FDA Regulation of In Vitro Diagnostics: Current Perspectives and Initiatives

Transcription

1 FDA Regulation of In Vitro Diagnostics: Current Perspectives and Initiatives Katherine Donigan, Ph.D. Office of In Vitro Diagnostics and Radiological Health, FDA Life Science Tennessee Annual Conference September 30,

2 Overview Overview of FDA mission and structure FDA oversight of in vitro diagnostic devices FDA draft guidances on LDT oversight President Obama s Precision Medicine Initiative 2

3 FDA s Mission To Protect and Promote the Public Health A consumer protection agency A regulatory agency FDA is an agency within the Department of Health and Human Services and consists of nine Centers and Offices 3

4 What does FDA do? Assure the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products, and medical devices Assure the safety of the food supply, cosmetics, and radiation emitting products Regulate tobacco products Advance Public Health By helping speed innovations that make products more effective, safer, and more affordable Help the public get accurate, science based information about these products What does FDA not do? FDA does not dictate medical practice, service, or the price of medical products 4

5 How does FDA accomplish its work? New product review and pre market approval Monitoring Safe manufacturing Safe handling New risks Enforcement/Compliance Research 5

6 FDA Regulatory Framework Overview Existing Statutory Provisions Primary Sources of Statutory Authority Federal Food, Drug, and Cosmetic Act (FD&C Act) Encompasses many individual bills e.g. User Fee Acts, Family Smoking Prevention and Tobacco Control Act, FDA Food Safety Modernization Act Public Health Service Act Other relevant statutory sources with impact on FDA Authority 6

7 FDA Regulatory Framework Overview New Statutory Enactments implementation Provisions may mandate certain health policy position and direct specific manner of implementation Provisions may directly require: Rulemakings and/or Guidances FDA issues regulations to implement its statutory authority. The regulations can create binding obligations and have the force of law. Guidances can provide implementation recommendations, clarify statutory provisions, or provide technical assistance. Guidance documents represent FDA's current thinking on a topic. They do not create or confer any rights for or on any person and do not operate to bind FDA or the public. Public Meetings/Advisory committee Meetings Change in internal procedures Creation of a new office/program to handle particular matters 7

8 outfda/centersoffices/ OrganizationCharts/uc m htm Office of Women s Health Office of Minority Health Office of the Chief Scientist FDA Organization Office of the Commissioner Office of the Chief Counsel Office of the Executive Secretary Office of Counselor to Commissioner Office of External Affairs Office of Foods and Veterinary Medicine Office of Global Regulatory Operations & Policy Office of Medical Products and Tobacco Office of Operations Office of Policy, Planning, Legislation and Analysis CFSAN CVM ORA NCTR CBER CTP CDER CDRH 8

9 Center for Devices and Radiological Health (CDRH) 9

10 FDA oversight of in vitro diagnostic devices 10

11 IVD Regulation In Vitro Diagnostic tests (IVDs) are a critical component of current clinical care, influencing ca. 80% of all clinical decision making Through the 1976 Medical Device Amendments to the FFDCA, FDA has the authority to regulate all laboratory tests intended for use in the diagnosis of disease or other conditions, regardless of whether they were commercially distributed or developed by a laboratory FDA is charged with ensuring that IVDs are safe and effective (do what they say they will do) for their intended use so that patients are not unnecessarily harmed 11

12 FDA s Risk Based Approach to Regulation Premarket submission 3 classification levels: Class I: common, low risk devices 510k (usually exempt) Class II: more complex, moderate risk usually 510k Class III: most complex, high risk usually PMA Risk is based on consequences of a false result in the context of clinical care Decision is based on risk benefit analysis (safety and effectiveness) Clinical trial using investigational device 3 categories: IDE exempt Nonsignificant risk Significant risk Risk is based on the consequences of a false result in the context of a clinical protocol Decision is primarily focused more on risk (primarily safety) 12

13 Reasonable Assurance of Safety and Effectiveness Safety. There is reasonable assurance that the probable benefits outweigh any probable risks. [21CFR860.7(d)(1)] Effectiveness. There is reasonable assurance that in a significant portion of the target population the use of the device will provide clinically significant results. [21CFR860.7(e)(1)] 13

14 Elements of FDA Premarket Review Analytical validity Correctly detects analyte Accuracy, precision, limits of detection/measurement, other information/data relevant to test performance Clinical validity Correctly identifies disease/condition Clinical sensitivity, clinical specificity, predictive values Data are usually from clinical studies, literature, or other sources, but randomized controlled trials are usually not required. Labeling Includes claims you make about analytical and clinical validity Assessment based on intended use 14

15 FDA Draft Guidances on LDT Oversight Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs) 15

16 FDA LDT Definition An LDT is an IVD that is intended for clinical use and is designed, manufactured and used within a single laboratory. Test systems, instrumentation, IVD kits, software, etc. that are intended for clinical uses, even if developed and used in a single laboratory, meet the definition of a device. 16

17 test kit manufacturer Today s LDTs are marketed under enforcement discretion by FDA. CLIA certified lab FDA Enforcement Discretion Performed in CLIAcertified Performed within same lab lab that developed test 17

18 Public Health Need for Greater Oversight Evolution of LDT technology, marketing, and business models has: Increased risk associated with LDTs Created gaps in LDT Oversight Potential consequences Significant adverse health consequences Unnecessary healthcare costs Could undermine progress of personalized medicine, which depends on tests that work 18

19 Recent Timeline July 2010 Public Meeting Oversight of Laboratory Developed Tests July 2014 Congress notified October 2014 Release of draft guidances January 2015 Public Workshop Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) February 2015 Comment period closes April 2015 FDA CMA Task Force on LDT Quality Requirements announced 19

20 Goals of the Proposed Framework 1. Collect basic information on all LDTs through optional notification process (i.e., no fee alternative to R&L) 2. Use public process (i.e., advisory committees) to obtain input on risk and priority for oversight 3. Phase in enforcement of premarket review over ~9 years based on risk 4. Continue some enforcement discretion for specific categories determined by FDA to be in the best interest of public health 20

21 Phased in Enforcement of Premarket Review Risk based phase in Highest risk first Premarket submission PMA or 510(k) depending on classification Premarket review decision from FDA FDA proposes to enforce manufacturer reporting requirements of the MDR regulation (adverse event reporting) Serious injuries, deaths (potential or actual) Device malfunctions Obligation to report when manufacturer becomes aware FDA does not intend to enforce the premarket submission requirements for certain categories of LDTs 21

22 Continued Enforcement Discretion Notification MDRs Premarket Review LDTs used solely for forensic purposes X X X X X QSRs R&L LDTs used in CLIA certified, high complexity histocompatibility labs for transplantation X X X X X low risk medical devices, including low risk LDTs LDTs used for rare diseases per HUD definition X X X* X X X* Traditional LDTs X X X* LDTs for unmet needs when no FDA cleared/approved alternative exists *FDA intends to continue exercising enforcement discretion for R&L provided notification is completed X X X* 22

23 Traditional LDTs Proposed oversight: Enforcement discretion for premarket review and quality systems Enforcement of R&L (with option for notification) and adverse event reporting Proposed factors for enforcement discretion: Designed, manufactured and used within a single lab; A health care facility lab so that a patient that is being diagnosed and/or treated at that same health care facility or within the facility s healthcare system; Components and instruments that are legally marketed for clinical use; and Interpreted by qualified laboratory professionals without the use of automated instrumentation or software for interpretation. 23

24 Proposed oversight: LDTs for Rare Diseases Enforcement discretion for premarket review and QS Enforcement of R&L (with option for notification) and adverse event reporting Proposed factors for enforcement discretion: Designed, manufactured and used within a single lab; and Meet the definition of a Humanitarian Use Device (HUD) under 21 CFR (a)(5) (i.e., number of persons who may be tested is fewer than 4,000 per year in the United States) 24

25 Proposed oversight: LDTs for Unmet Needs Enforcement discretion for premarket review and QS Enforcement of R&L (with option for notification) and adverse event reporting Proposed factors for enforcement discretion: Designed, manufactured and used within a single lab; No cleared or approved IVD available for the specific intended use; and Manufactured and used by a health care facility lab for a patient that is being diagnosed and/or treated at that same health care facility or within the facility s healthcare system. 25

26 Proposed Phase In (based on final guidance publication date) Highest risk LDTs already on market LDTs with same intended use as cleared/approved companion diagnostics LDTs with same intended use as approved Class III medical devices Certain LDTs for determining safety or effectiveness of blood or blood products Subsequent high risk LDTs in priority order developed with input through public process Notification* MDRs Premarket Review QS Reg. 6m 6m 1y Upon PMA submission 6m 6m 2 5y Upon PMA submission R&L Upon PMA approval (if notification has been provided) Upon PMA approval (if notification has been provided) Moderate risk LDTs in priority order developed with input through public process * Notification is not a requirement but an option to R&L. 6m 6m 5 9y Upon 510k clearance Upon 510k clearance(if notification has been provided) 26

27 Where are we today? t=0 6m 1y 2y 3y 4y 5y 9y Somewhere over here! FDA does not intend to implement the proposed enforcement policy for LDTs prior to publication of final guidances. 27

28 LDT Public Comments Highlights Labs need more time extend timelines Notification First round of PMA submissions (LDTs with same intended use as existing Class III device) Quality Systems compliance Labs need more certainty and clarity Classification and prioritization should occur as soon as possible, use advisory panels Specify which modifications result in a new LDT Describe how CLIA labs could comply with QS regulations What current activities could be leveraged What QS reg requirements may not be enforced FDA should provide outreach and education Continued engagement during phase in Educational inspections 28

29 LDT Public Comments Highlights Categories under continued enforcement discretion for premarket review should be modified Traditional LDTs Should be under complete enforcement discretion LDTs for unmet needs Ending enforcement discretion once one test is cleared or approved could lead to market monopolies, access issues Healthcare system factor is problematic Concerns about patient access, testing external samples Certain LDTs for public health purposes should also remain under continued enforcement discretion 29

30 Announced in April 2015 FDA CMS Task Force Overarching goal: to clarify and coordinate roles of CMS and FDA with respect to LDT quality 30

31 FDA CMS Task Force FDA and CMS have a longstanding relationship. FDA CMS understand the important role Accrediting Organizations (AO)s play in the implementation of CLIA FDA CMS have invited all AOs to discuss their requirements for laboratories, and how these requirements relate to LDTs The task force reviewed the intersection of FDA and CLIA regulations. FDA QS reg and CMS CLIA regulations do not specify how a lab should meet requirements, leaving room for labs to implement processes that meet their unique business operations and needs. FDA and CLIA regulations are not in conflict. The task force confirmed that there are no activities required by CLIA that would put a laboratory in violation of the FDA QS reg, and vice versa. 31

32 Getting to Final Guidance Review and synthesize public comments Modify guidance documents based public input received Provide robust response to comments Intend to issue final guidance in 2016 Provide ongoing education and training Questions? 32

33 The President s Precision Medicine Initiative (PMI) To enable a new era of medicine through research and technology that empowers patients, researchers, and providers to work together toward development of individualized treatments. 33

34 Doctors have always recognized that every patient is unique, and doctors have always tried to tailor their treatments as best they can to individuals. You can match a blood transfusion to a blood type that was an important discovery. What if matching a cancer cure to our genetic code was just as easy, just as standard? And that s why we re here today. Because something called precision medicine gives us one of the greatest opportunities for new medical breakthroughs that we have ever seen. President Obama, January 30,

35 Success of Precision Medicine Requires: Safe and accurate diagnostic tests that reliably identify individual variation Learning health systems that enable researchers and clinicians to learn from and inform the patient experience Development of targeted therapies that are more efficacious or have less deleterious side effects for specific individuals Updated research and regulatory policies that catalyze the development of new treatments while protecting patients 35

36 FDA A Long History of Enabling Precision Medicine 23 companion diagnostics cleared or approved 50 biomarkers used in targeting 147 approved drugs* Cystic Fibrosis, Cancer, Cholesterol, Psychiatric, Pulmonary, Infectious Diseases, etc. More than 60 approved/cleared human nucleic acid based tests** More than 24 Guidances issued since ** and 36

37 Disclaimer Thoughts presented here on new regulatory and policy issues related to the Precision Medicine Initiative are preliminary and do not represent proposed or finalized FDA policy. 37

38 Next Generation Sequencing and Precision Medicine The human genome is composed of about 3 billion bases, and each individual carries millions of genetic variants. Next generation sequencing (NGS) is a technology that can rapidly and cheaply determine the entire sequence of an individual s genome. Next generation sequencing (NGS) tests are critical for precision medicine, because they have an unprecedented ability to identify individual level variation. 38

39 In Vitro Diagnostics in the Age of Precision Medicine Traditional Diagnostics Precision Medicine Low/medium resolution technology High resolution technology ( omics ) Detect a finite number of analytes (usually one) One test one disease Clinical evidence from randomized controlled trials research separate from practice Undefined (millions?) One test many diseases Clinical evidence from learning health systems merging of research and practice 39

40 Regulatory Issues NGS tests often lack a specific intended use Can t predefine the results that will be obtained Often don t know the disease that will be diagnosed until the test is performed Incidental findings Traditional requirements for review Each claim Modifications that affect the safety and effectiveness of a test 40

41 Precision Medicine Initiative: Modernizing FDA Regulation of Genomic Laboratory Tests Need to ensure that the information that patients receive from NGS tests is accurate and relevant to their condition (analytically and clinically valid) Differences in data volume and interpretation may warrant a new regulatory approach that will ensure that patients and providers are able to make treatment decisions based on accurate test results 41

42 Precision Medicine Initiative: Modernizing FDA Regulation of Genomic Laboratory Tests Vision: Implement new regulatory policies to promote research and accelerate the translation of precision medicine technologies into treatments that benefit patients. Near Term: Implement standards and shared resources that would enable the development of knowledge for research and patient decision making Longer Term: Implement standards based regulation of diagnostic tests that would ensure that the tests patients receive provide accurate, reproducible, and meaningful results 42

43 Precision Medicine Initiative: Modernizing FDA Regulation of Genomic Laboratory Tests New regulatory strategies for next generation sequencing Develop and implement standards to ensure quality Develop open source tools to help test developers meet standards Promote translation and innovation to advance precision medicine by adopting a flexible, adaptive regulatory system 43

44 Precision Medicine Initiative: Enabling Discovery and Knowledge Generation Enable the clinical interpretation of genomic test results Development of high quality, publically available databases Create a data commons for a variety of sources of information 44

45 FDA s Concepts for NGS Regulation 1. Technical standards for NGS. Test developers that meet these standards may not have to submit an application to FDA. Standards would be developed with the scientific community, and can be updated as science and technology advance. FDA would develop and provide open source software to enable test developers to meet standards. 2. Use of curated databases to provide clinical evidence. Use regulatory grade databases as information sources to support the link between genetic variation and health/disease. Test developers may be able to use such databases in lieu of traditional clinical studies. Such databases may also be used by laboratories and physicians as part of a genomic test. 45

46 Advancing the accuracy and reproducibility of NGS Crowd sourced, cloud based platform Will provide tools and open access resources Will allow the community to test, pilot, and validate approaches to NGS Community NGS-Based Test Developers (large and small), NIST, FDA Scientists, Standards Bodies, Academic Centers, Patient-Facing Providers, Consortiums FastQ Approve Quality Threshold Analysis and Pipeline(s) VCF Reject Reference Data Slide courtesy of Taha Kass Hout, FDA Chief Health Informatics Officer Security and Privacy HIPAA/HITECH, CAP, ISO27001 Uniquely identified and immutable data Version-controlled applications

47 Future Work Standards architecture Technical standards for a specific intended use Technical standards for multiple use cases Draft policy development Organization of technical efforts Analytical standards (e.g., GIAB) Clinical performance (pilot with ClinVar/ClinGen) Informatics, including open source computational solutions for validating NGS test performance Engagement of external stakeholders Discussion papers on specific topics Follow on public workshops on specific topics Development of a draft policy 47

48 Precision Medicine Initiative: Next Steps FDA workshop on Feb 20, 2015 discussed the overall vision: Optimizing FDA s Regulatory Oversight of Next Generation Sequencing Diagnostic Tests nces/ucm htm Upcoming workshops will focus on technical specifics Analytical performance Nov 12, s/ucm htm Clinical interpretation Nov 13, s/ucm htm Patient/provider perspectives early

49 Questions? 49