v2.0 - 2013-03-26

NIDCR National Institute of Dental and Craniofacial ResearchNational Institutes of Health

CROMS Clinical Research Operations and Management SupportRho, Inc., Federal Division

ICH E6 Good Clinical Practice Guidance and 45 CFR 46: Protection of Human Subjects

Investigator Responsibilities and Good Clinical Practice (GCP)

Note that this is a general slide presentation designed for a broad audience of clinical researchers.

Accordingly, some sections may not apply to your protocol. Information that may not be applicable for all studies is

indicated via blue italics.

Disclaimer

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Examples include references to:◦ Investigational Product (IP), the Investigator’s Brochure (IB),

or a study pharmacist◦ Safety reporting and adverse events◦ Randomization and unblinding procedures◦ Regulatory authorities◦ Clinical treatment (for a behavioral or study or a registry)

Information that may be helpful but does not come directly from ICH or 45 CFR 46 is identified by this icon.

Disclaimer (continued)

Good Clinical Practice (GCP) Guidelines (ICH-E6)◦ Widely accepted international research standards

Title 45 Code of Federal Regulations (CFR) Part 46 ◦ Applies to federally funded research◦ Federal regulations to protect human subjects◦ Subpart A: The Common Rule◦ IRB roles and responsibilities/Informed Consent

Basis for Research Roles and Responsibilities: Guidelines & Regulations

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Additional sections of the Code of Federal Regulations apply to clinical trials ◦ 21 CFR 11: Electronic Records/Electronic Signatures◦ 21 CFR 50: Protection of Human Subjects◦ 21 CFR 54: Financial Disclosure by Clinical Investigators◦ 21 CFR 56: Institutional Review Boards

Additional Guidance◦ FDA Information Sheets

Basis for Research Roles and Responsibilities: Guidelines & Regulations (continued)

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A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials [studies],

that provides assurance that the data and reported results are credible and accurate,

and that the rights, integrity, and confidentiality of study subjects are protected.

What is GCP? ICH 1.24

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Sets minimum quality standards for the conduct of clinical research

Compliance with GCP◦ Ensures that the rights, safety, and well-being of study

participants are protected◦ Ensures the integrity of the data submitted for approval

Sets standards for a system of mutual accountability among sponsors, regulatory authorities, investigators, and IRBs

Why is GCP Important?

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The regulations and guidelines concerning the establishment of good clinical practice apply to all studies involving human subjects

Applies to ◦ Interventional studies, including studies without an

investigational product

◦ Observational studies (specimen collection studies, natural history, etc.)

◦ Device studies

Realm of GCP in NIDCR Studies

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Specific to research involving human subjects conducted or funded by the DHHS

Federal Policy for the Protection of Human Subjects Designed to make uniform human subject protection

across all federal agencies and departments

The Common Rule: 45 CFR 46 Subpart A45 CFR 46

Properly qualified to assume responsibility for conduct of the study

Thoroughly familiar with the investigational product (IP), and its appropriate use

Willing to comply with GCP and applicable regulations and be prepared for audits and monitoring

Maintain a Delegation of Responsibilities log

PI Commitments: Investigator Qualifications and Agreements ICH 4.1

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Ability to recruit in sufficient numbers and on time Sufficient time to complete the study Adequate number of qualified staff and adequate

facilities to complete the study Staff who are well informed about the protocol, the

IP, and their study responsibilities

PI Commitments: Adequacy of Resources ICH 4.2

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Ensure that all trial-related medical decisions are made by an investigator who is a qualified physician

Provide adequate medical care for participants who experience adverse events

Notify the participant’s primary physician of his/her participation (as appropriate)

Make an effort to learn why participants withdraw

PI Commitments: Medical Care of Trial Participants ICH 4.3

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Obtain written approval before the study begins

Provide the IRB with the current Investigator’s Brochure

Provide the IRB/IEC with all documents subject to its review throughout the trial

PI Commitments: Communication with the IRB/IEC ICH 4.4

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Conduct the trial in compliance with the protocol

Deviate only with agreement from the sponsor and prior review/approval from the IRB/IEC There can be exceptions – see next slide!

Document and explain all deviations

PI Commitments: Compliance with the Protocol ICH 4.5

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The investigator may deviate from the protocol before obtaining agreement from the sponsor and review/approval from the IRB/IEC only:

◦ When the changes are logistical/administrative, or◦ To eliminate an immediate hazard to study subjects.

This requires immediate submission to: the IRB the sponsor regulatory authorities (if required)

PI Commitments: Compliance with the Protocol ICH 4.5

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Responsible for the product, its usage, and its storage

May delegate to a Pharmacist under the PI’s supervision

Maintain IP records Store as specified by the sponsor and in accordance

with applicable regulatory requirement(s) Use IP in accordance with the protocol

PI Commitments: Investigational Products (IP) ICH 4.6

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Follow the study randomization procedures

Ensure that the randomization code is only broken in accordance with the protocol

Promptly document and notify the sponsor of any unblinding (for blinded trials)

PI Commitments: Randomization and Unblinding Procedures ICH 4.7

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These require the same basic elements of consent.

Regulations and Guidance◦ ICH 4.8◦ 45 CFR 46

45 CFR 46 must be followed for research involving human subjects that is conducted, supported, or otherwise subject to regulation by any federal department or agency.

PI Commitments: Informed Consent Process

Adhere to GCP and the ethical principles that have their origin in the Declaration of Helsinki

Update consent document when new information becomes available

Avoid:◦ Coercion or undue influence◦ Language that causes the participant to waive any legal

rights

PI Commitments: Informed Consent ICH 4.8

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Fully inform participant of all pertinent aspects of the trial

Use lay and non-technical language Should be understandable to the subject

8th grade reading levelTranslated to native language as applicable (IRB must approve translations)

Provide enough time for participant to review the consent document and ask questions

PI Commitments: Informed Consent ICH 4.8

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The consent document must be signed and datedObtain consent prior to start of any study-related activities. Initial phone screening can precede consenting.

If a participant or representative is unable to read, a witness should be present during the consenting process

Provide the participant with a copy of the signed and dated consent form

PI Commitments: Informed Consent ICH 4.8

The informed consent discussion and the consent document should include all essential and additional elements

Essential elements include:◦ Statement that the study involves research

◦ Statement that participation is voluntary

◦ Information about purpose, duration, and procedures

PI Commitments: Informed Consent ICH 4.8

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Essential elements (continued):◦ Number of subjects involved in the study

◦ Description of risks, benefits, and alternatives

◦ Information about compensation/care for injury

◦ Statement regarding confidentiality of records

◦ Description of possible unforeseen risks

PI Commitments: Informed Consent ICH 4.8

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Essential elements (continued):◦ Circumstances for termination without subject consent

◦ Consequences of withdrawing from the study

◦ Additional costs that may result from participation

◦ Statement that new research findings will be shared

◦ Contact information for questions/concerns

PI Commitments: Informed Consent ICH 4.8

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Additional elements from Title 45 CFR 46:◦ Subpart B: Additional protections for pregnant women,

human fetuses, and neonates

◦ Subpart C: Additional protections for prisoners

◦ Subpart D: Additional protections for children

PI Commitments: Informed Consent 45 CFR 46

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Explain the study to the extent it can be understood by participants who can only be enrolled with the consent of a legally acceptable representative (LAR)

Follow guidelines for nontherapeutic trials (trials in which there is no anticipated direct clinical benefit to the participant)

If participant and LAR can’t provide consent, follow measures described in the protocol

PI Commitments: Informed Consent ICH 4.8

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ICH 4.9 (Records and Reports) ICH 4.10 (Progress Reports)

PI Commitments: Records and Reports

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Data must be ALCOA (Accurate, Legible, Contemporaneous, Original, and Attributable) and complete◦ How and where the data is recorded is key!◦ If it is not documented, it does not exist

Data on CRFs should match the source documents (raw data)

PI Commitments: Records and Reports ICH 4.9

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All changes to a CRF must be dated and signed such that the original data is not obscured

Retain essential documents for at least 2 years after the last approval of a marketing application

Provide monitors, auditors, IRB/IEC, or regulatory authorities with direct access to trial records

PI Commitments: Records and Reports ICH 4.9

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Record UP/SAE events thoroughly◦ Meets criteria

◦ PI to determine causality

◦ Follow-up information

Make records available to monitors, auditors and inspectors Record retention

◦ Institutional requirements

◦ ICH GCP – 2 years after last approval of marketing application in an ICH region

◦ Follow protocol, NIH, and local institutional requirements

◦ Longest requirement should be followed

Records and Reports

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Essential Documents◦ Permit evaluation of the conduct of the study and the

validity of the data◦ ICH GCP E6 section 8.0 provides a table of essential

documents, the purpose of the document, and the location broken down according to the stage of the study

◦ Approved documents maintained at centralized location with copies (protocol, MOP) at satellite locations

◦ Reviewed for completeness and accuracy

Records and Reports

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Essential Documents (Examples)◦ Investigator of Record (IoR) or 1572◦ CVs for PI and Sub-Investigators◦ Licenses, as appropriate◦ Training records for all study personnel◦ Protocol / amendment signature page◦ IRB membership list or roster ◦ IRB approvals – of protocol, consents, ads, handouts◦ Communication – with IRB, sponsor, CRO, if applicable

Records and Reports

Submit a written report at least annually and in accordance with the IRB’s request

Submit a written report if there are changes that might significantly change the conduct of the trial and/or increase risk to subjects

PI Commitments: Progress Reports to Sponsor/IRB/IEC ICH 4.10

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ICH 4.11 (Safety Reporting) ICH 4.12 (Premature Termination or Suspension of a

Trial)

PI Commitments: Safety and Safety Reporting

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Immediately report all SAEs to the sponsor; follow-up with a written report

EXCEPTION: SAEs identified in protocol as not requiring immediate reporting

Identify study participants using codes rather than personal identifiers

Comply with applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the IRB/IEC

PI Commitments: Safety Reporting ICH 4.11

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Report AEs and/or lab abnormalities critical to safety evaluations to the sponsor per protocol

Provide the sponsor and IRB with additional requested information ◦ Autopsy report in the event of a death◦ EKG or other supporting documentation

PI Commitments: Safety Reporting ICH 4.11

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* Notify in writing

Condition Notify

Study terminated/suspended All participants

PI terminates study Institution, sponsor, IRB*

Sponsor terminates study Institution, IRB*

IRB terminates study Institution, sponsor*

PI Commitments: Premature Termination or Suspension of a Study ICH 4.12

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*Where applicable

Documentation Provided to

Notification of study completion Institution*

Summary of the trial’s outcome IRB/IEC

Any required report(s) Regulatory Authority(ies)

At study completion, the investigator should provide:

PI Commitments: Final Report(s) ICH 4.13

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Insufficient evidence of Investigator involvement/oversight No documented delegation of responsibility/scope of work Failure to adhere to protocol requirements Inadequate source documents Changes made to original records without audit trail of when,

why, by whom Failure to report UPs/SAEs appropriately Participants not signing most current version of consent form Inadequate product accountability records

Examples of Common Non-Compliance

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Non-compliance runs the gamut from simple mistakes to fraud.

Even simple mistakes can be costly! ◦ Consent◦ Specimen handling and processing (labeling, etc.)

Consequences can range from:◦ Loss of data (Subject, Site, or Study data considered invalid)◦ Professional/reputational risk for PI and institution

Consequences of Non-Compliance

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Understanding is key to protecting subject safety and integrity of data

Monitoring and quality management help ensure compliance

Ultimately, it is the PI’s responsibility

Applying GCP to Your Study

Q&A Resources NIDCR Forms

Wrapping It All Up

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Questions?

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Electronic Code of Federal Regulations◦ http://www.ecfr.gov/cgi-bin/text-idx?c=ecfr&tpl=%2Findex.tpl

Office for Human Research Protections (OHRP)◦ http://www.hhs.gov/ohrp/

ICH E6 Guideline◦ http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelin

es/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf

Resources

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Objective ResourceProtection of human subjects 45 CFR 46

Staff qualifications/training ICH E6, Sec 4.1, Sec 4.2

Research resources ICH E6, Sec 4.2

Protocol adherence ICH E6, Sec 4.5

Record keeping ICH E6, Sec 4.4.1, Sec 4.9, Sec 8

FAQs (OHRP Investigator Responsibilities)

http://answers.hhs.gov/ohrp/categories/1567

Resources

NIDCR Investigator of Record Agreement Delegation of Responsibilities Log Training Log Site Screening and Enrollment Log Subject Code List Adverse Event Forms Monitoring Visit Log

These forms and other tools are available through NIDCR’s Toolkit for Clinical Researchers:

http://nidcr.nih.gov/research/toolkit

NIDCR Forms

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