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Investigator Responsibilities for Clinical Trials Research
Julie Bouma, Jacob Holloway and Cathy Peterson WMed HRPP
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Introduction This comprehensive, educational presentation for Clinical Trials Research is a resource tool provided by WMed Homer Stryker M.D. School of Medicine for researchers involved in sponsor- and/or investigator-initiated studies regulated by the Food and Drug Administration (FDA). It was specifically designed for investigators who are new to clinical research or who have not been actively involved in research for some time to answer questions you may encounter as a clinical trials research investigator. The WMed Human Research Protection Program (HRPP) and Institutional Review Board (IRB) Handbook outlining a more condensed version of Investigator Responsibilities (Section 19) is available on the HRPP website (provide link). In addition, a condensed version of Investigator Responsibilities is available on the HRPP website (provide link) If you have any other questions or concerns that are not answered in this slide presentation, please do not hesitate to call the Education-Quality Improvement Program (E-QIP) Team at: or
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What is GCP? Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. GCP compliance provides public assurance that the rights, safety and well-being of human subjects involved in research are protected GCP = Ethics + Quality Data
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The Common Rule: 45 CFR 46 Subpart A
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
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Investigator Responsibilities: Investigator Qualifications & Agreements
Investigators must be: Properly qualified to assume responsibility for the 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 monitoring and audits Responsible for maintaining a Delegation of Responsibilities Log
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Investigator Responsibilities: Adequacy of Resources
Investigators must have: 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 Investigational Product (IP), and their study responsibilities Ability to recruit sufficient number of subjects within enrollment timeline
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Investigator Responsibilities: Medical Care of Trial Participants
Investigators must: Ensure adequate time is allotted to address all study-related responsibilities as required Ensure that all trial-related medical decisions are made by a designated qualified investigator Provide adequate medical care for participants who experience adverse events Notify the participant’s primary care physician of his/her participation in a research study (as appropriate if authorized by subject/LAR)
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Investigator Responsibilities: Communication with IRB
Investigators are responsible to: Submit IRB application and provide the IRB with the current Investigator’s Brochure, protocol and protocol amendments, case report forms (if applicable), informed consent form(s), written information to be provided to subjects, advertisements for subject recruitment (if applicable), etc. for review Obtain written approval from the IRB before the study begins and prior to implementation of any subsequent changes to the protocol Provide the IRB with all documents subject to its review throughout the trial (i.e., SAEs, protocol amendments, updated informed consent forms, subject material, updated Investigator’s Brochure and other important safety information, etc.)
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Investigator Responsibilities: Compliance with the Protocol
Investigators are responsible to: Conduct the trial in compliance with the protocol Deviate only with written agreement from the sponsor and prior review/approval from the IRB Document and explain all deviations
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Investigator Responsibilities: Compliance with the Protocol
The Investigator may deviate from the protocol before obtaining approval from the sponsor and review/approval from the IRB only: When the changes are logistical/administrative To eliminate an immediate hazard to study subjects. This requires immediate submission to: The IRB The sponsor Regulatory authorities (if required)
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Investigator Responsibilities: Investigational Products (IP)
Investigator is responsible for the IP, its usage, storage and destruction. This responsibility may be delegated to a Pharmacist under the PI’s supervision. Responsibilities include: Maintaining IP Accountability records (Receipt of product, dispensing of product, return of product not used by subject, if applicable, and destruction or return of product to sponsor, if applicable) Storing IP as specified by the sponsor and in accordance with applicable regulatory requirement(s) Investigator is responsible for using the IP in accordance with the protocol
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Investigator Responsibilities: Randomization and Unblinding Procedures
Investigator is responsible to: Follow the study randomization procedures Ensure that the randomization code is only broken in accordance with the protocol provisions Promptly document and notify the sponsor if any unblinding occurs
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Investigator Responsibilities: Informed Consent Process
Investigators must adhere to the following regulations and guidance: E6 Good Clinical Practice: Consolidated Guidance Section 4.8 45 CFR 46 21 CFR 50 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. 21 CFR 50 must be followed for research involving human subjects that is conducted, supported, or otherwise subject to regulation by the FDA These require the same basic elements of consent.
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Investigator Responsibilities: Informed Consent
Investigators must: 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
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Investigator Responsibilities: Informed Consent
Investigators are responsible to: Fully inform subjects of all pertinent aspects of the trial Use lay and non-technical language to ensure consent is understandable to the subject 8th grade reading level Translate to native language as applicable (IRB must approve translations) Ensure subject has sufficient time to review the consent document and ask questions prior to consenting to participate. The PI or designee is encouraged to use the “teach- back” method to confirm that the subject understands the information presented. Ensure the consent document is signed and dated prior to the start of any study- related activities (Initial phone screening can precede consenting)
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Investigator Responsibilities: Informed Consent
Investigators are responsible to ensure: a witness is present during the consenting process if a participant or representative is unable to read the participant is provided with a copy of the signed and dated consent form the informed consent discussion and the consent document include all essential/additional elements of consent inclusive of HIPAA-required elements, if applicable
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Investigator Responsibilities: Informed Consent
Essential elements of informed consent include: Statement that the study involves research Statement that participation is voluntary Information about purpose, duration, and procedures Number of subjects involved in the study Description of risks, benefits, and alternative procedures or treatment options Information about compensation/care for injury Statement regarding confidentiality of records Statement that there may be possible unforeseen risks Circumstances for termination without subject consent Consequences of withdrawing from the study Additional costs that may result from participation Statement that significant new research findings will be shared that may affect the subject’s willingness to continue participation Contact information for questions/concerns Information about study being registered on clinicaltrials.gov if it is an applicable clinical trial
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Investigator Responsibilities: Informed Consent
Additional elements for Vulnerable Populations 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 If a participant or representative is unable to read, a witness should be present during the consenting process 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)
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Investigator Responsibilities: Informed Consent
Investigator must: Follow guidelines for nontherapeutic trials (trials in which there is no anticipated direct clinical benefit to the participant)
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Investigator Responsibilities: Records and Reports
Investigator should ensure that: Data meets ALCOA (Accurate, Legible, Contemporaneous, Original, and Attributable) standards How and where the data is recorded is key! If it is not documented, it does not exist Data recorded on CRFs should match the source documents All changes/corrections to a CRF must be dated and signed such that the original data is not obscured Essential documents are retained for at least 2 years after the last approval of a marketing application
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Investigator Responsibilities: Records and Reports
Investigator must provide monitors, auditors, IRB/IEC, or regulatory authorities with direct access to trial records Investigator is responsible for: Documenting and reporting Serious Adverse Events (SAEs) and to ensure: The SAE meets reporting criteria Causality is determined Follow-up information is provided until SAE has resolved Making records available to monitors, auditors and inspectors Retaining records in accordance with sponsor, institutional, and/or regulatory requirements Institutional requirements ICH GCP – 2 years after last approval of marketing application in an ICH region Follow protocol, NIH, state and local institutional requirements Records should be retained according to the longest record retention requirement for the study
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Investigator Responsibilities: Records and Reports
Essential Documents: Essential documents are those documents that individually and collectively permit evaluation of the conduct of the study and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of GCP and with all applicable regulatory requirements. Establishing trial master files at the beginning of the trial and filing essential documents in a timely and organized manner can greatly assist in the successful management of a study. These documents are also the ones that are subject to audit by the sponsor and regulatory authority(ies) as part of the process to confirm the validity of the trial conduct and integrity of data collected. Guidance for Industry. E6 Good Clinical Practice: Consolidated Guidance (April 1996, ICH), 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
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Investigator Responsibilities: Records and Reports
Essential Documents (continued): Approved documents are reviewed for completeness and accuracy, and are maintained at a centralized location or satellite locations, if applicable Examples of essential documents are not limited to and may include: Investigator’s Brochure Signed protocol and amendments Signature and Delegation of Authority Log Training Records 1572 or Investigator Agreement CVs for PI and Sub-Investigator Licenses, as appropriate IRB submissions, approvals, communications, and IRB membership list or roster Communications with sponsor, CRO, if applicable
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Investigator Responsibilities: Progress Reports to Sponsor/IRB/IEC
Investigators are responsible for: Submitting a written report (Continuing Review Report) at least annually or in accordance with the IRB’s request Submitting a written report (Study Modification Form) if there are changes that might significantly change the conduct of the trial and/or increase risks to subjects Ensuring that any protocol changes are not implemented prior to IRB review and receipt of IRB approval documentation
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Investigator Responsibilities: Safety and Safety Reporting
Investigator is responsible for: Immediately reporting all unanticipated problems (e.g., SUSARs/SAEs, protocol deviations, etc.) to the sponsor with available information and providing follow-up reports as additional information becomes available EXCEPTION: SAEs identified in protocol as not requiring immediate reporting or SAE is not reportable according to IRB reporting requirements Identifying study participants by assigning codes rather than using personal identifiers Complying with applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the IRB Reporting AEs and/or lab abnormalities critical to safety evaluations to the sponsor in accordance with protocol requirements Providing the sponsor and IRB with additional requested information, i.e: Autopsy report in the event of a death EKG or other supporting documentation
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Investigator Responsibilities: Premature Termination or Suspension of a Study
If the study is terminated/suspended, Investigator should ensure that subjects are notified in accordance with IRB’s/Sponsor’s request. If the PI terminates study, the Investigator should ensure that the Institution, Sponsor and IRB are notified of this decision in writing. If the Sponsor terminates study, the Investigator should ensure that the Institution and IRB are notified of this decision in writing. If the IRB terminates study, the Investigator should ensure that the Institution and Sponsor are notified of this decision in writing.
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Investigator Responsibilities: Final Report(s)
At study completion, the Investigator should provide: Notification of study completion (Study Closeout Report) to the IRB A Summary of the trial’s outcome to the IRB Any other required reports to the IRB, Sponsor and/or Regulatory Authorities
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Investigator Responsibilities: Examples of Common Non-Compliance
Following are examples of Investigator Non-Compliance: Insufficient evidence of Investigator involvement/oversight in study No documented delegation of responsibility/scope of work Failure to adhere to protocol requirements Inadequate source documents Changes were made to original records without audit trail of when, why, or by whom changes were made Failure to report SAEs appropriately within required timelines Participants did not sign most current version of consent form Inadequate product accountability records
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Investigator Responsibilities: Consequences of Non-Compliance
Non-compliance runs the gamut from simple mistakes to fraud Even simple mistakes can be costly! Informed Consent Form errors, including written documentation of informed consent process can result in an observation from the FDA Specimen handling and processing errors (labeling, etc.). If improper labelling occurs (i.e. erroneous Subject Identification), data would not be valid. Fines could be incurred if non-certified personnel are involved in shipping specimens. Consequences can range from: Validity of data Loss of data due to validity of data (Subject, Site, or Study data may be considered invalid) Loss of revenue due to validity of data Professional/reputational risk to the PI and Institution
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Investigator Responsibilities: Applying GCP to Your Study
Understanding is the key to protecting subject safety and integrity of data Monitoring and quality management help to ensure compliance REMEMBER: The PI is ultimately responsible for all aspects of the study conduct!
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Resources Guidance for Industry. E6 Good Clinical Practice: Consolidated Guidance (April 1996, ICH) Widely accepted international research standards Title 45 Code of Federal Regulations (CFR) Part 46 Applies to federally funded research (U.S. Department of Health and Human Services [HHS]) Federal regulations to protect human subjects Subpart A: Basic HHS Policy for Protection of Human Research Subjects Also known as the Federal Policy or the “Common Rule” Subpart B: Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research Subpart C: Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects Subpart D: Additional Protections for Children Involved as Subjects in Research Institutional Review Board (IRB) Roles and Responsibilities/Informed Consent Guidance for Industry. E6 Good Clinical Practice: Consolidated Guidance (April 1996, ICH) Widely accepted international research standards Title 45 Code of Federal Regulations (CFR) Part 46 Applies to federally funded research (U.S. Department of Health and Human Services [HHS]) Federal regulations to protect human subjects Subpart A: Basic HHS Policy for Protection of Human Research Subjects Also known as the Federal Policy or the “Common Rule” Subpart B: Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research Subpart C: Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects Subpart D: Additional Protections for Children Involved as Subjects in Research Institutional Review Board (IRB) Roles and Responsibilities/Informed Consent
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Resources Title 21 CFR Part 50
Applies to all clinical investigations regulated by the FDA Informed Consent of Human Subjects Exception from general requirements General requirements for informed consent Exception from informed consent requirements for emergency research Elements of informed consent Documentation of informed consent Subpart D: Additional Safeguards for Children in Clinical Investigations
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Resources Clinical Research Operations and Management Support Presentation, “Investigator Responsibilities and Good Clinical Practice (GCP).” 2013 Good Clinical Practice 101: An Introduction Presented by: Lester “Jao” Lacorte, MD Electronic Code of Federal Regulations Office for Human Research Protections (OHRP) Guidance for Industry. E6 Good Clinical Practice: Consolidated Guidance. April ICH. ( guidancecomplianceregulatoryinformation/ guidances/ ucm pdf) Title 45 CFR Part 46 ( regulations/ 45-cfr-46/index.html Title 21 CFR Part 50 ( /cfcfr/ cfrsearch.cfm?cfrpart=50&showfr=1) Title 21 CFR Part 312 (=/ecfrbrowse/Title21/ 21cfr312_main_02.tpl)
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