1. Mark Barnes David Forster October 19, 2010 SUBCOMMITTEE ON HARMONIZATION (SOH) UPDATE

2. Membership  Susan Alpert, Ph.D, M.D. (new member)  Mark Barnes, J.D., LL.M. - Co-Chair  David Forster, J.D., MA, CIP – Co-Chair  Dean Gallant, A.B.  Karen N. Hale, RPh, MPH, CIP  Justin P. McCarthy, J.D.  Marjorie A. Speers, Ph.D.  Susan Stayn, J.D.

3. Meetings  Convened meetings:  April 15-16, 2010.  September 21-22, 2010.  Monthly teleconferences.

4. Approach Adopted  At initial meeting the subcommittee identified “constellations” of issues in which harmonization among the agencies could benefit the regulated community.  Then prioritized initial constellations to work on.

5.  Recommendation regarding adoption of a single conflict of interest standard across DHHS entities.  Adopted by SACHRP at July 21, 2010 meeting. Completed Activity – HHS Conflict of Interest Policies

6.  Minor changes in research that can be reviewed through the expedited procedure.  Started with SACHRP panel prior to creation of SOH.  SOH working group reviewed previous panel suggestions, participated in phone call with FDA and OHRP, and submitted examples and draft SOPs for agency consideration.  No further SOH involvement planned. Completed Activity – Minor Changes in Research

7.  Started with the same SACHRP panel as the minor changes in research.  Is a much wider and more difficult issue than minor changes.  Wide variety of policies across regulated community.  SOH working group had teleconference with OHRP and FDA, with no resolution.  Issue brought back to full SOH meeting, will be topic of further discussion and work. Activity in Process – Planned Protocol Deviations

8.  SOH drafted a Request For Information to gather public input on harmonization issues.  Submitted to agencies for finalization and release.  Still in process. Activities in Process - RFI

9.  Reviewed differences between Common Rule FDA at SOH meeting of September 21-22, 2010.  Many of the differences are based in unique roles of the agencies and are not problematic:  Differences in waivers of documentation of consent  FDA emergency use regulation. Activity in Process – Comparison of Common Rule and FDA Regulations

10.  Other differences between the regulations are worth further consideration:  Definition of “clinical investigation” and “human subject.” Would it be advantageous to change FDA definitions so that they are more similar to HHS regulations?  Clarify that FDA definition of “human subject” does not include deceased persons.  Waiver of consent regulations, with emphasis on FDA’s possible adoption of wider use of waivers of consent.  Difference between OCR and FDA/OHRP – recordkeeping requirements, 6 versus 3 years. Activity in Process – Comparison of Common Rule and FDA Regulations

11.  Recommendation will be considered by SACHRP latter today.  Five topics:  Compound Authorizations  Future/Secondary Research  Minimum Necessary  Business Associates  Restriction on Sale of PHI Activity in Process – Commentary on NPRM on HITECH

12.  Recommendation will be considered by SACHRP latter today.  Effort to harmonize guidance. Activity in Process – Definition of Non-Scientist

13.  Includes:  Activities done in preparation to design or conduct of research.  Identification of potential subjects.  Recruitment of subjects.  Substantial differences among OCR, FDA, and OHRP regulations and guidance on these issues.  Discussed at SOH meeting of September 21-22, 2010, further work necessary. Activity in Process – When does Research Begin?

14.  SOH working group provided FDA with nine examples of research activities that may or may not constitute “clinical investigations” under the FDA definition:  A clinical investigation of a device is being set up. As a preparatory step, diagnostic devices need to be calibrated on a human being.  A practicing physician wants to perform a retrospective review of his medical records for all patients treated with drug X for on-label use. Activity in Process – When do FDA Regulations Apply

15.  An investigator wishes to interview patients about their quality of life and opinion about the effectiveness of an acne medicine.  If a clinical investigation involves a historical control arm, are the subjects “human subjects” under 21 CFR 56.102(e), who thus must provide consent (or can the review of the medical records of the subjects in the historical control arm qualify for a waiver of consent under DHHS regulations)?  An investigator wants to study oatmeal or a marketed dietary supplement to see if it lowers cholesterol (regardless of whether it needs an IND). Activity in Process – When do FDA Regulations Apply

16.  FDA requires a company to establish a post-marketing registry to collect data about the safety and efficacy of a regulated approved product.  FDA requests rather than requires a company to establish a post- marketing registry to collect data about the safety and efficacy of a regulated approved product. Activity in Process – When do FDA Regulations Apply

17.  In a research study of a surgical technique for separation of co- joined fetuses in the womb, the investigator proposes to use a certain narrow scope for observation that is not approved for use in the US. He wants to import it from Europe for use. The study does not have the goal of establishing the safety or efficacy of the scope.  An investigator will be testing a computer program that may eventually be used to assist with early detection of arrhythmias. Initial phases of study involve simulations using existing clinical records. Activity in Process – When do FDA Regulations Apply

18.  SOH working group will work on algorithm based on these examples. Activity in Process – When do FDA Regulations Apply

19.  QA/QI activities, especially QA/QI activities involving FDA regulated products or products that may or may not be FDA regulated (example, skin cleaner on wash cloth versus a marketed product for cleaning skin.).  CDC definition of research vs. QI vs. epidemiology. Future Topic – Standard practice vs. Innovative care vs. research vs. clinical investigation

20.  Testing on tissue samples and biological sample banking.  Unspecified future research.  Identifiable versus non-identifiable.  Extension of IVD assay consent waiver to IND assays.  Most potential overlap with Subpart A Subcommittee (SAS) is in this area. Possible Future Topic – Tissue Research

21.  How and when should community be engaged in research.  No clear protocol or method, subjects are involved in design.  HPTN, HVTN, NIADA CAB utilize community participation.  Community consultations under 50.24. Future Topic – Engagement of Community in Research

22.  Use of partially translated short form for non- English speakers. OHRP versus FDA. OCR silent.  Documentation of consent/signature requirements. HHS signature vs. FDA signature and date vs. ICH signed copy and witness signature for illiterate subjects. Future Topic –Consent Issues

23.  Unequal application of the subparts across agencies. Future Topic –Application of Subparts B, C, D

24.  Common Rule vs. FDA vs. ICH vs. OCR.  Also European laws, other laws around the world.  Preemption issues. Future Topic –International

25.  Broadest issue, outside current focus of SOH. Possible Future Topic – State laws, Non-HHS agencies

26.  SIIIDR report.  VA guidance.  new FDA information sheets.  ICH.  OHRP FAQ on LAR.  NIH Points to Consider.  Could and should all these be harmonized? Future Topic – Incapacitated Adults

27.  Unanticipated problems and overall protocol safety assessment by sponsors and others.  FDA guidance on DSMBs and NIH requirements for DSPs.  Continuing difference between FDA and OHRP UP guidances. Mostly issue of seriousness. Could it be a single guidance? Future Topic – Safety Issues

28.  FDA versus OHRP guidance. Future Topic – Local Attitudes

29.  What is exculpatory language?  Issue mostly focused on property rights in tissues.  FDA and OHRP working on guidance.  ESCRO standards, state laws, DOD differ. Future Topic – Exculpatory Language

30.  Creation of a single new agency to oversee all human subjects research in the US.  Procedural changes in the way that the common rule agencies establish guidance in order to promote harmonized guidance.  Procedural changes to require or promote joint regulations and/or guidance from OHRP and FDA and other HHS agencies. Future Topic – Procedural Issues

31.  Feedback or Questions?