FDA發(fā)布藥物診斷共同開發(fā)的指南草案_圖文

1、FDA在指南草案中寫到，“IVD伴隨診斷和治療產(chǎn)品的共同開發(fā)對(duì)于精準(zhǔn)醫(yī)療的推進(jìn)至關(guān)重要。FDA試圖通過(guò)向開發(fā)者提供一套準(zhǔn)則，幫助他們進(jìn)行有效的共同開發(fā)以及執(zhí)行FDA的監(jiān)管要求，進(jìn)而加速精準(zhǔn)醫(yī)療方面的創(chuàng)新?！盧x/Dx共同開發(fā)方案的監(jiān)管對(duì)FDA來(lái)說(shuō)，理想的Rx/Dx共同開發(fā)方案是，在藥物研發(fā)的最早期確定需要開發(fā)的伴隨診斷，兩者同時(shí)開發(fā)并同時(shí)進(jìn)入市場(chǎng)。兩年前FDA發(fā)布伴隨診斷的指南時(shí)闡述了上述理想方案。但后來(lái)FDA意識(shí)到，對(duì)藥物和伴隨診斷同時(shí)進(jìn)行評(píng)估并不總是可行，因此允許將伴隨診斷的評(píng)估時(shí)間推后，先確定藥物是否對(duì)某種無(wú)藥可用的威脅生命的疾病有效。通常情況下，F(xiàn)DA認(rèn)為伴隨診斷屬于ClassIII、

2、高風(fēng)險(xiǎn)產(chǎn)品，需要售前批準(zhǔn)。但在共同開發(fā)指南中，F(xiàn)DA認(rèn)為，一些Rx/Dx共同開發(fā)產(chǎn)品中的伴隨診斷可歸類為ClassII、中度風(fēng)險(xiǎn)產(chǎn)品，得到510(k許可或de novo request后即可進(jìn)入市場(chǎng)。藥物和檢測(cè)開發(fā)的推進(jìn)過(guò)程是明顯不同的，該指南提供了一個(gè)圖表，告訴開發(fā)者如何調(diào)整計(jì)劃以及何時(shí)應(yīng)該向FDA尋求意見(jiàn)。FDA建議，開發(fā)者需對(duì)治療和診斷的研發(fā)都有一定的了解，并且治療和診斷研發(fā)雙方都要出席與FDA藥物和診斷部門的會(huì)議。FDA對(duì)伴隨診斷的定義是，一種必需的驗(yàn)證藥物安全性和有效性的檢測(cè)。因此，F(xiàn)DA建議，伴隨診斷（CDx）的性能分析需在它應(yīng)用在藥物的臨床試驗(yàn)前進(jìn)行。當(dāng)沒(méi)有足夠的數(shù)據(jù)證明一種試驗(yàn)

3、性新藥對(duì)患者的風(fēng)險(xiǎn)時(shí)，F(xiàn)DA會(huì)對(duì)這項(xiàng)研究下達(dá)“clinical hold（臨床試驗(yàn)暫停）”通知。但FDA表示，伴隨診斷性能分析的不確定性不會(huì)導(dǎo)致這種暫停。如果一種藥物的伴隨診斷之前未得到FDA批準(zhǔn)用于這種特定用途，開發(fā)者必須提出申請(qǐng)并獲得器械臨床研究豁免（IDE）。在該指南草案中，F(xiàn)DA概述了IDE申請(qǐng)應(yīng)該包含的信息類型，以及在什么情況下體外診斷（IVD）可以不需要這個(gè)過(guò)程。該指南還討論了檢測(cè)開發(fā)者在利用訓(xùn)練樣本集、檢測(cè)設(shè)計(jì)變更的影響和IVD橋接試驗(yàn)中應(yīng)該考慮的一些因素。樣本采集近一段時(shí)間，F(xiàn)DA一直在告誡開發(fā)者，醫(yī)生越來(lái)越多地預(yù)篩選病人，以明確他們進(jìn)行生物標(biāo)志物臨床試驗(yàn)的資格，而這種行為會(huì)給

4、Rx/Dx共同開發(fā)帶來(lái)問(wèn)題。FDA表示，“預(yù)篩查會(huì)產(chǎn)生具有偏好性的臨床試驗(yàn)人群，這個(gè)群體不能代表真實(shí)世界中使用IVD伴隨診斷的群體。因此，F(xiàn)DA強(qiáng)烈地反對(duì)挑選測(cè)試對(duì)象?！盕DA建議，開發(fā)者應(yīng)該要求臨床試驗(yàn)參與單位提交的樣本來(lái)自于所有潛在候選檢測(cè)人群，而不是經(jīng)過(guò)本地檢測(cè)篩選出來(lái)的人群。FDA說(shuō)，這樣才能夠評(píng)估IVD真實(shí)的分析能力，并且能夠確保意向治療人群不具有任何偏好性。該指南草案還表示，F(xiàn)DA將在很多方面更加靈活，例如，允許在早期研究中使用臨床試驗(yàn)分析，可展示NGS檢測(cè)中有代表性的標(biāo)記物的分析驗(yàn)證結(jié)果，當(dāng)真實(shí)的病人樣本無(wú)法獲取時(shí)可利用人為樣本研究某種特定標(biāo)記物。但是FDA在指南中還指出，樣本采

5、集對(duì)一個(gè)共同開發(fā)方案的成功至關(guān)重要，鼓勵(lì)開發(fā)者從所有招募的檢測(cè)對(duì)象中獲取樣本。這樣可確保臨床試驗(yàn)分析進(jìn)行不下去的情況下，開發(fā)者仍然能夠?qū)Π殡S檢測(cè)進(jìn)行驗(yàn)證且使其商業(yè)化。生物標(biāo)記物相關(guān)試驗(yàn)的設(shè)計(jì)該指南指出，制藥公司可以進(jìn)行不同類型的生物標(biāo)記物試驗(yàn)設(shè)計(jì)，一種設(shè)計(jì)是按照陽(yáng)性和陰性生物標(biāo)記物狀態(tài)將患者隨機(jī)分為兩組，另一種設(shè)計(jì)是僅將陽(yáng)性生物標(biāo)記物狀態(tài)的患者隨機(jī)分到治療組。FDA表示，在衡量生物標(biāo)記物的預(yù)后和預(yù)測(cè)價(jià)值方面，第一種試驗(yàn)設(shè)計(jì)最有用。但是當(dāng)有證據(jù)表明生物標(biāo)記物陰性的患者對(duì)治療沒(méi)有應(yīng)答時(shí)，F(xiàn)DA會(huì)加速對(duì)只招募陽(yáng)性生物標(biāo)記物患者的精準(zhǔn)藥物研究的審批工作。FDA還討論了一些方案，使制藥公司在一項(xiàng)前瞻性研

6、究完成后，可以基于生物標(biāo)記物回顧性地評(píng)估病人的應(yīng)答情況。根據(jù)伴隨診斷是如何在藥物試驗(yàn)中使用的，它將獲得一份聲明文件表明它的作用，是用于預(yù)測(cè)療效，監(jiān)測(cè)藥物劑量或者停藥，還是用于篩選進(jìn)行臨床試驗(yàn)的病人。FDA表示，“就篩選病人的伴隨診斷聲明來(lái)說(shuō)，如果主要藥效試驗(yàn)表明，該藥品對(duì)IVD篩選的人群具有足夠的安全性和有效性，這就說(shuō)明該IVD得到了臨床驗(yàn)證，其選擇的群體能從該治療產(chǎn)品中獲益。”指南草案的意見(jiàn)征集1998年，F(xiàn)DA批準(zhǔn)了第一個(gè)乳腺癌治療藥物Herceptin（trastuzumab）和其伴隨診斷HercepTest。近年來(lái)，Rx/Dx共同開發(fā)產(chǎn)品快速增多，尤其是腫瘤類產(chǎn)品。該指南草案中關(guān)于共同

7、開發(fā)的建議都來(lái)自FDA多年來(lái)批準(zhǔn)這類產(chǎn)品的經(jīng)驗(yàn)。個(gè)性化醫(yī)學(xué)聯(lián)盟（Personalized Medicine Coalition，PMC）的執(zhí)行副總裁Amy Miller說(shuō)，“FDA藥品和診斷部門 開發(fā)了內(nèi)部流程，使腫瘤藥物通過(guò)FDA審查。我們建議FDA利用這些經(jīng)驗(yàn)，為開發(fā)者和FDA其他審查領(lǐng)域的員工起草一份“如何做”的指南，所以他們就制定了這份指南草案。”該共同開發(fā)指南草案已經(jīng)制定了很長(zhǎng)一段時(shí)間了，多年來(lái)FDA與利益相關(guān)人士在研討會(huì)和行業(yè)會(huì)議上就文件中的相關(guān)準(zhǔn)則進(jìn)行了交流。Miller說(shuō)，PMC會(huì)進(jìn)一步研究這份草案并提出改進(jìn)意見(jiàn)。公眾有90天時(shí)間對(duì)該指南草案提出意見(jiàn)。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