RTRN Good Clinical Practice Series Coordinated by Mayer B. Davidson, M.D., Charles Drew University Federal Regulations & Good Clinical Practices (GCPs) - PowerPoint PPT Presentation

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RTRN Good Clinical Practice Series Coordinated by Mayer B. Davidson, M.D., Charles Drew University Federal Regulations & Good Clinical Practices (GCPs)


RTRN Good Clinical Practice Series Coordinated by Mayer B. Davidson, M.D., Charles Drew University Federal Regulations & Good Clinical Practices (GCPs) – PowerPoint PPT presentation

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Title: RTRN Good Clinical Practice Series Coordinated by Mayer B. Davidson, M.D., Charles Drew University Federal Regulations & Good Clinical Practices (GCPs)

RTRN Good Clinical Practice SeriesCoordinated
byMayer B. Davidson, M.D., Charles Drew
UniversityFederal Regulations Good Clinical
Practices (GCPs)
  • Susan Partridge, BSN, MBA, CCRC
  • LA Biomedical Research Institute
  • at Harbor-UCLA Medical Center

Speaker Disclosure Statement
  • The speaker does not have any financial or
    personal interest that would conflict with any of
    the material presented in this lecture.

Why do we need to knowabout Federal Regulations
and GCPs?
  • Rules of the road for conducting research
  • A national and international standard
  • Adopted/endorsed by
  • Sponsors of drug, biologics and device studies
  • Federal agencies that fund research (NIH, CDC,
  • Universities and research sites
  • Professional research organizations

What is Good Clinical Practice?
  • A standard for the
  • design
  • conduct
  • performance
  • monitoring
  • auditing
  • recording
  • analysis, and
  • reporting of clinical trials

What are GCPs?
  • Based on a set of regulatory and ethical
    requirements, standards and recommendations that
    apply to thousands of tasks, processes and roles
    in the conduct of clinical research
  • The current standard for the conduct of
    clinical trials

Why do we need to know about GCPs?
  • Demonstrates high standards for the conduct of
    clinical research
  • Required for studies (US or foreign) where data
    will be submitted to FDA for licensure
  • Sponsors and study sites require evidence of
  • Essential for any research with human subjects
    sponsored or unsponsored

The pillars of GCPs
Protection of Subjects Rights
Data Integrity
To provide assurance that the data and reported
results are credible and accurate
To ensure that the rights, integrity and
confidentiality of trial participants are
Where did GCPs come from?
  • The International Conference on Harmonization
    (ICH) founded 1990
  • Develop a consensus among countries regarding the
    requirements for the conduct of clinical trials
  • Harmonize efforts to help reduce drug development
    expense and duplication

Composition of ICH
ICH Co-Sponsors United States Japan European
ICH Observers Canada WHO European Free Trade Area
IFPMA International Federation
of Pharmaceutical Manufacturers Ass. (represents
56 countries)
Pharmaceutical Research Manufacturers of
Advantages of ICH for the pharmaceutical industry
  • Mutual acceptance of data in many countries
  • Ensures the credibility of investigators and the
    validity of the data
  • New Drug Application (NDA) data to be presented
    in a standardized format
  • Review time for drug applications shortened
  • Reduction in drug development time
  • Reduction in cost and use of resources

August 1995 FDA publishes in the Federal Register
draft of Good Clinical Practice April 1996 E6
Good Clinical Practice A Consolidated
Guideline Endorsed by ICH
ICH Good Clinical Practice (GCP) guidelines were
published in the Federal Register, accepted by
the U.S. FDA and became effective May 7, 1997
What are GCPs based on?
  • Code of Federal Regulations
  • Title 21 (FDA)
  • Part 11 Electronic Records Electronic Signature
  • Part 50 Protection of Human Subjects
  • Part 54 Financial Disclosure by Clinical
  • Investigators
  • Part 56 Institutional Review Boards
  • Part 312 Investigational New Drug Application
  • Title 45 (HHS)
  • Part 46 Protection of Human Subjects (DHHS)

ICH GuidelinesWhere do GCPs fit in?
  • Q Quality Topics
  • E Efficacy Topics
  • S Safety Topics
  • M Multidisciplinary
  • Topics
  • Chemical pharmaceutical quality assurance
  • Clinical research in human subjects
  • E6 Good Clinical Practices
  • E7 Special populations
  • E8 General considerations
  • E9 Statistical principles for clinical
  • E10 Choice of control group
  • In vivo and in vitro pre-clinical studies
  • M1 Medical terminology
  • M2 Electronic standards for submission of
  • data
  • M3 Timing of pre-clinical studies in
  • to clinical trials

Where Can IFind TheseDocuments?
www.gpoaccess.gov www.regsource.com www.ich.org ww
w.fda.gov www.nih.gov
GCPs at the research site
  • Know the GCPs so you can be ready to discuss the
    basic requirement and any expectations above that
  • Document GCP training at your site
  • Recognize that sponsors require that you follow
    their interpretation of GCPs (each funding agency
    has SOPs)
  • If faced with different interpretations of GCPs,
    usually the more stringent criteria applies

GCP Contents
  • Glossary
  • Principles
  • Investigator
  • Sponsor
  • Protocol
  • Investigators Brochure
  • Essential Documents for the Conduct of a Trial

GCP Contents - Today
  • Glossary
  • Principles
  • Investigator
  • Sponsor
  • Protocol
  • Investigators Brochure
  • Essential Documents for the Conduct of a Trial

Future sessions
  • May 11, 2011
  • Essential documents for clinical trials
  • May 25, 2011
  • Data collection standards for clinical trials
  • Other presenters
  • Institutional Review Boards (IRB) and informed
    consent Dr. Junko Nishitani
  • Data and Safety Monitoring Dr. Roger Lewis

Key Concepts Principles
  • 2.3 The rights, safety and well-being of
  • trial subjects are the most important
  • considerations and should prevail over
  • interests of science and society
  • 2.5 Clinical trials should be scientifically
  • sound and described in a clear,
  • protocol
  • 2.9 Each individual involved in conducting a
    clinical trial should be qualified by
    education, training, and experience to perform
    his or her respective task

Protocols Amendments ICH GCP Part 6
Key Concepts Protocol
  • ICH Guidelines provide required content for a
  • Note These guidelines can also be found in FDA
    regulations 21 CFR 312.23 IND Content and Format

Key Concepts Protocol
  • 6.3 The protocol should contain a detailed
    description of the objectives purpose of the
  • The scientific integrity of the trial and the
    credibility of the data depend on trial design
  • Primary and secondary endpoints
  • Type of trial design (double-blind,
  • Measures to minimize/avoid bias (randomization,

Protocol elements
  • Dosing regimen of investigational product(s)
  • Expected duration of subject participation
  • Stopping rules for individual subjects, parts of
    the trial, entire trial
  • Maintenance of randomization codes and procedures
    for breaking codes
  • Subject inclusion, exclusion criteria
  • Subject withdrawal criteria
  • Procedures for eliciting reports of adverse events

Protocol elements
  • Methods and timing for assessing, recording and
    analyzing safety parameters
  • Description of statistical methods to be used,
    including planned interim analyses
  • Sample size with description of the calculations
    used and justifications
  • Description of selection of subjects to be
    included in the analyses
  • Criteria for termination of the trial
  • Ethical considerations

  • All versions of the study protocol
  • are submitted to the FDA (as part of the IND
  • must be retained in the site study file
  • must be submitted to the IRB for approval
  • must be given to all members of the study team

  • There is a signature line in the protocol
    for the PI to sign. What is the PI affirming?
  • A. The protocol was received
  • B. The protocol was reviewed
  • C. The terms of the protocol have been
    accepted by the investigator
  • D. The protocol has been submitted to the IRB
    and other institutional departments

C. The terms of the protocol have been accepted
by the investigator
  • NIH
  • www.NIDCR.nih.gov
  • www.NIAID.nih.gov
  • University/research institute sites
  • UTHSC www.uth.tmc.edu

Investigators Brochure ICH GCP Part 7
Investigators Brochure (IB)
  • A compilation of the clinical and nonclinical
    data on the investigational product(s) that are
    relevant to the study of the product(s) in human
  • Purpose To provide investigators and study
    personnel with information about the test product
  • pre clinical and clinical data to date
  • dose, frequency
  • precautions
  • metabolism, excretion
  • potential adverse events

  • All versions of the IB
  • are submitted to the FDA (as part of the IND
  • must be retained in the site study file
  • must be submitted to the IRB (acknowledgement)
  • must be given to all members of the study team
  • IND safety reports are added to the IB
  • Typically, the PI signs an IB receipt form

Investigators ICH GCP Part 4
Key Concepts Investigators
  • GCPs have helped to define the role of study
    investigator as distinct from that of primary
    care physician
  • Investigators are accountable to
  • Study subjects
  • IRB
  • Institution
  • OHRP (Office of Human Research Protections)
  • Sponsor
  • For IND studies, FDA (Form 1572)

  • ICH Guidelines address
  • 4.1 Investigator qualifications
  • 4.2 Adequacy of resources
  • 4.3 Medical Care of trial subjects
  • 4.4 Communication with IRB/IEC
  • 4.5 Compliance with protocol
  • 4.6 Investigational Product(s)
  • 4.7 Randomization procedures and
  • unblinding

  • ICH Guidelines address (cont)
  • 4.8 Informed consent of trial subjects
  • 4.9 Records and reports
  • 4.10 Progress reports
  • 4.11 Safety reporting
  • 4.12 Premature termination or suspension
  • of a trial
  • 4.13 Final report by investigator/institution

  • Investigator GCPs can also be found in
  • 21 CFR 50 Protection of Human Subjects
  • 45 CFR 46 Protection of Human Subjects
  • 21 CFR 56 Institutional Review Board
  • 21 CFR 312.60-312.70
  • Responsibilities of investigators

Investigator responsibilities
  • FDA Form 1572 Statement of Investigator (an
    agreement with the federal government)

FAQs About the 1572 Form
Key Concepts Investigators
  • 4.1.5 The investigator should maintain a list of
    appropriately qualified persons to whom the
    investigator has delegated significant
    trial-related duties

Key Concepts Investigators
  • 4.2.1 The investigator should be able to
    demonstrate (based on retrospective data) a
    potential for recruiting the required number of
    suitable subjects within the agreed recruitment
  • 4.2.2 The investigator should have sufficient
    time to properly conduct and complete the trial
    within the agreed trial period
  • 4.2.3 The investigator should have an adequate
    number of qualified staff and adequate facilities
    for the foreseen duration of the trial to conduct
    the trial properly and safely

Key Concepts Investigators
  • 4.3.2 During and following a subjects
    participation in a trial, the investigator/institu
    tion should ensure that adequate medical care is
    provided to a subject for any adverse events,
    including clinically significant laboratory
    values, related to the trial. The
    investigator/institution should inform a subject
    when medical care is needed for intercurrent

Key Concepts Investigators
  • 4.5.1 The investigator should conduct the trial
    in compliance with the protocol which was given
    favorable opinion by the IRB. The investigator
    should sign the protocol, or an alternative
    contract to confirm their agreement
  • 4.5.3 The investigator, or person designated,
    should document and explain any deviation from
    the approved protocol

Key Concepts Investigators
  • 4.6.1 Responsibility for investigational
    product(s) accountability at the trial site(s)
    rests with the investigator/institution
  • 4.6.2 The investigator/ institution may assign
    some or all of the investigators/institutions
    duties for investigational product(s)
    accountability to an appropriate pharmacist or
    another appropriate individual who is under the
    supervision of the investigator/institution

  • Who is responsible for the conduct of a study?

  • The Principal Investigator (PI)
  • The PI is responsible for the integrity of
    the data at their site(s) and for the safety of
    the subjects
  • By completing an FDA form 1572, the PI signs
    an legally binding agreement with the federal
  • Tasks can be delegated to others.
    Responsibility for the study cannot be delegated

  • Who is responsible for ensuring that
    individuals assisting with the study are
    adequately informed of the protocol,
    investigational product and the duties of the
  • A. Sponsor
  • B. Monitor
  • C. Site institution
  • D. Investigator

D. Investigator
Added FDA Guidance Supervisory Responsibilities
of Investigators
  • Draft Guidance issued May 10, 2007 Federal
  • Final version released October 30, 2009
  • Key to FDA approach in their oversight/audit of
    clinical trials

4 Major Areas of Concern
  • Are study personnel qualified
  • to perform protocol activities?
  • What is adequate training
  • for study staff?
  • What is adequate
  • supervision of a clinical trial?
  • What are investigator responsibilities for
    oversight of other parties involved in the
    conduct of a clinical trial?

Application Demonstrateinvestigator involvement
  • Develop SOPs that include the role of the PI
  • Document communication with PI
  • Copy on study related email and retain in
    regulatory binder
  • Retain records of meetings/telephone
    discussions with PI (particularly related to
    subject eligibility or safety)

  • PI sign off on key documents
  • Consent forms
  • Case report form (study subject data)
  • Serious adverse event reports
  • Progress notes
  • Protocol deviations
  • Regulatory documents (1572, IRB correspondence,
    protocol signature page, IB signature page)
  • Correspondence from sponsor

  • Hold regular project meetings draft a quick list
    of topics and keep an attendance sheet.
  • Document ongoing oversight during the trial (PI
    sign off on QA/QC reports, progress reports)
  • Make sure the PI attends monitor debriefings (in
    person or by phone)

Application Documentation of staff
qualifications, PI delegation
  • SOPs should document staff roles for various
    study procedures, including communications.
  • On the Signature and Responsibility list, leave
    room for the PI to sign off
  • In the Study Regulatory Binder, include evidence
    of personnel training and experience including
    CV, license, human subjects training,
    certificates, evidence of courses taken

  • Document individuals who attended training
    sessions. If they did not attend, document how
    they were trained and by whom.
  • Training sessions for study procedures should
    include return demonstration.
  • Extra effort should be made to document the roles
    and qualifications of collaborating site
    personnel who are not under the direct
    supervision of the PI.

Proposed FDA Rule for Disqualification of a
Clinical Investigator
  • Issued 4/13/2011
  • Amend the regulations to expand the scope of
    clinical investigator disqualification. When the
    FDA Commissioner determines that an investigator
    is ineligible to receive certain test articles
    (drugs, devices, or new animal drugs), the
    investigator also will be ineligible to conduct
    any clinical investigation
  • Comments are due July 12, 2011

Sponsors ICH GCP Part 5
Key Concepts Sponsors
  • A sponsor is an individual, company, institution,
    or organization that takes responsibility for the
    initiation, management, and/or financing of a
    clinical trial
  • A sponsor-investigator is an individual who
    initiates and conducts a clinical trial. The
    obligations include both those of a sponsor and
    those of an investigator

Key Concepts Sponsors
  • 5.1.1 The sponsor is responsible for
    implementing and retaining quality assurance and
    quality control systems with written SOPs, to
    ensure that trials are conducted and data are
    generated in compliance with the protocol, GCP.
  • A sponsors SOPs for the conduct of a clinical
    trial may be more stringent than GCP Guidelines.
    Upon signing the protocol and accepting a new
    study, the investigator is stating that they will
    comply with the sponsor SOPs.

Key Concepts Sponsors CROs
  • 5.1.2 A sponsor may transfer any or all of the
    sponsors trial-related duties and functions to a
    Contract Research Organization (CRO).
  • The CRO may be an individual or a company
  • The ultimate responsibility for the quality and
    integrity of the trial data always resides with
    the sponsor
  • 5.2.2 Any transfer of activity to a CRO should
    be in writing. The CRO can only take on the
    sponsor tasks that are agreed to in a contract
  • A CRO must abide by the same regulations as the

Key Concepts Sponsors
  • 5.5.2 The sponsor may consider establishing an
    independent data monitoring committee (IDMC) to
    assess the progress of a clinical trial,
    including the safety data and the critical
    efficacy endpoints at intervals and to recommend
    to the sponsor whether to continue, modify, or
    stop a trial. The IDMC should have written
    operating procedures and maintain written records
    of all of its meetings.

Key Concepts Sponsors
  • 5.6.1 The sponsor is responsible for selecting
    qualified investigators.
  • 5.6.3 The sponsor should obtain the
    investigators/institutions agreement
  • To conduct the trial in compliance with GCP and
    with the protocol
  • To comply with procedures for data
  • To permit monitoring, auditing and inspection
  • To retain essential documents
  • The sponsor and the investigator should sign the
    protocol to confirm this agreement

Key Concepts Sponsors
  • 5.14.2 The sponsor should not supply an
    investigator/institution with the investigational
    product until the sponsor obtains all of the
    required documentation.
  • 5.14.4 The sponsor should
  • Ensure timely delivery of investigational
  • Maintain records that document shipment, receipt,
    disposition, return and destruction of the
    investigational product(s)
  • Take steps to ensure that the investigational
    product is stable over the period of time

Key Concepts Sponsors
  • 5.14.5 (continued)
  • Maintain sufficient quantities of the
    investigational product(s) to reconfirm
    specifications and maintain records of batch
    sample analyses and characteristics
  • 5.16.1 The sponsor is responsible for the ongoing
    safety evaluation of the investigational
  • 5.17.1 The sponsor should expedite the reporting
    to all concerned investigator(s), to the IRB, and
    to the regulatory authorities all adverse drug
    reactions that are both serious and unexpected

Key Concepts Sponsor Monitoring
  • 5.18.1 The purposes of trial monitoring - to
    verify that
  • The rights and well-being of human subjects are
  • The reported trial data are accurate, complete
    and verifiable from source documents
  • The conduct of the trial is in compliance with
    the currently approved protocol/amendment(s),
    with GCP, and with regulatory requirements

Key Concepts Sponsor Monitoring
  • 5.18.2 Monitors should be appointed by the
  • 5.18.3 The sponsor should ensure that trials are
    adequately monitored (the sponsor determines the
    frequency and duration of monitoring)
  • The monitor acts as the main line of
    communication between the sponsor and the

Key Concepts Monitor Responsibilities (GCP ICH
  • Verify that the investigator has adequate
    qualifications and resources
  • Ensure that the investigator receives the
    current Investigator Brochure, all documents and
    all trial supplies needed
  • Ensure that the investigator (and staff) are
    adequately informed about the trial

Key Concepts Monitor Responsibilities
  • Verify that informed consent was obtained for
    each subject
  • Verify re investigational product
  • Storage times and conditions are acceptable
  • The investigational product is given only to
    subjects eligible to receive it
  • The receipt, use and return of the
    investigational product at the trial sites are
    controlled and documented

Key Concepts Monitor Responsibilities
  • Data required by the protocol are reported
    accurately on the CRFs and are consistent with
    the source documents
  • Adverse events, concomitant medications, and
    intercurrent illnesses are reported
  • Visits that the subjects fail to attend, tests
    that are not conducted and examinations that are
    not performed are clearly documented
  • Subject withdrawals and dropouts are reported and

Key Concepts Monitor Responsibilities
  • Informing the investigator of CRF entry errors,
    and ensuring that changes are made correctly and
    by an individual who is authorized to initial CRF
    changes for the investigator
  • Determining whether all adverse events are
    appropriately reported within the time periods
    required by GCP, ICH Standards, IRB, sponsor
  • Determining whether a site is maintaining
    essential documents (regulatory file)

Key Concepts Sponsors
  • Audits
  • The purpose of an audit, which is independent of
    and separate from routine monitoring or quality
    control functions, should be to evaluate trial
    conduct and compliance with the protocol, SOPs,
    GCP, and the applicable regulatory requirements

  • Sponsor monitoring GCPs can also be found
  • Guideline for Monitoring of Clinical
  • 21 CFR 312.55 Informing investigators
  • 21 CFR 312.56 Review of ongoing investigations
  • 21 CFR 312.62 Investigator record keeping and
    record retention
  • 21 CFR 312.64 Investigator reports
  • ICH GCP Guideline 5.18 Monitoring

  • ICH Adopted GCP Guidelines have been in place for
    14 years
  • Provided more explicit instructions about the
    role of the sponsor and investigator
  • Created a benchmark for conducting clinical
  • Used as an industry standard by FDA
  • Universally accepted in the field of clinical
    research now globally

Impact of ICH Guidelines
  • Challenges
  • Increased documentation regulatory burden
  • Need for increased training
  • Growth of outsourced services (CROs, SMOs)
  • Greater cost
  • Positives
  • Higher standards greater consistency
  • Basis for best practices
  • Ability to accept foreign data and reduce
    redundancy in clinical trials

Wrap up
  • Do you have GCP questions???
  • Email to spartridge_at_labiomed.org.
  • Answers will be given during the next class.
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