Introduction to GCP and 21CFR312

Dear Clinical Investigator…

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

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…”

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…”

• 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

• 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

Guidance for Investigators

• Declaration of Helsinki

• International Conference on Harmonisation

• U.S. Code of Federal Regulations

• FDA Guidance Documents

• IRB

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

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

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

• 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

ICH Publications

www.ich.org

ICH E6: Good Clinical PracticeGCP

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/GuidanceComplianceRegulatoryInformation/Guidances/ucm073122.pdf

ICH E6: Good Clinical Practice

• Contents:1. Glossary2. The Principles of ICH GCP3. Institutional Review Boards4. Investigator5. Sponsor6. Clinical Trial Protocol(s)7. Investigator Brochure8. Essential Documents for the Conduct of a

Clinical Trial

• Get to know this document!

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

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!

21CFR312http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/

CFRSearch.cfm

21CFR312

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

Control of Investigational Drug312.60 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

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

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

“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

21CFR50

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.”

21CFR56

21CFR812

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

IRB

U Iowa IRB

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