Transcript Slide 1

Introduction to 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
AND
We are using low risk diagnostic doses anyway…
Radiopharmaceuticals don’t have side effects…
Patients get images which can help their diagnosis…
Nuclear Guinea Pigs
• 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
Not Just Radiation
• 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
Change Agents
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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
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
Ethical Basis for Regulations
• Nuremburg Code
• Declaration of Helsinki
Declaration of Helsinki
• 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 wellbeing of the individual research subject must take
precedence over all other interests.”
• http://www.wma.net/en/30publications/10policies/b3/inde
x.html
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
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
ICH
• 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 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 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)
US regs and ICH
• 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
21CFR312
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/C
FRSearch.cfm
21CFR312
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
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
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
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
Form FDA-1572
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM074728.pdf
Sponsor Responsibilities
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
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312
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.
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.
In a nutshell…
• The FDA is ultimately concerned with:
– Protection of human subjects (including privacy)
– Control of the investigational product
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?