Appendix C
Clarifying Protocol Accountability

Although research organizations and research sponsors will include a variety of offices and activities in their formal Human Research Participant Protection Programs (HRPPP, “program,” or “protection program”), the functional units that work together to review and oversee a particular proposal are the system elements of greatest significance to individual participant protection. In this way, the HRPPP acts as a “virtual” entity, with the relevant actors coming together on a protocol-by-protocol basis, depending on the methodology utilized, the risks posed, the research setting and objectives (e.g., a drug study carried out through individual physicians’ offices), and participant concerns, such as the involvement of vulnerable populations. A basic template that defines accountability throughout the life cycle of a research protocol can serve as a useful tool to facilitate the tracking of human research participant protection in the context of the protocol-specific program unit. Such a template can be adapted to suit various research paradigms and institutional needs and may be most useful as an electronic, Web-based application that guides investigators preparing Research Ethics Review Board1 (Research ERB) submis-

1  

Recommendation 3.1 calls for “Institutional Review Boards” (IRBs) to be named and referred to within research organizations by a title reflective of their focus on the ethics underlying participant protection activities. The committee has adopted the term “Research Ethics Review Board” (Research ERB) for this purpose. Therefore, Research ERB refers herein to the committee’s idealized protection program, and IRB to descriptions of the current system.



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Responsible Research: A Systems Approach to Protecting Research Participants Appendix C Clarifying Protocol Accountability Although research organizations and research sponsors will include a variety of offices and activities in their formal Human Research Participant Protection Programs (HRPPP, “program,” or “protection program”), the functional units that work together to review and oversee a particular proposal are the system elements of greatest significance to individual participant protection. In this way, the HRPPP acts as a “virtual” entity, with the relevant actors coming together on a protocol-by-protocol basis, depending on the methodology utilized, the risks posed, the research setting and objectives (e.g., a drug study carried out through individual physicians’ offices), and participant concerns, such as the involvement of vulnerable populations. A basic template that defines accountability throughout the life cycle of a research protocol can serve as a useful tool to facilitate the tracking of human research participant protection in the context of the protocol-specific program unit. Such a template can be adapted to suit various research paradigms and institutional needs and may be most useful as an electronic, Web-based application that guides investigators preparing Research Ethics Review Board1 (Research ERB) submis- 1   Recommendation 3.1 calls for “Institutional Review Boards” (IRBs) to be named and referred to within research organizations by a title reflective of their focus on the ethics underlying participant protection activities. The committee has adopted the term “Research Ethics Review Board” (Research ERB) for this purpose. Therefore, Research ERB refers herein to the committee’s idealized protection program, and IRB to descriptions of the current system.

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Responsible Research: A Systems Approach to Protecting Research Participants sions. Undoubtedly, within the confines of academic settings there are likely to be many instances for which the assignment of responsibilities would remain constant, and template forms could be standardized accordingly. An example of one such template is included in this appendix to illustrate the committee’s conception of such a document. This example is oriented toward clinical trials, and it presents several case scenarios to demonstrate the variety of partnerships that are possible within this one research domain. Because it is not possible to include all possible collaborative arrangements among clinical investigators, private industry, and federal or private funding sources, these scenarios attempt to embrace a range of illustrative potential collaborative relationships. When an HRPPP is assembled to review and monitor any given protocol, accountability for the required participant protection functions must be clear. An individual representing the research organization must meet with the Principal Investigator (PI) or sponsor to identify all organizations potentially participating in study conduct that may play a role in the protection of research participants. Responsibilities for tasks ranging from protocol review to ongoing monitoring should be assigned before study initiation, and for every project conducted, an official with overall responsibility for the participant protection program should be identified. The template presented in this appendix is provided as an example of an internal tool that can be utilized by a program in establishing a hierarchy of accountability. Research organizations may or may not choose to make such documents available for public review (i.e., by participants already enrolled or considering enrollment in a study), although the document may also serve as a useful communication tool for external as well as internal purposes. It should be emphasized that these templates are not intended to become an example of documentation without function. The potential utility of this tool lies in its explicit delineation of responsibilities in a consistent format that is accessible to all elements within a particular HRPPP. It also provides an instrument that may be useful to safety monitoring, auditing, and even HRPPP accreditation activities. CASE SCENARIO #1 – A SINGLE-SITE, INVESTIGATOR-INITIATED, FEDERALLY FUNDED STUDY A. Introduction A clinical investigator on the faculty of the Medical University of America (MUA—the sample academic institution in this case scenario) receives funding from a federal agency (e.g., the National Institutes of Health [NIH]) to conduct a single-site study (at MUA) evaluating a new indication

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Responsible Research: A Systems Approach to Protecting Research Participants for an approved therapeutic agent. The pharmaceutical company that produces the agent has agreed to provide the oral drug and placebo free of charge. The investigator contacts the MUA HRPPP to develop a research participant protection accountability plan, although the official with overall ultimate responsibility for human protection of his protocol is the President of MUA. (The president’s authority is likely to have been delegated to a subordinate official such as the dean for research). B. Protocol Development The protocol was designed by the PI and his collaborators, and because the drug is not approved for this indication, the PI is the holder of the investigational new drug application (IND). The pharmaceutical company is responsible for product manufacturing, packaging, labeling, and distribution; the PI, however, will be responsible for storage, usage, and disposal at his site, and he ensures that all study procedures are standardized with well-established protocols and that all co-investigators and research staff are properly credentialed and trained. The PI has found an accredited laboratory at MUA to perform the laboratory assays. The director of the laboratory has provided the PI with documentation that the laboratory is approved according to the Clinical Laboratory Improvement Act and Amendment and that it has normative values available. C. Protocol Review Process The study receives scientific review both from NIH and the General Clinical Research Center (GCRC) Advisory Committee (GAC). Conflict of interest review is performed by the MUA’s Conflict of Interest Committee, if necessary, which assures that the investigator does not have a significant financial interest in the pharmaceutical company and that he or she is not receiving financial remuneration. An external oversight committee established by MUA carries out a similar review examining potential institutional conflicts of interest. The ethical research review is performed by the MUA’s Research ERB. The protocol is also reviewed by MUA’s Radiation Safety Committee because patients will undergo Magnetic Resonance Imaging procedures. The PI establishes a data and safety monitoring plan. D. Ongoing Monitoring Because the study involves young children, the Research ERB requests consent monitoring. Protocol amendments are submitted to MUA’s Research ERB. The PI requests that NIH establish a Data and Safety Monitoring Board/Data Monitoring Committee (DSMB/DMC) for review of the

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Responsible Research: A Systems Approach to Protecting Research Participants protocol. The PI is responsible for all adverse event (AE) reporting with timely submission of reports to NIH, the Research ERB, and the Food and Drug Administration (FDA), based upon FDA guidelines. Safety monitoring for the study is provided by the GCRC through its research subject advocate (RSA) program. The DSMB/DMC has two scheduled interim reports that are forwarded to the Research ERB. Onsite monitoring is performed by MUA’s GCRC compliance officer, who limits the review to key outcomes. E. Other Protection Considerations Security, privacy, and confidentiality of the data are the responsibility of the PI, who will have control of the data and be responsible for preparation of all presentations and manuscripts. He will also inform the participants of the results of the study. Both NIH and the pharmaceutical company are providing financial support for the study. NIH funding will cover patient care and travel costs as well as the cost of the investigators and their research staff to conduct the trial; the company will provide the drug and placebo free of charge. The company also is providing medical coverage for unanticipated AEs related to study conduct (indemnification). No inducements are being provided beyond the cost of conducting the study. Training of the investigators and personnel is the responsibility of MUA. CASE SCENARIO #2 – A MULTISITE DRUG STUDY INVOLVING A CONTRACT RESEARCH ORGANIZATION A. Introduction A pharmaceutical company is sponsoring a trial to evaluate the safety and efficacy of a new therapeutic agent for which it plans to submit a new drug application to FDA. This is a large, multicenter Phase 3 trial involving 100 sites throughout the United States. The investigators at all of these sites are practicing physicians in community clinics or hospitals. The pharmaceutical company has contracted with a large contract research organization (CRO), as permitted under 21 CFR 312.52: “Transfer of Obligations to a Contract Research Organization.” The duties of the CRO versus the sponsor have been delineated in the development of this contract. The PI is a well-regarded physician with substantial expertise in caring for patients who have the medical condition of interest (e.g., coronary artery disease, rheumatoid arthritis) and who will potentially benefit from the proposed therapeutic intervention. She has a clinical faculty position with an academic institution, and her practice is 90 percent community

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Responsible Research: A Systems Approach to Protecting Research Participants based. She has been a consultant for the pharmaceutical company for many years, but is currently receiving no financial support from the company and has no equity interest in it. The official with daily responsibility for the protection program is the president/Chief Executive Officer (CEO) of the CRO based upon the terms of the contract. The committee does not imply in this instance that the contractual delegation of direct HRPPP authority relieves the CEO of the pharmaceutical sponsor from her overall responsibility for assuring that participant protections are in place for any study sponsored or conducted by the company. B. Protocol Development A research team within the pharmaceutical company develops the protocol. The PI reviewed the protocol, but had limited input. The pharmaceutical company holds the IND and is responsible for the manufacturing of the drug. Packaging, labeling, and distribution will be the responsibility of the CRO, which will also review storage, usage, and disposal at the clinical sites with the investigators. However, the investigators are ultimately responsible for the integrity of the product at the clinical site. The pharmaceutical company is also responsible for developing standardized operating procedures for all procedures conducted during the study and for ensuring, along with the CRO, that the individuals are credentialed or trained and have proper documentation to that effect. The pharmaceutical company will assure that all laboratory assays have been validated and that they are being conducted at accredited laboratories. The PI at each site will provide appropriate laboratory documentation. C. Protocol Review Process The sponsor has contracted with an independent Research ERB to assume responsibility for the review process and ongoing safety monitoring. The pharmaceutical company initially conducts the scientific review, and subsequently, the independent Research ERB establishes an ad hoc scientific review board. Financial conflict of interest review of the investigators and their institutions is provided by the Conflict of Interest Office of the CRO, which requests financial disclosure statements from all investigators and relevant research organizations (i.e., the clinic through which an investigator will conduct the research). Potential CRO conflicts will be assessed by an independent entity, and the determination will be forwarded to the Research ERB. The ethical review, including assurance of informed consent, is conducted by the independent Research ERB. Because it is a multicenter study, this Research ERB will conduct the initial review process and will modify the disclosure documents to be consistent with each of the

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Responsible Research: A Systems Approach to Protecting Research Participants individual site’s institutional (hospital, clinic) guidelines. Each investigator must meet with his or her own institutional Research ERBs to ascertain whether he or she will accept the independent Research ERB review or will also conduct a subsequent review. Because the study involves computed tomography imaging, a separate Radiation Safety Committee is established by the independent Research ERB. D. Ongoing Monitoring Plans for ongoing monitoring during the study conduct are the responsibility of the sponsor, although it has contracted much of the day-to-day responsibilities to both the independent Research ERB and the CRO. This study does not involve pediatric or other vulnerable patients, and no consent monitoring is recommended by the independent Research ERB. All protocol amendments will be submitted to the independent Research ERB for review. If community Research ERBs are also involved, the CRO will distribute the protocol amendments to the PIs, who are responsible for submitting them to their community Research ERBs. A DSMB/DMC is established by the sponsor specifically for this trial. The sponsor has chosen a group of scientists knowledgeable in the field who are not investigators in the study or employees of the company. A biostatistician, pharmacologist, and participant/public representative independent of the company also are chosen. These individuals submit financial disclosure statements to the independent Research ERBs to ensure that there are no financial conflicts of interest. Two interim safety reviews are planned during the study. AE reporting is the responsibility of the CRO. The PIs are responsible for reporting AEs at their clinical sites to the CRO, which forwards the AE reports to the sponsor, which will in turn report them to FDA. All serious AE (SAE) reports are sent to the independent Research ERB, and the DSMB/DMC will receive summary reports of the SAEs. Ideally, the DSMB/DMC will submit its interim review report to the Research ERBs, although this is not mandated. Onsite monitoring for safety and compliance as well as data integrity will be performed on all sites and on all data by the CRO. E. Other Protection Considerations Data management, including security, privacy, and confidentiality as well as electronic data collection, transfer, and maintenance are the responsibility of the CRO. The PIs will control the data at their sites until two years after the publication of the results. The interpretation and dissemination of study results are the responsibility of the sponsor. The PI may or may not be the first author on the paper. All financial support, including

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Responsible Research: A Systems Approach to Protecting Research Participants indemnification, is the responsibility of the sponsor, as is the training of all investigators and key research staff. The sponsor is also responsible for selecting the investigators and ensuring that they understand their responsibilities. The sponsor may contract with the CRO to help in these efforts. CASE SCENARIO #3 – A MULTISITE, INVESTIGATOR-INITIATED, FEDERALLY FUNDED STUDY A. Introduction The third case scenario is an NIH-supported multicenter trial awarded to a PI based at an academic institution (again, known as MUA). The study involves gene transfer studies on a rare genetic disorder. The therapeutic vector was developed by a scientist at MUA who is not the PI. A small biotechnology company was formed to develop the vector. The scientist has equity in the company and has fully disclosed this to MUA, which does not have any financial interest in the company. The company is receiving a small business grant from NIH. All participating institutions have National Center for Research Resources-funded GCRCs. The official with overall responsibility for the HRPPP is the President of MUA (in this case, MUA is the research organization, because it has assumed responsibility for conducting the study by virtue of the investigator’s employment). B. Protocol Development The PI and his collaborators developed the study design. The biotechnology company holds the IND and is responsible for manufacturing the vector. The company has contracted, as permitted under 21 CFR 312-52, with a CRO for the packaging, labeling, and distribution of the vector. The storage, usage, and disposal at the site are the responsibility of the investigators. The complex procedures for vector administration have been standardized by the PI, who is responsible for training the other investigators. Laboratory assays were established by the biotechnology company, which performed these assays in its own accredited laboratory following Good Laboratory Practice. C. Protocol Review Process Scientific review of the study was conducted by NIH and the GAC at each participating academic institution. Extensive conflict of interest review was undertaken by the Conflict of Interest Office at each academic institution to assure that neither the investigators nor the institution had financial

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Responsible Research: A Systems Approach to Protecting Research Participants or other conflicts.2 The inventor scientist’s financial interest has been disclosed to the participants in the course of the informed consent process. This individual is not involved in the clinical trial. The ethical review was initially conducted by the Research ERB of the PI’s institution. Most other participating institutions followed the recommendations of the primary Research ERB, although some institutions conducted their own reviews The investigator submitted the proposal to the Recombinant DNA Advisory Committee (RAC) of NIH as well as the Recombinant DNA Usage Committees at each institution. A radiation safety review was conducted at each institution, and MUA’s technology transfer office reviewed the intellectual property issues between the inventor scientist and the biotechnology company. D. Ongoing Monitoring A plan for ongoing safety monitoring during the study is prepared by the PI and is reviewed and approved by both the primary Research ERB and the GAC at each participating site. The Research ERB at the PI’s site and the RAC mandate that monitoring of consent be performed at all sites. This monitoring is provided by the GCRC RSA at each site. All protocol amendments have been reviewed by the PI’s institutional Research ERB. A DSMB/ DMC is established through NIH, and three interim safety reviews are proposed. AE reporting is the responsibility of the investigators at each site, who submit AE reports to the biotechnology company, which in turn submits them to FDA. The investigators also submit AE reports to their respective Research ERBs and GCRCs. The PI submits the SAEs to NIH. The biotechnology company contracts with a CRO for onsite monitoring of all sites and all data. E. Other Protection Considerations The CRO is contracted to perform data management services and is responsible for security, privacy, and confidentiality, as well as electronic data transfer and maintenance. The final data are submitted to the PI and to the biotechnology company. The PI and the company are jointly responsible for interpreting and disseminating study results and for informing the research participants of results. Financial support for the trial was provided by both NIH and the company. NIH paid for patient care costs and travel, as well as all clinical trial procedures and also supported all safety monitoring and data manage- 2   Institutional interests were assessed by an independent mechanism and the summary report forwarded to the Conflict of Interest Office for communication to the Research ERB.

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Responsible Research: A Systems Approach to Protecting Research Participants ment expenses. The biotechnology company supported all vector production, laboratory assays, and indemnification of sites. The training of the investigators was the responsibility of each institution. Selection of investigators was the responsibility of the PI, who also conducted the initial training of the other investigators.

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Responsible Research: A Systems Approach to Protecting Research Participants HRPPP ACCOUNTABILITY TEMPLATE Project Title: _____________________________________________________ Principal Investigator: _____________________________________________ Sponsors: ________________________________________________________ Date of Study Initiation: ________ Date of Study Completion: _______ Official with Overall Responsibility for Human Research Participant Protection Program: _______________________________________________ Risk Assessment: ❏ Minimal ❏ More than Minimal For each category listed below, please write the name of the individual or body (e.g., Research ERB) responsible for overseeing the task. Please circle either Yes or No (Y or N) where appropriate to indicate if the item is applicable. PROTOCOL DEVELOPMENT Applicable? If yes, please identify responsible party. 1. Research Design: ___________________ 2. If drug, biological agent, or device is administered:   Is the dose/route/indication FDA approved? Y / N   If not, is there an IND, IDE? Y / N   Who is the holder of the IND, IDE? ___________________   Who is the responsible party for the following:   Manufacturing product following GMP? ___________________   Ensuring availability of adequate supply of product to conduct trial? ___________________   Packaging, labeling, and distribution? ___________________   Storage, usage, disposal, and accountability at clinical sites following GCP? ___________________ 3. For procedures conducted during the study (e.g., cardiac catheterization, psychological profile), who is responsible for ensuring that:   Procedures are standardized, well established, and clearly defined? ___________________   Individuals conducting procedure(s) are properly credentialed and/or trained? ___________________

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Responsible Research: A Systems Approach to Protecting Research Participants 4. For laboratory assays (i.e., drug levels), who is responsible for ensuring that:   Assays have been validated? ___________________   Assays are being conducted at an accredited laboratory(ies) following GLP? ___________________ 5. For multicenter studies, who is responsible for:   Selecting investigators? ___________________   Ensuring investigator understanding of responsibilities and duties? ___________________   Training of investigators not affiliated with the primary institution/organization? ___________________ REVIEW PROCESS Applicable? If yes, please identify responsible party. 1. Scientific Review:   Internal (e.g., GCRC Advisory Committee, Scientific Review Committee)   ___________________   and/or     External (e.g., NIH, NSF, FDA, foundations, etc.)   ___________________ 2. Financial Conflict of Interest Review:   Investigator(s)   ___________________   Institutional   ___________________ 3. Ethical Research Review:   For multicenter studies, is there a primary review board? Y / N _______________   Is there medical and rehabilitative coverage in the event of an unanticipated event related to study conduct (indemnification)? Y / N _______________ 4. Review of Other HRPPP Issues:   Use of recombinant DNA Y / N _______________   Institutional review (e.g., Recombinant DNA Usage Committee) Y / N _______________

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Responsible Research: A Systems Approach to Protecting Research Participants   Federal review (e.g., Recombinant DNA Advisory Committee) Y / N _______________   Biosafety Y / N _______________   Radiation safety Y / N _______________   Intellectual property Y / N _______________   Grants and Contracts Y / N _______________   Other Y / N _______________ RECRUITMENT AND ENROLLMENT Applicable? If yes, please identify responsible party. 1. Informed Consent Process: Y / N _______________   Consent from Y / N _______________ 2. Inclusion/Exclusion Criteria: Y / N _______________   Please check appropriate box:   Vulnerable population ❏     Normal (healthy) volunteer ❏   ONGOING MONITORING DURING STUDY CONDUCT Applicable? If yes, please identify responsible party. 1. Data Safety Monitoring Plan: Y / N _______________   Data Safety Monitoring Board Y / N _______________   Are interim reviews planned? Y / N _______________   Stopping authority? Y / N _______________   Consent monitoring Y / N _______________ 2. Approval of Protocol     Amendments: Y / N _______________   Revisions to informed consent process and disclosure document Y / N _______________

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Responsible Research: A Systems Approach to Protecting Research Participants 3. Reporting of Adverse Events: Y / N _______________   Training of investigators/research staff in identification of adverse events   _______________   Adverse event reporting     Research ERB(s)   _______________   Sponsor   _______________   FDA   _______________   Other agencies   _______________ 4. Reporting of Protocol Violations (e.g., ineligible patients enrolled):   _______________ 5. Onsite Monitoring for Safety and Compliance: Y / N _______________   Please check appropriate box:     All sites, all data? ❏     Limited review of key outcomes? ❏     For cause only? ❏   DATA MANAGEMENT AND ANALYSES/ DISSEMINATION OF STUDY REPORTS Please identify responsible party. 1. Who controls access to data? _______________ 2. Security, Privacy, Confidentiality of Data Collected _______________ 3. Electronic Data Collection, Transfer, and Maintenance: Y / N   Compliance with FDA and HIPAA regulations for security, privacy, and confidentiality _______________ 4. Interpretation and Dissemination of Study Results: _______________ 5. Informing Study Participants of Results: _______________

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Responsible Research: A Systems Approach to Protecting Research Participants TRAINING OF INVESTIGATORS AND HRPPP PERSONNEL Please identify responsible party. 1. Training of Investigators and Key Research Staff in the Ethical Conduct of Human Research: ___________________ 2. Training of HRPPP Personnel in the Ethical Conduct of Human Research: ___________________ SIGNATURES I have reviewed this Accountability Template and attest that the correct individuals are identified in each category. Signed,   HRPPP Official (Head of research organization or sponsors, as applicable): Principal Investigator:   _______________________ _________________________________   signature signature   _______________________ _________________________________   printed name printed name   _______________________ _________________________________   date date