1. Feldman 20 February 20031 Clinical Trials Design Martha A. Feldman, RAC Drug & Device Development Co., Inc. P.O. Box 3515 Redmond, WA 98073-3515 USA 1-425-861-8262 FAX: 1-425-869-5854 mfeldman@druganddevice.com

2. Feldman 20 February 20032 Clinical Trials Design Purposes of conducting clinical studies Types of clinical studies Ethical considerations Regulatory requirements Monitoring Database management issues Statistical considerations Reports for submissions or papers

3. Feldman 20 February 20033 Purposes of Clinical Studies Further scientific knowledge Prove concept Evaluation of product features, capabilities Obtain initial safety data Substantiate claim/indication for use Establish degree of efficacy or effectiveness Compare with competitor product; marketing evaluation

4. Feldman 20 February 20034 Types of Clinical Studies Prospective or retrospective Blinded/masked or open label Randomized or not Active control or placebo Normal subjects or patients Actual or surrogate clinical endpoints Statistically significant or “anecdotal”

5. Feldman 20 February 20035 Ethical Considerations Human Subject Review: IRB, Declaration of Helsinki Informed consent, community consent, waiver of consent Use of placebos versus positive control Use of normal subjects Use of investigational material in addition to standard care Vulnerable populations

6. Feldman 20 February 20036 Regulatory Considerations

7. Feldman 20 February 20037 Drug/Therapeutic Biologic Studies Overall investigation Plan –Phase 1 - Normal subjects: usually < 50 subjects, at one facility, safety parameters –Phase 2 - Patients: about 50 - 100 subjects; at two sites; may do some dose-range assessment; safety and some initial efficacy –Phase 3 - Patients: few hundred to several thousand; multiple sites; main support study –Phase 4 - Patients (post-marketing): varies

8. Feldman 20 February 20038 Phase 1 Clinical Study Normal subjects; occasionally use patients See if/how pharmacokinetics data from animal studies extrapolates to human data Document pharmacodynamic effects Usually open label with ascending doses; establish dose-range Build safety profile: monitor adverse effects

9. Feldman 20 February 20039 Phase 2 Clinical Study Patients or people with clinical condition Confirm dose range is similar in such people; if not, re-define range Blinding, randomization, controls used Strict entry criteria Initial efficacy determination

10. Feldman 20 February 200310 Phase 3 Clinical Study Few hundred to few thousand patients Multiple sites Blinding, randomization, controls, prospective May have slightly broader entry criteria - age, severity of disease, Continue developing safety and efficacy profiles

11. Feldman 20 February 200311 Post-marketing Study Surveillance or study Numbers to be negotiated Parameters determined as a result of Phase 3 study May involve labeling issues

12. Feldman 20 February 200312 Device Clinical Studies “It Depends” Steps in Investigation Plan –Proof of concept/Feasibility: < 5 subjects or patients; one site, safety and some effectiveness –Pilot study: 20-50 subjects; “test drive” protocol, case report forms, initial effectiveness and safety; two sites –Pivotal study: 50 - 500 subjects; multiple sites; main supporting study for claims

13. Feldman 20 February 200313 Proof of Concept/Feasibility Study few patients (<5) limited to one site usually investigator-sponsored study goal: prove concept, check instructions for use; early safety and effectiveness assessments

14. Feldman 20 February 200314 Pilot Study More rigorous protocol May be up to 50, but usually around 20 subjects One or two sites Company-sponsored study “Test drive” protocol, comparison of use at two sites, safety and some effectiveness data; finalize training plan Adjust final protocol for pivotal trial

15. Feldman 20 February 200315 Pivotal Study The main study to support the submission Subject number could be from around 100 to several hundred Multicenter study; each site should enroll sufficient subjects for separate analyses Should demonstrate device is independent of inventors

16. Feldman 20 February 200316 IVD Studies May be done in two parts: collection of samples (may take > 1 year) and use of IVD (may take < 1month); separate protocols Collection of samples may involve dozens of sites; testing phase may be at minimum of three sites Study size may range for 100 (for some monitoring studies) to several thousand (for screening indication) May enrich samples with stored, known, positive samples: special IRB and consent issues

17. Feldman 20 February 200317 Monitoring At least one a year on-site Between visits: by telephone, e-mail, FAX and courier services

18. Feldman 20 February 200318 Prestudy Activities Investigator selection and qualification Site qualification: –additional staff –sufficient number of subjects –laboratories, pharmacies –special needs Conduct Pre-study site visit

19. Feldman 20 February 200319 Prestudy Site Visit Meet investigator, coordinators, other staff Review protocol, case report forms Emphasize consent procedure, requirements Review adverse event procedures Review investigator documentation Review Regulatory Notebook Visit, as needed, labs, pharmacy, etc. “Build” study team

20. Feldman 20 February 200320 Routine, Interim Visit Review regulatory notebook Verify consent procedures followed Ensure study eligibility criteria met Compare data entries on CRFs and source data Check investigational product accountability Check for unreported adverse events Resolve queries

21. Feldman 20 February 200321 “For Cause” Visit Possible reasons –too little/too much enrollment –much greater number adverse events –badly completed case report forms –new coordinator/investigator needing training –results “too good” –Monitor has concerns about investigator or coordinator compliance with regulations

22. Feldman 20 February 200322 Close-Out Visit Regulatory Notebook is complete Supplies accountability checks out All queries resolved No unreported, unresolved adverse events All patient follow-up completed Investigator’s report done Files prepared for FDA inspections and for storage

23. Feldman 20 February 200323 Database Management Issues Programming for the case report entries Developing a data entry plan; data entry verification plan Generating queries for the monitors to have coordinators resolve Entering amended data; database clean-up Data editing plan Closing database; data validation plan; send to statistician Developing tables for the reports, submissions, etc.

24. Feldman 20 February 200324 Statistical Considerations Developing hypotheses Calculating sample size requirements Developing plan for interim analysis, if needed, and for final analysis (including sub-analyses) Determining how interim analysis results impact sample size Perform analysis and data evaluation Write statistical report

25. Feldman 20 February 200325 Sponsor Reports - Submissions Adverse event reports Use of investigational product without consent IRB withdrawal of approval Annual reports Updating submissions with each advance in the investigational plan (e.g., study completion or termination)

26. Feldman 20 February 200326 Investigator Reports Withdrawal of IRB approval Use of product without consent Adverse events - to sponsor and IRB Study status reports; study close-out report For device studies: malfunction, repair or replacement

27. Feldman 20 February 200327 Other Reports Publications, posters, presentations –can review manuscript for proprietary information –cannot stop the publication of negative results –off-label use: company may not promote it, but can distribute articles written by health care practitioners

28. Feldman 20 February 200328 References Code of Federal Regulations, Title 21 –Part 50 - Informed Consent –Part 56 Institutional Review Boards –Part 312 - Investigational New Drug, antibiotic, Biotechnology-Derived Product regulations –Part 812 - Investigational New Device regulations FDA Guidance Document on Good Clinical Practices, January 1988 ICH Guidance Document E6 - Good Clinical Practices

29. Feldman 20 February 200329 More References Center for Drug Evaluation and Research, List of Guidance Documents (Jan 2003) http://www.fda.gov/cder/guidance/guidlist.pdf –Clinical Evaluation of (type of) drugs –FDA Requirements for approval of drugs to treat (disease or clinical condition) –General considerations for the clinical evaluation of drugs infants and children –Study and evaluation of gender differences in the clinical evaluation of drugs

30. Feldman 20 February 200330 Even More References –Clinical trial sponsors on the establishment and operation of clinical trial data monitoring committee –ICH Safety Efficacy Quality –Good Clinical Practices - January 1988 –ICH - E6: Good Clinical Practices