GCP Overview by Compliance Insight, Inc.

GCP Overview

Copyrighted Compliance Insight, Inc. 2013

Background
In 2007, the average cost of developing a
new drug reached $1.2 billion.
•

None of this cost is effective unless the drug is
acceptable to drug regulatory authorities.

To ensure Clinical Trials are performed in a
scientific, humane and ethical manner, and
also promote regulatory compliance, the
codes of Good Clinical Practice (GCP) have
been defined by most countries.


.

2

Background
The International Conference on
Harmonization defines GCP as:
“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.”


3

Background
Traditionally, the term GCP has been used by





U.S. Federal Regulations
Regulatory Authorities
Industry
Clinical Researchers

We identify GCP as the collection of guidelines
defining trial-related responsibilities for sponsors,
clinical investigators, monitors, institutional
review boards (IRBs) and other personnel involved
in the clinical research process.

.

4

GCP Guidance
GCP encompasses dynamic procedures that are
continually being affected by evolving thought and
standards.
The most recent significant standard document is the
International Conference on Harmonization (ICH)
“Good Clinical Practice: Consolidated Guideline”
 Aka E6, adopted by the conference in 1996
 FDA adopted guidance - May 1997

E6 provides a unified standard for designing,
conducting, recording and reporting trials that involve
the participation of human subjects.

5

The Declaration of Helsinki
In June 1964, at a meeting in Helsinki, Finland, the
World Medical Association adopted the “Declaration of
Helsinki” which outlines “a statement of ethical
principles to provide guidance to physicians and other
participants in medical research involving human
subjects.”
GCP standards throughout the world note openly that
they derive largely from the Declaration of Helsinki.
Revised several times since 1964.


6

In the ICH consolidated GCP guideline under Section 2
- The Principles of ICH GCP that
“clinical trials should be conducted in accordance with
the ethical principles that have their origin in the
Declaration of Helsinki, and that are consistent with
GCP and the applicable regulation requirement(s).”


7

For many years, the FDA used the Declaration of Helsinki
as a standard for accepting data from certain foreign
clinical studies supporting safety and efficacy claims for
drugs and biologics not conducted under a U.S.
Investigational New Drug Application (IND)
These studies had to meet whichever provided the greater
protection for human subjects:
1)
2)

The ethical principles contained in the 1989 version of
Declaration of Helsinki
The laws and regulations of the country in which the research
was conducted.

8

FDA no longer relies on the Declaration of Helsinki as
a standard for accepting data from foreign, non-IND
studies.
The Declaration is “independent of FDA authority,”
therefore future revisions might include provisions that
are inconsistent with U.S. law or regulations.
FDA’s long-standing preference for placebo controls in
many circumstances conflicted with the 2000
modifications to the Declaration.

9

FDA will accept “a well-designed and well-conducted
foreign clinical study not conducted under an IND,”
provided that



The study is conducted in accordance with Good Clinical Practice.
The FDA is able to validate the data from the study through an
onsite inspection if the agency deems it necessary.


10

Clinical Regulations
U.S. Clinical trial responsibilities were defined (primarily)
in a series of documents released in the 1980’s, including:





1981 - Regulation on the informed consent of clinical subjects
(21 CFR Part 50)
1981 - Regulation on the responsibility of IRBs
(21 CFR Part 56)
1987 - IND Rewrite regulations, defining the responsibilities of
the investigator and the sponsor (21 CFR Part 312)
1988 - Guideline for the Monitoring of Clinical Investigations*
outlined the responsibilities of monitors
*Recently withdrawn - new guidance on Risk-based Monitoring released
in August 2013.

11

Two additional draft guidelines, issued in 1994 as
separate documents, were integrated into the
consolidated ICH guideline (E6):



Guideline for the Investigator’s Brochure
Guideline for Essential Documents for the Conduct of a
Clinical Study

Other FDA regulations and documents are thought to
fall under GCP standards:



21CFR Part 11: Electronic Records/Signatures - relevant to
electronic clinical study records
21CFR Part 54: Financial disclosures for clinical investigators

12

April 2008, FDA released a final regulation revising the
agency’s standards for accepting foreign clinical studies
that are not conducted under an IND


Both research and marketing purposes

Most recently FDA’s latest thinking on GCP standards:





October 2009 guidance - “Investigator ResponsibilitiesProtecting the Rights, Safety, and Welfare of Study Subjects”
January 2009 guidance - “Adverse Event Reporting to IRBs”
Information Sheets released for IRBs and Clinical Investigators
FDA Compliance program guidance manuals (ICECI)


13

Other documents impacting clinical research standards:
 Department of Health and Human Services (DHHS) “Basic

DHHS Policy for Protection of Human Subjects”- known as
the Common Rule


U.S. federal policy (Subpart A of Part 46 of Title 45)



Provides regulations for human subject protections in research
conducted, supported or otherwise subject to regulation by a
federal government agency that has formally adopted the policy.



Seventeen U.S. government agencies have signed on to comply
with the provisions of the Common Rule, including the
Department of Veterans Affair, the Department of Justice, the
Department of Education, Department of Energy, National
Aeronautics and Space Administration (NASA).

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Common Rule (cont’d)


Studies involving FDA regulated products are
funded/supported by HHS, the research must
comply with both FDA GCP standards and the
Common Rule.



Sponsors should be aware of those institutions and
generally be operating in compliance with Common
Rule requirements


.

15

ICH GCP Guideline. FDA formally adopted the ICH
GCP guideline (E6) in the United States.
 In 1997, FDA stated the ICH GCP Guideline represents the

agency’s current thinking on the good clinical practice.
 The Guideline is more specific in several areas and may
provide additional standards to ensure data quality and subject
protection in certain areas.

FDA officials maintain that they will consider clinical
studies conducted under ICH GCP as meeting GCP
standards acceptable to FDA.

16

WHO Guidelines for Good Clinical
Practice


In 1994, the World Health Organization (WHO) issued its
Guidelines for GCP for trials on pharmaceutical products to set
globally applicable standards for the conduct of such biomedical
research in human subjects.” Based on GCP standards
implemented in highly developed countries, WHO guidelines are
relevant in many developing countries that may lack or have
limited standards for clinical research.


17

Regulations and You
If you’re a Sponsor, Investigator or IRB member what standards do you follow?
Generally follow the ICH GCP as being more
specific, but consider two exceptions:



FDA requirements for IRBs differ slightly with respect
to membership and function
Requirements for informed consent under 21 CFR Part
50 for particular clinical trials (e.g., emergency research
and clinical trials involving pediatric subjects- under
Subpart D)

18

FDA vs. ICH Comparison
Slides 20 – 28 offer a practical outline on
the differences that may impact your trial
Identify the main topical differences
between the regulations and established
guidelines
Familiarize yourself with these differences

COVER THE BASES!

19

FDA vs. ICH
FDA GCP
1.

2.

3.

ICH GCP

Physician Notification - FDA draft
guidance (2007) recommends that a
subject’s primary care physician be
informed if the subject agrees to this
notification.
Source Data - FDA regulations and
guidance documents have no such
provision that source data recorded in
CRFs should be specified in the protocol.
Delegation of Responsibility - The form
is not mentioned in any FDA regulation
or guidance, but it is often referenced by
FDA investigators during inspections.

1.

2.

3.

Physician Notification Recommends that a patient’s
primary care physician be notified
that the patient is enrolling in a
clinical trial.
Source Data - Any source data
recorded directly in the CRF
should be specified in the
protocol.
Delegation of Responsibility Calls for the completion of a staff
delegation of responsibility form.


20

FDA vs. ICH
FDA GCP
4.

5.

ICH GCP

Financial Disclosure - Requires
4.
investigators responsible for key
clinical studies complete a financial
disclosure form , and that the clinical
trial sponsor collect such information
and report on the relevant financial
interests of and compensation paid to
such investigators in premarketing
applications (e.g., NDA’s, BLAs).
Informed Consent - Only a copy of 5.
the Informed consent should be
provided. However, 1998 information
sheets recommend that the copy
provided to subjects be a signed copy.

Financial Disclosure - No such
provisions for financial disclosure.

Informed Consent - Explicitly states
that the copy of the Informed consent
form provided to the subject be a copy
of the signed form.


21

FDA vs. ICH
FDA GCP
6.

ICH GCP

Informed Consent - Require a
witness be present during the oral
presentation of the elements of the
informed consent when the short
form* is used, but do not specify
that the witness be impartial.

6.

Informed Consent - Impartial
witness be present in those cases
in which an Informed Consent
Document (ICD) is read to a trial
subject/legally authorized
representative (e.g., when the
subject/legally acceptable
representative cannot read).

7.

Informed Consent - Disclosure
of the important potential benefits
and risks of the alternatives.

*Rarely used in the US
7.

Informed Consent - Provisions for
informed consent process call for the
disclosure of appropriate alternative
procedures or courses of treatments
that may be advantageous to the
subject.


22

FDA vs. ICH
FDA GCP
8.

9.

ICH GCP

Informed Consent - As part of the
Informed Consent Process, FDA
regulations require only a statement that
notes the possibility that the agency may
inspect the records. The Privacy Rule,
which took effect in April 2003 in the
United States, calls for a document that
informs the subject of the persons, classes
of persons, and organizations who will
create, disclose, and/or receive protected
health information during research.
Informed Consent - FDA regulations
have no provisions for nontherapeutic
trials to be conducted in those subjects
who personally provide their consent.

8.

Informed Consent - As part of the
Informed Consent Process, a statement
that monitors, auditors, the IRB and
regulatory authorities will be granted
direct access to medical records and a
statement that, by signing the consent,
the subject is authorizing such access.

9.

Informed Consent - With a few
exceptions, ICH GCP specifically calls
for nontherapeutic trials (i.e., studies in
which there is not anticipated direct
clinical benefit to the subject) to be
conducted only in those subjects who
personally provide their consent.


23

FDA vs. ICH
FDA GCP
10.

ICH GCP

Informed Consent - FDA has no such
specific provision. Regulations state that
child assent is required in pediatric trial
unless child is not capable of giving
assent, or the intervention or procedure is
intended to provide direct benefit that is
important to the child’s well-being. FDA
regulations require additional safeguards
to protect the rights and welfare of
subjects who are vulnerable to coercion or
undue influence. While not specifically
required by regulation, the IRB may
determine that the assent of those subjects
not able to decide for themselves is
necessary as an appropriate safeguard.

10.

Informed Consent - When subject
can only be enrolled with the consent
of legally authorized representative
(e.g., minors, patients with severe
dementia), ICH GCP states that the
subject should be informed about the
trial to the extent compatible with the
subject’s understanding, and if
capable, the subject should assent,
sign and personally date the written
informed consent.


24

FDA vs. ICH
FDA GCP
11.

12.

ICH GCP

Informed Consent - Requires only one
signature – that of the subject or legally
authorized representative (LAR). When a short
form written consent document is used to
establish that the elements of informed consent
have been presented orally to the subject or
subject’s LAR, the FDA requires three (3)
signatures: the person conducting the consent
interview, the witness to the oral presentation,
and the subject or LAR. The subject/LAR sign
the short form, the witness signs the short form
and a copy of the summary of what was said to
the subject/LAR, and the person obtaining
consent shall sign the copy of the summary.
Compensation for Injury- FDA regulations
require explanation of whether any
compensation and any medical treatments will
be available only for studies that involve greater
than minimal risk.

11.

Informed Consent - All informed
consents to be signed and dated by the
person who conducts the informed consent
discussion.

12.

Compensation for Injury - explanation
of whether any compensation and any
medical treatments will be available if
injury occurs for all studies.


25

FDA vs. ICH
FDA GCP
13.

14.

ICH GCP

IRB Review - FDA regulations require IRBs to
review “all research activities,” which is
generally understood to include all of these
elements (subject recruitment procedures, the
investigator’s brochure, payments and
compensation to study subjects and curriculum
vitae of the investigators). FDA guidance
documents also call for IRB review of certain
recruitment materials.
IRB Review - FDA regulations do not
explicitly call on IRBs to review investigator
qualifications. However in a recent Warning
Letter to an IRB, the FDA cited the IRB for
“failing to adequately assess the professional
qualifications of the clinical investigator under
21 CFR 56.107(a)”.

13.

IRB Review - Specifically calls
for IRB review of subject
recruitment procedures, the
investigator’s brochure, payments
and compensation to study
subjects, and the curriculum vitae
of the investigators.

14.

IRB Review - Calls on the IRB to
review investigator qualifications.


26

FDA vs. ICH
FDA GCP

ICH GCP

14.

IRB Review - FDA regulations allow
and expedited initial review of certain
types of studies involving no more
than minimal risk.

14.

IRB Review - ICH GCP has no
guideline for expedited initial review.

15.

IRB Documents - FDA regulations
require only IRBs provide copies of
their written procedures and
membership lists to regulatory
authorities upon request.

15.

IRB Documents - Calls on IRBs, when
asked, to provide copies of their written
procedures and membership lists to
investigators, sponsors, or regulatory
authorities.


27

FDA vs. ICH
FDA GCP
17.

ICH GCP

Record Retention - FDA sets records
retention period at three (3) years for IRBs
and two (2) years for sponsors and
investigators. However, records retention
standards differ in some ways, particularly
with the starting point for the retention
period. FDA requires sponsors and
investigators to retain required records and
reports for two years after a marketing
application has been approved for the drug
or if an application is not approved for the
drug, until two years after shipment and
delivery of the drug for investigational use
is discontinued and the FDA has been so
notified.

17.

Record Retention - Investigators and
sponsors should retain essential documents
until at least two (2) years after the last
approval of a marketing application in an
ICH region and until there are no pending
or contemplated marketing applications in
an ICH region, or at least two (2) years
have elapsed since the formal
discontinuation of clinical development of
the investigational product. It should be
noted that some localities and regions have
longer retention requirements than either
FDA or ICH.


28

Clinical Trial - Practical
A clinical study is…
 Initiated and Monitored by a Sponsor

 Planned and Performed by Investigator(s)
 Reviewed and Approved by an

Institutional Review Board (IRB)


29

Sponsor
The Sponsor:





Usually performs the development of the
investigational product and
Either the preclinical testing of safety and efficacy
in its own laboratories, or had some or all of its
work conducted by a Contract Research
Organization (CRO)
The Sponsor’s responsibility is to ensure that
Investigators follow the protocols and comply with
GCP in all aspects of trial conduct.

30

Sponsor
The Sponsor:










Applies to the regulatory authorities for permission to
perform the clinical study based on findings from preclinical findings.
Selects the Investigator(s)
Writes the Investigator’s Brochure
Prepares the study protocol jointly with the Investigator
Supplies the investigational product
Monitors the clinical study
Submits the final report(s) from the Investigator(s) to
the regulatory agency.

31

Clinical Investigator





Holds the prime position in the study environment
Education training and experience must be
sufficient to permit full responsibility for the
conduct of the study and for well-being of the
subjects.
Must ensure full responsibility of all aspects of the
study at the individual subject level are in full
compliance with GCP.


32

Once the design of the study is established and the
IRB has approved the trial protocol, GCP refers to
the way in which the supervising clinician and all of
his or her staff go about their study duties on a dayto-day basis.
Quality and integrity of the data generated by the
study depend entirely on these operations.
These operations are confirmed by monitoring and
auditing procedures.

33

Contract Research
Organizations
Contract research organizations (CROs)






May help support Sponsors in the design, conduct and
analysis of clinical trials.
Hired in the hope that CROs compliance expertise will
be greater than that of the Sponsor.
CROs may offer specialized clinical and statistical
knowledge and easier access to prime clinical research
sites.
The Sponsor has the ultimate responsibility for GCP
compliance including adequate monitoring of the studies
whoever is performing them.

34

IRB/IEC
IRB/IEC Purpose





Ethical aspects of clinical studies - include safeguarding
the safety and welfare of subjects.
Responsible review bodies that are independent of the
study, but qualified to determine its acceptability.
An Institutional Review Board may be set up by the
institution in which the study will be performed.
An Independent Review Board – not affiliated with the
institutions or clinics in which the study will be
performed.


35

IRB/IEC Duties
Protect the rights, safety, and well-being of trial
participants
Review and approve trial documents that impact
trial participants

Ensure Informed Consent procedures and
documents are clear, complete and provide
sufficient information for trial participants
Continuing review of trial documents, including
protocol amendments and adverse event reports

36

IRB/IEC Duties
The IRB has the power and responsibility to…




approve or disapprove a study and
monitor and review its progress and
may require that a study be suspended or stopped, if
there is potential for damage to the subject(s) rights,
safety or well-being.

In Europe, Independent Ethics Committees (IEC)
provide advice to the research institution.
The IEC will hand down opinions and the
institution will take the executive action.

37

IRB/IEC Composition
Critical to GCP
 Members

must be of varying backgrounds,
one should be a scientist and
 one other should have primary concerns in
a non-scientific area.

Cannot consist of only one profession


38

IRB/IEC Composition
Members should be comprised of both men
and women, selection should not be made on
a gender basis.
At least one member should not be affiliated
with the institution and not of the immediate
family of a person who is affiliated with the
institution.

39

IRB/IEC Composition
Members should be sufficiently qualified
through experience, expertise and diversity
that the advice and counsel of the IRB in
safeguarding the rights and welfare of
human subjects will be respected.
Members should demonstrate understanding
of, and sensitivity to such issues as
community attitudes.

40

Sponsor-IRB Communications
Regulations do not prohibit direct Sponsor-IRB
contact, but the Clinical Investigator or CRO
generally provide the communication link.
Usually the means of communication linkage is
agreed upon by the Sponsors and
Investigator(s) and CRO when they sign
clinical trial agreements.

41

Non-compliance: The Fallout
For the Investigator and institution where
she or he is affiliated, noncompliance
may result in:




Loss of recognition by regulatory authorities as
being acceptable as an Investigator for future
studies.
Listing on the FDA’s website.



Debarment List - “Black List”
Disqualified/Restricted List

42

Lack of GCP compliance may result in:
 Refusal to approve an application for marketing
 Adversely affect a companies plans to launch a new drug

product, device or diagnostic.
 Sanctions (Fines, Litigation, Seizure)

FDA evaluated 104 applications submitted in 2010:


Rejection of data occurred for 4% of clinical investigators
inspected in association with related BLAs and NDAs



Significant data integrity concerns affected 5% of the
applications.

43

Commercial implications:





Significant sums of money are spent on studies
Even if they appear to demonstrate safety and
effectiveness of the product, they do not lead to
marketing approval if they do not comply with
GCP regulations and guidance documents.
Loss of Reputation due to Observations,
Warning Letters, Fines, Litigation


44

CONTACT US:
Send Questions to info@compliance-insight.com
Corporate office: (513) 860-3512
East Coast area: (862) 236-5533
www.compliance-insight.com


45

GCP Overview by Compliance Insight, Inc.

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