向治疗人群不具有任何偏好性。该指南草案还表示，FDA将在很多方面更加灵活，例如，允许在早期研究中使用临床试验分析，可展示NGS检测中有代表性的标记物的分析验证结果，当真实的病人样本无法获取时可利用人为样本研究某种特定标记物。但是FDA在指南中还指出，样本采

5、集对一个共同开发方案的成功至关重要，鼓励开发者从所有招募的检测对象中获取样本。这样可确保临床试验分析进行不下去的情况下，开发者仍然能够对伴随检测进行验证且使其商业化。生物标记物相关试验的设计该指南指出，制药公司可以进行不同类型的生物标记物试验设计，一种设计是按照阳性和阴性生物标记物状态将患者随机分为两组，另一种设计是仅将阳性生物标记物状态的患者随机分到治疗组。FDA表示，在衡量生物标记物的预后和预测价值方面，第一种试验设计最有用。但是当有证据表明生物标记物阴性的患者对治疗没有应答时，FDA会加速对只招募阳性生物标记物患者的精准药物研究的审批工作。FDA还讨论了一些方案，使制药公司在一项前瞻性研

6、究完成后，可以基于生物标记物回顾性地评估病人的应答情况。根据伴随诊断是如何在药物试验中使用的，它将获得一份声明文件表明它的作用，是用于预测疗效，监测药物剂量或者停药，还是用于筛选进行临床试验的病人。FDA表示，“就筛选病人的伴随诊断声明来说，如果主要药效试验表明，该药品对IVD筛选的人群具有足够的安全性和有效性，这就说明该IVD得到了临床验证，其选择的群体能从该治疗产品中获益。”指南草案的意见征集1998年，FDA批准了第一个乳腺癌治疗药物Herceptin（trastuzumab）和其伴随诊断HercepTest。近年来，Rx/Dx共同开发产品快速增多，尤其是肿瘤类产品。该指南草案中关于共同

7、开发的建议都来自FDA多年来批准这类产品的经验。个性化医学联盟（Personalized Medicine Coalition，PMC）的执行副总裁Amy Miller说，“FDA药品和诊断部门 开发了内部流程，使肿瘤药物通过FDA审查。我们建议FDA利用这些经验，为开发者和FDA其他审查领域的员工起草一份“如何做”的指南，所以他们就制定了这份指南草案。”该共同开发指南草案已经制定了很长一段时间了，多年来FDA与利益相关人士在研讨会和行业会议上就文件中的相关准则进行了交流。Miller说，PMC会进一步研究这份草案并提出改进意见。公众有90天时间对该指南草案提出意见。Draft - Not f

8、or Implementation Principles for Codevelopment of an 1In Vitro Companion Diagnostic 2Device with a Therapeutic Product 345Draft Guidance for Industry and 6Food and Drug Administration Staff 78DRAFT GUIDANCE 9This guidance document is being distributed for comment purposes only. 10Document issued on:

9、 July 15, 2016 1112You should submit comments and suggestions regarding this draft document within 90 days 13of publication in the Federal Register of the notice announcing the availability of the draft 14guidance. Submit written comments to the Division of Dockets Management (HFA-305, 15Food and Dr

10、ug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit 16electronic comments to . Identify all comments with the docket 17number listed in the notice of availability that publishes in the Federal Register. 1819For questions about this document, contact C

11、DRHs Office of In Vitro Diagnostics and 20Radiological Health at 301-796-5711 or Pamela Bradley at 240-731-3734 or 21Pamela.B; CBERs Office of Communication, Outreach and Development, 22at 1-800-835-4709 or 240-402-8010; or for CDER, please contact Christopher Leptak at 301-23796-00

12、17 or Christopher.L.242526 U.S. Department of Health and Human Services 27Food and Drug Administration 28Center for Devices and Radiological Health 29Center for Drug Evaluation and Research 30Center for Biologics Evaluation and Research31Draft - Not for Implementation32Preface 333435

13、Additional Copies 36373839 404142434445464748495051525354555657585960Contains Nonbinding RecommendationsDraft - Not for ImplementationTable of Contents 6162I. Introduction . . 463II. Background. 664III. Principles of the Codevelopment Process . . 765A. General . . 866B. Regulation of Investigational

14、 IVDs and Therapeutic Products.9671. Risk Assessment and IDE Requirements . 682. 69Drugs or Biological Products . 703. . . 1471C. 721. 73Therapeutic Product Trials . 742. New Intended Uses for IVDs . 753. 764. 775. . . 18786. . 797. 80D. 811. 822. . 22833. 844. 855. 86E. . . 28871. 888990. . 3191F.

15、921. 932. . 37943. 95. . 3796G. 971. Claims for IVD Companion Diagnostics Based on Use in Trial . 3898H. Postmarketing Considerations . 4099APPENDIX 1: Critical Points of the Codevelopment Process . . 41100APPENDIX 2: Subject Specimen Handling Considerations . 43101APPENDIX 3: BIMO Information to Su

16、bmit in a PMA . . 46102APPENDIX 4: Letters of Authorization . 47103Principles for Codevelopment of an In 104Vitro Companion Diagnostic Device 105with a Therapeutic Product 106107108109 110111112113114115116117118119120121122123124262. 2 As used in this guidance, therapeutic product includes therapeu

17、tic, preventive, and prophylactic drugs and biological products. Although this guidance does not expressly address therapeutic devices intended for use with in vitro diagnostics, the principles discussed in this guidance may also be relevant to such devices. 3 FDA defined the term “IVD companion dia

18、gnostic device” and described certain regulatory requirements in the guidance entitled “In Vitro Companion Diagnostic Devices”(/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM262327.pdf. This guidance also states that FDA expects that most therapeutic prod

19、uct and IVD companiondiagnostic device pairs will not meet the definition of “combination product” under 21 CFR 3.2(e. FDAan IVD companion diagnostic should be approved, granted a de novo request or cleared by 125FDA contemporaneously with the approval of the corresponding therapeutic product for th

20、e 126use indicated in the therapeutic product labeling.4 127128This guidance document is intended to be a practical guide to assist therapeutic product 129sponsors and IVD sponsors in developing a therapeutic product and an accompanying IVD 130companion diagnostic, a process referred to as codevelop

21、ment . 5 This guidance is also 131intended to assist FDA staff participating in the review of candidate IVD companion 132diagnostics 6 or their associated therapeutic products. 133134135136137138139140companion diagnostic. 141142143144145146147148149150151152153154155 4de novo request. Thus, in the

22、context of this guidance document, the term contemporaneously with the clearance, grant of de novo, or approval (as appropriate of the associated IVD companion diagnostic, where the appropriate premarket review standard(s for each product has been met. 5 For the purposes of this document, the term c

23、odevelopment is used in reference to the development of atherapeutic product and an IVD companion diagnostic that is essential for the safe and effective use of thetherapeutic product. Note that codevelopment more generally may refer to any development of a therapeutic product with an IVD. 6 For the

24、 purposes of this document, the term candidate IVD companion diagnostic is used to refer to an IVD that the sponsor(s believes is necessary to support the safe and effective use of the corresponding therapeutic product and is the version of the IVD that will be reviewed by FDA in a premarket submiss

25、ion.Contains Nonbinding RecommendationsDraft - Not for ImplementationII. B ackground 156The concept of codevelopment of a therapeutic product and an IVD companion diagnostic 157was first applied when the therapeutic product trastuzumab (Herceptin was paired with an 158immunohistochemical IVD compani

26、on diagnostic (HercepTest that measures expression 159levels of human epidermal growth factor receptor 2 (HER-2; also known as ERBB2 in 160breast cancer tissue and identifies patients more likely to have a therapeutic response. These 161two products were approved in 1998. Since that time, interest i

27、n identifying biomarkers that 162163164165accompanying IVD companion diagnostic.7 1661678 IVD 1681691701711721731741751769 177178179180181182183184185186without the prior or 18710 regardless of 188189190191192advancement of precision medicine. FDA seeks to facilitate innovations in precision 193medi

28、cine by providing sponsors with a set of principles that may be helpful for effective1947See current list of IVD companion diagnostics (. 8 See note 3. 9 See note 3. 10 See FDA guidance on “In Vitro Companion Diagnostic Devices,” note 3, for further details.outlines fundamental principles that have

29、been developed to assist sponsors in 196codevelopment. 197III. Principles of the Codevelopment Process 198Therapeutic products and IVDs typically are developed on different schedules, are subject to 199different regulatory requirements,12 and have different points of interaction with the 200appropri

30、ate review centers at FDAeneral understanding of both processes. 204205206207of the investigational IVD1420820921021121221321421521621721821922022122222311de novo request or cleared under the device authorities of the Federalregulations. 12 See note 11. 13 Therapeutic products are revie

31、wed by FDA in either the Center for Biologics Evaluation and Research(CBER or the Center for Drug Evaluation and Research (CDER. IVDs are medical devices reviewed byCBER or the Center for Devices and Radiological Health (CDRH. CDRH reviews the great majority of IVD submissions. CBER reviews human le

32、ukocyte antigen (HLA test kits and diagnostic tests for humanimmunodeficiency virus (HIV and human T-lymphotropic virus (HTLV. CBER also reviews IVDs used in blood and tissue donation and administration practices, including compatibility tests. 14 Investigational IVDs and applicable regulatory requi

33、rements are described in Section III.B of this document.contemporaneous marketing authorizations. 225A. General 226Ideally, the need for an IVD companion diagnostic would be identified early in the course of 227therapeutic product development so that an analytically validated test can be prospective

34、ly 228incorporated into the design of the therapeutic product clinical trials. For example, the 229230231232233234235236237238diagnostic. 23924024124224324424524615 24724824925025116 and meets the therapeutic product 252253254determine whether the 17 demonstrates adequate 25525615yet approved, grant

35、ed a request or cleared when the therapeutic product is intended to treat a serious or life-threatening condition for which no satisfactory available therapy exists and the benefits from the use of the therapeutic product are so pronounced as to outweigh the risks from the lack of an IVD companion d

36、iagnostic with marketing authorization. This will be determined by FDA during product review. 16 For the purposes of this document, analytical validation is the demonstration that the IVD can accurately and reliably detect or measure the analyte it is intended to detect or measure. 17 For the purpos

37、es of this document, the term developmental IVD companion diagnostic is used to refer to a version of the test that is under investigation. This could be a prototype clinical trial assay (CTA (see also Section III.C.3., an intermediate version of the test, or even the version of the test that will u

38、ltimately besubmitted for FDA review.Contains Nonbinding RecommendationsDraft - Not for Implementationproduct. Whether initiated at the outset of development or at a later point, codevelopment 257should generally be conducted in a way that will facilitate obtaining contemporaneous 258marketing autho

39、rizations for the therapeutic product and the associated IVD companion 259diagnostic. 260261Given that the need for an IVD companion diagnostic may become apparent at different 262points in the development of the therapeutic product, sponsors should be aware of and plan 263for the various opportunit

40、ies for interactions with the Agency, and requirements for 264265266codevelopment process.1826719 In either 268269270B. 27127227327427527627727827928020 28128228321284285286FDA can place a trial on clinical hold (i.e., prohibit 28723 For example, the trial28818Staff”(. 19 FDA guidance, “Formal Meeti

41、ngs between the FDA and Sponsors or Applicants”( describes the types of meetings available during therapeutic product development. 20 FDA intends to release guidance that addresses the topic of investigational IVDs used in clinicalinvestigations of therapeutic products in the near future, which will

42、 include information about determininginvestigational IVD risk. 21 See 21 CFR Part 312. 22 21 CFR 312.23(a(6(iii(g. 23 21 CFR 312.42 and 21 U.S.C. 360j(g.Contains Nonbinding RecommendationsDraft - Not for Implementationmay be placed on clinical hold if participation would pose unreasonable and signi

43、ficant risks 289to human subjects, or the IND does not contain sufficient information to assess the risks to 290subjects. 24 In addition, a trial may be placed on hold if the investigational plan is clearly 291deficient in design to meet its stated objectives, which may include uncertainty about the

44、 292analytical validity of an IVD being used to enroll subjects into the trial.25 The party taking 293responsibility for the investigational IVD (also referred to in this document as the sponsor of 294the investigational IVD whether it is the manufacturer of the investigational IVD or the 295sponsor

45、 of the therapeutic product trial that includes an investigational IVD should ensure 296297298responsibility for the investigational IVD. 2993001. 3013023033043053063073082630931031128 Note that FDAs 31229 31331431531631730 A determination that an investigational 31831932032132232332424 21 CFR 312.4

46、2. 2521 CFR 312.42 (b(2(ii. 26 21 CFR 812.2(b(1(ii. 27 21 CFR 812.66. 28 See note 18. 29 21 CFR 812.2(b(1 and 812.20(a. 30 21 U.S.C. 360c.Contains Nonbinding RecommendationsDraft - Not for Implementationneeded if FDA determines that the IVD is essential for the safe and effective use of the 325thera

47、peutic product. 326327Codevelopment clinical trial designs can incorporate use of an investigational IVD in ways 328that are categorized by the IDE regulation as 1 exempt, 2 significant risk, and 3 non-329significant risk. Each category has specific requirements under the IDE regulation. These 330re

48、quirements are described in the following sections. 331332i. Exempt Investigational IVDs 333334335336337product or procedure.3133833934034134234334434534621 CFR Part 812. 34734834935035132 35235335433 355356357358359360361362sponsors should also note that although an IDE application is not required

49、for an IDE-exempt 363investigational IVD, the therapeutic product review center may require submission of data36431See 21 CFR 812.2(c for full criteria pertaining to exempted investigations. 32 21 CFR 812.3(k. 33 Noninvasive sampling procedures are defined in 21 CFR 812.3(k and include sampling meth

50、ods such asurine collection, buccal swabs, and saliva collection. Under 21 CFR 812.3(k, blood sampling that involvessimple venipuncture is also considered noninvasive.Contains Nonbinding RecommendationsDraft - Not for Implementationsupporting the IVDs analytical validity to determine whether the inv

51、estigation conducted 365under the IND will be able to meet its stated objectives (see Section III.B.2. 366367ii. Non-exempt Investigational IVDs 368If a developmental IVD companion diagnostic (which is investigational used in the 369therapeutic product trial does not meet the criteria for exemption

52、under 21 CFR 812.2(c, the 370IVD will be considered either significant risk or non-significant risk, depending on the risk 371its use presents to trial subjects. 372373374375376377378or welfare of a subject.34379380381382383384385386387388389care. 35 39039139236,37 The sponsor must 39339439539638 do

53、es not 397398399400401402scenarios, a non-significant risk use of an investigational IVD usually means that an incorrect4033421 CFR 812.3(m. 35 See also note 20. 36 See 21 CFR 812.20(a. 37 The components of an IDE application are described in 21 CFR 812.20, 812.25, and 812.27. See also Section III.B.3. of this guidance which describes some of the information that FDA typically requests in IDEapplications for codevelopment trials. 38 See 21 CFR Part 312.Contains Nonbinding RecommendationsDraft - Not for Implementationtest result d