FDA's Initiative to Regulate Lab- Developed Tests (LDT) will Harm Patients and Academic Pathology

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2 FDA's Initiative to Regulate Lab- Developed Tests (LDT) will Harm Patients and Academic Pathology Edward Ashwood President and CEO, ARUP Laboratories Tenured Professor of Pathology, University of Utah 19 May 2015

3 Disclosures 1. Ed Ashwood receives a professor s salary from University of Utah 2. His administrative duties include being Chief Executive Officer of ARUP Laboratories 3. His clinical duties include directing Maternal Serum Screening for ARUP 4. ARUP Laboratories is a non-profit enterprise of the University of Utah (no private ownership)

4 Objectives 1. Understand the history and current regulatory process for clinical laboratory tests Lab Developed Tests under CMS/CLIA Medical Devices under FDA 2. Explain the negative impact of dual regulation on patient care and competition 3. Act to prevent or mitigate FDA s intent to regulate LDT

5 Lab Developed Tests LDT are clinical tests offered by laboratories that do not use FDA-approved kits, instruments, or reagents. LDT include the off-label use of FDAapproved kits, instruments, and reagents.

6 FDA Background 1906: Pure Food and Drugs Act 1938: Federal Food, Drug, and Cosmetic Act passed sulfanilamide poisoning crisis drug dissolved in diethylene glycol, no animal safety studies >100 deaths

7 FDA Background 1976: Medical Device Amendments enacted In 1970 HEW Cooper Committee recommended medical device regulations based on risk Harm caused by Dalkon Shield facilitated passage by Congress Law does not mention clinical labs

8 The Issue 1976 to 1992, FDA ignores LDT 1992 to 2010, FDA s stance on LDT: Enforcement Discretion June 2010, FDA announces intent to regulate LDT Labs vocally against FDA s plan Many meetings with FDA, Congress, and the Office of Management and Budget (OMB) July 31, 2014, FDA notifies Congress of intent to regulate LDT October 3, 2014, draft guidance published in the Federal Register January 8-9, 2015, FDA Public workshop February 2, 2015, comments closed FDA is reviewing the comments. Public awaits FDA s action.

9 Primary Arguments For given by FDA LDT are more complicated than in 1976 Some LDT are unsafe LDT have not been proven effective FDA has authority to regulate

10 Primary Argument Against LDT are medical services, not medical devices Therefore, FDA has no LDT authority Regulating LDT per the FDA draft guidance will Be very expensive and establish monopolies Stifle innovation of new LDT and slow improvement of existing LDT Harm patients Protect manufacturers

11 History of FDA Regulations For IVD regulations, FDA must consider Safety and efficacy Manufacturer claims of intended use Quality of design and manufacturing process The 1976 Act defines 3 classes of devices Class I: lowest risk Class II: moderate risk Class III: high risk

12 Test Device Classification Class I (low risk) exempt from premarket submission Manufactured under GMP (21 CFR 820) Class II (moderate risk) FDA clearance via 510(k) premarket notification 90 day review clock (true average 121 days) 3,500 applications/year, 95% approval Class III (high risk) FDA approval via premarket application (PMA) 180 day review clock (true average >1 year) 35 applications/year, 80% approval

13 CLIA Background CLIA 1967 and 1988: Comprehensive legislation that directs HHS to regulate labs under a single statute. Representative Dingell explained, [CLIA] should end duplicative and confused regulation under a tangled web of statutory authorities. FDA did not comment on CLIA 88

14 CMS/CLIA (FDA) 42 CFR Standard: Establishment and verification of performance specifications. (b)(1) Verification of performance specifications. Each laboratory that introduces an unmodified, FDA-cleared or approved test system must do the following before reporting patient test results: (i) Demonstrate that it can obtain performance specifications comparable to those established by the manufacturer for the following performance characteristics: (A) Accuracy. (B) Precision. (C) Reportable range of test results for the test system. (ii) Verify that the manufacturer's reference intervals (normal values) are appropriate for the laboratory's patient population.

15 CMS/CLIA (non-fda) 42 CFR Standard: Establishment and verification of performance specifications. (b)(2) Establishment of performance specifications. Each laboratory that modifies an FDA-cleared or approved test system, or introduces a test system not subject to FDA clearance or approval (including methods developed in-house and standardized methods such as text book procedures), or uses a test system in which performance specifications are not provided by the manufacturer must, before reporting patient test results, establish for each test system the performance specifications for the following performance characteristics, as applicable:

16 CMS/CLIA (non-fda) (b)(2) must establish (i) Accuracy. (ii) Precision. (iii) Analytical sensitivity. (iv) Analytical specificity to include interfering substances. (v) Reportable range of test results for the test system. (vi) Reference intervals (normal values). (vii) Any other performance characteristic required for test performance. Clinical validity fits nicely under this last requirement.

17 2014 Draft Guidances from FDA

18 Requirements of Guidance Clinical Labs providing LDT services are manufacturers, subject to same oversight as IVD companies Premarket review and approval for class 2 and 3 LDT with some exceptions Quality System Regulation Requirements Medical Device Reporting of adverse events

19 Exceptions: Traditional LDT IVD devices that reflect the types of LDT available [in 1976]? No Mass Spect, HPLC, ELISA, PCR, or DNA? both manufactured and used by a health care facility laboratory for a patient that is being diagnosed at that same health care facility comprised only of components legally marketed for clinical use No RUO? without the use of software for interpretation How about calibration curves?

20 Other Exceptions LDT for unmet needs LDT for rare diseases Fewer than 4000 patients tested per year in USA Bizarre, newborn screening is for rare diseases and millions of infants are tested each year LDT used for forensics LDT used in HLA labs for transplant

21 Harm of Dual Regulation Economic Harm Patient Harm

22 Premarket Review Class 2 require 510K Class 3 require PMA Review very slow Cost of preparing submissions is very high

23 Submission Complexity Estimated Cost and Time to prepare and obtain FDA clearance/approvals Approximate Time, Complexity, and Cost of IVD Approvals 510(k) PMA $5,000,000 $2,500,000 $250,000 $50, Years to Approval

24 ARUP Economic Analysis Number of LDT on ARUP menu More than 500 Class II More than 60 Class III Cost of pre-market approval alone $316,000,000 $316,000,000

25 Practical Effect ARUP would abandon about 400 LDT Some would become extinct Some would become sendouts Some would be replaced with inferior FDA approved tests Other labs will make the same evaluations and will draw the same conclusions

26 Major Economic Impacts Increased costs to patients The costs are real and someone must bare them Hindered innovation New test development will be slowed Old test improvement will be stifled Reduced competition LDT will move out of smaller labs into larger ones

27 Will patients be safer? Many LDT exist because they are better than the obsolete FDA tests

28 Action Needed (and Taken) Convince FDA guidance unwise Judicial (i.e. sue FDA) Executive (i.e. convince OMB that economic impact is too high) Congressional (i.e. pass a new law)

29 Actions Taken: Convince FDA June 2013, ACLA files Citizen Petition challenging FDA July 31, 2014, FDA denies the Citizen Petition

30 Actions Taken: Convince FDA From 10/3/2014 to 2/2/2015 comments were accepted by FDA on the guidances 236 comments were submitted. Over 50 people spoke at the FDA public workshop. 90% opposed the regulations. Ashwood s speech starts at 1:07:40

31 Judicial: Challenge Authority ACLA has hired Larry Tribe and Paul Clement for legal advice The Medical Device Act of 1976 did not mention LDT or clinical labs explicitly Law unenforced for 38 years

32 Judicial: Guidance versus Rulemaking FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Rulemaking would require More time for review and feedback An economic impact analysis

33 Executive: OMB OMB reviews all regulations and guidances Has the power to delay implementation OMB created a 4 year delay of FDA guidance (2010 to 2014)

34 Congress: Pass a Law Representative Burgess (TX-R) proposed a bill, LDT are not medical devices Never got out of committee House Energy and Commerce committee interested in having LDT section in their 21 st Century Cures Act (under development) DTWG working with FDA and HEC Members include 3 reference labs and 3 manufacturers

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