Proposed Goals and Benefits of Personalized Medicine, and How We Are Trying to Make It Happen

1. Proposed Goals and Benefits of Personalized Medicine, and How We Are Trying to Make It Happen Elizabeth Mansfield, PhD Director, Personalized Medicine Staff OIR/CDRH/FDA

2. Disclaimer • This is not regulatory advice • Some of what I will discuss is “forward looking” • Seems like a good idea • We haven’t done it yet • Things may come out slightly differently • “Approval” applied to diagnostic means approval or clearance

3. Outline • Goals and Benefits of Personalized Medicine • IVD Companion Diagnostic Guidance (draft) • What it says • What it means • Possible business challenges in the model • Therapeutic, diagnostic, regulatory, reimbursement • How next-gen sequencing affects the model • Concepts and clinical implementation

4. Personalized Medicine: What Is It? • Personalized Medicine, precision medicine, targeted medicine, stratified medicine • Ultimately: “The right drug for the right patient at the right dose” • For now: Use of a biomarker test to direct therapeutic use • HER2/Herceptin • KRAS/Erbitux • Numerous others

5. Potential Benefits Drug pipelines invigorated Drugs with Improved Risk/benefit Better patient Outcomes (for some) ??? Healthcare Savings?

6. How Will We Get There?

7. IVD Companion Diagnostic Guidance (draft) • Guidance intended to express FDA’s current thinking on • Regulation of therapeutic products that rely on a test result to select population or dose • E.g., Herceptin, Cetuximab, Xalkori, Zelboraf • Regulation of tests that support therapeutic product approval and use • E.g., HER2, KRAS, ALK, BRAF tests

8. Why Guidance? FDA guidance is intended to express current thinking on a subject, through a managed, open process Draft conveys FDA intent to Public for comment Comments considered, draft revised Final guidance articulates current thinking For therapeutic products, the requirement for a contemporaneous device approval when a test is necessary has been in place, but not consistently articulated, and not openly announced to stakeholders for comment. The IVD Companion Diagnostic (draft) is intended to remedy this.

9. Why Companion Diagnostics? • Companion diagnostic devices are those medical devices that are essential for safe and effective use of a therapeutic product • Without the device, the drug cannot be used in a manner consistent with its approval, i.e., would not be considered safe and effective • Approval of a companion diagnostic assures that a test with the required performance is available

10. Companion Diagnostic Guidance (draft) Principles • Defines companion diagnostic device • Likely scenarios; what is not a companion diagnostic • Explains need for review, and contemporaneous approval • Discusses labeling issues • States need to consider investigational status of diagnostic as well as therapeutic

11. “Subtle” Issues in Policy • Responsibility is on therapeutic sponsor to assure test is brought forward • Agnostic with regard to device manufacturer • Labeling intended to allow addition of tests • Proving a test is “better” than existing test will be challenging

12. What Does It All Mean? • Where a sponsor believes that a test will be needed to identify the appropriate treatment population or dose • Plan for use of validated test in clinical trials • Demonstration that marker tested is useful • Plan for business interaction with diagnostic provider • Get timing right so that therapeutic/diagnostic can be approved together • Work closely with FDA: therapeutic and diagnostic review Centers

13. When Does Companion Diagnostic Decision Need to be Made? Timing of decision on when to introduce a test into the clinical trial process (i.e., expect a companion diagnostic to be required) can vary • Early—drug design, preclinical data • Later—new information on marker use, early phase trials • Latest—prior to “pivotal” therapeutic trial

14. Effects of Timing on Development • Early decision • Refinement of test over time • More data to support companion Dx role • Possible availability of to-be-marketed device for “pivotal” trial (best scenario) • Late decision • Less time for product development of device • Probable bridging test-to-test required • No test, no drug* *some exceptions will exist

15. Marketing Exclusivity • Therapeutic product • Market exclusivity often applies for new drugs and new uses for approved drugs • Diagnostic product • No market exclusivity conferred by diagnostic device approval • Competitor devices can co-exist • IP may control test availability

16. “A” Test vs “The” Test • Guidance not intended to limit companion diagnostic to a single test • Other tests with same intended use can be approved, e.g., HER2 testing • Other tests can be used at the discretion of physician • Assures at least one test with known performance characteristics is available

17. Reimbursement Issues • FDA does not regulate reimbursement • I am not an expert in reimbursement • Reimbursement (coverage/payment) landscape is changing • CPT codes did not specify test • New molecular codes might • Check with your reimbursement specialist

18. Next Generation Sequencing

19. Next Generation Sequencing • What it is: • Collection of technologies that enable rapid, affordable nucleic acid sequencing with improved sensitivity* • System: nucleic acid preparation, sequencer/reagents, several levels of software • Provide for sample to result capabilities *theoretical; platform dependent

20. NGS Applications • NGS: • Targeted—”narrow” look at specific genes, changes • Exome—broad, hypothesis-free look at coding regions • Genome—broad, hypothesis-free look at everything • Transcriptome—broad look at what actually gets used by cells

21. Targeted Sequencing • Most likely approach for companion diagnostic use—ability to find changes in genes known to be in drug-modified pathways • Sequences genes containing biomarkers of interest, e.g., mutations • Can create “panels” of sequences • Efficient for candidate screening • Monetary and sample cost-effective

22. Other Types of Sequencing • Non-targeted sequencing may also play a role • Look for genetic changes when gene is not obvious from phenotype • Quantify expression of gene(s) • Hypothesis-generating

23. NGS as Companion Dx • Model • Validated platform used to indentify appropriate patients for clinical trial • Investigational mode • Data submitted to FDA in PMA to establish companion use • First PMA contains base set of information • Next drug/use, repeat • Build panel over time, as new markers are identified • Single platform used to test for all relevant markers • Investigation-to-clinical use simplified • One platform needed in a lab to run all tests

24. NGS Outstanding Issues • Sponsor must choose to come to FDA • Unknown how many platforms could meet FDA Quality System requirements • Approved test systems tend to be static • Versus constant rev cycle of research use • Ability to rev at intervals will need to be worked out • Validate NGS systems against already approved tests • Can’t substitute for IHC or other non-nucleic acid tests

25. Forecast • Companion diagnostic model is a qualified winner (in oncology) • Benefit > risk, from pharma POV? • Introduces extra considerations into business model • Game changers still out there • NGS • Other technologies • New knowledge/information

26. Thanks for your attention! • Elizabeth.mansfield@fda.hhs.gov