Research and Funding

Division of Extramural Activities

Implementation of Policies for Human Intervention Studies

Introduction

The following policies are based on two goals:

  1. Protecting the participants' safety in all intervention studies. This goal applies to any study whether it is a Phase III trial or a more limited intervention study. Policies to achieve it are described in the "NIA Data and Safety Monitoring Policies section.
  2. Assuring Phase III clinical trials are likely to improve public health. Phase III clinical trials are usually based on prior studies of the safety and efficacy of the interventions under study. This goal reduces the possibility that nonefficacious or harmful interventions will be implemented in practice, based on trial results. An NIH-defined Phase III Clinical Trial (see Clinical Trial section of Human Subjects Section Instructions for the PHS 398 or SF424-R&R), is any broadly based prospective study that evaluates an experimental human intervention with a control or standard or compares two or more existing treatments or interventions where the study's outcome is likely to contribute to change in either standard of care or public health policy.

The following policies describe NIA's requirements for extramurally supported projects. They apply to all projects to be submitted. They do not replace any of the following:

  • Existing NIH grant policy or policies of U.S. Department of Health and Human Services (DHHS)/NIH regulations on protection of human subjects.
  • Policies and guidelines for conduct of clinical research, inclusion of women and minorities, research project administration, reporting, and financial management.
  • Requirements of local Institutional Review Boards (IRBs).

DHHS regulations for the protection of human subjects are described in 45 CFR46 (see www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html). The implementation of these regulations for PHS research grants involving human subjects is found in the PHS 398 and the SF424 (R&R), available on the NIH OER web site (http://grants1.nih.gov/grants/funding/phs398/phs398.html; http://grants1.nih.gov/grants/funding/424/index.htm)

Applicants also should be aware of the following NIH policies (see OER Human Subjects web site: http://grants1.nih.gov/grants/policy/hs/hs_policies.htm):

  • Guidance on Reporting Adverse Events to Institutional Review Boards for NIH-Supported Multicenter Clinical Trials (NIH Guide for Grants and Contracts, June 11, 1999).
  • NIH Policy on Data and Safety Monitoring (NIH Guide for Grants and Contracts, June 10, 1998).
  • Further Guidance on a Data and Safety Monitoring for Phase I and Phase II Trials (NIH Guide for Grants and Contracts, June 5, 2000).

This NIA policy document describes further action to: (1) ensure the protection of human subjects when the study involves a potentially harmful intervention, and (2) increase the likelihood that interventions will result in a favorable risk/benefit ratio for participants. In individual cases, NIA may find it beneficial to have additional levels of involvement or oversight beyond those described in these policies.

NIA Data and Safety Monitoring Policies

Applicants for any intervention study should state—per the instructions for the "Human Subjects" section of the PHS-398 /SF424 (R&R)—whether the proposed study intervention could have harmful effects or whether the proposed study meets criteria for an NIH-defined Phase III trial. Applicants also should provide justification for this opinion. The Program Officer will review the intervention and the data and safety monitoring plan (DSMP), taking into account any comments from the Initial Review Group (IRG) and may seek further information from the principal investigator (PI) and/or guidance from NIA staff or the National Advisory Council on Aging (NACA).

The following requirements apply to all human intervention applications and all human interventions funded studies.

Requirements for Investigators:

All applications proposing human interventions must describe a data and safety monitoring plan (DSMP) including management of monitoring procedures for human intervention studies. These plans must include a structured adverse event (AE) and serious adverse event (SAE) determination, monitoring and reporting system with standardized protocols and forms for referring and/or treating study participants who experience adverse events. AEs should be reported to the IRB, the NIA Program Officer and the study’s Data and Safety Monitoring Board (DSMB) if one is established, as appropriate.

All deaths require expedited reporting (usually within 24 hours of study’s knowledge of death). The report of death should be submitted to NIA Program Officer and to the DSMB Chair (or a Safety Officer, for studies without the DSMB) or to the designated DSMB member if a DSMB is established. When SAEs occur that are unanticipated (i.e., not listed in the Data and Safety Monitoring Plan) and that are related to the intervention, they should be reported to NIA Program Officer and to the DSMB Chair (or a Safety Officer, for studies without the DSMB) or to the designated DSMB member if a DSMB is established within 48 hours of study’s knowledge of SAE. The summary of all other SAEs should be reported to NIA Program Officer and to the DSMB (or a Safety Officer) quarterly, unless otherwise requested by the DSMB or a Safety Officer. Expected SAEs should be listed in the Data and Safety Monitoring Plan.

Where masking is part of the design, applications should describe criteria and procedures for unmasking and should designate individuals or committees who have access to unmasked data.

NIA requires studies that propose human interventions to include a plan for a DSMB when the study is a Phase III clinical trial or when it involves multiple field sites. The study team should also include a plan for a DSMB if the investigators believe the intervention incurs high risks of adverse events or if the team believes that a DSMB is the most effective way to monitor data and participant safety, such as when the study involves large numbers of participants. (See the DSMP Decision Tree (MS Word, 36K) for further guidance.)

In addition, NIA may require that a Safety Officer be appointed or a DSMB be established following consideration of IRG comments, NIA’s National Advisory Council on Aging (NACA) advice, and/or input from NIA staff.

The DSMB is an independent group of experts that advises the NIA Director and the study investigators. The members of the DSMB serve in an individual capacity and provide their expertise and recommendations. The primary responsibilities of the DSMB are to: 1) review and approve the study’s protocol and Manual of Procedures (MOP); 2) periodically review and evaluate the accumulated study data for participant safety, study conduct and progress, and, when appropriate, efficacy, and, 3) make recommendations to NIA concerning the continuation, modification, or termination of the trial.

When a DSMB is established, the plan should include a schedule for reporting adverse events to the DSMB and show how the IRB, NIA Program Officer, and FDA (if appropriate) will also be informed.

For trials involving multiple field sites, the plan should stipulate that the overall study principal investigator is responsible for distributing adverse event reports to the local site PI’s who are responsible for providing the reports to the local IRBs. The plan should also show how other DSMB communications will be shared with local site PI’s.

Multiple-site applications and multiple-PI applications should include a plan showing which PI is responsible for the principal investigator tasks described in this document.

When NIA is the sponsor of the new test agent (i.e., when NIA holds the Investigational New Drug application), investigators must submit individual adverse event reports to the NIA in accordance with FDA regulations.

Consistent with NIH grant policies, after review and approval of the study protocol(s) by the Program Officer, investigators shall not modify protocols, nor implement any new protocols, without prior review and approval of any modifications or additions by the NIA Program Officer, and the study DSMB or Safety Officer if one has been established.

Additional Requirements for Studies with a DSMB:

The frequency of DSMB meetings (usually twice per year), a proposed list of data items to be provided to the DSMB, and estimates for DSMB-related expenses should be included in the application, if a DSMB is proposed.

A data processing and analysis unit (often termed Data Coordinating Center) or function administered by a designated individual other than the PIs of the trial must be included. (In the case of multiple-award studies, the designated individual may be the PI of an administratively separate award). This individual may report to the PI or, in multiple-award studies, may report to the steering committee, of which an NIA Project Scientist may be a member. In all cases, all data from this unit must be directly available to the DSMB and Program Officer on request.

Protocols for quality assurance/quality control, data management, and analysis and stopping rules must be included. In addition, plans for notifying subjects of trial results after the conclusion of the trial and providing the subjects' health providers with the appropriate information from the trial, as needed, concerning the individual subject (e.g., cessation of drugs, changes in dosage, etc.) should also be included.

Although a detailed MOP is not required in the application, the applicant should prepare the MOP for review and approval by the DSMB and Program Officer at the first DSMB meeting and prior to the study’s participant recruitment.

Applicants should not nominate specific individuals for the DSMB in the application. If notified by the Program Officer that the project is likely to be funded, the investigators should nominate prospective DSMB members. The below stated information should be submitted to the Program Officer. These nominations are subject to approval by the NIA Director.

Information that will be needed about the nominated DSMB members include:

  1. A Curriculum vitae (CV)
  2. A Conflict of Interest Statement (COI). DSMB members should have no direct involvement with the study or conflict of interest with the investigators or institutions conducting the study. The COI must include current affiliations if any with all pharmaceutical and / or biotechnology companies, including the name of the company. DSMB members should report all financial interests such as salary, consulting and / or speaker fees, honoraria, research support, equity interests (e.g., stocks, stock options, or other ownership interests), and intellectual property rights (e.g., patents, copyright and royalties from such rights). No amounts need to be included. Any other relationship that could be perceived as a conflict of interest related to the study and associated with commercial interests shall also be disclosed.

Requirements for the DSMB:

The initial tasks of the DSMB are to:

Review the entire IRB-approved study protocol and the MOP, with regard to subject safety, recruitment, randomization, intervention, data management, quality control and analysis and the informed consent document with regard to applicability and readability.

Recommend changes to the protocol to the PI.

Identify the relevant data parameters and the format of the information to be regularly reported.

Recommend subject recruitment be initiated after receipt of a satisfactory protocol. If the need for modifications to the protocol, the MOP, consent form, etc., is indicated by the DSMB and/or the Program Administrator, the DSMB will postpone its recommendation for the initiation of subject recruitment until after the receipt of satisfactory revised protocol(s), etc.

DSMB meetings, often conducted via conference calls, will be attended by the PI and his/her designated staff, NIA program staff and the DSMB members. During closed sessions of the DSMB meetings only DSMB members and the NIA Program Officer may attend. The DSMB may request that a designated individual from the study (often the study’s biostatistician) who has been approved to have access to unmasked data will also attend the closed session. The DSMB must meet on a regular schedule (usually at least twice a year) during the study (with additional meetings as needed) to:

Review masked or unmasked data as needed and appropriate during the trial.

These data can be related to efficacy, recruitment, randomization, compliance, retention, protocol adherence, trials operating procedures, form completion, intervention effects, gender and minority inclusion, and subject safety.

Identify problems relating to safety during the study.

Identify needs for additional data relevant to safety issues, and request these data from the study investigators.

Propose appropriate analyses and periodically review developing data on safety and endpoints.

Semi-annually (and on other occasions if necessary), consider the rationale for continuation of the study, with respect to progress of randomization, retention, protocol adherence, data management, safety issues, and outcome data (if relevant) and make a recommendation for or against the trial's continuation.

Review and make recommendations on proposed protocol changes, and or new protocols proposed during the trial.

Send written reports following each DSMB meeting to the Program Officer and PI. Send additional reports on all issues reviewed by the DSMB as needed.

Provide timely advice on issues regarding data discrepancies found by the data auditing system or other sources.

Review manuscripts of trial results as requested; the NIA Program Officer may seek DSMB review of manuscripts reporting major outcomes prior to submission for publication.

The DSMB may modify its processes and procedures at any time.

Requirements for the Program Officer:

For applications receiving a peer review rating that is potentially in the fundable range, the Program Officer will review the intervention and data and safety monitoring plan. If the information required is not included in the application, the Program Officer will notify the applicant of which items are missing and indicate NIA will not fund the project until this information is received, reviewed, and approved by the Program Officer. The Program Officer may obtain additional consultation from NIH staff or NACA members.

If NIA plans to fund the proposed project and the applicant has not proposed a DSMB, the Program Officer will determine whether a DSMB is required for adequate subject safety. If a DSMB is required, the Program Officer will request that the applicant include the appropriate information regarding establishing the DSMB and its tasks and procedures:

For awards that are to be funded, the Program Officer will:

Review and approve the protocol (with the advice of the DSMB if one has been established).

Review and approve data and safety monitoring plans (with advice from the DSMB or safety officer).

Verify applicants have sent a detailed monitoring plan to the IRB(s) involved in the study.

Include a condition in the Notice of Grant Award stating that the awardee's site cannot recruit participants until both NIA program staff and the awardee's IRB have approved the protocol and monitoring plan and that the NIA ProgramOfficer also has documentation of the IRB's approval of that site's monitoring plan.

Institute any other appropriate terms in the award needed for subject safety (e.g., data reporting formats and schedules, restrictions on expenditure of funds pending completion of particular activities, etc.).

For funded awards, the Program Officer will:

Review regular data reports (including unmasked data if needed) on adverse events.

Request, as needed, additional data from investigators on safety issues arising during the study.

Review proposed protocol changes or proposed new protocols, including recommendations by the DSMB or Safety Officer, and approve if indicated.

Semi-annually (and on other occasions if necessary), review the rationale for continuing the trial, including recommendations on continuation bythe DSMB or Safety Officer. Terminate the project if indicated (e.g., due to inadequate recruitment, retention or compliance, or excessive adverse events) with concurrence from the NIA Director.

For studies with a Safety Officer or a DSMB, the Program Officer also will:

Include (in the Notice of Grant Award) a condition stating that recruitment for this award is restricted until a NIA approved Safety Officer or DSMB has met and approved the study’s IRB-approved protocol and informed consent document.

Review DSMB reports and consult with the DSMB chair and other NIA staff (as needed) regarding serious adverse events (SAEs) and trial safety.

Request—as needed—that the DSMB provide advice to the study on trial protocol and safety issues arising during the study.

Obtain recommendations from DSMB annually (and more frequently as needed) on continuation or termination of the study.

Facilitate implementation of DSMB recommendations by the Institute.

Acknowledge reports of serious data discrepancies found by the DSMB, or other sources within 2 weeks of the receipt of this information by the Program Officeer. This acknowledgment should be in writing and include a plan describing the steps that are to be taken next, and should be sent to the PI, the Chair of the DSMB, and the Director of NIA.

Assure preparation and dissemination of a clinical alert in the event of a clinically significant finding. This dissemination also should include informing the subjects of this clinical alert and providing them and their health provider with as complete information as possible that may affect the subjects' well-being.

Reserve the option, at any point in the trial, to obtain an independent audit of a sample of primary subject records for comparison with the trial's regular audit reports. Auditors engaged will report directly to NIA and be reimbursed directly by NIA (i.e., reimbursement will not be drawn from the award for the trial, and costs of such audits will not be borne by the awardee institution[s]).

May seek DSMB review of manuscript reporting major outcomes prior to submission for publication.

DSMB Meetings – research grants

DSMB meetings will consist of open and closed sessions, both closed to the public because discussions may address confidential participant data. The study PI and key staff members, DSMB members and NIA Project Scientist attend the open sessions. Discussions at these sessions focus on the review of the aggregate data, conduct and progress of the study, including participant accrual, protocol compliance, and problems encountered. Data by blinded treatment group and unblinded data are not presented in the open session.

The primary objective of the closed sessions is to review data by blinded study group and, if requested by the DSMB, unblinded data. The closed sessions are attended by the DSMB members, the NIA Program Officer and an unblinded study statistician. The NIA Program Officer attends the closed and open sessions as an observer, not as a DSMB member to answer any policy or administrative questions the DSMB members may have.

If necessary, an executive session may be requested by the DSMB and will be attended only by voting DSMB members. The NIA Program Officer is not permitted to attend the executive sessions.

DSMB Meetings – Cooperative Agreements

Under the cooperative agreement, the NIA purpose is to support and stimulate the recipients' activities by NIA involvement and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Under this funding mechanism, one or more of NIA staff serve(s) as the Project Scientist(s) and has/have substantial involvement that is above and beyond the normal stewardship role in an award. Additionally, a separate staff member, the NIA Program Officer, is responsible for the normal scientific and programmatic stewardship of the award and is named in the award notice.

As with research grants, DSMB meetings will consist of open and closed sessions, both closed to the public because discussions may address confidential participant data. The study PI and key staff members, DSMB members, NIA Project Scientist(s) and NIA Program Officer attend the open sessions. Discussions at these sessions focus on the review of the aggregate data, conduct and progress of the study, including participant accrual, protocol compliance, and problems encountered. Data by blinded treatment group and unblinded data are not presented in the open session.The NIA Project Scientist(s) attend(s) the open sessions as one of the investigators and has/have no voting rights.

The primary objective of the closed sessions is to review data by blinded study group and, if requested by the DSMB, unblinded data. The closed sessions are attended by the DSMB members, the NIA Program Officer and an unblinded study statistician. The NIA Program Officer attends the closed and open sessions as an observer, not as a DSMB member to answer any policy or administrative questions the DSMB members may have.

If necessary, an executive session may be requested by the DSMB and will be attended only by voting DSMB members. The NIA Program Officer is not permitted to attend the executive sessions.

Peer Review of Applications to NIA for Human Intervention Studies

Applications will be reviewed by an IRG. The review will specifically address the adequacy of plans, budgeting, and staffing to implement the requirements listed under "Requirements for Investigators."

Inquiries

NIA welcomes questions and comments from potential applicants. Inquiries are encouraged and may be directed to the NIA program staff member with whom the applicant/grantee has been in contact. For questions regarding policy issues, please contact:

Dr. Robin Barr
Division of Extramural Activities
National Institute on Aging
Suite 2C218, MSC 9205
7201 Wisconsin Avenue
Bethesda, MD 20892-9205
Phone: 301-496-9322
rb42h@nih.gov