FDA Regulation of Diagnostic Tests

1. AIPLA Annual Meeting Joint Biotechnology Committee/ Special Committee on FDA Law Program October 21, 2010 Marriott Wardman Park Hotel – Washington, DC FDA Regulation of Diagnostic Tests Jeffrey N. Gibbs Hyman, Phelps & McNamara, P.C. Washington, DC jgibbs@hpm.com

2. Introduction • In Vitro Diagnostics (IVDs) are playing an increasingly important role in medicine. • Many new types of diagnostics being developed. • Introducing new diagnostics to the market presents potential regulatory challenges.

3. Definition of an IVD • A product intended to be used to “diagnose a disease or other condition” is regulated as a device. • “Diagnose” has been given a broad interpretation by the courts. • “Diagnose” also encompasses screening, monitoring, prognosis, etc. • Technology does not determine whether product is regulated as a device. • Not all tests are diagnostic, e.g., genealogy, ancestry, etc.

4. Intended Use: A Pivotal Concept • “Intended Use” is governed by the objective intent of the company – 21 C.F.R. § 801.4. • Intended use can determine whether Premarket Approval (PMA), 510(k) Premarket notification, or no FDA review. • Intended use can determine how much data and what type, e.g., prospective large scale study for screening study vs. small retrospective study for monitoring. • Affects reimbursement. • Relationship to IP?

5. Intended Use: A Pivotal Concept (cont’d.) • Needs to be considered at an early stage and integrated with regulatory, clinical and marketing input. • Needs to match clinical data and study population. • Controls claims for IVD once cleared/approved. • Subtle differences can have a large regulatory impact, e.g., “rule out” vs. “rule in.”

6. Intended Use: A Pivotal Concept (cont’d.) • Intended use can include population tested, purpose of test, etc. • An intended use is more specific than “A test for Cancer X.” • Closely related term is “indications for use.” • Subject to intensive negotiations with FDA. • What companies end up with can be very different from their starting point. To sum up: Can determine whether PMA or 510(k), what data need to be collected (time and cost), reimbursement coverage, and marketing strategy.

7. In Vitro Diagnostics (IVDs):Routes to the Market • Premarket Approval Application • 510(k) premarket notification • De Novo Reclassification • Investigational Use Only • Research Use Only • Analyte Specific Reagents • Laboratory Developed Tests

8. FDA Classification Scheme • Level of regulation linked to product risk. • Class I – low risk. • 510(k) generally not needed; may be exempt from Good Manufacturing Practice (GMP) regulation. • Example: Equine encephalomyelitis virus serological reagents. • Class II – moderate risk. • Usually subject to 510(k) and GMP. • Example: Glucose. • May also need to meet special controls. • Class III – highest risk. • PMA required. • Example: Human Papilloma Virus assays and cancer screening tests. • Risk is independent of performance of the assay.

9. 510(k) Premarket Notification • Most common route to market with new assay. • Need to show “substantial equivalence” to a “predicate device.” • Predicate devices on the market beforeMay 28, 1976 or cleared by FDA through a 510(k). • PMA approved device cannot be a predicate device for a 510(k), unless reclassified.

10. 510(k) Premarket Notification (cont’d.) • Substantial equivalence. • Same intended use, though FDA has some flexibility in applying requirement. • Same technology, or technological differences do not raise different issues of safety or effectiveness. • Typically, the use of novel technology, such as protein-based markers, does not preclude 510(k) clearance. • Will need to provide performance data. • The kinds of data requested may be affected by type of technology and its novelty. • Clinical data will be required for new types of assay. • Analytical test data, e.g., reproducibility, will be required.

11. 510(k) Premarket Notification (cont’d.) • FDA can find Substantially Equivalent, allowing IVD to be marketed. • Can find 510(k) Not Substantially Equivalent, i.e., reject it. • Ask for more information. • 90 days per review cycle. • Recently, many criticisms of 510(k) process. • FDA has unveiled internal reports on the 510(k) process, with many recommendations. • In general, will make 510(k)s more challenging.

12. De Novo Classification • Some low or moderate risk devices lack predicate device. • For these products, FDA can use de novo classification process. • Company submits 510(k). • Found Not Substantially Equivalent. • Then submit petition for de novo classification. • FDA can then clear the device. • FDA will issue special controls guidance document.

13. De Novo Classification (cont’d.) • FDA has used de novo process about two times per year for IVDs, e.g., circulating tumor cells for breast cancer, and recent ovarian cancer test. • FDA prefers to use 510(k) if possible because less work, since no guidance document needed. • Subsequent applicants can use 510(k) process.

14. Premarket Approval Application • Requires clinical data. • Voluminous submission. • 180 day review cycle. • Advisory panel for at least the first submission for that type of assay. • Pre-approval GMP inspection. • FDA typically monitors study sites. • More costly than 510(k)s and generally takes longer. • Once obtain approval, harder to make changes. • 510(k) route is preferred. • Potential exclusivity impact of IVD intended to be used diagnostically with drug? • Can get patent term extension.

15. Investigational Use Only (IUO) • IUO products are intended for use in clinical investigations. • Vehicle for generating clinical data to support marketing application. • Can charge for IUO products within limits. • Product must be labeled as IUO. • Sponsor needs to receive some data back from investigators. • Limited promotional claims. • Manufacturer can sell IUO products. • Clinical trial agreement between sponsor and investigator. • Should include IP-related clauses • IUO products may have protection from patent infringement claims.

16. Investigational Use Only (IUO) (cont’d.) • Generally, FDA approval not needed to begin study. • Typically will need approval from an institutional review board for prospective studies, and possibly for retrospective. • May need to obtain patient informed consent. • Banked specimens can be used under some circumstances. • Exempt from GMP regulation.

17. Research Use Only (RUO) • RUO products are intended for use in basic research or to identify a potential clinical application. • Cannot claim safe, effective, or has diagnostic utility. • Can charge for RUO products. • No need to collect data. • Exempt from GMPs. • Can create reimbursement issues for laboratories. • Useful for niche products, but not a successful long-term strategy for products with diagnostic value. • FDA has been concerned about misuse of RUO category, and plans to issue a new draft guidance document aimed at RUO manufacturers.

18. Analyte Specific Reagents (ASRs) • ASRs are building blocks for assays developed by laboratories. • They are generally exempt from 510(k) or PMA, but do need to comply with GMPs. • In a guidance document issued in September 2007, FDA substantially narrowed the scope of ASRs. • Can contain only a single marker, e.g., no primer/pair probes. • Cannot be on a bead or something similar.

19. Laboratory Developed Tests (LDTs) • LDTs are subject to the Clinical Laboratory Improvement Amendment. • FDA first said it could regulate LDTs in 1992. • According to FDA, all LDTs are medical devices and subject to full device regulation. • FDA did not seek to exercise power until a few years ago. • Exercising it more frequently, e.g., Warning Letter to LabCorp regarding OvaSure. • Issue: How much work does a lab need to do for a test to qualify as LDT?

20. Laboratory Developed Tests (LDTs) (cont’d.) • FDA has stated it intends to no longer exercise “enforcement discretion” over LDTs, but will actively regulate them. • Two-day public meeting in July to discuss. • Commenters did not oppose concept of FDA regulation. • Considerable concern about manner in which regulation would occur, particularly for rare/orphan diseases and emerging diseases, and cost of regulation. • FDA has said prioritization scheme will be risk-based. • Diagnostics that guide drug therapy will be priorityfor being brought under FDA regulation.

21. Laboratory Developed Tests (LDTs) (cont’d.) • Will take some time for details of framework to be developed. • FDA has said does not intend to disrupt current testing. • Grandfather period for tests on the market. • Grace period, i.e., delayed effective date. • Impact on innovation? • Impact on FDA workload? • FDA’s regulation of LDTs may prompt litigation. • Begin by requiring registration of laboratories?

22. Conclusion • Public health impact increasing. • IVDs represent a large and growing industry. • Complex, evolving regulatory environment.