“ CATCH-22” INTENDED USE DEFINITION

1. The Second Annual Medical Device Regulatory, Reimbursement and Compliance Congress - March 28-30, 2007 “CATCH-22” INTENDED USE DEFINITION The FDA and CMS: Changes in Regulatory and Surveillance Proximity Beverly H. Lorell, MD, FACC Senior Medical & Policy Advisor King & Spalding LLP Washington, D.C.

2. FDA and CMS: A Changing Proximity • Device and Drug Innovation: Tensions between Regulatory and Public Expectations • Ensuring rapid access to new devices and drugs for unmet clinical need, and • Freedom from late low-frequency serious safety events (near-complete safety), and • Physician use for individual patient benefit through practice-of-medicine, and • No additional cost (or, maybe, Value =  benefit /  cost compared to current therapy).

3. FDA and CMS: A Changing Proximity • The Evolution of CMS Oversight and Authority in the Federal Research Agenda: • CMS and FDA interaction past and present • Mandates for conduct and evaluation of clinical research • Payment for research • Coverage with Evidence Development • Challenges • Outsourcing of responsibilities to external partners • The challenge of rapid innovation: Case example

4. FDA and CMS: A Changing Proximity • The Statutory Basis for FDA and CMS Separation: • 1976 Medical Device Amendments – FDA risk-based regulation of devices • Premarket Approval (“PMA”) for Class III (highest risk) devices: “reasonable assurance of safety & efficacy” • Premarket Notification for Class I and II devices: “Substantial equivalence” to a device already marketed • Social Security Act Section 182(a)(1)(a) – CMS National Coverage Decision: determination on a national level of items and services that are “reasonable and necessary”

5. FDA and CMS: A Changing Proximity • FDA and CMS Interaction in the Federal Research Agenda • Categorization of Investigational Devices for Coverage under Medicare: Sept, 1995 - The HCFA/FDA Interagency Agreement; Nov, 1995 - The related HCFA Final Rule. • FDA categorizes all IDE devices: Category A (experimental/ investigational) Category B (nonexperimental/ investigational) • CMS contractors determine coverage of Category B, whereas Category A = non-coverage • CMS Clinical Trial Policy • Sept, 2000 - Routine costs implemented through the NCD process following a June 2000 Executive Order • July, 2006 - Now under reconsideration: Redefinition and expansion of “good clinical studies” that qualify for coverage

6. FDA and CMS: A Changing Proximity • Tensions between FDA and CMS Perspectives: • FDA “reasonable safety and efficacy” determination does not equal: • CMS determination of “reasonable and necessary,” or • Beneficiary entitlement to an FDA approved device • Determinations can differ from the FDA-approved labeling • Coverage with Evidence Development (CED): April, 2005 -Patient data collection as a Condition of Coverage • MCAC • Dec, 2006 - Now MedCAC (Medicare Evidence Development & Coverage Advisory Committee) • New charter and expanded focus on CED collection and evaluation of clinical data

7. FDA and CMS: A Changing Proximity • Ongoing Changes in the Congressional Agenda: • The Medicare Data Access and Research Act (S.3897) • Sept 14, 2006 - Introduced by Senators Charles Grassley and Max Baucus (Chairman and Ranking Member of the Finance Committee); Likely to be reintroduced this session. • Require the Secretary of HHS to enter annual data release agreements with the FDA, CMS, CDC, AHRQ and NIH; • Link hospital and ambulatory care data to CMS data on benefits to Medicare beneficiaries, and permit federal agencies and qualified researchers to analyze drug safety and health care use; • “More concretely, analyzing the Medicare claims data can help agencies, such as the FDA, identify situations like the one involving Vioxx more quickly and provide a new valuable tool to enable the FDA to take swifter action to protect the public’s health and well-being.” Senator Grassley, Sept 14, 2006

8. FDA and CMS: A Changing Proximity Could Should Must! FDA Regulatory Approval Post-Approval Studies National Guidelines JCAHO Credentialing Clinical Trials Peer-review Publication CMS National Coverage Decision Coverage with Evidence Development Performance Benchmarks Clinical Value Enablers: Does Science Support It? Economic Value Enablers: Will Someone Pay for It? Social Value Enablers: Public Health Mandates

9. FDA and CMS: A Changing Proximity • The CMS Authority to Mandate CED - • “The statutory authority for linking coverage decisions to the collection of • additional data is derived from Sec.1862(a)(1)(A) of the Act, which states • that Medicare may not provide payment for items and services unless they are • ‘‘reasonable and necessary’’ for the treatment of illness or injury. In some • cases, CMS will determine that an item or service is only reasonable and • necessary when specific data collections accompany the provision of the service. In these cases, the collection of data is required to ensure that the care provided to individual patients will improve health outcomes.” • The Purpose of CED - CMS Guidance Document July 12, 2006: • Document appropriateness of use in beneficiaries; • Consider future changes in coverage; • Generate clinical information that will improve the evidence base on which providers base medical recommendations.

10. FDA and CMS: A Changing Proximity CMS National Coverage With Evidence Development Broad National Coverage Yes Is existing evidence sufficient to support Medicare coverage? Limited Coverage with Evidence Development (ICD Registry) Coverage with Evidence Development (colon cancer drugs) No Non-coverage

11. FDA and CMS: A Changing Proximity National Coverage DeterminationCED • Cochlear Implantation None scheduled at present 2. Chemotherapy Colorectal Cancer National Cancer Institute: Clinical Trials Covered Under the Medicare Anti-Cancer Drug NCD 3. PET (FDG) for Brain, Cervical, National Oncologic PET Registry Ovarian, Pancreatic, Small Cell Lung, and Testicular Cancers • Implantable Cardioverter Defibrillators American College of Cardiology- National Cardiovascular Data Registry • Carotid Stenting American College of Cardiology-NCDR • PET (FDG) for Dementia and Medicare-Approved PET for Dementia Neurodegenerative Diseases Trial 6. Long term oxygen treatment NHLBI

12. FDA and CMS: A Changing Proximity • FDA Clinical Standards for “Reasonable Efficacy and Safety” are Better Defined than those of CED • Clinical evidentiary standards: Prospective, randomized, blinded clinical trial as highest clinical standard of proof-of-efficacy (predefined questions to be tested and endpoints) • Control of bias in the groups to be compared • Formal adjudication of events, and stopping rules • Evidence needed for decision making: 2 confirmatory studies (drug approval) • “ p < .05” Statistical standard – the level of confidence required to conclude that the result is not due to play of chance

13. FDA and CMS: A Changing Proximity • Clinical Evidentiary Standards for CED Registry Research are Still Rudimentary and Evolving • Registry Strengths • Demographics and patterns of real-world use • Registry Weaknesses - Less consensus regarding • Methods of monitoring and analysis • Acceptable statistical boundaries of certainty • Bias • Adjudication • Stopping rules - Does a CED registry ever end? • Longitudinal patient data and protection of privacy • Poor tools to ask the REAL QUESTION: “Does it really work?” or," Does A work better than B?” or, “Is A safer than B?”

14. FDA and CMS: A Changing Proximity Outsourcing of CED data collection, “American College of Cardiology-National Cardiovascular Data Registry, a confidential quality measurement program for cardiac and vascular facilities. It now operates four national registries.”: ICDs Carotid Artery Stents Angioplasty and Drug Eluting Stents Acute Coronary Syndrome Drugs, Devices, Processes

15. FDA and CMS: A Changing Proximity • Drug Eluting Stents - A Case Example • Emerging combinatorial science: • Novel combination products: drug, polymer, device • Reduce coronary restenosis (and need for 2nd invasive procedure) compared with bare metal stents • FDA approval: 2003 (Cypher) and 2004 (Taxus) • CMS anticipatory reimbursement: New DRG • Postmarket surveillance: • FDA condition-of-approval: 5-year follow-up of patients enrolled in pivotal premarket trials, and • Single-arm real world registries:at least 2000 pts followed for one year (but, no control group)

16. FDA and CMS: A Changing Proximity • Drug Eluting Stents - A Case Example Postmarket challenges for FDA and CMS • Rapid penetrance: >80% of coronary stent use • Practice-of-medicine: >60% of real world use is in complex patients and complex arteries • Variable use of adjunctive drugs (aspirin and Plavix) Detecting late and rare safety signals: late stent thrombosis • Determining causality vs. the play of chance • FDA - Dec 2006: public panel; Jan 2007: safety statement including consideration of change in product labeling • CMS - 2007: Possible reconsideration of coverage policy

17. FDA and CMS: A Changing Proximity

18. FDA and CMS: A Changing Proximity Life Cycle of Device Approval & Iteration FDA Postmarket Surveillance CMS Coverage Decision FDA Approval

19. FDA and CMS: A Changing Proximity Life Cycle of Continuous Change in Benefit–Risk New Clinical Information Increased Interagency Interaction Physician Practice Iteration Changes In Patient Choice Evolution of CMS Policy Evolution of FDA Policy Changes in Practice of Medicine

20. FDA and CMS: A Changing Proximity • What are the Opportunities to Enhance FDA and CMS Interaction to Improve Patient Care and Assure Innovation? • Recognize: Strengths and limitations of registries • Align: FDA condition-of-approval and CMS CED clinical data collection • Innovate: Use the Medicare claims data base to ask specific questions • Simplify: Avoid redundant postmarket clinical data collections • Assure: Transparency for all stakeholders

21. FDA and CMS: A Changing Proximity Thank you

22. FDA and CMS: A Changing Proximity Backups