1. Drugs vs. Devices Jeng Mah & Gosford A Sawyerr Sept 16, 2005

2. Outline Design Challenges Analysis Issues: Device Database Challenges Challenges with Diagnostics Post-marketing surveillance Working with Clinical Investigators Regulatory Landscape

3. Design Issues Double-blind device trials not common with device trials Single blind possible within device type Difficulty in going head to head with competitor devices Pre-market trials tend to be simpler to demonstrate safety with regard to intended use Compliance is easier to measure in device trials than in drug trials In medical devices, single arm trials with Objective Performance Criteria are used to determine safety of leads Single arm pharma trials may appear in early Phase II where the objective may be to rule out drugs with little possibility of clinical benefit (e.g., two-stage designs; ref: Simon)

4. Design Issues (2) Dose of drug may be an issue; size of device may be an issue Implanting carries greater risk than prescribing a drug Device trials offer more opportunity to be Bayesian – lots of prior information re: pacemakers and defibrillators Device implant studies drive revenue much more than prescription drug trials Post-market device trials are important in providing clinical evidence for physicians, payors and patients

5. Design Issues (3) More precise endpoint determination due to electronic information storage on device Drug trial endpoints subjective at times Consideration of recurrent episodes may provide increased statistical power and hence fewer patients Some endpoint definitions in device trials may vary from device to device (e.g., AF burden calculation) Memory capacity may lead to missing episodes Device date stamp resets may lead to inaccurate information re: endpoints

6. Analysis Issues Analysis cohort may differ from full randomized set: e.g., analysis of proportion of VT/VF episodes appropriately treated may include only patients with episodes Device storage limitations may miss episodes Heterogeneity in occurrence of episodes between patients needs to be considered in choice of statistical method so that few patients do not drive the results Sensitivity and specificity defined only relative to what the device records and hence are biased estimates

7. Challenges with Diagnostics Thresholds (cutpoints) which determine diagnostic action need to be established a priori (in drug trials retrospective analysis may be possible to determine sensitivity to various definitions) Co-development of drug with diagnostic difficult (studying two drugs simultaneously not necessarily at same level of difficulty) –see FDA Concept Paper: http://www.fda.gov/cder/genomics/pharmacoconceptfn.pdf Sensitivity and specificity issues critical Clinical utility of test – drug only trials do not have this challenge

8. Post-marketing Surveillance In both device and drug trials, registry/observational studies can play a key role in better understanding of endpoints Possible to trace all patients with device: problematic in drugs Data from return products, MDRs and registry studies can assist in better assessment of system longevity and adverse device effects –Extent of exposure difficult to measure for all patients who may have taken a drug MDR analysis may help trend analysis

9. Working with Clinical Investigators Strong partnership between device company personnel and implanting physicians (EP, Cardiologist, etc.) –Development of study design highly collaborative with PI –Delivery of device at implant and device programming requires participation by company personnel –Steering committee actively involved in assessment of study and publication –Events adjudication by clinicians on periodic basis

10. Regulatory Process Drugs: –INDs, NDAs, sNDAs etc. Devices/Diagnostics –IDEs, 510(k)s, PMAs, PMA-Ss etc.