IRB PRESENTATION REGULATORY PATHWAYS HDE – PMA

1. IRB PRESENTATIONREGULATORY PATHWAYSHDE – PMA William Hellenbrand MD Director – Pediatric Cardiology Columbia University College of Physicians & Surgeons Morgan Stanley Children’s Hospital of New York-Presbyterian

2. DISCLOSURE • Medtronic • Investigator • Consultant • Proctor

3. REGULATORY PATHWAYS • Paucity of high level evidence for therapy in congenital heart disease(CHD) • Reviewed 3317 articles over 3 year period(2004-2007) related to therapy for CHD • Surgery (49%), Catheter Interventions (23%), medications (9%)… • Case reports & series (52%), non randomized - controlled series (45%), RCT (3%) • Over a 10 year period there were 213 RCTs in pediatric cardiology, 3263 in neonatology & 5394 in adult ischemic heart disease Senthilnathan, Selvi ; Postgraduate course in Pediatric Cardiovascular Disease; Feb 2008

4. REGULATORY PATHWAYS • Randomization: • Reduces the likelihood of patient selection bias • Enhances likelihood that comparable groups of subjects are actually compared • Supports use of common statistical tests Randomization is the gold standard for evaluating new Device and Drug therapies Zuckerman TCT 2005

5. ADVANTAGES OF MULTI-CENTER TRIALS • No single center has the resources to answer a question • Collaboration will speed the resolution of the research question • Collaboration will resolve the question more authoritatively

6. REGULATORY PATHWAYS • Barriers to randomized multi-center trials • Congenital cardiovascular diseases are rare and diverse disorders • Randomization is difficult • Proper endpoints are difficult • Lack of clinical equipoise • Lack of equal maturity of the techniques being compared

7. RANDOMIZATION IS DIFFICULT • Many medical devices are already approved and available • Off label use is not regulated as the IRB does not require informed consent if we promise not to collect data or learn anything about the procedure • We have to have informed consent if we randomize and perform the procedure in only half the patients instead of all of them

8. RANDOMIZATION IS DIFFICULT • Due to all of these issues and patient knowledge from physicians and especially the internet; patient entry into these clinical trials may preclude adequate patient numbers

9. ENDPOINTS ARE DIFFICULT • They must be important • The FDA traditionally interested in mortality(do you live longer) or feel better (symptoms) • They must be achievable • Outcomes must be measurable in a reasonable time frame or have surrogate markers that accurately predict outcome

10. ENDPOINTS ARE DIFFICULT • Patients are not likely to die (30% of the population and 2% of the deaths) • Symptoms are difficult to quantify • Patients are a moving target as they grow and develop

11. HDE VS PMA • How does the FDA view these two different regulatory pathways and the need for multi-center randomized trials in a population of diverse disorders and a small number of patients

12. HDE • The regulation provides for the FDA submission of a humanitarian device exemption (HDE) application, which is similar in both form and content to a premarket approval (PMA) application. However, unlike a PMA application, an HDE application is not required to contain the results of scientifically valid clinical investigations demonstrating that the device is effective for its intended purpose. The HDE application must, however, contain sufficient information for the FDA to determine that the device does not pose an unreasonable or significant risk of illness or injury, and that the probable benefit to health outweighs the risk of injury or illness from its use; taking into account the probable risks and benefits of currently available devices or alternative forms of treatment. Additionally, the HDE applicant must demonstrate that no comparable devices are available to treat or diagnose the disease or condition, and that the device could not otherwise be brought to market unless it is granted HUD status.

13. OFF LABEL USE OF AN APPROVED DEVICE • Off-Label Use of a Humanitarian Use Device in Emergency or Compassionate Situations: It is recognized that there may be circumstances in which “off-label” use of a HUD may be necessary to save the life or protect the well-being of a given patient. Under either of these situations, the involved physician and manufacturer of the device should, on a case-by-case:

14. MELODY® - TPV

15. INDICATIONS & INTENDED PERFORMANCE • Indications • RVOT conduit regurgitation • RVOT conduit stenosis • Intended Performance • Restore pulmonary valve competence • Relieve conduit stenosis without inducing regurgitation Prolong conduit life

16. MELODY® - TPV • RVOT conduits used to palliate complex congenital heart defects • RVOT conduit dysfunction is common • Functional lifespan of RVOT conduits limited due to progressive regurgitation & stenosis • Current options for management • Medical management • Surgical pulmonary valve replacement • Transcatheter management

17. MELODY® - TPV

18. MELODY® - TPV

19. OFF LABEL USE • Why is there a difference in off label use of a PMA vs an HDE approved device • With a PMA approved device it is not regulated by the FDA or the IRB and left to clinical judgment