So you think you know GCP ...

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“So You Think You Know GCP ...”

Northern California Chapter ACRP

March 21, 2013

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Presenter

Paul Below, MS, CCRA• Clinical Project Leader, American Medical Systems

• Trainer for ACRP

• Former President Minnesota Chapter ACRP (2004, 2010)

• Adjunct instructor for the St. Cloud State University Master’s Degree Program in Applied Clinical Research

• Recipient of ACRP’s Leadership in Clinical Research as a CRA Award in May 2011

• Recipient of ACRP’s Top Speaker Award for the 2012 Global Conference

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Disclosure

• Paul has no relevant financial relationship in relation to this educational activity

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Background

• This presentation was developed to correct numerous errors and myths about Good Clinical Practice overheard by the presenter throughout his clinicalresearch career

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Are you sure this is right? I’ve

never been asked to document it

this way before.

Yes, you have to do it this way. It’s an FDA requirement.

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I never heard of this FDA requirement before but it

must be true. He is the monitor and he should

know …

I wouldn’t count on it

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Learning Objectives

• Define Good Clinical Practice (GCP)

• Differentiate between GCP requirements (stated in regulation) and recommendations (stated in guidance documents) in several key areas

• Identify several circumstances where “industry best practices” exist that go above and beyond what the FDA requires or even recommends

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What is Good Clinical Practice (GCP)?

• Good Clinical Practice (GCP) is a unified standard for designing, conducting, recording, and reporting trials that involve human subjects

• GCP is composed of many parts that cannot be foundin any one book or place

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Sample TitleSample Text

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GCP

Other Federal Regulations

FDA Regulations(21 CFR)

State Law

Local Law (Institutional

and IRB Policies)

FDA GuidanceDocuments

InternationalStandards

Sponsor SOPs

IndustryBest Practices

1010


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GCP


State Law


and IRB Policies)



Sponsor SOPs


• Informed Consent (21 CFR 50)• Institutional review boards (21 CFR 56)• Financial disclosure (21 CFR 54)• Electronics records and signatures (21 CFR 11)• Investigational new drugs (21 CFR 312) and application to

market a new drug (21 CFR 314)• Investigational device exemptions (21 CFR 812) & premarket

approval of medical devices (21 CFR 814)


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GCPState Law


and IRB Policies)



Sponsor SOPs



• Nuclear Regulatory Commission regulations for the medical use of radioactive substances (10 CFR 35 and 21 CFR 361)

• Department of Transportation regulations for the shipment of hazardous materials (49 CFR)

• HIPAA Privacy Rule (45 CFR 160-164) for the use and disclosure of protected health information

• “Common Rule” (45 CFR 46) - Human subjects protection rules for federally funded research

Other FederalRegulations

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GCP


State Law


and IRB Policies)


Sponsor SOPs



• FDA Information Sheets

• ICH Guidelines for Good Clinical Practice (1997)

• Investigator Responsibilities (2009)

• Adverse Event Reporting to IRBs (2009)

• FAQs on the Form FDA 1572 (2010)

• Risk-Based Approach to Monitoring (Draft, 2011)


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GCP


State Law


and IRB Policies)


Sponsor SOPs



• Ethical Doctrines: Declaration of Helsinki Nuremberg Code

• Clinical Research Guidelines: ICH Guidelines for GCP (E6) ICH Guidelines for Safety Reporting (E2A) ISO 14155 – Medical Devices

• EU Directives

• Country-Specific Requirements


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GCP



and IRB Policies)



Sponsor SOPs


FDA Regulations(21 CFR) • Age of consent

• Legally authorized representatives

• Clinical research registration

• Medical records privacy

• Gene research

• STD/HIV reporting

• Gifts to practitioners

State Laws

151515

GCP


State Law



Sponsor SOPs



• Institutional Policies: Internal Protocol Review Committee Approval Investigational Product Storage / Dispensing Personnel Training Requirements

• IRB Policies: Protocol Deviation Reporting Requirements SAE Reporting Requirements Frequency of Continuing Review and Reporting Format Informed Consent Requirements


and IRB Policies)

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GCP


State Law


and IRB Policies)





• CRF Completion Guidelines

• SAE Reporting Requirements

• Regulatory Document Organization

• Sponsor-Specific Form Completion

• Source Documentation Practices

• Investigator Signature Requirements

• Investigational Product Storage and Accountability Requirements

SponsorSOPs

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Sample Text

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GCP


State Law


and IRB Policies)



Sponsor SOPs


• Good Documentation Practices

• GCP Training Requirements

• Site SAE Reporting Requirements

• Investigational Product Storage

• Handling Lost to Follow-Up Subjects

• Curriculum Vitae Requirements

• Form 1572 and Clinical Investigator Agreement Requirements


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GCP



State Law


and IRB Policies)



Sponsor SOPs


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Learning all of the parts of GCP can take some time and may seem daunting to those new to the

clinical research industry

2020

Time to Test Your GCP Knowledge

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• The following slides are a series of questions to test your knowledge of GCP

• You will be able to submit your answers by text messaging orthrough the web

• All answers areanonymous (no oneis identified by name or phone number)

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How to Vote by Text Message

Example Question: What is your favorite color?

• Red 3544

• Blue 3545

• Green 3546

• Orange 3546

To vote, text the corresponding keyword to 22333 NOTE: Standard carrier text messaging rates apply but there are no additional fees to participate in the quiz

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Informed Consent

Questions

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FDA Regulations (21 CFR 50) specify the following:Question Keyword

The ICF must be signed and dated by the subject 624626

The ICF must be signed and dated by the person obtaining consent

624627

The ICF must be signed and dated by the Principal Investigator 624628

The ICF must be signed by a child subject if the IRB determines that assent is required

624651

All of the above 624655

Question

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2525




624627



624651


Text your answer (keyword) to 22333

Question

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2626




624627



624651


Specified in 21 CFR 50.27a

Answer

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• The ICF must be signed and dated by the person obtaining consent – Specified by ICH GCP (4.8.8).

• The ICF must be signed and dated by the Principal Investigator – Not specified by FDA Regulation or Guidance but sometimes required by IRBs.

• The ICF must be signed by a child subject if the IRB determines that assent is required – The method of documenting assent is determined by the IRB (21 CFR 50.55) and does not necessarily have to be by child signature.

Explanation

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FDA Guidance (Guide to Informed Consent Info Sheet & ICH GCP) specifies the following:

Question Keyword

The ICF should be written at a 6th grade reading level 624669

When it is anticipated that consent interviews will be conducted in a foreign language, a translated ICF should be prepared

624727

A subject who can understand and comprehend spoken English, but is physically unable to talk or write, should not be enrolled in a clinical trial

624773

All study personnel involved in the informed consent process should be trained in Human Subjects Protection

624774


Question

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FDA Guidance (Guide to Informed Consent Info Sheet & ICH GCP) specifies the following:

Question Keyword

The ICF should be written at a 6th grade reading level 624669

When it is anticipated that consent interviews will be conducted in a foreign language, a translated ICF should be prepared

624727

A subject who can understand and comprehend spoken English, but is physically unable to talk or write, should not be enrolled in a clinical trial

624773

All study personnel involved in the informed consent process should be trained in Human Subjects Protection

624774


Answer

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However, the Guide to Informed Consent indicates that if a non-English speaking subject is unexpectedly encountered, investigators will not have a written translation of the ICF and must rely on oral translation.

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• The ICF should be written at a 6th grade reading level – No specific grade level requirement is defined. Instead, the FDA Information Sheets say:

“The IRB should ensure that technical and scientific terms are adequately explained or that common terms are substituted. The IRB should ensure that the informed consent document properly translates complex scientific concepts into simple concepts that the typical subject can read and comprehend.”

Similarly, ICH (4.8.6) specifies that the consent language should be “as non-technical as practical and should be understandable to the subject.”

Explanation

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• A subject who can understand and comprehend spoken English, but is physically unable to talk or write, should not be enrolled in a clinical trial – They can be enrolled if an impartial witness is present during the entire informed consent discussion.

• All study personnel involved in the informed consent process should be trained in Human Subjects Protection – Required for NIH studies but not currently specified by FDA.

Explanation

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Financial DisclosureQuestion

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Part- or full-time employees of the sponsor may not participate as Clinical Investigators in that sponsor’s trials

624803

Clinical Investigators may not have a proprietary interest (i.e., patents, royalties) in the tested product in a trial

624804

Clinical Investigators may not receive more than $25,000 a year in “payments of other sorts” (i.e., grants, consulting fees, speaker honoraria)

624812

In general, financial disclosure is not required for large open safety studies conducted at multiple sites

624813

None of the above 625046

Question

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Part- or full-time employees of the sponsor may not participate as Clinical Investigators in that sponsor’s trials

624803

Clinical Investigators may not have a proprietary interest (i.e., patents, royalties) in the tested product in a trial

624804

Clinical Investigators may not receive more than $25,000 a year in “payments of other sorts” (i.e., grants, consulting fees, speaker honoraria)

624812

In general, financial disclosure is not required for large open safety studies conducted at multiple sites

624813


Answer

Specified in 21 CFR 54.2e. Financial disclosure applies to any study of a drug or device in humans submitted in a marketing application that the applicant or FDA relies on to establish efficacy or any study in which a single investigator makes a significant contribution to the demonstration of safety.

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• Part- or full-time employees of the sponsor may not participate as Clinical Investigators in that sponsor’s trials – This is allowed but financial disclosure is required.

• Clinical Investigators may not have a proprietary interest (i.e., patents, royalties) in the tested product in a trial – Same as above.

• Clinical Investigators may not receive more than $25,000 a year in “payments of other sorts” (i.e., grants, consulting fees, speaker honoraria) – Same as above.

Explanation

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• Sponsors may include individuals as Investigators who have these financial interests but they have to explain any steps taken to minimize the potential for bias resulting from any of the disclosed arrangements, interests, or payments (21 CFR 54.4a)

• FDA then decides if the steps are adequate to ensure the reliability of the study (21 CFR 54.5a)

• Interestingly, there is no requirement for financial disclosure by monitors or other sponsor personnel who have the capacity to bias the data

Explanation

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IRBQuestion

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An IRB must be composed of five (5) members 625047

An IRB must have at least one female member 625048

If an IRB regularly reviews research involving prisoners, a prisoner representative should be included on the board

625049

An IRB member that has a conflicting interest in a project under review may not participate in the IRB's review proceedings

625076


Question

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An IRB must be composed of five (5) members 625047

An IRB must have at least one female member 625048

If an IRB regularly reviews research involving prisoners, a prisoner representative should be included on the board

625049

An IRB member that has a conflicting interest in a project under review may not participate in the IRB's review proceedings

625076


Answer

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• An IRB must be composed of five (5) members – Must have at least 5 members (21 CFR 56.107a).

• An IRB must have at least one female member – The FDA Regulations (21 CFR 56.107b) specify:

“Every nondiscriminatory effort will be made to ensure that no IRB consists entirely of men or entirely of women, including the institution's consideration of qualified persons of both sexes, so long as no selection is made to the IRB on the basis of gender.”

Explanation

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Explanation

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• If an IRB regularly reviews research involving prisoners, a prisoner representative should be included on the board – Consideration shall be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with those subjects (21 CFR 56.107a).

• An IRB member that has a conflicting interest in a project under review may not participate in the IRB's review proceedings – These individuals can participate in order to provide information requested by the IRB (21 CFR 56.107e).

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MonitoringQuestion

4343

FDA Guidance (ICH GCP) specifies the following:Question Keyword

A monitoring report should be submitted to the sponsor after each site visit or trial-related communication

627475

Monitors should not make any notations or corrections on the CRF pages

627539

Monitors should ensure that all corrections to the CRF are completed with a single line through the incorrect entry and initiated and dated by the completer

627540

Monitors should attempt to meet in person with the Investigator at every visit to discuss the progress of the trial

627541


Question

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FDA Guidance (ICH GCP) specifies the following:Question Keyword

A monitoring report should be submitted to the sponsor after each site visit or trial-related communication

627475

Monitors should not make any notations or corrections on the CRF pages

627539

Monitors should ensure that all corrections to the CRF are completed with a single line through the entry and are initiated and dated by the completer

627540

Monitors should attempt to meet in person with the Investigator at every visit to discuss the progress of the trial

627541


Answer

Specified in ICH 5.18.6a

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• Monitors should not make any notations or corrections on the CRF pages – Sponsors should have written procedures to assure that changes or corrections in CRFs made by sponsor's designated representatives are documented, are necessary, and are endorsed by the investigator (ICH 4.9.3).

• Monitors should ensure that all corrections to the CRF are completed with a single line through the entry and are initiated and dated by the completer – Any change or correction to a CRF should be dated, initialed, and explained (if necessary) and should not obscure the original entry (ICH 4.9.3).

Explanation

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• Monitors should attempt to meet in person with the Investigator at every visit to discuss the progress of the trial – There are several sections of ICH that address the monitors responsibility to communicate with the Investigator but the frequency of these communications is not specified (ICH 5.18.4). This is often specified in sponsor SOPs.

Explanation

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SourceDocumentation

Question

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FDA Regulations (21 CFR 312/812) specify the following:Question Keyword

It is prohibited to use CRFs (other than questionnaires) directly as source documents

625078

Each subject’s case history should document that informed consent was obtained prior to participation in the study

625079

All source documents must be signed by the completer 625089

If a site uses electronic medical records as source documents, the EMR system must be compliant with 21 CFR part 11

625090


Question

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FDA Regulations (21 CFR 312/812) specify the following:Question Keyword

It is prohibited to use CRFs (other than questionnaires) directly as source documents

625078

Each subject’s case history should document that informed consent was obtained prior to participation in the study

625079

All source documents must be signed by the completer 625089

If a site uses electronic medical records as source documents, the EMR system must be compliant with 21 CFR part 11

625090


Answer

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Specified in both 21 CFR 312.62b and 812.140a. “Case histories” include CRFs, signed and dated consent forms, and medical records (physician progress notes, individual's hospital chart and the nursing notes)

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• It is prohibited to use CRFs (other than questionnaires) directly as source documents – There is no regulation preventing this practice or from using copies of CRFs as source documents.

• All source documents must be signed by the completer – There is no requirement for this but several FDA Guidances do specify that data should be “attributable.”

Explanation

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• If a site uses electronic medical records as source documents, the EMR system must be compliant with 21 CFR part 11 – There is currently no FDA Regulation or Guidance specifying this. However, a recent FDA Draft Guidance does indicate:

“For those who use electronic signatures based upon the use of identification codes in combination with passwords, the clinical site must employ controls to ensure the security and integrity of the authorized user names and passwords (21 CFR 11.300a).” Draft Guidance on Electronic Source Documentation in Clinical Investigations (December 2010)

Explanation

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InvestigatorResponsibilities

Question

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FDA Guidance specifies the following:Question Keyword

A Trial Delegation List should identify the training that individuals have received that qualifies them to perform delegated tasks

625092

In device studies, the field clinical engineer’s activities should be described in the protocol and informed consent (if face-to-face contact with subjects)

625093

Investigators should develop a plan for the oversight of the clinical trial that might include the creation of specific SOPs

625096

Investigators conducting studies of drugs with potentially fatal toxicity should be readily available 24 hours/day and in reasonably close proximity to study subjects

625097


Question

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5454

FDA Guidance specifies the following:Question Keyword

A Trial Delegation List should identify the training that individuals have received that qualifies them to perform delegated tasks

625092

In device studies, the field clinical engineer’s activities should be described in the protocol and informed consent (if face-to-face contact with subjects)

625093

Investigators should develop a plan for the oversight of the clinical trial that might include the creation of specific SOPs

625096

Investigators conducting studies of drugs with potentially fatal toxicity should be readily available 24 hours/day and in reasonably close proximity to study subjects

625097


Answer

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Study Records Storage

Question

5656

FDA Regulations (21 CFR 312/812) and Guidance (ICH GCP) specify the following:

Question Keyword

It is the Investigator’s responsibility to inquire with the sponsor when study records no longer need to be retained

625099

In general, study records should be obtained indefinitely because it is never certain when product development will be permanently discontinued by the sponsor

625114

Sponsors should pay for the costs of records storage by Investigators

625115

For device studies, an Investigator may transfer custody of study records to anyone who will accept responsibility for them

625116


Question

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5757

FDA Regulations (21 CFR 312/812) and Guidance (ICH GCP) specify the following:

Question Keyword

It is the Investigator’s responsibility to inquire with the sponsor when study records no longer need to be retained

625099

In general, study records should be obtained indefinitely because it is never certain when product development will be permanently discontinued by the sponsor

625114

Sponsors should pay for the costs of records storage by Investigators

625115

For device studies, an Investigator may transfer custody of study records to anyone who will accept responsibility for them

625116


Answer

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Specified in 21 CFR 812.140e (however, there is no comparable language in Part 312)

5858

• It is the Investigator’s responsibility to inquire with the sponsor when study records no longer need to be retained – Per ICH 4.9.5, it is sponsor’s responsibility to do so. In addition, ICH 5.5.12, indicates:

“The sponsor should inform the investigators/ institutions in writing of the need for record retention and should notify the investigators/institutions in writing when the trial related records are no longer needed.”

Explanation

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• In general, study records should be obtained indefinitely because it is never certain when product development will be permanently discontinued by the sponsor – The FDA Regulations and ICH GCP both have criteria for retention that are well defined. The current reality is that sites and sponsors usually plan to hold onto records for many decades.

Explanation

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• Sponsors should pay for the costs of records storage by Investigators – There is no FDA Regulation or Guidance that address this but many experienced sites now demand this as a line item in their Clinical Trial Agreements.

Explanation

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In Conclusion

That doesn’t sound right to me. Where

exactly is that listed in the CFR?

Yes, you have to do it this way. It’s an FDA requirement.

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In Conclusion

Well, uh …OK, maybe it’s not a

regulation but it’s what the FDA

expects.

That still doesn’t sound right. What

guidance document is that from?

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In Conclusion

I’m not sure but it doesn’t matter. It’s a

requirement of my sponsor company.

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In Conclusion

OK, that’s fine. Why didn’t you just say so in the first place? I’m happy to do it to satisfy

your company policy. You didn’t have to use those FDA excuses to justify your request.

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Learning Objectives

• Define Good Clinical Practice (GCP)

• Differentiate between GCP requirements (stated in regulation) and recommendations (stated in guidance documents) in several key areas

• Identify several circumstances where “industry best practices” exist that go above and beyond what the FDA requires or even recommends

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Closing Thoughts

• Much of what we do in clinical research is driven by our own industry best practices and not by FDA requirements or even recommendations

• It takes a serious effort to understand all of the component parts of GCP and to stay up-to-date with changes

• As sponsor representatives, we often act as trainers for new site staff and they rely on us to provide accurate information

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Closing Thoughts

• Be careful when telling an investigator site, “You have to do this because the FDA requires it” unless you are certain that it is specified by regulation – it can seem like a very heavy handed play if you are wrong

“The

FDA re

quire

s it”

Compliance Toolbox

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Thank You

• Thanks for the Northern California Chapter for the invitation to present

• Thanks also to the chapter leadership for all that they do for ACRP and the local research community

• Consider volunteering with the outstanding group – it is well worth the time!

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• Paul Below, [email protected]

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You are welcome to use these slides for your own internal training purposes but they remain the copyrighted property of the presenter. Please contact Paul for permission to reuse.

So you think you know GCP ...

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