Drugs vs. Devices

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.