1. Investigator Responsibilities for Clinical Trials Research
Julie Bouma, Jacob Holloway and Cathy Peterson
WMed HRPP

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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)

8. 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.)

9. 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

10. 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)

11. 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

12. 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

13. 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.

14. 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

15. 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)

16. 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

17. 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

18. 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)

19. Investigator Responsibilities: Informed Consent
Investigator must:
Follow guidelines for nontherapeutic trials (trials in which there is no anticipated direct clinical benefit to the participant)

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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.

27. 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

28. 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

29. 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

30. 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!

31. 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

32. 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

33. 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)