GCP Overview by Compliance Insight, Inc.

GCP Overview

Copyrighted Compliance Insight, Inc. 2013

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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.


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Background

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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.”


Background

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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.


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Background

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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.


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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.


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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).”



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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) The ethical principles contained in the 1989 version of Declaration of Helsinki

2) The laws and regulations of the country in which the research was conducted.



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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.



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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.



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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.


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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



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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 Responsibilities-

Protecting 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)



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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


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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.



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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.



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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)


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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!


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FDA vs. ICHFDA GCP

1. Physician Notification - FDA draft guidance (2007) recommends that a subject’s primary care physician be informed if the subject agrees to this notification.

2. Source Data - FDA regulations and guidance documents have no such provision that source data recorded in CRFs should be specified in the protocol.

3. Delegation of Responsibility - The form is not mentioned in any FDA regulation or guidance, but it is often referenced by FDA investigators during inspections.

ICH GCP1. Physician Notification -

Recommends that a patient’s primary care physician be notified that the patient is enrolling in a clinical trial.

2. Source Data - Any source data recorded directly in the CRF should be specified in the protocol.

3. Delegation of Responsibility - Calls for the completion of a staff delegation of responsibility form.


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FDA GCP4. Financial Disclosure - Requires

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).

5. Informed Consent - Only a copy of the Informed consent should be provided. However, 1998 information sheets recommend that the copy provided to subjects be a signed copy.

ICH GCP4. Financial Disclosure - No such

provisions for financial disclosure.

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


FDA vs. ICH

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FDA GCP6. 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.

*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.

ICH GCP6. 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.


FDA vs. ICH

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FDA GCP8. 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.

9. Informed Consent - FDA regulations have no provisions for nontherapeutic trials to be conducted in those subjects who personally provide their consent.

ICH GCP8. 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.


FDA vs. ICH

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FDA GCP10. 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.

ICH GCP10. 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.


FDA vs. ICH

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FDA GCP11. 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.

12. 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.

ICH GCP11. 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.


FDA vs. ICH

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FDA GCP13. 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.

14. 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)”.

ICH GCP13. 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.


FDA vs. ICH

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FDA GCP14. IRB Review - FDA regulations allow

and expedited initial review of certain types of studies involving no more than minimal risk.

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

ICH GCP14. IRB Review - ICH GCP has no

guideline for expedited initial review.

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


FDA vs. ICH

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FDA GCP17. 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.

ICH GCP17. 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.


FDA vs. ICH

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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)


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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.


Sponsor

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The Sponsor: Applies to the regulatory authorities for permission to

perform the clinical study based on findings from pre-clinical 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.Copyrighted Compliance Insight, Inc. 2013

Sponsor

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Clinical Investigator

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.


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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 day-to-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.


Clinical Investigator

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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.


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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.


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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


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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.


IRB/IEC Duties

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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


IRB/IEC Composition

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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.


IRB/IEC Composition

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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.


IRB/IEC Composition

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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.


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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


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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.



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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



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GCP Overview by Compliance Insight, Inc.

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