1. Oversight of Laboratory Developed Tests (LDTs) Andrew C. Fish, Executive Director NCCS Cancer Policy Advocate Training November 13, 2014

2. AdvaMedDx.org2 Presentation Overview  Who is AdvaMedDx?  What are diagnostics and how are they currently regulated?  What are the concerns with LDTs?  How does FDA plan to oversee LDTs?  Questions/Discussion

4. AdvaMedDx.org4 What are Diagnostics?  Diagnostics are tests performed on samples taken from the body, such as blood, tissue, and urine.  Clinical Chemistry  Examples: Urinalysis; blood glucose monitor. Measuring essential chemicals to monitor basic bodily functions and uncover abnormalities.  Hematology & Cytology  Examples: Pap tests; blood cell counts. Assessment of blood functions; identification of cellular pathologies.  Immunochemistry and Microbiology  Examples: tumor marker tests, HIV antibody tests, streptococcal throat tests, and urinary tract tests. Detection and identification of disease-causing agents, like bacteria and viruses, as well as the proteins, hormones, and anti- bodies related to the functions of the body’s immune system.

5. AdvaMedDx.org5 What are Diagnostics? cont’d  Molecular Diagnostics  Molecular diagnostic tests detect target proteins and specific genetic sequences (“biomarkers”) to help identify disease presence, type, progression, and recurrence risk.  Examples: multivariate-index test to determine risk of breast cancer recurrence; BRAF mutation test to determine late stage melanoma patient candidates for targeted drug therapy.  These advanced diagnostic tests help clinicians tailor care to subpopulations and individuals—enabling targeted “personalized medicine.” An important component of personalized medicine is the emerging field of companion diagnostics, in which a molecular diagnostic test is used to identify whether a specific drug (companion with the test) is right for an individual patient.

6. AdvaMedDx.org6 Cancer Diagnostics  Screening  Diagnosis (taxonomy of cancer evolving from site-specific to genetic)  Prognosis/Recurrence Risk  Treatment Selection  Monitoring/Follow up

7. AdvaMedDx.org7 Evaluating Diagnostics  Food, Drug, & Cosmetic Act: “safe and effective” as determined by FDA  Means:  Analytically valid – meets claim of what it measures and how accurately  Clinically valid – the thing measured is relevant to the disease (and, in many cases, to a care decision)

8. AdvaMedDx.org8 What is Risk?  Risk = possibility of harm to patient that could result if test results are incorrect  Higher risk:  When a false result could lead to incorrect and harmful clinical management, an unnecessary invasive procedure, or failure to follow up on a serious condition  The purpose of FDA review is to assure availability of safe and effective tests – for the protection of patients.

9. AdvaMedDx.org9 What are Laboratory Developed Tests?  Diagnostic tests are  (1) produced by manufacturers for distribution to laboratories or other users, or  (2) produced in and offered by laboratories for use in their own facilities – these are laboratory developed tests (LDTs).  In addition to LDTs used in professional settings, some labs are marketing their own tests directly to consumers – including genetic tests claiming to identify disease risk.

10. AdvaMedDx.org10 So What is the Issue?  Although both statute and regulation cover LDTs, FDA does not currently enforce its regulations for LDTs.  FDA does enforce regulate diagnostics that manufacturers sell to laboratories and other users – requiring pre-market assurance of safety and effectiveness.  Since 1976, FDA has generally exercised enforcement discretion for LDTs.  Why? Because, at that time, LDTs generally were well- understood and relatively simple low risk-tests, or used for rare conditions for which adequate validation would not be feasible.  Now, LDTs encompass even the most advanced molecular diagnostics, such as technically complex genetic tests that guide cancer treatment.

11. AdvaMedDx.org11 Why the Concern with LDTs? FDA:  “Diagnostic tests are playing an increasingly important role in clinical decision making and disease management, particularly in the context of personalized medicine.”  “LDTs are often used to assess high-risk but relatively common diseases and conditions and to inform critical treatment decisions.”  “Even when FDA-approved tests are available for a disease or condition, laboratories often continue to use LDTs that have not been reviewed by the agency.”  “LDTs that have not been properly validated for their intended use put patients at risk. Risks include risk of missed diagnosis, wrong diagnosis, and failure to receive appropriate treatment.”

12. AdvaMedDx.org12 So Who Oversees Lab Developed Tests Now?  The Centers for Medicare and Medicaid Services (CMS) has oversight authority of clinical laboratories under the Clinical Laboratory Improvement Amendments of 1988 (CLIA).  CLIA establishes laboratory quality standards and ensures that labs are following good lab practices, including testing procedures and the employment of credentialed lab personnel. But  CLIA is not a substitute for FDA oversight.  Only FDA has the resources and expertise to review LDTs for safety and effectiveness.

13. AdvaMedDx.org13 What CLIA Does Not Do  CMS itself has said CLIA regulations are not a substitute for FDA oversight. Many critical features of FDA oversight are missing from CLIA. Furthermore, CMS does not have the expertise or resources to oversee LDTs in the same manner as FDA.  Unlike FDA oversight of diagnostics, CLIA:  Does not regulate the safety and effectiveness of diagnostic tests;  Does not require pre-market review of tests;  Does not require demonstration of clinical validity (whether the test is meaningful for clinical decision making);  Does not require systematic adverse event reporting;  Does not have a process for corrections or recalls.  A test is a test—and presents the same risk for patients regardless of whether it is developed by a manufacturer or a laboratory. Potential harms to patients whose tests return incorrect results include unnecessary treatments, with their accompanying costs and side effects, and treatment delay or failure to obtain appropriate treatment, all of which lead to worse outcomes for those patients.

14. AdvaMedDx.org14 Calls for Reform Are Not New  April 2008: HHS Secretary’s Advisory Committee on Genetics, Health, and Society (SACGHS) issues report: US System of Oversight of Genetic Testing: A Response to the Charge of the Secretary of Health and Human Services  Calls upon FDA to “address all laboratory tests, regardless of how they are produced (i.e., as a commercial test kit or laboratory- developed test)”.

15. AdvaMedDx.org15 Stakeholders Endorse FDA Oversight  Numerous Cancer Advocacy Groups, incl.  American Cancer Society  American Association for Cancer Research  Ovarian Cancer National Alliance  Cancer Leadership Council  National Coalition for Cancer Survivorship  American Society of Clinical Oncology  American Heart Association  College of American Pathologists  National Health Council  College of American Pathologists  Society for Women’s Health Research  AIDS Institute  Alliance for Aging Research  Men’s Health Network

16. AdvaMedDx.org16 FDA Proposed LDTs Framework  October – Draft Guidance: “Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs).”  Defines LDT as a test “intended for clinical use and designed, manufactured and used within a single laboratory”  A risk-based approach – start with high risk tests and phase in enforcement over time (9 years).  LDTs divided into current three risk categories – Class I (low), Class II (moderate), and Class III (high)

17. AdvaMedDx.org17 Exceptions For Low Risk and Special Needs Enforcement discretion re. Premarket Review & Quality Systems Requirements* Low risk LDTs (Class I) LDTs for rare diseasesTraditional LDTsLDTs for unmet needs Continued Enforcement Discretion LDTs for solely forensic LDTs used in organ, stem cell, and tissue transplantation *Notification/registration and listing and adverse events reporting required

18. AdvaMedDx.org18 LDTs for Rare Diseases must meet definition of a Humanitarian Use Device (fewer than 4,000 patients per year tested with the LDT) LDTs for rare diseases

19. AdvaMedDx.org19 Traditional LDTs Both manufactured and used by a health care facility laboratory (such as a hospital or clinic) for a patient being diagnosed and/or treated at that same health care facility or within the facility’s healthcare system Comprised of only legally marketed components and instruments; AND Interpreted by qualified lab professionals, without the use of automated instrumentation or software interpretation “Traditional LDTs” factors include:

20. AdvaMedDx.org20 LDTs for Unmet Needs Both manufactured and used by a health care facility laboratory (such as a hospital or clinic) for a patient being diagnosed and/or treated at that same health care facility or within the facility’s healthcare system; AND No FDA cleared or approved IVD available for that specific intended use LDTs for Unmet Needs factors include:

21. AdvaMedDx.org21 Regulatory Requirements for All LDTs Notification or Registration and listing Adverse event reporting

22. AdvaMedDx.org22 Regulatory Requirements for High and Moderate Risk LDTs (9 Year Phase In) Notification or Registration and listingPremarket reviewQuality system requirementsAdverse event reporting

23. AdvaMedDx.org23 Implementation Timeline for All LDTs After Final Guidance At Six months– Notification completed and/or Registration and listing and adverse event reporting At 12 months– Premarket review for initial high risk (class III) devices At 24 months– Priority list for remaining high risk (Class III) devices with submission starting 12 months later At 4 years– FDA releases priority list for moderate risk (Class II ) devices At 5 years– FDA completes phased-in enforcement of premarket review for Class III & commences Class II Phase in At 9 years– moderate risk LDTs phased in

24. AdvaMedDx.org24 What Happens Now?  Stakeholders will comment on draft guidance (comments close February 2 nd )  FDA will issue final guidance (timing uncertain)  Stay tuned regarding Congressional interest

25. Questions?