Current Topics in Clinical Research

1. Current Topics in Clinical Research prEN/ISO 14155 Parts 1-2Declaration of HelsinkiHIPAA Privacy Rules Clinical Device Group Inc Evaluations for Medical Devices Biomedical Focus 01—Minneapolis, MN

2. prEN/ISO DIS 14155-Part 1 Clinical Investigation of Medical Devices for Human Subjects— General Requirements

3. US Delegation • Co-chairs • Kimber Richter, FDA • Nancy J Stark, CDG Inc

4. Administrative • Merged with ISO 14155 • Expanded for more depth and breadth • Harmonized with ICH-GCPs • Split into Part 1—General Information and • Part 2—Investigational Plans • Now ISO 14155: Parts 1 & 2

5. Part 1: General Requirements • Scope • New definitions • Adverse event • Adverse device effect • Serious adverse event • Serious adverse device effect • Justification for clinical study-literature review (Annex A)

6. Part 1: General Requirements • Current Declarations of Helsinki and Lisbon must be followed • Helsinki—Clinical Research • Lisbon—Patient Rights • Both published by World Medical Association • Investigators must allow auditing

7. Informed Consent • Process • comply with Helsinki • avoid coercion or undue influence • not waive subject’s rights • non-technical language • ample time for consideration • dated signature of subject or guardian • provisions for emergency circumstances

8. Informed Consent • Content • description/purpose of research • forseeable risks • potential benefits • altenative therapies • confidentiality • compensation • questions and/or termination • new findings

9. Informed Consent • Informed consent statement • participation is voluntary • no penalty for refusal • may discontinue at any time • consequences of withdrawel • acknowledgment of information provided • May be separate document

10. Investigator’s Brochure Clinical investigation plan (protocol) Curriculum vitae—signed EC opinion Correspondence Agreement Case report forms Adverse event reports Names/addresses of monitors Final report Documentation

11. Responsibilities • Sponsor—unchanged • Monitor—unchanged • Clinical Investigator—unchanged

12. Annexes • Literature review • Information for ethics committees • Final reports

13. Literature Review • Methodology • establish a plan for identification, selection, collation and review of studies/data • define objectives of the review • establish selection criteria for articles • assess articles per selection criteria

14. Literature Review • Evaluation of Literature • justify exclusion of any documents • review remaining documents • identify any data gaps • dated signature of authors

15. Justification Health status of subjects Risks and mitigations Supervision Consent procedure and forms Confidentiality protections Consent process and documents Concurrent treatment of subjects Insurance Protocol Investigator’s Brochure “Progress in final report” All SAEs and adverse device effects Information for ECs

16. Title page Summary Table of contents Introduction Materials & methods Device description Protocol summary Results Discussion & conclusions Abbreviations & definitions Ethics statement Investigators & administrative structure Signatures Final Report

17. prEN/ISO DIS Part 2 Clinical Investigation of Medical Devices for Human Subjects— Clinical Investigation Plans

18. Part 2-CIPs(Clinical Investigation Plans) • New definitions • Primary end point • Secondary endpoint • Follow-up period • Point of enrollment • Recruitment • Clinical investigator • Principal clinical investigator • Coordinating clinical investigator • Clinical investigation center

19. Part 2-CIPs • Monitoring arrangements • Data and quality management • Literature review • Preclinical testing • Objectives, design, statistics • Early termination • Publication policy • Case report forms

20. Annex • Case report forms • ID of study • ID of subject • Serial or lot number of device • Subject selection/diagnosis • Subject compliance • Previous medication or treatment • Baseline • Concomitant illness, medication, treatment • Procedures • Findings • Follow-up • Adverse events and effects • Signatures

21. US Problems & Issues • No clear statement of purpose or underlying principles—just a checklist • Insufficient harmonization with ICH-GCPs • Unclear definitions

22. US Problems & Issues • Declaration of Helsinki • FDA guidance “Acceptance of Foreign Data” March 2001. • Device studies must conform to Declaration of Helsinki of 1983 • Drug studies must conform to Declaration of Helsinki of 1989

23. Voting & Timeline • Voting on ISO/DIS (initial draft) is in November 2001 • FDA’s vote will be “no” • US vote will be “yes” with condition of immediate revision • Voting of FDIS (final draft) in 2002

24. Declaration of Helsinki World Medical Association

25. Revised October 2000 • Continuous review • 1996 version not appropriate for developing countries • Changing research environment: genetics, data privacy. • Harmonize with other CIOMS, ICH, other guidelines.

26. Structure of 2000 Text • 32 Articles • 9 Introduction • 18 Basic Principles for Medical Research • 5 Additional Principles for Medical Research combined with Medical Care

27. Article 1-Scope Medical research involving human subjects includes research on identifiable human material or identifiable data.

28. Article 9-Legal Standing • 1996: …the standards…are only a guide; physicians are not relieved from criminal, civil & ethical responsibilities under the laws of their own countries. • 2000: …No national, ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of the protections for human subjects set forth in this Declaration.

29. Article 13-ECs Ethics committees: • Have right to monitor ongoing trials • Must be given reports on SAEs. • Must review information on funding, sponsors, institutional affiliations, other potential conflicts of interest and incentives for subjects.

30. Article 16-Availability • The design of all studies should be publicly available.

31. Article 17-Cease Investigation • Physicians should cease any investigation…if there is conclusive proof of positive and beneficial results.

32. Article 19-Benefit to Populations • Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research.

33. Article 22-Information to Subject • Each potential subject must be…informed of the… sources of funding, conflicts of interest, institutional affiliations…

34. Article 24 & 25-Legally Incompetent • Now includes: • Physically or mentally incapable • Legally incompetent minor • Should not be included unless research necessary to promote health of population, cannot be performed on others • Subject to give assent if possible

35. Article 26-Lack of Consent If no consent, proxy, or advanced consent: • Physical/mental condition must be necessary to research • Protocol to explain reasons for inclusion • Protocol to be approved by IEC • Protocol to state consent to remain in study be obtained asap from subject or legal representative.

36. Article 27-Publications • Negative and positive results should be published. • Sources of funding, institutional affiliations, conflicts of interest specified. • Research not in accordance with Helsinki should not be accepted for publication.

37. Article 29-Placebo • …new method…should be tested against…best proven prophylactic, diagnostic, and therapeutic methods…does not exclude use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.

38. Article 30-Ongoing Treatment • At conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study.

39. US Problems & Issues • Declaration of Helsinki • FDA guidance “Acceptance of Foreign Data” March 2001. • Device studies must conform to Declaration of Helsinki of 1983 • Drug studies must conform to Declaration of Helsinki of 1989

40. HIPAA Privacy Rules Health Information Portability and Accountability Act

41. HIPAA • 45 CFR Part 164—Security & Privacy • Effective April 14, 2001 • Providers, insurers, information clearinghouses

42. Enforcement • Enforced by DHHS Office of Civil Rights • Civil and criminal penalties • Does not apply to sponsors

43. Three Important Features • Investigator access to medical records • De-identified medical information • Patient access to case report forms

44. Access to Medical Records • Protocol design process • Estimates of enrollment capabilities • Subject recruitment

45. IRB Waiver • Work is preparatory to research • Medical records will not be removed from premises • Access to medical records is necessary

46. Requirements for Waiver • Minimal risk to patients • Privacy not adversely affected • Research cannot be done without waiver • Research cannot be done without access • Privacy risks reasonable in relation to benefits • Adequate plan to protect identifiers • Adequate plan to destroy identifiers asap • Written assurances that information will not be used or disclosed for other purposes

47. Additions to Informed Consent • Description of historical medical records needed for study • Statement of when authorization expires • Statement that treatment, payment, insurance, etc. not conditioned on signing • Description of information that will not be disclosed. • When/if crfs will be available to subject.

48. Other Areas Affected • Estimating subject availability • Case report forms • Leftover tissue samples • Access to tissue banks • Patient registries • Consents • Deceased persons

49. Names Zip codes Months/days Phone & fax #’s Email addresses SS numbers Medical record numbers Health plan numbers Account numbers Vehicle numbers Device serial numbers Web addresses Full face photos De-identified Information

50. EU Data Privacy Directive • EU Directive 95/46/EC • Privacy rules make US compatible with EU