1. INVESTIGATOR RESPONSIBILITIES
April 2016

2. 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.
This presentation is designed to look at various key aspects of the Investigator’s responsibilities per U.S. federal guidelines and regulations, the financial disclosure requirement for investigators, the importance of protocol compliance and the impact of noncompliance, and the Investigator’s role in clinical oversight- particularly with respect to the informed consent process, drug accountability, safety monitoring, maintaining essential study documents and delegation of responsibilities.

3. Investigator Responsibilities
The Investigator is ultimately responsible for all study-related activities at his or her site, regardless of who has been delegated the individual study responsibilities.

4. What Does This Mean?
The FDA’s focus is on the Principal Investigator listed on FDA Form 1572.
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.
So, what does this mean?
Each Clinical Research Site (CRS) has a number of leadership positions associated with it. Within the DAIDS structure, specifically, there is the CTU PI, the CRS leader and the Investigator of Record (or IoR). Each of these has unique responsibilities and expectations associated with it.
But, it’s the Investigator of Record or IoR who is the Principal Investigator on a given protocol; and, it is this person that the FDA will want to communicate with in the event of an audit. The IoR signs the protocol cover sheet and, for IND studies, the FDA Form as an indication of their understanding and assumption of full responsibility for the execution of the protocol. It is the IoR that we are gearing this presentation towards, to ensure that the role and its responsibilities are clear.

5. 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.
An Investigator’s primary responsibilities are to ensure that the clinical investigation is conducted according to the protocol and in compliance with relevant sections of the U.S. Code of Federal Regulations, the ICH-GCP standards and all in-country regulations and guidelines, to protect the rights, safety and welfare of subjects under their care and control the drugs, biological products and devices under investigation.
One of the U.S. requirements that must be fulfilled by the Investigator is to complete FDA Form 1572 for studies conducted under an Investigational New Drug application, often referred to as an IND. A DAIDS Investigator of Record Form is required for DAIDS-funded studies that are not IND studies.
Let’s take a look at some of these regulations in the next slide.
Reminders (all referenced on the CFR handout):
Investigator responsibilities in conducting clinical investigations is also detailed in 21 CFR Part 312 (drugs) or 21 CFR Part 812 (devices).
For a comprehensive list of FDA expectations for the conduct of drug and biologic studies refer to 21 CFR Parts 11, 50, 54, 56 and 312.
For a comprehensive list of FDA expectations for the conduct of device studies refer to 21 CFR Parts 11, 50, 54, 56 and 812.
The ICH expectations on the Investigator’s responsibilities, as discussed in the FDA Guidance, are extensively described in several sections of the ICH-GCP Guideline (e.g. 2.3, 2.7, 2.8, 2.12, 4.1, 4.2.3, 4.2.4, 4.4, 4.5, 4.6 and 4.8).

6. 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.
This slide provides an overview of the regulations and guidances that are applicable for all DAIDS studies, as well as IND studies specifically. Each of these has been provided as a handout.
ICH E6 Sections 4 and 8- ICH guidelines for Good Clinical Practice (E6, Section 4) provides a comprehensive list of Investigator responsibilities separated into thirteen different categories. Section 8.0 provides a list of essential study documents that, at minimum, are required to be collected and maintained by the IoR.
Code of Federal Regulations (CFR)- Relevant parts of the CFR have been summarized and included in the handout. These include the FDA’s expectations for the conduct of drug and biologic studies- 21 CRF Parts 11, 50, 54, 56, and CFR Part 312 details the U.S. federal government regulations regarding IND studies, with Subpart D specifically addressing the Investigator’s responsibilities.
FDA Guidance for Industry: Investigator Responsibilities- The October 2009 FDA Guidance for Industry on Investigator Responsibilities provides very useful information about the agency’s current thinking on this topic. It was created to help Investigators better meet their responsibilities with respect to protecting human subjects and ensuring the integrity of the data from clinical investigations.
FDA Information Sheet Guidance: Frequently Asked Questions- Statement of Investigator (Form FDA 1572)- The May 2010, FDA Information Sheet Guidance regarding FDA Form 1572 describes how to complete the Statement of Investigator form (1572).
FDA Form 1572 and the DAIDS IoR Form: Both provide a general list of the Investigator’s responsibilities and commitments for the conduct of the study on page 2. These responsibilities are essentially identical on both forms.
We’ll go through some of these in more detail now.

7. ICH E6: Good Clinical Practice: Consolidated Guideline
Objective: to provide a unified standard for the EU, Japan, U.S. to facilitate mutual acceptance of clinical data by the regulatory authorities
The ICH E6: Good Clinical Practice– Consolidated Guideline is an international quality standard developed by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The ICH E6 Guidance includes ethical and scientific standards on how clinical trials should be conducted. It defines the roles and responsibilities of clinical study sponsors, Investigators and monitors and provides public assurance that the rights, safety, and wellbeing of clinical research subjects are protected and that the research data are credible.
Development of this guidance took into consideration the current good clinical practices of the European Union, Japan and the United States, as well as those of several other countries and the World Health Organization (WHO). This guidance should be followed whenever generating clinical trial data intended for submission to the regulatory authorities.
Published as official guidance in U.S. Federal Register in 1997

8. ICH E6 GCP – Section 4.0 Investigator Responsibilities
Investigator’s Qualifications
and Agreements
Informed Consent of
Trial Subjects
4.1
4.8
Adequate Resources
Records and Reports
4.2
4.9
4.3
Medical Care of Trial Subjects
Progress Reports
4.10
Communications with IRB/IEC
Safety Reporting
4.4
4.11
Compliance with Protocol
Premature Termination or Suspension of a Trial
4.5
The ICH E6 Good Clinical Practice Guidance for Industry [handout]: Section 4.0, Investigator Responsibilities, starts on page 13.
This section of the guidance outlines 13 key responsibilities of the Investigator. We will be further discussing 6 of these responsibilities today- (4.5) compliance with the protocol, (4.8) informed consent, (4.3) medical care of trial subjects, (4.11) safety reporting, (4.6) investigational product(s) and (4.9) records and reports. But, reading through the ICH guidelines will provide more detail on each of these. If you have questions on any of them or would like further information, please, let us know.
4.12
Investigational Product(s)
Final Report(s) by Investigator
4.6
4.13
Randomization Procedures and Unblinding
4.7

9. 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.
This presentation reviews the U.S. federal requirements for the clinical Investigator. There may be additional responsibilities for Investigators that are applicable only for your institution, local area, state, or country. Investigators must become familiar with these responsibilities also. If you have any questions regarding these requirements, please, contact your IRB/IEC or CTU PI for additional information.
It is necessary to adhere to both the regulations of the country in which your site is located, as well as the ICH-GCP requirements. When a discrepancy is noted between the ICH-GCP and a local or country-level requirement, you should adhere to the guideline with the most stringent requirement.

10. 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.
The FDA Guidance for Industry: Investigator Responsibilities [handout] provides further discussion of the Investigator’s responsibilities in conducting a clinical trial: (1) supervision of the [trial] conduct of the clinical investigation, (2) delegation of tasks to study staff, (3) training of study staff, (4) supervision of staff to whom tasks are delegated, (5) reporting protocol deviations, (6) supervision of third parties (if applicable), (7) protection of the rights, safety and welfare of participants, (8) provision of reasonable medical care and (9) provision of reasonable access to medical care.
These responsibilities really emphasize the supervision aspect of the Investigator’s role, as clearly one person is not implementing the trial single handedly; but, Investigators who conduct clinical investigations commit themselves to either personally conduct or supervise every aspect of the investigation.
This list shows the importance of both FDA Form 1572 and the Delegation of Authorities Log.

11. Review of FDA Form 1572
As mentioned earlier, one of the U.S. requirements for conducting an IND clinical study is the completion of FDA Form 1572 by the Principal Investigator (IoR).

12. Form FDA 1572 Include screen shot here.
This is a familiar form to most of you.
There is one space for the name of the Principal Investigator (i.e. Investigator of Record) at the top (Section 1) and space for additional sub-investigators at the bottom (Section 6.).
Note that the FDA Form1572 version found on the FDA website should always be the current version. Check the expiration date in the right-hand side of the header.
Let’s review briefly what it means to be listed as the Investigator on this form.

13. 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.
By signing the the Investigator is agreeing that he or she will (1) personally conduct or supervise the described investigations, (2) be intimately involved with the study, (3) have a full understanding of the protocol, as well as stay informed of all participant and site issues and (4) ensure procedures are established to escalate issues quickly when needed.
Does anyone have any questions about the items on this slide?

14. 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
Page 2 of FDA Form 1572 lists eight commitments of the Investigator of Record: (1) Maintain protocol adherence, (2) Personally conduct or supervise the conduct of the study, (3) Ensure informed consent of study subjects, (4) Report adverse events, (5) Provide training to sub-investigators, (6) Ensure adequate and accurate recordkeeping, (7) Ensure proper IRB/IEC review and reporting and (8) Comply with all regulatory requirements.
_______________________
The eight commitments presented on page 2 of the FDA Form1572 are: [handout]
I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of subjects.
I agree to personally conduct or supervise the described investigation(s).
I agree to inform any patients, or any persons used as controls, that the drugs are being used for investigational purposes and I will ensure that the requirements relating to obtaining informed consent in 21 CFR Part 50 and institutional review board (IRB) review and approval in 21 CFR Part 56 are met.
I agree to report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 21 CFR I have read and understand the information in the investigator’s brochure, including the potential risks and side effects of the drug. **describe what this means (312.64)** [Add specific text of what’s to be said.]
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments.
I agree to maintain adequate and accurate records in accordance with 21 CFR and to make those records available for inspection in accordance with 21 CFR **What makes this adequate and accurate? Give examples to make this more concrete.**
Drug disposition  dates/quantity/use by subjects or disposition as directed by the study sponsor.
Case histories  including: case report forms (CRFs), signed and dated informed consent forms (ICFs) and conducted before participation, all other observations and data that are pertinent to the investigation, such as source documents, progress notes, etc.)
Record retention for 2 yrs following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application filed or if the application is not approved for such indication, until 2 yrs following the discontinuation of the investigation and the FDA is notified.
I will ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible for the initial and continuing review and approval of the clinical investigation. I also agree to promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others. Additionally, I will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.
I agree to comply with all other requirements regarding the obligations of clinical investigators and all other pertinent requirements in 21 CFR Part 312.
Any questions about any of these responsibilities?

15. 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 1572.
It is not necessary to include someone with only an occasional or ancillary role.
We know the name of the IoR is added to Section 1; but, who should be listed as a sub-investigator in Section 6?
We leave this up to the IoR at each site to determine; however, the guidelines presented in the FDA Information Sheet Guidance: Frequently Asked Questions- Statement of Investigator (Form FDA 1572), May 2010, [handout] are that 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. Please refer to the Guidance for more information.

16. 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, …
According to the May 2010 FDA Guidance regarding the 1572 [handout], the Form must only be updated when a new protocol has been added to the IND or a new Investigator is added to the study. However, [next slide] ….

17. 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.
DAIDS requires that the FDA Form 1572 or Investigator of Record Form be updated within 30 days of any major change in the information recorded on the form (see DAIDS Protocol Registration Manual).
Since it is necessary to comply with both FDA and DAIDS requirements, this conflict is resolved by adhering to the guideline with the most stringent requirement, in this case, the DAIDS requirements. Therefore, the 1572 should be updated within 30 days of any change to the information recorded on it. Examples are when: (1) the Investigator of Record changes, (2) a new sub-investigator is added to the study or removed, (3) at the time of continuing IRB/IEC review (if required by the local IRB/IEC), (4) if a laboratory is added, removed or changed or (5) if the clinical site location is added, removed or changed.

18. Investigator of Record Form
[Insert page 1 of Investigator of Record Form]
The DAIDS Investigator of Record Form is similar to the FDA Form 1572 in intent but is only relevant for DAIDS funded studies that are not being conducted under an Investigational New Drug application (IND).

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

20. 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
In the interest of preserving the objectivity of clinical research and the protection of human subjects, the U.S. FDA has issued regulations (21 CFR 54) requiring each clinical investigator to either attest to the absence of relevant significant financial interests or to disclose any financial interests that may be affected by the outcome of the research.

21. 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.
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 , these disclosures must be completed before the Investigator or sub-investigator begins their study related duties.

22. 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.
To ensure that study documentation supports the FDA’s requirement that the FD is collected before permitting an Investigator or sub-investigator to begin their study related duties, MTN has established the following procedure:
Whenever a new Investigator or sub-investigator is being added to the study, the Financial Disclosure Form, FDA Form 1572 (DAIDS IoR Form for non-IND/IDE studies) and the Study Delegation of Authority Log (DoA) must be completed in the sequence just stated. Any two or three of these documents may be signed and dated on the same day but none of the latter documents may be completed and dated before the preceding ones.
Please note that an Investigator or sub-investigator’s DoA start date must be no sooner than the signature dates appearing on their FD and the corresponding 1572.

23. When to Report: 4 Time Points
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).
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)
As part of the MTN Study Activation Process, all investigators and sub-investigators listed on the FDA Form 1572 or the DAIDS IoR Form must have completed, signed and dated Financial Disclosure Forms uploaded to DPRS. This is one of the regulatory requirements that must be met in order for a site to receive authorization to initiate screening and enrollment for the trial. (Excluded are non-medical, behavioral studies.)
NOTE: Any time a Financial Disclosure Form is completed (at any of the time points shown in the slides), the signed and (hand) dated form must be uploaded to DPRS and the original, completed form must be filed with the regulatory documents at the site.

24. When to Report: 4 Time Points
(continued from last slide)
When an Investigator or Sub-Investigator is removed from the FDA Form 1572 prior to study completion.
At the completion of all study-specific activities, that is, the date of the last follow-up for the study at that site.
The IND holder for the trial may request additional reporting time points. Some sponsors, for instance, require that Investigators and sub-investigators complete a Financial Disclosure Form, again, one year following the completion of the study.
NOTE: Any time a Financial Disclosure Form is completed (at any of the time points shown in the slides), the signed and (hand) dated form must be uploaded to DPRS and the original, completed form must be filed with the regulatory documents at the site.

25. 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.
How to report: A study-specific, Financial Disclosure Form will be posted on the MTN website ( under Study Implementation Materials. Abbreviated definitions of reportable financial interests (as per 21 CFR 54) and instructions for completion of the form will appear on the form itself but also available is a second page, the Guidance for Completing the Financial Disclosure/Certification Form.

26. 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.
(1) Print the study-specific, Financial Disclosure Form from
(2) Complete the form – remember to sign and (hand) date it.
(3) Upload a scanned copy of the completed, signed and dated form to DPRS.
(4) File the original, completed, signed and dated form in the study binder with the associated 1572 form.

27. 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.
How are financial conflicts of interest managed?
The IoR must ensure all study team members are properly trained regarding their Financial Disclosure obligations and should review each completed Financial Disclosure Form for potential conflicts of interest before accepting an individual to participate in study conduct.
All financial disclosure statements will also be reviewed by the MTN Leadership and 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.

28. ICH E6 – Section 4.0 Investigator Responsibilities
Investigator’s Qualifications
and Agreements
Informed Consent of
Trial Subjects
4.1
4.8
Adequate Resources
Records and Reports
4.2
4.9
Medical Care of Trial Subjects
Progress Reports
4.3
4.10
Communications with IRB/IEC
Safety Reporting
4.4
4.11
Compliance with Protocol
Premature Termination or Suspension of a Trial
4.5
The ICH E6 GCP Guidance for Industry [handout]: (Section 4.0, Investigator Responsibilities, starts on page 13).
We will next discuss the Investigator responsibility, Compliance with the Protocol.
4.12
Investigational Product(s)
Final Report(s) by Investigator
4.6
4.13
Randomization Procedures and Unblinding
4.7

29. Compliance with the Protocol
ICH E6 Section 4.5
FDA Form 1572
21 CFR
21 CFR
Protocol compliance is covered by both the ICH-GCP standard and in the CFR requirements.
ICH E Compliance to the protocol;
FDA Form Compliance with the protocol;
21 CFR General responsibilities of the investigator;
21 CFR (Applies only to investigational medical device studies).

30. 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.
(1) 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.
(2) The Investigator’s dated signature on the protocol cover sheet signature page confirms this agreement.

31. 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).
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).
What does this mean? This would include planned deviations to the study protocol. For example, a modification such as a Letter of Amendment (LoA) is a planned deviation from the protocol, but would be viewed as a deviation from the protocol until it is approved by the sponsor, as well as the appropriate regulatory bodies and the local IRB/IEC. Once approved, the protocol, plus any approved clarification memo’s or Letters of Amendment, would guide the conduct of the trial. Any deviations from what is currently approved is considered a protocol deviation or noncompliance.
Protocol deviation(s) occur for many reasons, some of which may be unforeseen. As such, every clinical researcher should anticipate that deviations will occur; however, every effort should be made to prevent them.
There are several mechanisms for identifying and tracking protocol deviations; and, these are managed by different stakeholders:
Internal QA/QC at the site: This results in site reported, protocol deviations.
a). It is always best for the site, itself, to identify (and correct, if possible) any protocol deviations. This provides the best assurance for the integrity and validity of the research.
Data management identification of noncompliance (missed procedures, missed holds, etc.).
Site assessment visits conducted by FHI 360 Clinical Research Managers (CRMs).
External monitoring conducted by a third-party, such as DAIDS.

32. 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.
DAIDS Policy: Requirements for Source Documentation, DWD-POL-CL and DWD-POL-CL-04.00A1 [handout]-- Provide documentation guidance for achieving and maintaining data quality.

33. 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?
When there is a noncompliance:
We want to stress that every site is likely to experience some deviations from the protocol, despite everyone’s best efforts. These should be carefully and promptly documented and reported to the appropriate study management team member.
The study management team will carefully track these occurrences in an effort to identify any correctable, systematic problems and will modify the protocol, if necessary. The goal in this process is to ensure both the safety of the study participants and the collection of high quality data that will provide reliable research information.
What are some of the consequences of protocol noncompliance?

34. 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
Noncompliance could adversely affect participant safety. Tests could be overlooked, dosages altered, treatments withheld. If a site were to forego protocol-required re-testing of out-of-range laboratory results, they might miss the emergence of a worsening medical condition caused by the study drug, thereby putting the participant’s health at risk. All are examples of noncompliance which could have severe consequences for enrolled participants. Noncompliance can also include other types of risk, such as physical, psychological, or privacy issues.
Noncompliance with study requirements could affect the overall quality of the data generated by the site, possibly jeopardizing the overall statistical power of the study. This could lead to lack of integrity and credibility within the scientific community, minimizing the impact of any positive treatment effects in the minds of fellow researchers.
Continued noncompliance issues over the course of a study could eventually lead to the study data from the site being excluded from the trial altogether. Depending on the trial size, this could have disastrous effects on the overall trial, possibly preventing conclusive evidence of the treatment effect from being collected. It is possible the entire study may have to be disregarded if significant noncompliance issues have occurred.
Continued noncompliance issues could also raise the suspicions of outside entities such as the Sponsor, OHRP and the FDA and possibly cause the site to be inspected/audited. The results of an inspection could be very serious, such as suspension or disbarment of the Investigator. Depending on the severity of the noncompliance issues, a temporary or permanent closure of the study site could occur. 34

35. 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.

36. ICH E6 – Section 4.0 Investigator Responsibilities
Investigator’s Qualifications
and Agreements
Informed Consent of
Trial Subjects
4.1
4.8
Adequate Resources
Records and Reports
4.2
4.9
Medical Care of Trial Subjects
Progress Reports
4.3
4.10
Communications with IRB/IEC
Safety Reporting
4.4
4.11
The ICH E6 GCP Guidance for Industry [handout]: (Section 4.0, Investigator Responsibilities, starts on page 13).
We will next discuss the Investigator responsibility, ensuring Informed Consent.
Compliance with Protocol
Premature Termination or Suspension of a Trial
4.5
4.12
Investigational Product(s)
Final Report(s) by Investigator
4.6
4.13
Randomization Procedures and Unblinding
4.7

37. Declaration of Helsinki ICH E6 Section 4.8 FDA Form 1572 21 CFR 50
Role of the Investigator in Ensuring Informed Consent and Some Consenting Challenges
Declaration of Helsinki
ICH E6 Section 4.8
FDA Form 1572
21 CFR 50
ICH E6, section 4.8, covers the Informed Consent of Trial Subjects.
21 CFR 50 Subpart B, covers Informed Consent of Human Subjects.
The GCP guidelines (ICH E6) for Informed Consent are pretty extensive in this section and I think everyone here is pretty familiar with them.
The ethical principles to be followed (GCP, ethical principals of the Declaration of Helsinki, IRB approval) in the Informed Consent Process include: (1) providing new information to the study participant when available, (2) guarding against coercion, (3) excluding language that would waive legal rights, (4) providing all information to make an informed decision, (5) using language that is easy to understand (also use of his/her native language), (6) providing sufficient time to decide, (7) gaining participant’s dated signature, (8) providing an impartial witness when enrolling illiterate participants, (9) covering essential aspects of the Informed Consent, (10) providing a copy of the ICF to take home, (11) providing information on what to do in study-related emergency situations.

38. The Consenting Process
Discuss study, risk/benefits, etc.
Provide informed consent form
Update participants
Assess understanding
and willingness
Allow time for understanding
The ICF Process is ongoing and is not a one time event. It begins when the potential research participant is initially contacted.
What are some ways you engage participants in ongoing IC activities throughout the trial?
What are some of the more challenging aspects of the IC process?
Encourage questions
Ensure comprehension

39. Key Points of the Informed Consent Process
Translation
Role of the witness
Timing
Signing/Dating
There are a number of challenges associated with IC, that we’d like to discuss a bit further:
Translation (complying with IRB/IEC requirements): The consent document must be in a language that the participant can understand. If the participant population includes non-English speaking people, the Investigator or the IRB should anticipate the consent interviews are likely to be conducted in language other than English. The MTN requires that all translations are back-translated and reviewed by FHI 360 prior to implementation.
The witness (complying with IRB/IEC requirements): Is the advocate for the participant and must be present during the entire consenting process. 21 CFR and ICH GCP E6 section provide clear requirements for the witness’ signature on the informed consent. A witness should be an impartial third party that is present to attest to the adequacy of the consent process and to the participant’s voluntary consent.
Signing and dating the ICF: There are no set regulations or guidance regarding the timing of when a participant should sign and date the consent. Should there be a delay in the signing and dating of the consent (example: participant takes the consent document home to discuss with significant other), site staff must ensure the participant’s status has not changed; this includes verifying that the participant still meets the inclusion/exclusion criteria. Enrollment procedures cannot be conducted until the IC is signed and dated. A re-assessment of the participant’s understanding is imperative prior to their signing and dating the informed consent.
Version control: May also be a consenting challenge. In order to avoid a protocol noncompliance issue, consenting staff must ensure they are using the most currently approved IRB/IEC consent version when obtaining the participant’s informed consent. It is important for FHI 360 to always have the current versions of the ICFs on file; any updates made to the ICF that are not administrative should be reviewed by FHI 360 prior to implementation.
Re-signing of a consent: May occur for several reasons (examples: the wrong version of the consent form was signed or the use of a nickname instead of the participant’s legal name). When the participant returns to the site to re-sign the consent, thorough documentation of this re-signing must be clearly evident in the source document progress notes. Both signed consent forms should be kept in the study records.
Version
Re-signing the consent

40. Consenting a Vulnerable Population – Illiterate Participants
What are the consenting challenges?
What strategies could you use to mitigate challenges?
Group discussion:
Are participants predominantly literate at your site?
What are the ways the site evaluates literacy?

41. 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”.

42. ICH E6 – Section 4.0 Investigator Responsibilities
Investigator’s Qualifications
and Agreements
Informed Consent of
Trial Subjects
4.1
4.8
Adequate Resources
Records and Reports
4.2
4.9
Medical Care of Trial Subjects
Progress Reports
4.3
4.10
Communications with IRB/IEC
Safety Reporting
4.4
4.11
The ICH E6 GCP Guidance for Industry [handout]: (Section 4.0, Investigator Responsibilities, starts on page 13).
We will next discuss the Investigator responsibility, Investigational Product(s).
Compliance with Protocol
Premature Termination or Suspension of a Trial
4.5
4.12
Investigational Product(s)
Final Report(s) by Investigator
4.6
4.13
Randomization Procedures and Unblinding
4.7

43. Investigational Study Product(s)
ICH E6 Section 4.6
21 CFR (a)
21 CFR (a)
ICH E Investigational study product- in the next couple of slides we will discuss the requirements per this part of the GCP.
21 CFR (a)- maintenance of drug shipping information (not discussed in the slides).
21 CFR (a)- maintaining adequate records of drug disposition.

44. Investigational Study Product
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.
Bullet 3: Adhere to the storage requirements provided in the study protocol and product labeling.

45. 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.

46. 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.
Product Accountability Records should include date: (1) Product delivery to the trial site. (2) Inventory at the site. (3) Proper storage. (4) Use by each subject. (5) Return to the sponsor or alternative disposition of unused product. (6) Dates, quantities, batch/serial numbers, expiration dates (if applicable), unique code assigned to the product and trial participant.

47. ICH E6 – Section 4.0 Investigator Responsibilities
Investigator’s Qualifications
and Agreements
Informed Consent of
Trial Subjects
4.1
4.8
Adequate Resources
Records and Reports
4.2
4.9
Medical Care of Trial Subjects
Progress Reports
4.3
4.10
Communications with IRB/IEC
Safety Reporting
4.4
4.11
The ICH E6 GCP Guidance for Industry [handout]: (Section 4.0, Investigator Responsibilities, starts on page 13).
We will next discuss the Investigator responsibilities, Medical Care of Trial Subjects and Safety Reporting.
Compliance with Protocol
Premature Termination or Suspension of a Trial
4.5
4.12
Investigational Product(s)
Final Report(s) by Investigator
4.6
4.13
Randomization Procedures and Unblinding
4.7

48. 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
References: 4.3 (Medical Care of Trial Subjects) and 4.11 (Safety reporting)- will be discussed in the next couple of slides
EAE Manual (SAE/EAE).

49. 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.
Medical Care of trial Subjects: (1) 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. (2) It is recommended that the Investigator inform the participant’s primary physician about trial participation, if the participant agrees. (3) The Investigator should attempt to find the reason for premature withdrawal of participation in the trial when appropriate.

50. 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.

51. ICH E6 – Section 4.0 Investigator Responsibilities
Investigator’s Qualifications
and Agreements
Informed Consent of
Trial Subjects
4.1
4.8
Adequate Resources
Records and Reports
4.2
4.9
Medical Care of Trial Subjects
Progress Reports
4.3
4.10
Communications with IRB/IEC
Safety Reporting
4.4
4.11
Compliance with Protocol
Premature Termination or Suspension of a Trial
4.5
The ICH E6 GCP Guidance for Industry was provided as a handout: (Section 8.0, Essential Documents, starts on page 50.
We will next discuss the Investigator responsibilities, Records and Reports.
4.12
Investigational Product(s)
Final Report(s) by Investigator
4.6
4.13
Randomization Procedures and Unblinding
4.7

52. Essential Documents
ICH E6 Section 4.9 and 8.0

53. 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.
ICH-GCP Section 8.0 provides a clear and orderly presentation of those documents required to be kept in a hardcopy 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.

54. 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.
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 are also the ones that are usually audited by the sponsor's independent audit function and inspected by regulatory authorities.

55. ICH E6 – Section 4.0 Investigator Responsibilities
Investigator’s Qualifications
and Agreements
Informed Consent of
Trial Subjects
4.1
4.8
Adequate Resources
Records and Reports
4.2
4.9
Medical Care of Trial Subjects
Progress Reports
4.3
4.10
Communications with IRB/IEC
Safety Reporting
4.4
4.11
The ICH E6 GCP Guidance for Industry [handout]: (Section 4.0, Investigator Responsibilities, starts on page 13).
We will next discuss the Investigator responsibilities, Site Oversight.
We’ve seen this slide several times now. It lists the responsibilities of the Investigator of Record as presented in the ICH Good Clinical Practice Guideline (E6). Because clinical research is typically a team effort, these are the responsibilities that will inevitably be delegated in part, or in full, by other members of the team.
Looking at this slide now in terms of delegation: What responsibilities may Investigators delegate? In part or in full?
Compliance with Protocol
Premature Termination or Suspension of a Trial
4.5
4.12
Investigational Product(s)
Final Report(s) by Investigator
4.6
4.13
Randomization Procedures and Unblinding
4.7

56. Site Oversight
When a task is delegated- the Investigator role turns to one of supervision. If an error is made when the task is delegated, this is viewed as the Investigator’s failure to adequately supervise. Both the FDA and DAIDS hold the IoR responsible for the conduct of the study.

57. 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?
According to FDA guidance, there are four areas of focus when assessing whether the IoR provided adequate supervision in the conduct of the study: (1) were those to whom tasks were delegated qualified to do the tasks, (2) did the staff receive adequate training to perform the delegated tasks, (3) is there evidence demonstrating the ongoing involvement of the IoR in the conduct of the study and (4) was there adequate supervision of any third parties involved in study conduct (as applicable).

58. 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.
Tools useful in demonstrating adequate study supervision are: (1) up-to-date, signed and dated sub-investigator CVs and clinical licenses, (2) staff training records, (3) timely signature/initial/date of IoR on study documents, (4) the Study Delegation of Authorities Log (DoA) and (5) complete and accurate study product accountability records. It is a DAIDS requirement that CVs be updated at least every two years.

59. Study Delegation of Authority Log (continued on next slide)
[Insert page 1 of study Delegation of Authority Log (DoA)]
The purpose of this log is to document the staff members who are trained and qualified to conduct the different study procedures. It also indicates who can serve as the IoR’s designee.
It is important that start and stop dates for each staff member are provided- not only when they start working on the study and when they leave, but when roles change as well. One staff member may have more than one row on the DoA in the event he/she is promoted and takes on new responsibilities or a new position title.
This DoA should be in line with site SOPs and should have all necessary staff licensures (both current and archival) and training documentation on file to support the delegations outlined on the log.
What are some examples of appropriate vs. not appropriate delegation?
What does “qualified individuals” actually mean? Staff members to whom activities have been delegated must be qualified to carry out those activities either based on their education and/or experience. Signed and dated Curriculum Vitae (CV) for delegated staff should be current and include relevant education and experience. Copies of both current and archival CVs should be maintained in the site’s regulatory files.
An outside auditor should be able to match up the activities on this log with the individual’s education and experience.
What are the site and study training requirements in place at the site before people are added to the DoA?
How are training records documented at your site?
When we talk about training of site staff, it is the Investigators responsibility to ensure that the study staff participating in the study have received training for the tasks they have been assigned. This training must be documented in the regulatory files and must be ongoing (e.g. cover new protocol versions as they occur).
Tips:
Avoid using a catch-all such as “other duties as assigned by the IoR”. It would be better to clarify if these are “administrative duties as assigned”, “non-clinical duties as assigned” or “clinical duties as assigned” (as appropriate). If particular training is required for these “additional duties” it needs to be clear per the DoA so that the appropriate training/licensures needed to fulfill the role can be verified.
It is the Investigator’s responsibility to ensure that staff members are adequately trained. Documentation of all training activities provided by the Investigator or an outside entity should be maintained in the site’s regulatory files and available for review by the sponsor, monitors, and outside auditors.
In addition to providing requirements for Investigator Qualifications, the FDA also provides guidance on protocol training. The “Elements of Protocol Training” can be broken into four categories: general information, background information, trial design, and participant enrollment.

60. Key update: based on mock audit findings in ASPIRE and recommendations from PPD, added a column for IoR to sign off on each staff member when they start/stop study responsibilities.

61. DoA – Best Practices
Names should be printed legibly or typed, signatures and initials must be handwritten.
When staff roles and/or responsibilities change, add an end date and IoR initials/date to the current line listing, and add the staff member to a new line and list all responsibilities with the new start date and IoR initial/date
In the case where the DoA includes a list of staff from multiple clinical research sites (CRSs) as members of a single clinical trials unit (CTU), staff who are primary to the site should be distinguished from staff who are listed in “back-up/coverage‟ roles.

62. Summary of Required Pre-activation Regulatory Submissions
Paper FDFs
HANC online FD (IoR only)
CVs, GCPs, HSPs, clinical licenses
MTN IoR Training (IoR only)
FDF & IQ docs
Completed once all IoR & sub-IoR FD & IQ docs are in place
1572
IoRs & sub-IoRs can be added to DoA once 1572 is in place
DoA
Sites can start sending some of the required pre-activation documents (IRB approvals, IRB rosters, Investigator Signature Forms) as they become available.
The key will be for sites to (1) get all their FDF and Investigator Qualification documents for all investigators to be added to the 1572 prior to their being added to the 1572, and (2) to have the completed and signed 1572 in place prior to adding any investigators listed there onto the DoA. The above graphic summarizes the timing of completion of these documents.
Once MTN Regulatory has all the above items for a site, a “signoff” is sent to FHI 360, at which point the MTN Regulatory items are checked off the site’s activation checklist.

63. 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)

64. 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
The summary sheet of relevant CFR sections has two websites that provide additional information on the components of the CFR. The FDA website allows you to search for a term and it pulls up all relevant regulations about the topic.
Are there any questions?