1. Introduction to GCP and 21CFR312

2. 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 AND We are using low risk diagnostic doses anyway… Radiopharmaceuticals don’t have side effects… Patients get images which can help their diagnosis…

3. 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 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 Guinea Pigs

4. 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

6. Horror after WWII and Nazi abuses uncovered Investigative journalists uncovered abuses in US Presidential leadership: Roosevelt, Kennedy, Clinton 1962 thalidomide tragedy prevented in US due to Frances O. Kelsey Legislative and regulatory change Societal attitudes toward protection of “vulnerable subjects” Accumulated knowledge of radiation effects Change Agents

7. 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

8. Ethical Basis for Regulations Nuremburg Code Declaration of Helsinki

9. Statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data. “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/inde x.html

10. ICH International Conference on Harmonization ICH consists of regulatory authorities from Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of clinical research. ICH is considered the authority on clinical research theory and principles. www.ICH.org

11. ICH Principles The guiding principles of ICH are to: –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. Publications of the ICH include: –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 Practices ICH

13. ICH Publications 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 regs vs. ICH? The ICH does not override US regulations governing clinical research; instead they are complimentary –21 CFR 312(Requirements for an IND) –21 CFR 50(Protection of Human Subjects) –21CFR 54(Financial Disclosure) –21 CFR 56(IRBs) –45 CFR 46(HIPAA) –21 CFR 812(Investigational Devices)

17. 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. Control of Investigational Drug 21 CFR 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. Sec. 312.60 General responsibilities of investigators. An investigator is responsible for the control of drugs under investigation. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312

21. 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

22. 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

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. Form FDA-1572 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM074728.pdf

26. 21 CFR 312.53 Selecting investigators and monitors Select only investigators qualified by training and experience as appropriate experts to investigate the drug. Ship investigational new drugs only to investigators participating in the investigation. Ensure the investigation is in accordance with the IND Sponsor Responsibilities http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312

27. Responsibilities of Sponsors Sec. 312.53 Selecting investigators and monitors. (a)Selecting investigators. A sponsor shall select only investigators qualified by training and experience as appropriate experts to investigate the drug. (b)Control of drug. A sponsor shall ship investigational new drugs only to investigators participating in the investigation.

28. Responsibilities of Sponsors (c)Obtaining information from the investigator. Before permitting an investigator to begin participation in an investigation, the sponsor shall obtain the following: (1) A signed investigator statement (Form FDA-1572) (2) Curriculum vitae. (3) Clinical protocol. (4) Financial disclosure information.

29. In a nutshell… The FDA is ultimately concerned with: –Protection of human subjects (including privacy) –Control of the investigational product

30. 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 And, the bottom line….what if it is your loved one on the table? How would you want them to be protected?