Principles for Codevelopment of an 1 In Vitro Companion Diagnostic
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- Bu səhifədəki naviqasiya:
- Draft Guidance for Industry and
- U.S. Department of Health and Human Services
- Contains Nonbinding Recommendations Draft - Not for Implementation 2 32 Preface
- Contains Nonbinding Recommendations Draft - Not for Implementation 3 Table of Contents
- Contains Nonbinding Recommendations Draft - Not for Implementation 4 Principles for Codevelopment of an In
- Food and Drug Administration Staff
- Contains Nonbinding Recommendations
- Contains Nonbinding Recommendations Draft - Not for Implementation 6 II. Background
- Principles of the Codevelopment Process
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Contains Nonbinding Recommendations Draft - Not for Implementation
1 Principles for Codevelopment of an 1
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3 4 5 Draft Guidance for Industry and 6
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9 This guidance document is being distributed for comment purposes only.
10 Document issued on: July 15, 2016 11 12 You should submit comments and suggestions regarding this draft document within 90 days 13 of publication in the Federal Register of the notice announcing the availability of the draft 14 guidance. Submit written comments to the Division of Dockets Management (HFA-305), 15 Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit 16 electronic comments to http://www.regulations.gov. Identify all comments with the docket 17 number listed in the notice of availability that publishes in the Federal Register. 18 19 For questions about this document, contact CDRH’s Office of In Vitro Diagnostics and 20 Radiological Health at 301-796-5711 or Pamela Bradley at 240-731-3734 or 21 Pamela.Bradley@fda.hhs.gov ; CBER’s Office of Communication, Outreach and Development, 22 at 1-800-835-4709 or 240-402-8010; or for CDER, please contact Christopher Leptak at 301- 23 796-0017
or Christopher.Leptak@fda.hhs.gov .
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26 U.S. Department of Health and Human Services 27
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Contains Nonbinding Recommendations Draft - Not for Implementation
2 32 Preface 33 34 35 Additional Copies 36 37 CDRH
38 Additional copies are available from the Internet. You may also send an e-mail request to 39 CDRH-Guidance@fda.hhs.gov to receive a copy of the guidance. Please use the document 40 number 1400027 to identify the guidance you are requesting. 41 42
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44 (CBER) by written request, Office of Communication, Outreach and Development, Bldg. 71, 45 Room 3128, 10903 New Hampshire Ave., Silver Spring, MD 20993; by telephone, 1-800- 46 835-4709 or 240-402-8010; by email, ocod@fda.hhs.gov ; or from the Internet at 47 http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/de 48 fault.htm . 49
CDER
51 Additional copies of this guidance document are also available from the Center for 52 Drug Evaluation and Research (CDER) by written request to: Office of 53 Communications, Division of Drug Information, WO51, Room 2201, Center for Drug 54 Evaluation and Research, Food and Drug Administration, 10903 New Hampshire 55 Ave., Silver Spring, MD 20993, or by telephone, 301-796-3400; or from the Internet 56 at
57 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/de 58 fault.htm . 59 60 Contains Nonbinding Recommendations Draft - Not for Implementation
3 Table of Contents 61 62 I.
Introduction ................................................................................................................... 4 63 II.
Background ................................................................................................................... 6 64 III.
Principles of the Codevelopment Process ..................................................................... 7 65 A.
General .......................................................................................................................... 8 66 B. Regulation of Investigational IVDs and Therapeutic Products .................................... 9 67 1.
Risk Assessment and IDE Requirements .......................................................... 10 68 2. Submission of Investigational IVD Information Related to Investigational 69 Drugs or Biological Products ...................................................................................... 13 70 3.
IDE Applications for Investigational IVDs in Codevelopment Trials .............. 14 71 C. Planning Ahead for IVD Validation in Potential Codevelopment Programs ............. 15 72 1.
Expectation for Analytical Validation Prior to Investigational IVD Use in 73 Therapeutic Product Trials .......................................................................................... 15 74 2.
New Intended Uses for IVDs ............................................................................ 16 75 3. IVD Prototypes in Early-Phase Therapeutic Product Clinical Trials ............... 16 76 4.
Using Research Use Only Components as Part of a Test System .................... 17 77 5. Prescreening for Eligibility for Therapeutic Product Clinical Trials ................ 18 78 6.
Preanalytic Procedures and Testing Protocols .................................................. 19 79 7. Planning Ahead for Analytical Validation Studies ........................................... 19 80 D.
Therapeutic Product Clinical Trial Design Considerations ........................................ 20 81 1. General Considerations for Early Therapeutic Product Development ............. 21 82 2.
General Considerations for Late Therapeutic Product Development ............... 22 83 3. Prognostic and Predictive Markers ................................................................... 24 84 4.
Prospective-Retrospective Approaches ............................................................ 25 85 5. Considerations for Identifying Intended Populations ....................................... 26 86 E.
Considerations for IVD Development in Late Therapeutic Product Development .... 28 87 1. Training Samples Sets versus Validation Samples Sets ................................... 29 88 2.
Effect of Changes to the Test Design ............................................................... 29 89 3. IVD Bridging Studies ....................................................................................... 30 90 4.
Special Protocol Assessments ........................................................................... 31 91 F. Planning for Contemporaneous Marketing Authorizations ........................................ 32 92 1.
Coordinating Review Timelines ....................................................................... 32 93 2. When Contemporaneous Marketing Authorization is Not Possible ................. 37 94 3.
Shipment and Verification of an IVD Companion Diagnostic Prior to 95 Marketing Authorization ............................................................................................. 37 96 G.
Labeling Considerations ............................................................................................. 38 97 1. Claims for IVD Companion Diagnostics Based on Use in Trial ...................... 38 98 H.
Postmarketing Considerations .................................................................................... 40 99 APPENDIX 1: Critical Points of the Codevelopment Process ............................................... 41 100 APPENDIX 2: Subject Specimen Handling Considerations .................................................. 43 101 APPENDIX 3: BIMO Information to Submit in a PMA ........................................................ 46 102 APPENDIX 4: Letters of Authorization ................................................................................. 47 103
Contains Nonbinding Recommendations Draft - Not for Implementation
4 Principles for Codevelopment of an In 104
Vitro Companion Diagnostic Device 105
with a Therapeutic Product 106
107 108
Draft Guidance for Industry and 109
Food and Drug Administration Staff 110
111 112
This draft guidance, when finalized, will represent the current thinking of the Food and 113
Drug Administration (FDA) on this topic. It does not establish any rights for or on any 114
person and is not binding on FDA or the public. You can use an alternative approach if it 115
satisfies the requirements of the applicable statutes and regulations. To discuss an 116
alternative approach, contact the FDA staff or Office responsible for implementing this 117
guidance as listed on the title page. 118
119 I. Introduction 120 An in vitro companion diagnostic device (hereafter referred to as an “IVD companion 121 diagnostic”) is an in vitro diagnostic device 1 (IVD) that provides information that is essential 122 for the safe and effective use of a corresponding therapeutic product. 2 As described in the 123 FDA guidance entitled “In Vitro Companion Diagnostic Devices,” 3 in most circumstances, 124
1 Per 21 CFR 809.3(a), in vitro diagnostic devices (IVDs) are “those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body.” IVDs “are devices … and may also be biological products subject to section 351 of the Public Health Service Act.” 21 CFR 809.3(a). This guidance does not address IVDs regulated under section 351 of the Public Health Service Act (42 U.S.C. 262).
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 guidance may also be relevant to such devices.
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the guidance entitled “In Vitro Companion Diagnostic Devices” (http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM26 2327.pdf). This guidance also states that FDA expects that most therapeutic product and IVD companion diagnostic device pairs will not meet the definition of “combination product” under 21 CFR 3.2(e). FDA
Contains Nonbinding Recommendations Draft - Not for Implementation
5 an IVD companion diagnostic should be approved, granted a de novo request or cleared by 125
FDA contemporaneously with the approval of the corresponding therapeutic product for the 126
use indicated in the therapeutic product labeling. 4
127 128
This guidance document is intended to be a practical guide to assist therapeutic product 129
sponsors and IVD sponsors in developing a therapeutic product and an accompanying IVD 130
companion diagnostic, a process referred to as codevelopment. 5 This guidance is also 131 intended to assist FDA staff participating in the review of candidate IVD companion 132 diagnostics 6 or their associated therapeutic products. 133 134
This guidance describes: general principles to guide codevelopment to support obtaining 135
contemporaneous marketing authorization for a therapeutic product and its corresponding 136
IVD companion diagnostic, certain regulatory requirements that sponsors should be aware of 137
as they develop such products, considerations for planning and executing a therapeutic 138
product clinical trial that also includes the investigation of an IVD companion diagnostic, and 139
administrative issues in the submission process for the therapeutic product and IVD 140
companion diagnostic. 141
142 Although this guidance focuses on IVD companion diagnostics, many of the principles 143 discussed may also be relevant to the codevelopment of therapeutic products with IVDs that 144 do not meet the definition of an IVD companion diagnostic but that are nonetheless 145 beneficial for therapeutic product development or clinical decision making. Likewise, the 146 principles discussed in this guidance may be useful even if codevelopment is not planned 147 from the start of a therapeutic product’s development (e.g., the potential benefit of an IVD is 148 not established until later in the therapeutic product’s development lifecycle). 149 150
FDA’s guidance documents, including this guidance, do not establish legally enforceable 151
requirements. Instead, guidances describe the Agency’s current thinking on a topic and 152
should be viewed as recommendations, unless specific regulatory or statutory requirements 153
are cited. The use of the word “should” in Agency guidances means that something is 154
suggested or recommended, but not required. 155
updates guidance documents periodically. To make sure you have the most recent version of a guidance, check the FDA website: http://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
4 In FDA’s experience IVD companion diagnostics have generally been high-risk, Class III devices, which require FDA approval of a premarket approval application (PMA); however, FDA recognizes the possibility of a moderate-risk IVD companion diagnostic (i.e., Class II device), which would require clearance of a 510(k) premarket notification or grant of a de novo request. Thus, in the context of this guidance document, the term “contemporaneous marketing authorization(s)” refers to the approval of a therapeutic product 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 codevelopment is used in reference to the development of a therapeutic product and an IVD companion diagnostic that is essential for the safe and effective use of the therapeutic product. Note that codevelopment more generally may refer to any development of a therapeutic product with an IVD.
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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 submission. Contains Nonbinding Recommendations Draft - Not for Implementation
6 II. Background 156
The concept of codevelopment of a therapeutic product and an IVD companion diagnostic 157
was first applied when the therapeutic product trastuzumab (Herceptin) was paired with an 158
immunohistochemical IVD companion diagnostic (HercepTest™) that measures expression 159
levels of human epidermal growth factor receptor 2 (HER-2; also known as ERBB2) in 160
breast cancer tissue and identifies patients more likely to have a therapeutic response. These 161
two products were approved in 1998. Since that time, interest in identifying biomarkers that 162
could be used as biological targets for therapeutic product development, prognostic 163
indicators, or predictors of patient response to specific therapeutic products has grown 164
tremendously. There are now numerous examples of therapeutic products with an 165
accompanying IVD companion diagnostic. 7
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As stated in the FDA guidance entitled “In Vitro Companion Diagnostic Devices,” 8 IVD 168 companion diagnostics are, by definition, essential for the safe and effective use of a 169 corresponding therapeutic product and may be used to: 1) identify patients who are most 170 likely to benefit from the therapeutic product; 2) identify patients likely to be at increased 171 risk for serious adverse reactions as a result of treatment with the therapeutic product; 3) 172 monitor response to treatment with the therapeutic product for the purpose of adjusting 173 treatment (e.g., schedule, dose, discontinuation) to achieve improved safety or effectiveness; 174 or 4) identify patients in the population for whom the therapeutic product has been 175 adequately studied and found to be safe and effective (i.e., there is insufficient information 176 about the safety and effectiveness of the therapeutic product in any other population). 9
178 If an IVD companion diagnostic is essential to assuring safety or effectiveness of the 179 therapeutic product, FDA generally will not approve the therapeutic product or new 180 indication for a therapeutic product if the IVD companion diagnostic does not already 181 have marketing authorization or will not receive contemporaneous marketing 182 authorization for use with that therapeutic product for that indication. In certain 183 circumstances (i.e., when a therapeutic product is intended to treat a serious or life- 184 threatening condition for which no satisfactory available therapy exists or when the 185 labeling of an approved therapeutic product needs to be revised to address a serious 186 safety issue), however, FDA may approve a therapeutic product without the prior or 187
contemporaneous marketing authorization of an IVD companion diagnostic, 10
regardless of 188
whether the IVD companion diagnostic and the therapeutic product are developed by a 189
single sponsor or are independently developed by different sponsors. 190
191 Codevelopment of IVD companion diagnostics and therapeutic products is critical to the 192 advancement of precision medicine. FDA seeks to facilitate innovations in precision 193 medicine by providing sponsors with a set of principles that may be helpful for effective 194
7 See current list of IVD companion diagnostics ( www.fda.gov/companiondiagnostics ).
8 See note 3.
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10 See FDA guidance on “In Vitro Companion Diagnostic Devices,” note 3, for further details.
Contains Nonbinding Recommendations Draft - Not for Implementation
7 codevelopment and in fulfilling FDA’s applicable regulatory requirements. 11 This guidance 195 outlines fundamental principles that have been developed to assist sponsors in 196 codevelopment. 197 III. Principles of the Codevelopment Process 198 Therapeutic products and IVDs typically are developed on different schedules, are subject to 199 different regulatory requirements, 12 and have different points of interaction with the 200 appropriate review centers at FDA. 13 The merging of the two development processes to 201 facilitate the contemporaneous marketing authorization of a therapeutic product and its 202 corresponding IVD companion diagnostic requires that the sponsors of both products have a 203 general understanding of both processes. 204 205
Sponsors of therapeutic product development programs and their IVD partners face a range 206
of issues when launching a codevelopment program. There are often questions related to use 207
of the investigational IVD 14 in a therapeutic product clinical trial and how the goals of the 208 therapeutic product development program are dependent on the IVD. This section describes 209 many of the factors that sponsors should anticipate and plan for in the codevelopment process 210 and makes recommendations for both therapeutic product and IVD sponsors to facilitate their 211 obtaining contemporaneous marketing authorizations. 212 213
Various approaches may be acceptable to obtain the data needed to support contemporaneous 214
marketing authorization of a therapeutic product and the accompanying IVD companion 215
diagnostic. Because many novel or complex issues can be raised by including an 216
investigational IVD in therapeutic product clinical trial design, FDA strongly recommends 217
that the sponsors of both the therapeutic product and the IVD meet with the appropriate FDA 218
review centers prior to launching a trial intended to advance the development of the 219
therapeutic product and the IVD companion diagnostic. Whenever appropriate, both 220
sponsors should be present at meetings with the review centers responsible for the 221
therapeutic product and the IVD, so that each sponsor is clearly informed about the Agency’s 222
thinking on both products. Sponsors are responsible for providing timely information to the 223
11 Applications for an IVD companion diagnostic and its corresponding therapeutic product will be reviewed and approved according to applicable regulatory requirements. The IVD companion diagnostic application will be reviewed and approved, granted a de novo request or cleared under the device authorities of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and relevant medical device regulations; the therapeutic product application will be reviewed and approved under section 505 of the FD&C Act (for drug products) or section 351 of the Public Health Service Act (for biological products) and relevant drug and biological product regulations.
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13 Therapeutic products are reviewed 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 by CBER 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 human immunodeficiency 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 requirements are described in Section III.B of this document.
Contains Nonbinding Recommendations Draft - Not for Implementation
8 appropriate review centers to enable an efficient review process and to support obtaining 224
contemporaneous marketing authorizations. 225
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