Differences in OHRP, FDA and ICH Regulations/Guidelines

1. Differences in OHRP, FDA and ICH Regulations/Guidelines Monika Haugstetter, MHA, MSN, RN Human Subject Protection Office (HSPO) and Institutional Review Board (IRB), UCHC September 2010

2. Outline • Agencies • Applicable Regulations/Guidelines • Scope • Definition of Research • Differences by Topic

3. Agencies • Department of Human and Health Services (DHHS) • Office for Human Research Protections (OHRP) • Food and Drug Administration (FDA) • International Conference on Harmonization (ICH)

4. Scope • DHHS– human subject research conducted or supported by DHHS or conducted by institutions agreeing to abide by 45 CFR 46 regardless of funding • FDA – oversight of research for commercial biomedical products for human use (food/additives, drugs, medical devices, biological products, electronic products) • ICH – establishment of international guidelines for medical products in clinical research

5. Corresponding Rules/Guidelines • DHHS - Code of Federal Regulations (CFRs) – 45 CFR 46 Subpart A through D – Federal Policy for the Protection of Human Subjects (Part A - the “Common Rule”) • FDA - Code of Federal Regulations - Title 21 CRF (e.g. parts 50, 54, 56, 312, 812 for human subjects protection and other parts) • ICH - Good Clinical Practice – ICH E6

6. Definition of Research • DHHS – “[…] a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge” [46.102.d] • FDA – "clinical investigation" is synonymous with "research“ “Clinical investigationmeans any experiment that involves a test article and one or more human subjects, and that either must meet the requirements for prior submission to the FDA (...) or the results of which are intended to be later submitted to, or held for inspection by, the FDA as part of an application for a research or marketing permit.” [56.102.c] • ICH – “any investigation in human subjects intended to discover or verify the clinical, pharmacological and /or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s) with the object of ascertaining its safety and/or efficacy” [1.12]

7. Differences in Rules/Guidelines

8. Auditing/Monitoring • DHHS – not addressed • FDA – • Sponsor monitors trials [312.56] • Sponsor ensures trial is monitored [812.40] • Monitors are qualified by training and experience [312.53.d; 812.43.d] • “Guideline for the Monitoring of Clinical Investigations” • ICH – monitoring process discussed in details [5.18]

9. Case Report Forms (CRFs) • DHHS – not addressed • FDA – Investigators maintain CRF as part of case history for each subject [312.62.b]; provides no specific procedures related to management of discrepancies in CRFs & revisions • ICH – “… protocol required information to be reported to the sponsor on each subject” [1.11]; sponsors hold original CRFs, investigators hold copies; investigators maintain records of any changes to CRFs [4.9.4]; requires PI to document explanation for discrepancies in CRFs & source documents

10. Emergency Use of Test Article • DHHS – not addressed • FDA – emergency use – “the use of a test article on a human subject in a life-threatening situation in which no standard acceptable treatment is available and in which there is not sufficient time to obtain IRB approval” [56.102.d]; report use of emergency article to IRB within 5 working days [56.104.c] • ICH – emergency use creates a vulnerable subject [1.61]; IC not required if it is not possible to obtain & situation described in study protocol [3.1.7, 4.8.15]

11. Informed Consent – Elements • DHHS – basic & additional elements [45 CFR 46.116] • FDA – 21 CFR 50.25 (a); same as DHHS • ICH – additional elements to DHHS and FDA are required: 1. trial treatments and probability of random assignment, 2. subject responsibility, 3. anticipated payments to subjects, 4. risks and benefits of alternative treatment(s), 5. authorization to access medical records by regulatory authorities [4.8.10]

12. Informed Consent – Signatures/Dates • DHHS – subject (or LAR) signs informed consent form (ICF) and receives copy [117.a] • FDA – subject (or LAR) signs and dates consent form ICF and receives copy [50.25.a.5] • ICH – subject (or LAR) and consenter sign and date ICF [4.8.8]; subject receives signed/dated copy [4.8.11]

13. Informed Consent – Records Access • DHHS – “All records shall be accessible for inspection and copying by authorized representatives (…) [46.115.b] but does not require that subjects provide consent for that inspection • FDA – ICF must explain that FDA may inspect records [50.25.a.5] • ICH – ICF notes that monitors, auditors, IRB and regulatory authorities may access original medical records [4.8.10.n]

14. Informed Consent – Waivers • DHHS – waivers of documentation of Informed Consent and waiver of Informed Consent permitted [46.116.d] • FDA – waiver of documentation of Informed Consent and waiver of Informed Consent NOT permitted w/ exception to emergency research 50.23, 50.24] • ICH – not addressed

15. Waiver of Parent/Guardian Permission in Minimal Risk Studies • DHHS – permitted under certain circumstances [45 CRF 46.404 to 408] • FDA – FDA does not allow waivers of parental permission • ICH – not addressed

16. IRB Review of Exemptions/Waivers • DHHS – exemptions are listed but have minimal relevance to clinical research [101.b] • FDA – sponsors and sponsor- investigators may request waiver of any requirements, “including requirements for IRB review, for specific research activities or for classes of research activities,” but not of informed consent requirements [56.105] • ICH – not addressed

17. Protocol Amendment/Modifications All three entities require IRB approvals prior to implementation • DHHS • FDA • ICH

18. Protocol Noncompliance/Deviation • DHHS – see 46.103.b.5 • FDA – for devices, site documents dates and reasons for deviations [812.140.a.4] • ICH – deviations not permitted except with prior sponsor approval or immediate hazard to subjects – must be reported to IRB, sponsor and regulatory authorities [4.5]

19. Reporting • DHHS – requires written procedures for reporting “any unanticipated problems involving risk to subjects or others” or “serious or continuing non-compliance” [46.103.5.b] • FDA – “any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug” [312.64] and “unanticipated adverse device effect” [812.50] must be reported • ICH – “all serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol or other document identifies as not needing immediate reporting” [4.11]

20. Records Retention • DHHS – retain records for at least 3 yrs after completion of study [46.115.b] • FDA – retain records for 2 yrs after marketing application approved or investigation discontinued [312.62.c; 812.140.d] • ICH – retain essential documents for 2 yrs after last approval of marketing applications; longer if regulations require Note: UCHC HSPO policies state 3 yrs minimum; additionally per individual contract – the sponsor may require more than 2 yrs

21. Records Accessibility • DHHS – “All records shall be accessible for inspection and copying by authorized representatives (…) [46.115.b] • FDA – FDA has access to records and reports [312.58, 312.68, 812.145] • ICH – regulatory authorities have access to records and reports including communication [8.2.11]

22. Recruitment Practices • DHHS and FDA– IRB requires to review of recruitment materials (…) with regards to information given to subjects as part of informed consent [45 CFR 46.109 (b) and 21 CFR 56.109 (b)] • ICH – inform IRB of recruitment procedures [3.1.2]; PI qualification must demonstrate ability to recruit subjects [4.2.1]

23. Sanctions • DHHS – none listed; however, OHRP may withdraw assurance & prevent conduct of federally sponsored research • FDA – sanctions for non-compliance with regulations [56.120, 124]; procedures for “disqualification” of clinical investigator [312.70, 812.119]; process of preventing investigators from participating in FDA regulated research • ICH – not addressed

24. References • Byrdsong, Q., J & Goldfarb, N. M. (2009). Which Rules Apply? Journal of Clinical Research Best Practices, 5 (11), pg. 1-12. • Food and Drug Administration (FDA). http://www.fda.gov • Food and Drug Administration (FDA). (2009). Comparison of FDA and HHS Human Subject Protection Regulations. Retrieved on April 12, 2010 from http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/EducationalMaterials/ucm112910.htm • International Conference on Harmonization. ICH Guidelines. E6 Good Clinical Practice. Retrieved on April 12, 2010 from http://www.ich.org • John Hopkins Medicine, Institutional Review Board. (2009). Significant Differences in FDA and DHHS Regulations. Retrieved from on April 12, 2010 from http://irb.jhmi.edu/Guidelines/FDAvsOHRP.html • Office for Human Research Protections , DHHS. (2009) . Title 45, Public Welfare, DHHS, Part 46, Protection of Human Subjects. Retrieved on April 12, 2010 from http://www.hhs.gov/ohrp/ • http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm