INVESTIGATOR RESPONSIBILITIES April 2016

Objectives Review and Discuss:  Responsibilities of the clinical research Investigator as per relevant regulations and guidelines.  Responsibilities and commitments associated with signing the FDA Form (For non-IND studies, the DAIDS Investigator of Record Form applies instead of FDA Form 1572.)  Financial disclosure requirements.  Impact of protocol noncompliance.  Oversight responsibilities related to the informed consent process, drug accountability, safety monitoring, maintaining essential study documents and delegation of responsibilities.

Investigator Responsibilities

What Does This Mean?  The FDA’s focus is on the Principal Investigator listed on FDA Form For DAIDS-funded trials, this is the Investigator of Record or (IoR). Others in the DAIDS structure/chain of command (such as the CTU PI or CRS Leader) will not be important at the time of the audit. It is the IoR who is answerable for the execution of the protocol.

Investigator Responsibilities  Ensure that the clinical investigation is conducted according to the approved protocol and in compliance with all relevant sections of the U.S. Code of Federal Regulations (CFR), ICH-GCP standards, and in-country regulations and guidelines.  Protect the rights, safety and welfare of subjects.  Control drugs, biological products and devices under investigation.

Investigator Responsibilities: Regulations and Guidances  Investigator responsibilities are specifically described in: ICH E6 (Sections 4.0 and 8.0). U.S. Code of Federal Regulations (CFR). U.S. FDA Guidance – Investigator Responsibilities (October 2009). U.S. FDA Guidance– Q&A Form FDA 1572 (May 2010). FDA Form 1572 / DAIDS IoR Form.

ICH E6: Good Clinical Practice: Consolidated Guideline Published as official guidance in U.S. Federal Register in 1997 Objective: to provide a unified standard for the EU, Japan, U.S. to facilitate mutual acceptance of clinical data by the regulatory authorities

ICH E6 GCP – Section 4.0 Investigator Responsibilities Investigator’s Qualifications and Agreements Investigator’s Qualifications and Agreements Adequate Resources Medical Care of Trial Subjects Communications with IRB/IEC Compliance with Protocol Investigational Product(s) Randomization Procedures and Unblinding Informed Consent of Trial Subjects Informed Consent of Trial Subjects Records and Reports Progress Reports Safety Reporting Premature Termination or Suspension of a Trial Final Report(s) by Investigator

Country-Specific Requirements  This presentation reviews the U.S. federal requirements for the clinical Investigator.  All local and country-level requirements must also be met.  Contact your local IRB/IEC or CTU PI for additional information on these.

FDA Clarification of Investigator Responsibilities  Supervision of the conduct of the clinical investigation.  Delegation of tasks to study staff.  Training of study staff.  Supervision of staff to whom tasks are delegated.  Reporting protocol deviations.  Supervision of third parties (if applicable).  Protection of the rights, safety and welfare of participants in clinical trials.  Provision of reasonable medical care.  Provide reasonable access to medical care.

Review of FDA Form 1572

Form FDA 1572 Include screen shot here.

By Signing Form 1572…  The Investigator is agreeing that he or she will personally conduct or supervise the described investigations.  To do this, the Investigator must be intimately involved with the study. Depending on the size of the staff, the qualifications of the staff members, and the complexity of the protocol(s), this involvement may vary according to the site and protocol.  The Investigator must have a full understanding of the protocol, as well as stay informed of all participant and site issues.  The Investigator should ensure procedures are established to escalate issues quickly when needed.

FDA Form 1572: Eight Investigator Commitments  Maintain protocol adherence  Personally conduct or supervise  Ensure informed consent of subjects  Report adverse experiences  Provide training to sub- investigators  Ensure adequate and accurate recordkeeping  Ensure proper IRB/IEC review and reporting  Comply with all regulatory requirements

Who Should be Listed as a Sub-Investigator on the 1572?  The decision to list an individual as a sub- investigator depends on his/her level of responsibility-- whether he/she is performing significant clinical, investigation-related duties.  In general, if an individual is directly involved in the performance of procedures required by the protocol, and the collection of data, that person should be listed on the  It is not necessary to include someone with only an occasional or ancillary role.

When to Update the 1572 (U.S. Federal Regulation)  According to U.S. federal regulation, the FDA Form 1572 must only be updated when a new protocol has been added to the IND or a new Investigator is added to the study. However, …

When to Update the 1572 (DAIDS Protocol Registration Manual)  Within 30 days of any change in information, such as: The Investigator of Record changes. A sub-investigator is added to the study or removed. At the time of continuing IRB/IEC review (if required by the local IRB/IEC). A laboratory is added, removed or changed. Site location added, removed or changed.

Investigator of Record Form [Insert page 1 of Investigator of Record Form]

Requirement for Investigators and Sub-Investigators to File Financial Disclosure Forms

Reporting Financial Interests  Goal: preserve objectivity of clinical research and the protection of human subjects  Regulation: 21 CFR 54  Requirement: each clinical investigator must disclose any financial interests that may be affected by the outcome of the research or attest to the absence of relevant significant financial interests

Specific Requirement  Per 21 CFR 54, each clinical research Investigator and sub-investigator (anyone listed on the FDA Form 1572 for the study) is required to disclose the aggregated financial interests of themselves, their spouse and dependent children, as they relate to the study sponsor and/or study product(s).  Per 21 CFR , financial disclosures must be completed prior to study involvement.

Demonstrating Compliance Individual FD forms must be completed, signed and dated before the relevant1572 form, to which the investigator/sub-investigator is being added, is finalized, signed and dated. The 1572 must be finalized, signed, and dated before the Investigator or sub-investigator adds their signature and start date to the DoA. Note: The Investigator’s or sub-investigator’s DoA start date must be no sooner than the signature dates on their FD and corresponding 1572.

When to Report: 4 Time Points 1. Before an Investigator or sub-Investigator begins study activities (i.e., before final sign off by the IoR on the 1572 or DAIDS IoR Form). 2. Within thirty (30) days of discovering that relevant changes to their significant financial interests have occurred (during their study involvement and for one year following the end of their study involvement). (continued on next slide)

When to Report: 4 Time Points (continued from last slide) 3. When an Investigator or Sub-Investigator is removed from the FDA Form 1572 prior to study completion. 4. At the completion of all study-specific activities, that is, the date of the last follow- up for the study at that site.

How to Report Financial Disclosure  A study-specific, Financial Disclosure Form can be found on the MTN website ( - Study Implementation Materials.  Definition of reportable financial interests (as per 21 CFR 54) and instructions for completion of the form will appear with the form.

Steps to Report Financial Disclosure  Print the study-specific, Financial Disclosure Form from  Complete the form – remember to sign and (hand) date it.  Upload a scanned copy of the completed, signed and dated form to the the DAIDS Protocol Registration System.  File the original, completed, signed and dated form in the study binder with the associated 1572 form.

How are Conflicts Managed?  All financial disclosure statements will be reviewed by the MTN Leadership & Operations Center (LOC).  If potential conflicts of interest are identified, the LOC, in conjunction with the Investigator, will determine if steps need to be taken to minimize the potential for bias.

ICH E6 – Section 4.0 Investigator Responsibilities Investigator’s Qualifications and Agreements Investigator’s Qualifications and Agreements Adequate Resources Medical Care of Trial Subjects Communications with IRB/IEC Compliance with Protocol Investigational Product(s) Randomization Procedures and Unblinding Informed Consent of Trial Subjects Informed Consent of Trial Subjects Records and Reports Progress Reports Safety Reporting Premature Termination or Suspension of a Trial Final Report(s) by Investigator

Compliance with the Protocol ICH E6 Section 4.5 FDA Form CFR CFR

Protocol Compliance  The Investigator is expected to make every effort to ensure that the trial is conducted in compliance with the protocol approved by the IRB/IEC.  The IoR’s dated signature on the protocol signature page confirms this agreement.

Protocol Compliance  The Investigator agrees that he or she “will not make any changes in the research without IRB/IEC approval, except where necessary to eliminate apparent immediate hazards to human subjects” (see FDA Form 1572).

Protocol Compliance  Any departure from the protocol must be documented as a protocol deviation.  In the event you find a deviation has occurred at your site, follow the instructions provided to you in the DAIDS Source Documentation policy, the Protocol SSP and by the FHI 360 CRM for documenting deviations and making corrections.

Deviations from the Protocol  Recognizing that protocol deviations do sometimes occur, it is important to promptly document and report them.  Why is it critical that this happens?

Potential Impact of Noncompliance Impact on risk to the participant Impact on data quality Impact on scientific integrity and credibility Rejection of data by regulatory bodies Selection of the site for FDA Inspection Disqualification of the Investigator Suspension of site activities

Risks for Noncompliance  Insufficient investigator involvement/oversight in study conduct.  Poor supervision and training of study staff.  Inappropriate delegation of study tasks to unqualified persons.  Overworked investigator and study staff (e.g., too many subjects, complex study with large data collection, too many concurrent studies).  Failure to adequately protect study subjects.

ICH E6 – Section 4.0 Investigator Responsibilities Investigator’s Qualifications and Agreements Investigator’s Qualifications and Agreements Adequate Resources Medical Care of Trial Subjects Communications with IRB/IEC Compliance with Protocol Investigational Product(s) Randomization Procedures and Unblinding Informed Consent of Trial Subjects Informed Consent of Trial Subjects Records and Reports Progress Reports Safety Reporting Premature Termination or Suspension of a Trial Final Report(s) by Investigator

Role of the Investigator in Ensuring Informed Consent and Some Consenting Challenges Declaration of Helsinki ICH E6 Section 4.8 FDA Form CFR 50

Discuss study, risk/benefits, etc. Update participants Allow time for understanding Assess understanding and willingness Ensure comprehension Encourage questions Provide informed consent form The Consenting Process

Key Points of the Informed Consent Process Translation Role of the witness Timing Signing/Dating Version Re-signing the consent

 What are the consenting challenges?  What strategies could you use to mitigate challenges? Consenting a Vulnerable Population – Illiterate Participants

 Consider asking potential participants to read the informed consent form (ICF) out loud.  Test writing skills.  Read the informed consent form to the participant.  Ask participant to “teach back”. Illiterate Participants

ICH E6 – Section 4.0 Investigator Responsibilities Investigator’s Qualifications and Agreements Investigator’s Qualifications and Agreements Adequate Resources Medical Care of Trial Subjects Communications with IRB/IEC Compliance with Protocol Investigational Product(s) Randomization Procedures and Unblinding Informed Consent of Trial Subjects Informed Consent of Trial Subjects Records and Reports Progress Reports Safety Reporting Premature Termination or Suspension of a Trial Final Report(s) by Investigator

Investigational Study Product(s) ICH E6 Section CFR (a) 21 CFR (a)

 Responsibility for investigational product accountability lies with the Investigator/institution.  Some or all of these duties can be delegated to the pharmacist or other individual who is under the supervision of the Investigator.  The product should be stored as specified by the sponsor and in accordance with regulatory requirements. Investigational Study Product

 Investigator or designee should ensure products are only used in accordance with the approved protocol.  The Investigator or designee should explain the correct use of the product and should check throughout the trial that each participant is following instructions properly. Investigational Study Product

Product Accountability Records  These records should include the following information: Product delivery to the trial site. Inventory at the site. Proper storage. Use by each subject. Return to the sponsor or alternative disposition of unused product. Dates, quantities, batch/serial numbers, expiration dates (if applicable), unique code assigned to the product and trial participant.

ICH E6 – Section 4.0 Investigator Responsibilities Investigator’s Qualifications and Agreements Investigator’s Qualifications and Agreements Adequate Resources Medical Care of Trial Subjects Communications with IRB/IEC Compliance with Protocol Investigational Product(s) Randomization Procedures and Unblinding Informed Consent of Trial Subjects Informed Consent of Trial Subjects Records and Reports Progress Reports Safety Reporting Premature Termination or Suspension of a Trial Final Report(s) by Investigator

Medical Care of Trial Subjects and Safety Reporting ICH E6 Sections 4.3 and 4.11 DAIDS Expedited Adverse Events Reporting Policy, DWD-POL-CL

Medical Care of Trial Subjects  A qualified physician must be responsible for all trial-related medical decisions and ensure medical care is provided for any AEs while in the trial.  It is recommended that the Investigator inform the participant’s primary physician about trial participation, if the participant agrees.  The Investigator should attempt to find the reason for premature withdrawal of participation in the trial when appropriate.

Safety Reporting  AEs should be reported according to the requirements of the protocol.  All SAEs should be reported to DAIDS per the EAE Reporting Manual. PTIDs (not names or other unique identifiers) should be used in these reports.  Investigator must follow the site’s IRB/IEC requirements regarding reporting AEs, EAEs, SAEs and unanticipated problems to the IRB/IEC.

ICH E6 – Section 4.0 Investigator Responsibilities Investigator’s Qualifications and Agreements Investigator’s Qualifications and Agreements Adequate Resources Medical Care of Trial Subjects Communications with IRB/IEC Compliance with Protocol Investigational Product(s) Randomization Procedures and Unblinding Informed Consent of Trial Subjects Informed Consent of Trial Subjects Records and Reports Progress Reports Safety Reporting Premature Termination or Suspension of a Trial Final Report(s) by Investigator

Essential Documents ICH E6 Section 4.9 and 8.0

Essential Study Documents  ICH-GCP Section 8.0 provides a clear presentation of those documents required to be kept on-file at the Clinical Research Site (CRS) by the Investigator of Record.  These documents, individually and collectively, permit evaluation of the conduct of the trial and the quality of the data produced.

Essential Study Documents  Filing essential documents at the CRS in a timely manner can greatly assist in the successful management of a trial by the Investigator.  These documents may be audited by the sponsor's independent audit function and inspected by regulatory authorities.

ICH E6 – Section 4.0 Investigator Responsibilities Investigator’s Qualifications and Agreements Investigator’s Qualifications and Agreements Adequate Resources Medical Care of Trial Subjects Communications with IRB/IEC Compliance with Protocol Investigational Product(s) Randomization Procedures and Unblinding Informed Consent of Trial Subjects Informed Consent of Trial Subjects Records and Reports Progress Reports Safety Reporting Premature Termination or Suspension of a Trial Final Report(s) by Investigator

Site Oversight

How is Oversight Assessed?  Were those to whom tasks were delegated qualified to do the tasks?  Did staff received adequate training to perform the delegated tasks?  Is there evidence demonstrating the ongoing involvement of the IoR?  Was there adequate supervision of any third parties?

Demonstrating Adequate Oversight  Availability of sub-investigator CVs and clinical licenses.  Maintenance of staff training records.  Timely signature/initials/date of IoR on study documents.  Delegation of Authority Log (DoA).  Complete and accurate study product accountability records.

Study Delegation of Authority Log (continued on next slide) [Insert page 1 of study Delegation of Authority Log (DoA)]

References  ICH E6  U.S. FDA Form 1572  DAIDS IoR Form  U.S. Code of Federal Regulations (CFR)  U.S. FDA Guidance – Investigator’s Responsibilities, (October 2009)

References  U.S. FDA Guidance– Q&A Form FDA 1572 (May 2010)  DAIDS Policy: Requirements for Source Documentation, DWD-POL-CL and DWD-POL-CL-04.00A1  DAIDS Expedited Adverse Events Reporting Policy, DWD-POL-CL