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…”
Nuclear Experiments
• 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
Not Just Radiation Medicine
• 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
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
ICH Publications
• 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
www.ich.org
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
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!
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!
21CFR312
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/C
FRSearch.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 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
Control of Investigational Drug
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.
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
Signed Investigator Statement
“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.”
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