1. Introduction to GCP and 21CFR312

2. Dear Clinical Investigator…

3. Objectives Objectives: At the conclusion of this discussion, participants will be able to: –Describe the historical context in which clinical trial regulations were created –Define and describe the regulatory agencies and professional organizations which monitor clinical research –Demonstrate a basic understanding of GCP and 21CFR312

4. Highly Regulated Profession We’ve already got the NRC and CRCPD… We’ve already got wipe tests and calibrations and phantoms and surveys… We’ve already got MDs and CNMTs and PhDs… “We are using low risk diagnostic doses anyway…” “Radiopharmaceuticals don’t have side effects…” “Patients get images which can help their diagnosis…”

5. Highly Regulated Profession We’ve already got the NRC and CRCPD… We’ve already got wipe tests and calibrations and phantoms and surveys… We’ve already got MDs and CNMTs and PhDs… “We are using low risk diagnostic doses anyway…” “Radiopharmaceuticals don’t have side effects…” “Patients get images which can help their diagnosis…”

6. 1945-1947: 18 terminally ill patients injected with plutonium 1940’s: 800 pregnant poor women given radioactive iron 1950’s: mentally retarded boys given radioactive calcium and iron in their breakfast cereal 1960-1971: 88 poor, mostly African American, cancer patients exposed to experimental full body irradiation Over 4000 federally sponsored radiation experiments between 1944-1974, involving > 10,000 patients Nuclear Experiments

7. 1950-1972: Mentally disabled children deliberately infected with hepatitis in attempt to find a vaccine 1962: Injection of live cancer cells into 22 elderly patients 1932-1972: more than 400 African American men observed for the natural course of untreated syphilis Not Just Radiation Medicine

8. Guidance for Investigators Declaration of Helsinki International Conference on Harmonisation U.S. Code of Federal Regulations FDA Guidance Documents IRB

9. Declaration of Helsinki Statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data. Describes combining research and clinical care “In medical research involving human subjects, the well-being of the individual research subject must take precedence over all other interests.” http://www.wma.net/en/30publications/10policies /b3/index.html

10. ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Regulatory authorities from Europe, Japan and the US and experts from the pharmaceutical industry ICH is the international authority on clinical research theory and principles. www.ICH.org

11. ICH Principles develop scientific consensus through discussions between regulatory and industry experts assure wide consultation of draft consensus documents through normal regulatory channels before a harmonized text is adopted secure commitment by regulatory parties to implement the ICH harmonized text The Pharmaceutical Journal Vol 273, No. 7312, pp 24-226

12. Safety management in clinical trials, including periodic safety updates of research and marketed drugs Dose response data collection Statistical principles for clinical trials Publication of the final study report Choice of control groups in clinical trials Pediatric clinical trials Good Clinical Practice ICH Publications

13. www.ich.org

14. ICH E6: Good Clinical Practice GCP A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial subjects are protected. www.ich.org http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformat ion/Guidances/ucm073122.pdf

15. ICH E6: Good Clinical Practice Contents: 1. Glossary 2. The Principles of ICH GCP 3. Institutional Review Boards 4. Investigator 5. Sponsor 6. Clinical Trial Protocol(s) 7. Investigator Brochure 8. Essential Documents for the Conduct of a Clinical Trial Get to know this document!

16. US Code of Federal Regulations 21CFR312: Investigational New Drug Application 21CFR50: Protection of Human Subjects 21CFR54: Financial Disclosure by Clinical Investigators 21CFR56: Institutional Review Boards 21CFR812: Investigational Device Exemptions 45CFR46: Protection of Human Subjects 45CFR164: (HIPAA) Use or disclosure of protected health information for research

17. US Regs vs. ICH? The ICH does not override US regulations governing clinical research; instead they are complimentary Pharmaceutical and device sponsors know and follow both ICH and federal regulations governing clinical research Sponsors expect clinical sites to be familiar with the ICH and the federal regulations US Regs and ICH!

18. 21CFR312 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/C FRSearch.cfm

19. 21CFR312

20. General Investigator Responsibilities 21 CFR 312.60: General responsibilities of investigators Ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; Protecting the rights, safety, and welfare of subjects under the investigator's care; Obtain the informed consent of each human subject to whom the drug is administered. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312

21. Control of Investigational Drug 312.60 General responsibilities of investigators (cont). An investigator is responsible for the control of drugs under investigation. 312.61 Control of the investigational drug. An investigator shall administer the drug only to subjects under the investigator's personal supervision or under the supervision of a subinvestigator responsible to the investigator. The investigator shall not supply the investigational drug to any person not authorized to receive it. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312

22. Sec. 312.62 Investigator recordkeeping and record retention. Disposition of drug. An investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects. If the investigation is terminated, suspended, discontinued, or completed, the investigator shall return the unused supplies of the drug to the sponsor, or otherwise provide for disposition of the unused supplies of the drug under 312.59. Control of Investigational Drug http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312

23. Signed Investigator Statement Form FDA-1572 Statement of the investigator –Submitted to FDA by the sponsor –Must be signed by the investigator –Contains the name and address of the IRB, all clinical labs and locations at which the study will be conducted –Lists subinvestigators who are under the supervision of the primary (principal) investigator http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312

24. “I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of subject.” Signed Investigator Statement http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312

25. 21CFR50

26. 21CFR54 “Significant payments of other sorts, which are payments that have a cumulative monetary value of $25,000 or more made by the sponsor of a covered study to the investigator or the investigators' institution to support activities of the investigator exclusive of the costs of conducting the clinical study or other clinical studies, (e.g., a grant to fund ongoing research, compensation in the form of equipment or retainers for ongoing consultation or honoraria) during the time the clinical investigator is carrying out the study and for 1 year following completion of the study.”

27. 21CFR56

28. 21CFR812

29. 45CFR46 Applies to all research involving human subjects conducted, supported, or otherwise subject to regulation by any federal department or agency… NIH, DOD, any federal support Most university settings comply with the “Common Rule” Provides instructions and exceptions for IRB review

30. IRB

31. U Iowa IRB

32. Things to remember… All regulations and guidance for clinical trials exist to protect human subjects Fraud and unethical practices still occur today The appearance of fraud or unethical behavior can be detrimental to the investigator and sponsor Sponsors expect nuclear medicine investigators and study coordinators to be knowledgeable about the regulations and guidance documents