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for Industry and 6Food and Drug Administration Staff 78DRAFT GUIDANCE 9This guidance document is being distributed for comment purposes only. 10Document issued on: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 16number listed in the notice of availability that publishes in the Federal Register. 1819For questions about this document, contact CDRHs Office of In Vitro Diagnostics and 20Radiological Health at 301-796-5711 or Pamela Br

11、adley at 240-731-3734 or 21at 1-800-835-4709 or 240-402-8010; or for CDER, please contact Christopher Leptak at 301-23242526 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

12、 Biologics Evaluation and Research31Draft - Not for Implementation32Preface 333435Additional Copies 36373839 404142434445464748495051525354555657585960Contains Nonbinding RecommendationsDraft - Not for ImplementationTable of Contents 6162I. Introduction . . 463II. Background. 664III. Principles of t

13、he Codevelopment Process . . 765A. General . . 866B. Regulation of Investigational 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. . .

14、 18786. . 797. 80D. 811. 822. . 22833. 844. 855. 86E. . . 28871. 888990. . 3191F. 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:

15、Subject Specimen Handling Considerations . 43101APPENDIX 3: BIMO Information to Submit in a PMA . . 46102APPENDIX 4: Letters of Authorization . 47103Principles for Codevelopment of an In 104Vitro Companion Diagnostic Device 105with a Therapeutic Product 106107108109 110111112113114115116117118119120

16、121122123124262. 2 As used in this guidance, therapeutic product includes therapeutic, 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 guidan

17、ce may also be relevant to such devices. 3 FDA defined the term “IVD companion diagnostic device” and described certain regulatory requirements in the guidance entitled “In Vitro Companion Diagnostic Devices”diagnostic device pairs will not meet the definition of “combination product” under 21 CFR 3

18、.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 the 126use indicated in the therapeutic product labeling.4 127128This guidance document is intended to be a practic

19、al 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 codevelopment . 5 This guidance is also 131intended to assist FDA staff participating in the review of candidate IVD compa

20、nion 132diagnostics 6 or their associated therapeutic products. 133134135136137138139140companion diagnostic. 141142143144145146147148149150151152153154155 4de novo request. Thus, in the context of this guidance document, the term contemporaneously with the clearance, grant of de novo, or approval (

21、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 codevelopment is used in reference to the development of atherapeutic product and an IVD companion diagnostic that

22、 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 purposes of this document, the term candidate IVD companion diagnostic is used to refer to an IVD that the spons

23、or(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 submission.Contains Nonbinding RecommendationsDraft - Not for ImplementationII. B ackground 156The concept of codevelopm

24、ent of a therapeutic product and an IVD companion diagnostic 157was first applied when the therapeutic product trastuzumab (Herceptin was paired with an 158immunohistochemical IVD companion diagnostic (HercepTest that measures expression 159levels of human epidermal growth factor receptor 2 (HER-2;

25、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 in identifying biomarkers that 162163164165accompanying IVD companion diagnostic.7 1661678 IVD 1681691701711721731

26、741751769 177178179180181182183184185186without the prior or 18710 regardless of 188189190191192advancement of precision medicine. FDA seeks to facilitate innovations in precision 193medicine by providing sponsors with a set of principles that may be helpful for effective1947See current list of IVD

27、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 been developed to assist sponsors in 196codevelopment. 197III. Principles of the Codevelopment Process 198Therape

28、utic products and IVDs typically are developed on different schedules, are subject to 199different regulatory requirements,12 and have different points of interaction with the 200appropriate review centers at FDAeneral understanding of both processes. 204205206207of the investigational

29、IVD1420820921021121221321421521621721821922022122222311de novo request or cleared under the device authorities of the Federalregulations. 12 See note 11. 13 Therapeutic products are reviewed by FDA in either the Center for Biologics Evaluation and Research(CBER or the Center for Drug Evaluation and

30、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 leukocyte antigen (HLA test kits and diagnostic tests for humanimmunodeficiency virus (HIV and human T-lymphotropic

31、 virus (HTLV. CBER also reviews IVDs used in blood and tissue donation and administration practices, including compatibility tests. 14 Investigational IVDs and applicable regulatory requirements are described in Section III.B of this document.contemporaneous marketing authorizations. 225A. General 2

32、26Ideally, 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 prospectively 228incorporated into the design of the therapeutic product clinical trials. For example, the 22923023123223323

33、4235236237238diagnostic. 23924024124224324424524615 24724824925025116 and meets the therapeutic product 252253254determine whether the 17 demonstrates adequate 255submitted for FDA review.Contains Nonbinding RecommendationsDraft - Not for Implementationproduct. Whether initiated at the outset of dev

34、elopment or at a later point, codevelopment 257should generally be conducted in a way that will facilitate obtaining contemporaneous 258marketing authorizations for the therapeutic product and the associated IVD companion 259diagnostic. 260261Given that the need for an IVD companion diagnostic may b

35、ecome apparent at different 262points in the development of the therapeutic product, sponsors should be aware of and plan 263for the various opportunities for interactions with the Agency, and requirements for 264265266codevelopment process.1826719 In either 268269270B. 27127227327427527627727827928

36、020 28128228321284285286FDA can place a trial on clinical hold (i.e., prohibit 28723 For example, the trial28818Staff”(. 19 FDA guidance, “Formal Meetings between the FDA and Sponsors or Applicants”( describes the types of meetings available during therapeutic product development. 20 FDA intends to

37、release guidance that addresses the topic of investigational IVDs used in clinicalinvestigations of therapeutic products in the near future, which will include information about determiningContains Nonbinding RecommendationsDraft - Not for Implementationmay be placed on clinical hold if participatio

38、n would pose unreasonable and significant 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, whic

39、h may include uncertainty about the 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 in

40、vestigational IVD or the 295sponsor 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 3

41、1831932032132232332424 21 CFR 312.42. 25Contains Nonbinding RecommendationsDraft - Not for Implementationneeded if FDA determines that the IVD is essential for the safe and effective use of the 325therapeutic product. 326327Codevelopment clinical trial designs can incorporate use of an investigation

42、al 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 330requirements are described in the following sections. 331332i. Exempt Investigational IVDs 333334335

43、336337product or procedure.3133833934034134234334434534621 CFR Part 812. 34734834935035132 35235335433 355356357358359360361362sponsors should also note that although an IDE application is not required for an IDE-exempt 363investigational IVD, the therapeutic product review center may require submis

44、sion 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 methods such asurine collection, buccal swabs, and saliva collection. Under 21 CFR 812.3(k, blood samp

45、ling that involvessimple venipuncture is also considered noninvasive.Contains Nonbinding RecommendationsDraft - Not for Implementationsupporting the IVDs analytical validity to determine whether the investigation conducted 365367ii. Non-exempt Investigational IVDs 368If a developmental IVD companion

46、 diagnostic (which is investigational used in the 369therapeutic product trial does not meet the criteria for exemption 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. 372373374375376377

47、378or welfare of a subject.34379380381382383384385386387388389care. 35 39039139236,37 The sponsor must 39339439539638 does not 397398399400401402scenarios, a non-significant risk use of an investigational IVD usually means that an incorrect40334applications for codevelopment trials. 38 See 21 CFR Pa

48、rt 312.Contains Nonbinding RecommendationsDraft - Not for Implementationtest result does not pose a potential for serious risk to subjects in a trial. For example, 404subjects are not put at serious risk when a test result is used to assign them to different 405stratum for the purpose of balancing t

49、he characteristics of subjects assigned to different 406treatment arms (a process referred to as stratification because the test result itself does not 407determine the treatment the subject receives. Likewise, using a test to assess a baseline 408characteristic to be used in later analyses would no

50、t pose a serious risk. 409410If the investigational IVD used in a therapeutic product clinical trial does not meet the 41141239 even if the 413414415416417418419420421422423424425corresponding therapeutic product. 42642742842943043143243343443543643740 In addition, information about the IVD might be

51、 438439440sponsors about whether IDE requirements can be fulfilled by submitting IVD information to 441an IND.4424433921 CFR 812.2(b. 40 See 21 CFR Parts 312 and 812.Contains Nonbinding RecommendationsDraft - Not for ImplementationAs discussed above, if an investigational IVD presents significant ri

52、sk to subjects, an IDE 444application must be approved before the sponsor begins the therapeutic product clinical trial 445that uses the investigational IVD.41 Submission of IVD data to the IND will not satisfy the 446IDE submission requirement. In general, a sponsor who wishes to streamline the IDE

53、 or IND 447submission may cross-reference relevant information in the related IND or IDE submission 448by providing a letter of authorization from the other sponsor giving FDA permission to refer 449to items contained in the other submission.42 450451452exempt or non-significant risk investigational IVD,4345345444 For example, 4554564574584594604614624634644654664674684694704714724734744754763. 477Trials 478479480presents significant risk to study subjects. FDA