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NIA Guidance on Clinical Trials

Introduction

NIH defines a clinical trial as a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. Ensuring safety of participants enrolled in NIA-funded clinical trials is the highest NIA priority. This goal applies to any trial regardless of a study's phase, stage, size or intervention type.  Another important objective of the guidance is to assure that Phase III and stage IV clinical trials are likely to improve public health. This goal reduces the possibility that noneffective or harmful interventions will be implemented in practice, based on trial results.

This guidance does not replace any of the following:

  • NIH grant policy or policies of U.S. Department of Health and Human Services (DHHS)/NIH regulations on protection of human subjects.
  • NIH policies and guidelines for conduct of clinical research, inclusion of women and minorities, inclusion across the lifespan, research project administration, reporting, and financial management.
  • Requirements of Institutional Review Boards (IRBs).
  • DHHS regulations for the protection of human subjects as described in 45 CFR 46.
  • The implementation of regulations for PHS research grants involving human subjects as found in the PHS 398 and the SF424 (R&R), available on the NIH OER web site.

Applicants also should be aware of the following NIH policies (see OER Human Subjects web site):

This NIA guidance 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 this guidance.

Data and Safety Monitoring

Guidance for Investigators

Applicants requesting support for any intervention study must complete "PHS Human Subjects and Clinical Trials Information" form of the SF424 (R&R), describe a data and safety monitoring plan (DSMP), which discusses the need for an independent data and safety monitoring body or justifies why such a body is not needed to monitor the study and proposes an alternative safety monitoring mechanism.  For example, for a single-site, low risk study, the PI may propose a local safety monitor, instead of a DSMB.

The NIA Program Officer (PO) will review the form, including the proposed DSMP and will either approve the DSMP or may seek further information from the principal investigator (PI).  In the approval process, the PO will take into account any comments from the review panel and could ask for further guidance from NIA staff or the National Advisory Council on Aging (NACA).

DSMPs must propose adverse event (AE) and serious adverse event (SAE) definitions and discuss their monitoring and reporting. All clinical trials of drugs and biological products conducted under an Investigational New Drug Application (NDA) must use definitions of adverse events and adverse reactions and follow the reporting requirements established by 21 Code of Federal Regulations (CFR) Part 312.32.  Trials of medical devices conducted under an Investigational Device Exemption (IDE) must use the definitions and reporting requirements established by 21 CFR 812. All other interventional studies must propose their definitions of adverse events and their reporting procedures. Given that there are no commonly recognized definitions of adverse events or adverse reactions for non-drug interventions, investigators are encouraged to review and revise, as needed, definitions by the DHHS's Office For Human Research Protection and those provided in 21 CFR 321.32 and Good Clinical Practice Guideline (ICH E6).

All adverse events, regardless of their seriousness, severity or relatedness to the intervention are reportable to NIA PO and an independent data and safety monitoring body such as Data and Safety Monitoring Board (DSMB) or Safety Officer (SO), if one is appointed by NIA as shown below:

  • Trials of drugs, biological products and devices conducted under IND or IDE:  Copies of all adverse event reports shall be submitted to PO, DSMB or SO when the original reports are submitted to the US Food and Drug Administration.
  • All other interventional studies: Given a wide variety of types of interventions and outcome measures, an adverse event reporting schedule must be proposed and should be commensurate with the study risks, characteristics of the study population and risks to which participants will be exposed during the study. For example, the reporting frequency could range from reporting all individual death cases within 24 hours of study's knowledge of death in closely monitored, early phase, high risk trials or, in cluster-randomized pragmatic trials, where safety data are collected via review of periodically retrieved CMS records, death could be reported in a quarterly or semi-annual summary safety reports, depending upon frequency of data transfers from the CMS.  The content and frequency of the safety reports should be specified in the DSMP and approved by a DSMB or a safety officer, if one is appointed, and/or by the NIA PO.
  • All adverse events that are both serious (SAE) and unexpected (i.e., have not been previously reported for the study's intervention) should be reported to the IRB, NIA PO and to the independent data and safety monitoring body, if one is appointed, within 48 hours of the study's knowledge of SAE. The summary of all other SAEs should be reported to NIA PO and to the DSMB or a Safety Officer, if either is appointed, quarterly, unless otherwise requested by the DSMB or a Safety Officer. Expected SAEs should be listed in the Data and Safety Monitoring Plan.

Studies with a DSMB

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 investigators should use the Human Subjects and Clinical Trials Information form of the SF424 to discuss the need for a DSMB, its role and responsibilities and optimal expertise of its membership or provide a justification of why such Board is not needed. If a DSMB is proposed, applicants should not nominate specific individuals for the DSMB in the application. If notified by the NIA PO that the project is likely to be funded, the investigators should nominate prospective DSMB members. 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
  2. A Conflict of Interest Statement.

DSMB members should have no direct involvement with the study or conflict of interest with the investigators or institutions conducting the study. Any affiliations or support from, or ownership of, pharmaceutical and/or biotechnology companies should be reported as a conflict of interest and full identifying information should be provided about the nature of the conflict and its financial size in broad terms (where relevant). 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 should also be disclosed.

NIA may also require that a DSMB be established following consideration of review panel's comments, NIA's National Advisory Council on Aging (NACA) advice, and/or input from NIA staff.  As per "NIH Policy for Data and Safety Monitoring," NIA-appointed DSMBs will perform the following activities:

  1. Review and recommend approval or request modification to the IRB-approved research protocol and consent documents.
  2. Review and recommend approval of the study's DSMP, Manual of Procedures, DSMB periodic report templates and a DSMB charter.
  3. Periodically evaluate the progress of interventional study(s), including periodic assessments of data quality and timeliness, participant recruitment, accrual and retention, participant risk versus benefit, performance of trial sites, and other factors that can affect study outcome. 
  4. Make recommendations to NIA's Director concerning the continuation, modification, or conclusion of the trial.

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

In the study protocol, statistical analysis plan and manual of procedures (MOP), investigators should discuss data management, quality assurance and quality control procedures; the proposed data analysis; criteria, timing and the process for unmasking treatment assignments (for masked studies); and study stopping rules, where appropriate. Investigators should also discuss their plans for notifying participants of trial results during and after the conclusion of the trial and providing the participants' health providers with the appropriate information from the trial, as needed, concerning individual participants (e.g., important abnormalities in clinical laboratory test results, cessation of drugs, ApoE4 status or amyloid/tau positivity, changes in dosage, etc.).

DSMB Process, Role and Responsibilities

NIA expects that DSMB will meet regularly (e.g., every six to nine months) to perform the tasks listed below. Additional DSMB meetings could be called by NIA PO or the DSMB Chair. 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 PO 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.

Initial meeting

  • Review the entire IRB-approved study protocol and the MOP, with regard to participant safety, recruitment, randomization, intervention, data management, quality control and analysis and the informed consent document.
  • Recommend changes to the protocol and the informed consent form, when applicable.
  • Identify the relevant data parameters and the format of the information to be regularly reported.
  • Recommend participant recruitment be initiated after receipt of a satisfactory protocol. If the need for modifications to the protocol, the MOP, consent form, DSMP or any other study document is indicated by the DSMB and/or the NIA PO, the DSMB will postpone its recommendation for the initiation of participant recruitment until after the receipt of a satisfactory revised protocol(s) or other study documents.

During the study meetings

  • Review masked and unmasked data. These data can be related to safety, recruitment, randomization, retention, protocol adherence, trial operations, data completeness, form completion, intervention effects, gender and minority inclusion.
  • Identify needs for additional data relevant to safety issues and request these data from the study investigators.
  • Propose additional analyses and periodically review developing data on safety and endpoints.
  • At each meeting, 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. When the DSMBs are unblinded, the Boards may recommend to NIA to appoint a blinded working group of the DSMB to review the proposed protocol changes and make recommendations to NIA on whether to approve the requests.
  • Provide advice on issues regarding data discrepancies found by the data auditing system or other sources.
  • Review manuscripts of trial results if requested by the Board or the NIA PO   who may seek DSMB review of manuscripts reporting major outcomes prior to their submission for publication.

A report containing the recommendations for continuation or modifications of the study will be prepared by the DSMB, NIA PO or NIA contractors. The draft report will be sent to the DSMB members for review and approval not later than three weeks after the meeting. Once approved by the DSMB members, the PO will forward the DSMB recommendations to the Principal Investigator. It is the responsibility of the Principal Investigator to distribute the DSMB recommendation to all co-investigators and to ensure that copies are submitted to the IRB that reviewed and approved the study documents.

The DSMB may modify its processes and procedures at any time with the approval of the NIA PO.

Roles of NIA Program Officers

For applications receiving a peer review rating that is potentially in the fundable range, the NIA PO will review the application, including data and safety monitoring plan prior to signing off on the grant award. If the PO believes that the DSMP is incomplete or inadequate, s/he will notify the applicant of which items are missing, require clarification or should be modified, and indicate NIA will restrict or will not fund the project until this information is received, reviewed, and approved by the PO. During the review process, the PO may obtain additional consultation from NIA staff, NACA members or NIA contractors.

If NIA plans to fund the proposed project and the applicant has not proposed a DSMB, the NIA will determine whether a DSMB is required for adequate monitoring of participants' safety and data integrity. If a DSMB is needed, the PO will request that the applicant modifies the DSMP to include the appropriate information regarding establishing the DSMB. Prior to making an award or shortly thereafter, the PO will complete the Clinical Trial Characteristics and Clinical Trial Management Plan as per NIA's Clinical Trial Standard Operating Procedures.

NIA Program Officer Responsibilities:

  • Institute appropriate terms in the award needed for subject safety (e.g., restrictions on expenditure of funds pending completion of particular activities such as completion of a DSMP, etc.).
  • Inform the investigators that at any point in the trial, NIA may obtain an independent audit of a sample of primary participant records for comparison with data collected by the trial. Auditors will report directly to NIA and will 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]). Ensure that the consent form provides for access by a third party to participant records.
  • Review and approve the data and safety monitoring plan.
  • Review regular safety reports as per schedule proposed in the DSMP.
  • Request, as needed, additional data from investigators on safety issues arising during the study.
  • Review proposed protocol changes or proposed new protocols and approve if indicated.
  • Review Research Performance Progress Report (RPPR), including the rationale for continuing the trial and either approve study continuation or recommend to NIA Director early discontinuation of the intervention and/or the study due to inadequate recruitment, retention or compliance, excessive risks or low likelihood of the study meeting its objectives.

In addition, for studies with DSMBs or SOs:

  • Include a condition in the Notice of Award stating that recruitment for this award will be restricted until an NIA-appointed DSMB or SO has reviewed and recommended approval of the study's IRB-approved protocol and consent documents, and manual of procedures.
  • Attend DSMB meetings or designate a delegate (NIA staff) to attend a DSMB meeting.
  • Review and approve the study protocol, DSMP and MOP after considering recommendations by the DSMB or SO.
  • Review the DSMB and other study data reports (including unmasked data if needed). Consult with the DSMB Chair and other NIA staff (as needed) regarding adverse and serious adverse events and trial safety.
  • Request, as needed, that the DSMB provide advice to the study on trial protocol and safety issues arising during the study.
  • Review ongoing adverse event reports as established by this Guidance.
  • Request, as needed, additional data from investigators.
  • Review proposed protocol changes or proposed new protocols, and recommendations by the DSMB or Safety Officer, and approve if indicated.
  • At each DSMB meeting (in each SO report), obtain recommendations from DSMB or SO on continuation of the study. Either approve study continuation or recommend to NIA Director early discontinuation of the intervention and/or the study due to inadequate recruitment, retention, compliance, excessive risk or low likelihood of the study meeting its objectives.
  • Acknowledge reports of serious data discrepancies found by the data audit and propose a plan describing the steps that are to be taken next. The audit report and the plan should be sent to the PI, the Chair of the DSMB, Director of NIA and the PI within 2 weeks of the receipt of the audit report.
  • Assure preparation and dissemination of a clinical alert in the event of a clinically significant finding. This dissemination also should include informing the study participants of this clinical alert and providing them and their health provider with as complete information as possible that may affect the participants' well-being.
  • As appropriate, seek DSMB review of manuscript reporting major outcomes prior to submission for publication.

DSMB Meetings – Research Grants

DSMB meetings will consist of open, closed and optional executive sessions, all closed to the public because discussions may address confidential participant data. The study PI and key staff members, DSMB members and NIA Program Officer and/or authorized NIA staff 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 treatment group are not presented in the open session.

The primary objective of the closed sessions is to review data by study group. The closed sessions are attended by the DSMB members, the NIA PO and an unblinded study statistician. The NIA PO 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

In a 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 NIA staff serve(s) as the Project Scientist(s) and/or Program Coordinator 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, closed and optional executive sessions, all 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 PO 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 treatment group are not presented in the open session. NIA's 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 study group. The closed sessions are attended by the DSMB members, the NIA PO and an unblinded study statistician. The NIA PO 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 PO is not permitted to attend the executive sessions.

Studies with the Safety Officer

Some clinical trials do not meet the requirements for a DSMB but may require greater safety monitoring than minimal risk studies. For such studies, PHS Human Subjects and Clinical Trials Information form of the SF424 should discuss the need for a safety officer (SO) or provide a justification of why a SO is not needed. The Safety Officer is an independent individual who performs data and safety monitoring activities in lower risk, but greater than minimal risk single-site clinical trials. The SO advises NIA Program staff and the Principal Investigator (PI) regarding participant safety, study risks and benefits, scientific integrity, participant recruitment, and ethical conduct of a study.

Appointment of the SO - The SO should be a physician or another licensed health care professional with relevant study and disease-specific expertise. The PI submits the individual's name and biosketch for review and approval to the NIA PO. Approval of the SO is the responsibility of the NIA PO. Following approval, the SO receives the manual of operating procedures, which typically contains the study protocol and safety and data monitoring plan, before study enrollment begins. The tasks of the SO include reviewing the entire IRB-approved study protocol regarding subject safety and analysis, the informed consent document regarding applicability and readability, and participant recruitment and retention milestones.

Independence of the SO - The SO must maintain independence from the study. Accordingly, the SO should not be directly involved in the design and conduct of the study, and should not have scientific, proprietary, financial or other interests that may affect independent decision-making. In addition, potential SOs must sign a Conflict of Interest Statement prior to the appointment. Current collaborators of the PI are not eligible to be SOs. However, the SO can be located at the same institution as the PI.

Safety Reports - At predetermined intervals (e.g., biannually), the study team will prepare safety reports to be reviewed by the SO and NIA for recommendations for or against the trial's continuation, as well as any modification to the study. All applications proposing human interventions must include a data and safety monitoring plan (DSMP) which must propose adverse event (AE) and serious adverse event (SAE) definitions and discuss events' monitoring and reporting as described above.

The SO is unblinded to safety data, but not necessarily to outcome data. The data and safety monitoring plan should specify how data are to be presented and triggers for presenting outcome data in an unmasked manner.

In addition to safety data, the SO should consider recruitment and retention rates and whether delayed recruitment raises concerns of futility and ethical considerations.

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, D.Phil.
Division of Extramural Activities
National Institute on Aging
Suite 2W100, MSC 9205
7201 Wisconsin Avenue
Bethesda, MD 20892-9205
Phone: 301-496-9322
Email Dr. Barr