Module 4
1
History of Good Clinical Practice
Regulations
Barbara Novak
2
US Food and Drug Law
Chronology
•
•
1848 Congress banned importation of
adulterated drugs after a bad batch of
quinine was imported for U.S. Army.
(Did not affect domestic issues of
adulteration)
1879 Congress began investigating
incidents involving contamination of
food and drugs through the USDA
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US Food and Drug Law
Chronology
•
1902 Biologics Control Act
– Required licensing of serums and
vaccines
• 1906 Pure Food and Drug Act
– Congress began investigating
incidents involving contamination of
food and drugs through the USDA
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1906 Pure Food and Drugs Act
AKA Wiley or Heyburn Act
• Dr. Wiley’s lunch crew
• Upton Sinclair’s The Jungle
• Prohibited interstate transportation of
adulterated and misbranded foods and
drugs
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US Food and Drug Law
Chronology
•
1912 Sherley Amendment
– Prohibited false and fraudulent
curative claims or therapeutic claims
on labels (snake venom, elixirs,
wonder cures)
•
1938 Food, Drug and Cosmetic Act
– Added cosmetics to the 1906 Act
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1938 Food, Drug and
Cosmetic Act
• Elixir of Sulfanilamide - 1937
• Required pre-market approval of new
drugs for safety
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Food, Drug and Cosmetic Act
• Authorizes FDA to inspect at reasonable
times
• Authorizes FDA to promulgate and
enforce regulations
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US Food and Drug Law
Chronology
•
1962 Kefauver Act
– Amendments to the 1938 ACT that
set up a mandatory reporting system
for drug safety
– Led to the Spontaneous Reporting
System which catalogues ADR
reports for marketed drugs
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1962 Kafauver Act
• Thalidomide tragedy
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1987 IND Rewrite
• 21 CFR Part 312 Introduced
– Laid out the responsibilities of
sponsors, monitors and investigators
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Prescription Drug User Fee Act
(PDUFA)
•1992 & 1997
•FY2001 Fees
–Application fee - $309,647
–Establishment Fee - $145,987
–Annual product fee - $21,892
• FY 2005 Fees
–Application fee - $672,000/ 336,00 (SNDA)
–Establishment Fee - $262,000
–Annual product fee - $41,710
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Good Clinical Practices (GCPs)
• Phrase coined by industry
• Includes Regulations, Guidelines and Industry
practices which address responsibilities of:
– the Sponsor
– the Investigator
– Institutional Review Boards
and requirement for Informed Consent.
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Regulations vs Guidelines
• Regulations = LAW
• Guideline = Clarification
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Purpose of GCP’s
• To protect the rights and safety of
subjects
• To assure the quality and integrity of
the clinical research data
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GCP Regulations
• 21 CFR Part 312 – IND Regulations
• 21 CFR Part 312.50 to 312.59
– Sponsor/monitor responsibilities
• 21 CFR Part 312.60 to 312.69
– Investigator responsibilities
• 21 CFR Part 50
– Informed consent regulations
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GCP Regulations
• 21 CFR Part 56 - IRB regulations
• 21 CFR Part 11 – Electronic signatures
• 21 CFR Part 54 – Financial disclosure
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GCP Guidelines
• FDA Information Sheets
• Guidelines for Monitoring,
Investigators, etc
• ICH GCP Guideline
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FDA Organization
• FDA is 1 agency within the Dept. of
Health and Human Services (HHS)
– Reports to Secretary of HHS
– Funding is through the HHS budget
(FDA has a separate budget)
– Small agency – frequent visit to Capitol
Hill
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FDA
• FDA is comprised of 8 Centers/Offices
CDER – Center for Drug Evaluation
and Research (most therapeutic
biologics recently transferred to CDER)
CBER- Center for Biologics Evaluation
and Research)
CDRH – Center for Devices and
Radiological Health
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FDA
CFSAN – Center for Food Safety and
Applied Nutrition
CVM – Center for Veterinary Medicine
NCTR – Nat’l Center for Toxicological
Research
OC - Office of Commissioner (head of
FDA)
ORA – Office of Regulatory Affairs
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Office of Medical Policy
• Reports to CDER Director
• Division of Scientific Investigations
– Select sites for inspection
– Assist on inspections
– Review inspection reports
– Final classification of
reports/regulatory action
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Office of Regulatory Affairs
(ORA)
• Associate Commissioner for Regulatory
Affairs
• Office of Resource Management
• Office of Regional Operations
• Office of Enforcement
• Office of Criminal Investigations
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Field Set-Up
• Report to Office of Regional Operations
• 5 Regions
– Northeast Region
• Regional office in New England & NY
• District offices in NE, NYC, Buffalo
– Central Region
• Regional office in Phila, Baltimore & Chicago
• District offices in Philadelphia, Baltimore,
Chicago, NJ, Cincinnati, Detroit, Minneapolis
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Field Set-Up
– Southeast Region
• Regional office in Atlanta
• District offices in Atlanta, New Orleans, Florida,
San Juan
– Southwest Region
• Regional office in Dallas, Denver, KC
• District offices in Dallas, Denver, Kansas City,
and a Southwest Import District
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Field Set-Up
– Pacific Region
• Regional office in San Francisco & Seattle
• District offices in Los Angeles, San Francisco &
Seattle
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Submissions
• Drugs
– IND: Investigational New Drug
Application
– NDA: New Drug Application
• Biologics
– BB-IND: Biologics Investigational Drug
Application
– BLA: Biologics License Application
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FDA Website
• www.fda.gov
• Each center is represented
• Can access guidelines, regulations,
speeches
• Warning letters are posted, and
investigator disqualifications
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Module 9
29
International Conference on
Harmonization (ICH)
• US, EU, Japan
• Industry, trade organizations and
regulatory representatives
• 5 step process, with Step 5 being
FINALIZATION of the individual guideline
– i.e., acceptance of the guideline by
each country
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Purpose of ICH
•
•
•
•
•
•
Harmonize standards
Improve quality and reliability of data
Protect rights & welfare of subjects
Minimize human new drug exposure
Speed up marketing of new drugs
Decrease cost
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ICH GCP Guideline
• Published as guideline in US
• Includes requirements for
– Sponsors
– Investigators
– IRB/IEC
– Informed consent
– Essential documents
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ICH GCP Guideline
• Similar to FDA regulations
• FDA very involved in ICH process
• More detailed in most places
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FDA Bioresearch Monitoring
Program
• Kefauver Harris amendments
• Field survey 1972 – 1974
• Sponsors, Investigators, Contract
research Organizations (CROs), IRBs,
Toxicology Laboratories
• Drugs, Devices, Biologics, Foods,
Veterinary Medicine
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Why GCPs?
•
•
•
•
Mandated by regulatory authorities
History indicates need
Uniform way of conducting research
Drug/biologic/device development is
expensive – DO IT RIGHT THE FIRST
TIME
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Office for Good Clinical
Practice (OGCP)
•
•
•
•
Within the Office of the Commissioner
Agency-side coordinating functions
Work with OHRP
Improve conduct and oversight of clinical
research
• Ensure protection of participants in FDAregulated clinical research
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Responsibilities
• Promote protection of human research
participants
• Support quality and integrity of clinical
trials and applications
• Support global harmonization and
implementation of GCP standards
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HHS
• OHRP – Office of Human Research
Protections
• More inspections of IRBs
• Required training for sites
• Loss of funding
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Module 8
39
Obligations of Sponsors
21CFR 312.50 to 312.59
DEFINITION
Sponsor: An individual, company,
institution or organization that
takes responsibility for and
initiates (and/or finances per
ICH) a clinical investigation
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Obligations of Sponsors
21CFR 312.50 to 312.59
KEY POINTS:
Select and Update Investigators
Study Monitoring
Recordkeeping
Drug Distribution
Maintain the Regulatory Submissions
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Obligations Of Sponsors
21CFR 312.50 to 312.59
SPECIFIC OBLIGATIONS:
Sponsor commits to:
Obtain a signed FDA form 1572 and
Curriculum Vitae from each investigator
Ensure investigator understands his/her
obligations per the regulations
Provide investigator with a current
Investigator Brochure
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Obligations Of Sponsors
21CFR 312.50 to 312.59
SPECIFIC OBLIGATIONS:
Sponsor commits to:
Obtain sufficient, accurate financial
information to submit the required
certification or disclosure statements, and
obtain commitment from investigator to
update this information if relevant
changes occur
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Obligations Of Sponsors
21CFR 312.50 to 312.59
Continued...
Keep investigator informed of new
observations discovered or reported,
particularly with respect to adverse
effects and safety
Monitor study by on-site visits
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Obligations Of Sponsors
21CFR 312.50 to 312.59
Continued...
Ensure that investigator and staff are
following approved protocol and ensure
that case report forms are being
adequately completed
Assure that qualified IRB will be involved
Assure investigator will inform IRB of any
protocol changes except to eliminate an
immediate hazard to subjects
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Obligations Of Sponsors
21CFR 312.50 to 312.59
Continued...
Evaluate evidence relating to safety and
efficacy as it is received from the
investigator
Discontinue study if it is determined that
the study drug presents an unreasonable
and significant risk to subjects. Notify
FDA, all IRBs and all investigators of a
discontinuation for such reasons
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Obligations Of Sponsors
21CFR 312.50 to 312.59
Continued...
Submit to FDA annual progress reports,
updated Investigator Brochure, and IND
safety reports as required
Maintain records showing any financial
payments to clinical investigators
Maintain records of drug shipment, receipt,
and disposition, including date, quantity,
and batch
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Obligations Of Sponsors
21CFR 312.50 to 312.59
Continued...
Assure the return or disposition of unused
supplies
Retain all records for 2 years after NDA is
approved or study is discontinued
Allow for FDA inspections of records and
reports of clinical investigations
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Obligations Of Sponsors
21CFR 312.50 to 312.59
Continued...
Discontinue drug shipment or secure
compliance from any investigator who
has not maintained or made available
his/her records to FDA for inspection
Assure compliance with storage and
record-keeping requirements
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Obligations Of Sponsors
21CFR 312.50 to 312.59
Continued...
Notify FDA and all participating
investigators of any serious and
unexpected adverse experience
associated with the use of the study
drug
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Obligations Of Sponsors
21CFR 312.50 to 312.59
Continued...
Notify FDA and all participating
investigators of any preclinical findings
that suggest a significant risk for human
subjects (e.g., mutagenicity,
teratogenicity, or carcinogenicity
findings)
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Obligations Of Clinical
Investigators
DEFINITION
Investigator: An individual who actually
conducts a clinical investigation (i.e.,
under whose immediate direction the
drug is administered or dispense to a
subject). If conducted by a team, the
inv. is the responsible leader of the
team.
ICH: A person responsible for the conduct
of the clinical trial at a site
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Obligations Of Clinical
Investigators
REGULATION:
21CFR 312.60 to 312.70
KEY POINTS:
Conduct Clinical Study
Protection of Patients
Control of Drug
Compliance with IRB requirements
Recordkeeping
Reporting
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Obligations Of Clinical
Investigators
Specific Obligations:
The Investigator commits to:
Personally conduct or supervise the
described investigation
Provide a list of the names of
subinvestigators who will be assisting in
the conduct of the investigation
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Obligations Of Clinical
Investigators
Continued…
Ensure that all associates, colleagues, and
employees assisting in the conduct of
the study are informed about their
study obligations. Such associates,
colleagues, and employees must be
listed on the FDA form 1572
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Obligations Of Clinical
Investigators
Continued…
Assure that study is conducted in
accordance with the protocol, and only
make changes after notifying the
sponsor
Obtain informed consent from all patients
prior to their participation in the study
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Obligations Of Clinical
Investigators
Continued…
Prepare and maintain adequate and
accurate case histories that record all
observations relevant to the study.
Case histories include study CRFs,
informed consent forms, and medical
records including progress notes,
hospital charts, nurses notes, and lab
records
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Obligations Of Clinical
Investigators
Continued…
Promptly report to the sponsor all adverse
effects that may reasonably be
suspected to have been caused by the
study drug. If the adverse effect is
serious and unexpected, it should be
reported to the sponsor immediately
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Obligations Of Clinical
Investigators
Continued…
Assure that study drug is administered only
to subjects under the investigator’s
personal supervision or the supervision of
a subinvestigator in his/her study
Return or otherwise dispose of all unused
study medication in accordance with the
sponsor’s instructions
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Obligations Of Clinical
Investigators
Continued…
Maintain accurate and adequate records
of drug disposition and drug
accountability
Assure that an IRB that complies with the
IRB regulations will be responsible for
the initial and continuing review and
approval of the proposed protocol
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Obligations Of Clinical
Investigators
Continued…
Assure that the study informed consent form is
approved by an IRB prior to initiation of the
study
Assure that all changes in the protocol are
reported to an IRB, and assure that no
changes will be made to the protocol without
prior IRB approval, except where necessary
to eliminate apparent, immediate hazards to
human subjects
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Obligations Of Clinical
Investigators
Continued…
Submit annual progress reports to an IRB
Submit progress reports of study findings
to the sponsor
Provide sponsor with a final study report
shortly after completion of participation
in the clinical investigation
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Obligations Of Clinical
Investigators
Continued…
Maintain study records for 2 years after
NDA approval or 2 years after
discontinuation of study
Provide sponsor with sufficient, accurate
financial information to submit the
required certification or disclosure
statements, and obtain commitment
from investigator to update this
information if relevant changes occur
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Obligations Of Clinical
Investigators
Continued…
Permit access to, including copying of
study records and reports by FDA,
sponsor, or sponsor-designated
individual(s)
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Obligations Of Clinical
Investigators
Laboratory Records
Form 1572 lists laboratory and its location
Lab accreditation stored with investigator
Lab normals retained
Label lab samples with patient ID, study
number and date
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Module 6
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Obligations of IRBs
DEFINITION:
Institutional Review Board (IRB): any board,
committee or group formally designated by an
institution to review, approve and conduct
periodic review of biomedical research involving
human subjects.
ICH definition: An independent body constituted
of medical, scientific and nonscientific members
whose responsibility it is to ensure the
protection of the rights, safety and well-being of
human subjects involved in a trial.
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Obligations of IRBs
REGULATION: 21CFR 56
Purpose:
Protect the rights and welfare of research
subjects both before and during their study
participation
Determine:
Should the study be approved (do benefits
outweigh the risks)?
What constitutes adequate informed consent?
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IRB Membership &
Organization
• At least five members with appropriate
qualifications to review the research
• At least one member whose primary area of
interest is in a nonscientific area
• At least one member who is independent of
the institution/trial site
• Should not consist entirely of men or women
• A list of IRB members should be maintained
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IRB Functions
• Reviews protocols, consents, and ads
• Reviews amendments
• Provides expedited review—i.e. minor changes
to a protocol that don’t increase risk
• Provides continuing review of trials (at least
annually)
• Reviews qualifications of investigators
• Has the authority to suspend research
• Reviews all adverse drug reactions both serious
and unexpected
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IRB Records
• Copies of research proposals/protocol (and
accompanying documentation)
• Minutes of meetings
• Correspondence
• List of members
• Written operating procedures (SOPs) for IRB
• Kept for 3 years after completion of research
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IRB: Expedited Review
An IRB may use an expedited review
procedure to review minor changes in
previously approved research during the
period (1 year) for which the approval is
authorized
Expedited review may be carried out by the
IRB Chairperson or by one or more
experienced reviewers designated by the IRB
Chairperson from among the members of the
IRB
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IRB: Expedited Review
Procedures
 IRB’s which use expedited review must have
a method of keeping all IRB members
informed of research proposals which have
been approved under this procedure
 FDA may restrict, suspend, or terminate an
IRB’s use of expedited review when
necessary to protect the rights of subjects
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Module 5
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Informed Consents (IC)
IC overview
IC audit checklist
Class examples of IC showing
required elements
FDA Warning Letters from IC
Handout example of industry IC
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Informed Consent
REGULATION: 21CFR 50
Purpose:
Patient protection
Patient information
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Informed Consent Process
• Exchange of meaningful information
• Begins with subject first learns of the
study
• Ends when there is no more new
relevant information
• Prior to the performance of study
procedures
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Informed Consent Content
Required Elements
Additional Elements, as applicable
Institution, local, state requirements
Language understandable to subject
Provide information subject needs to
make an informed decision about
participation
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Informed Consent
Required Elements of Informed Consent:
21CFR 50.25
Purpose, duration and procedures of the
research
Foreseeable Risks to subject and benefits to
subject or others
Alternative procedures or courses of treatment
Confidentiality of records – must note the
possibility of FDA inspection or others
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Informed Consent
Required Elements of Informed Consent:
Explanation of compensation, if any, for
research-related injury
Contacts for pertinent questions or reports of
research related injuries
Statement of voluntary participation
-No penalty or loss of benefit upon refusal to
participate or withdrawal of consent
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Informed Consent
Additional Elements of Informed Consent
where applicable (required by ICH):
May involve unforeseeable risks to subject
(embryo/fetus)
Circumstances in which the study may be
terminated without subject’s consent
Any additional costs to subject from
participation
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Informed Consent
Additional Elements of Informed Consent
where applicable (required by ICH ):
Consequences of early withdrawal
Significant new findings during study
Approximate number of subjects in study
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Informed Consent Problems
50% of FDA inspections at clinical
investigator sites identify
inadequacies in the informed
consent
Lack of required elements
Lack of proper documentation
Not obtained prior to enrollment
Improper IRB approval
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HIPAA
Health Insurance Portability and
Accountability Act (HIPAA)
-Enacted in 1996 to protect the security and
confidentiality of electronic health information.
-Primarily directed at the health care industry,
insurers and medical providers.
-Original deadline for privacy rule by Congress
missed in 1999- finally published in Dec. 2000 ,
with a compliance date of April 14, 2003.
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HIPAA
Law applies to “Covered Entities and Business
Associates” that use or disclose protected
health information.
Requires the “de-identification” of individually
identifiable health information, and disclosure
of uses of protected health information (PHI).
Although no FDA regulation specifically addresses
HIPAA, clinical research certainly deals with
PHI.
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HIPAA
Clinical research now includes HIPAA
authorization –either in the IC directly or in a
separate document, depending on institutional
or IRB policy.
- must specifically give permission to use PHI for
the purpose of research
- have the right to withdraw permission to use
PHI
- expiration date of the authorization
- suspension of access rights to study records
until study is completed.
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Issues Noted in Recent Warning
Letters and FDA 483’s
Informed Consent
Study procedures performed prior to
signing and dating the IC
Failure to obtain appropriate IC (e.g., no
signature, incorrect signature/date, not
in a language understandable to the
subject)
Not current/correct version of IC
Elements missing from the IC
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