Introduction
The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. Human subjects research clearly supports each of these goals but in ways that are necessarily different from other forms of research. Each clinical issue presents its own special considerations and accordingly each study must be individually designed. Nonetheless there are fundamental principles that should be considered by applicants, reviewers, and Institute staff. Foremost among such considerations is the principle of ensuring patient/subject safety followed immediately by the principle that studies be soundly constructed and conducted so as to be likely to benefit public health.
A clinical trial is defined as clinical research involving the administration of an intervention (drug, biologic, surgery, device, behavioral counseling, lifestyle modification, etc.) to living human beings for the purpose of evaluating some aspect of the intervention. A Phase III clinical trial evaluates the efficacy of an intervention in a large group of human subjects by comparing the experimental intervention to standard treatment or no treatment, or by comparing combinations of two or more existing treatments.
Assessing safety and efficacy of particular interventions is central to the design and implementation of clinical studies. Safety is mostly determined from data on frequency of adverse events. Adverse events are defined by the FDA as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during the study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are defined by the FDA as any untoward medical occurrences that: (1) result in death, (2) are life threatening, (3) require (or prolong) hospitalization, (4) cause persistent or significant disability/incapacity, (5) result in congenital anomalies or birth defects, or (6) are other conditions which in the judgment of the investigators represent significant hazards.
All NIH clinical trials (intervention studies) require monitoring that is appropriate to the level of risk to the participants.
For each proposed clinical trial, NIH requires a data and safety monitoring plan (DSMP) as part of the research application that describes oversight and monitoring to ensure the safety of participants and Monitoring may be conducted in various ways or by various individuals or groups, depending on the size and scope of the research effort. These exist on a continuum from monitoring by the PI or NIH program staff in a small Phase I study to the establishment of an independent safety monitoring board for a large Phase III clinical trial. Regardless of the level of monitoring, regular reporting to NIGMS is required.
The following policies describe NIGMS’ requirements for extramurally supported clinical trials. They apply immediately 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. The implementation of these regulations for PHS research grants involving human subjects is found in Standard Form (SF) 424 and the PHS 398 form (rev. 4/98); which form to use depends on what mechanism will be used to support the research; both are available on the NIH Web site (http://grants.nih.gov/grants/forms.htm).
Applicants also should be aware of the following NIH policies:
- NIH Policy on Data and Safety Monitoring (NIH Guide for Grants and Contracts, June 10, 1998 [http://grants2.nih.gov/grants/guide/notice-files/not98-084.html])
- Further Guidance on a Data and Safety Monitoring for Phase I and Phase II Trials (NIH Guide for Grants and Contracts, June 5, 2000 [http://grants2.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html])
- Guidance on Reporting Adverse Events to Institutional Review Boards for NIH-Supported Multicenter Clinical Trials (NIH Guide for Grants and Contracts, June 11, 1999 [http://grants2.nih.gov/grants/guide/notice-files/not99-107.html])
This NIGMS policy document describes further action to: (1) ensure the protection of human subjects when the study involves a potentially harmful intervention, and (2) ensure participants receive an appropriate share of the benefits of these studies. In individual cases, NIGMS may find it beneficial to have additional levels of involvement or oversight beyond those described in these policies.
Clinical Trial Monitoring Policies
Applicants for any intervention study should state—per the instructions for the "Human Subjects" section of the PHS-398 form—whether the proposed study intervention could have harmful effects. Applicants also should provide justification for this opinion. After an Initial Review Group (IRG) review and IRB review and approval, the Program Administrator reviews the risks of the intervention. If the proposal for a study with a potentially hazardous intervention does not include the required information for such studies (described below), NIGMS will not fund the project until this information is received, reviewed, and approved by a designated Program Administrator. The Program Administrator may obtain additional consultation from NIH staff, members of the National Advisory General Medical Sciences Council (NAGMSC), or other experts as necessary or appropriate.
The following requirements apply to all studies employing interventions.
Each of the following sections (Requirements for Investigators, Requirements of Clinical Trial Monitors, and Requirements for Program Administrators), describes requirements for all Phase I and Phase II trials; the final section describes additional requirements for each of these groups specifically for Phase III trials. Note: Phase III trials are large and complex studies that have highly specialized features and requirements. Because NIGMS-supported Phase III trials are atypical, please be sure to contact a program director at the institute if you have questions about a Phase III trial.
Requirements for Investigators
All studies involving more than minimal risk to participants must describe a safety monitoring plan and management of monitoring procedures. The specific approach to monitoring will depend on features of the clinical trial to be conducted and oversight may range from:
- relatively low level of monitoring; e.g. reports from the study PI or an independent medical monitor (IMM)
- moderate level of monitoring; e.g., reports from the Institutional Review Board or a study-specific Safety Monitoring Board (SMB)
- high level of monitoring including a Data and Safety Monitoring Board (DSMB)
In general, each approach addresses the same responsibilities for ensuring patient safety and study integrity, and operates in a similar manner albeit with different degrees of structure and formalized reporting. At each monitoring interval, the NIGMS Program Director will receive notification by the trial monitor that she/he has reviewed the research protocol and ongoing study activities with emphasis on data integrity, protocol adherence and study participant safety issues. In particular, this will include the review of adverse events and reasons for losses to followup, raising any concerns or issues with the NIGMS and the Principal Investigator (PI), and recommending to the NIGMS and PI the continuation, modification or conclusion of the trial, while protecting the confidentiality of the trial data and the results of monitoring.
Independent Medical Monitor
An Independent Medical Monitor (IMM) may be appointed by the study Principal Investigator to oversee a clinical research project if there is more than minimal risk to the participants. The IMM will be independent of the study and have no real or apparent conflict of interest. The NIGMS Program Director must approve of the IMM and specific monitoring procedures she/he will follow. In general, the IMM will have responsibilities similar to that of a SMB/DSMB and will operate in a similar manner.
Study Monitoring Board
A Study Monitoring Board (SMB), appointed by the principal study investigator in consultation with the NIGMS, may appropriately monitor other types of trials. Study investigators might participate in the SMB depending on the nature of the data being monitored. Usually, however, the SMB will be composed of one or more scientists (generally physicians and a statistician) who are not involved in the study. The NIGMS may appoint its own representative. The NIGMS Program Director must approve the SMB membership and the specific monitoring procedures. In general, an SMB will operate in a manner similar to a DSMB.
Data and Safety Monitoring Board
As implied by the title, Data and Safety Monitoring Boards have broad oversight responsibilities; these include but are not limited to
- Performance (including recruitment/retention, protocol adherence, and data quality/completeness)
- Safety, and in some cases, efficacy (i.e. interim analyses)
- Review of ancillary studies and protocol modifications
In general, human intervention study proposals submitted to NIGMS should include plans for a Data and Safety Monitoring Board (DSMB) if the proposed study meets any of the following criteria:
- Is a Phase III clinical trial
- Is a multi-site clinical trial
- Has a high-risk intervention regardless of size
- Has more than 100 participants
- Involves special populations (e.g. persons with impaired ability to consent)
Applicants for studies that do not meet the above criteria for having a DSMB may propose to have a DSMB if they consider it to be useful for their study. If the applicants propose an independent DSMB is required for adequate subject safety, the applicant should indicate the proposed frequency of meetings for the DSMB and include a proposed list of data items to be provided to the DSMB and estimates for DSMB-related expenses in the proposed project budget. Applicants should not nominate specific individuals for the DSMB in the application. If notified by the Program Administrator the project is likely to be funded, the investigators should nominate prospective DSMB members, including information about the nominated DSMB member, such as:
- A Curriculum vitae (CV)
- A list from each of the nominated DSMB members of their current affiliations with pharmaceutical and biotechnology companies, including the name of the company and the type of affiliation (e.g., stockholder, consultant), and any other relationship that could be perceived as a conflict of interest related to the study and associated with commercial interests. These nominations are subject to approval by the Director of NIGMS. (DSMB members should have no direct involvement with the study or conflict of interest with investigators conducting the study.) If applicants have not proposed a DSMB, but prior to funding of the proposed project, the Program Administrator believes an independent DSMB is required, applicants will make arrangements for a DSMB as described in the "Requirements for Program Administrators" section.
All studies should have a structured adverse event determination, monitoring, and reporting system, including standardized forms and protocols for referring and/or treating subjects experiencing adverse events. The proposed schedule for reporting adverse events to the DSMB, the IRB (or IRBs for multisite studies), the Program Administrator and/or the FDA should be described. The proposed schedule should include a system for sending DSMBs reports regarding safety issues (see the "Requirements for Clinical Trial Monitors" section) to the study Principal Investigator (PI). In multisite studies, the study PI is responsible for sending the DSMB reports to individual site PIs, who are required to distribute these reports to their local IRBs.
Investigators must ensure NIH is informed of actions, if any, taken by the IRB as a result of their continuing review.
Applications must include the proposed human subjects consent form and describe procedures for protection of human subjects.
All masked studies should describe a randomization scheme and specific criteria and procedures for unmasking. If a DSMB is not proposed, the application also should designate individuals with access to unmasked data.
Under certain circumstances, the PI should also nominate a Medical Safety Monitor (MSM), independent of the study investigators, to be responsible for reviewing Serious Adverse Events as they occur and provide regular reporting of Serious Adverse Events (SAE) to the DSMB and others, as appropriate. In some cases, a SMB may also identify a MSM.
If the proposed project has additional clinical sites (besides the PI's), the application also should describe procedures by which the PI will notify sites of any problems as identified by the DSMB if one is established.
In specific cases where the funding IC is the sponsor of the test agent (i.e., holder of the Investigational New Drug application), investigators must submit individual adverse event reports to the IC (as sponsor) in accordance with FDA regulations.
Requirements for Clinical Trial Monitors
If an independent study monitor is established (including IMM, SMB or DMSB), its initial tasks are to:
- Review the protocol with regard to subject safety (including identification and data formatting to be regularly reported).
- Identify needs for protocol modification.
- Identify that the study protocol insures adherence to human subject protection policies.
- Recommend subject recruitment be initiated after receipt of a satisfactory protocol.
The Monitor must meet on a regular schedule (no less than twice a year) during the study, with additional meetings as needed, in order to:
- Review data (including masked data at their discretion) 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. Submit a written report to the PI, who will ensure all clinical site PIs receive this report.
- Review reports from the Medical Safety Monitor (as appropriate), 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.
- Make recommendations on study continuation with regard to recruitment, treatment effects, retention, compliance, and safety issues.
- Send written reports following each DSMB meeting to the Program Administrator and PI. Send additional reports on all issues reviewed by the DSMB as needed. The PI will send the report to their IRB.
If there is more than one clinical site, the PI is responsible for sending the reports to individual site PIs, who are required to distribute the report to their local IRBs, as detailed in the NIH "Guidance on Reporting Adverse Events to Institutional Review Boards for NIH-Supported Multicenter Clinical Trials" (NIH Guide for Grants and Contracts, June 11, 1999 [http://grants2.nih.gov/grants/guide/notice-files/not99-107.html).
Requirements for Program Administrators
For applications receiving a peer review rating that is potentially in the fundable range, the Program Administrator will review the risks of the intervention. If the information required in applications for studies having potentially harmful interventions is not included in the application, the Program Administrator will notify the applicant of which items are missing and indicate NIGMS will not fund the project until this information is received, reviewed, and approved by the Program Administrator. The Program Administrator may obtain additional consultation from NIH staff or National Advisory General Medical Sciences Council (NAGMSC) members, or other experts as necessary or appropriate.
If NIGMS plans to fund the proposed project and the applicant has not proposed a safety monitoring plan and management of monitoring procedures, the Program Administrator will determine the level of monitoring required. If monitoring is required (i.e. IMM, SMB, or DSMB), the Program Administrator will request the applicant to:
- Indicate the proposed frequency of reporting and meetings for the monitor(s).
- Submit a proposed list of data items to be provided to the monitor(s).
- Nominate one or more monitors (a SMB or DSMB should consist of no less than three persons), including information on the nominees such as:
- A CV
- A list from each of the nominees of their current affiliations with pharmaceutical and biotechnology companies, including the name of the company and the type of affiliation (e.g., stockholder or consultant), and any other relationship that could be perceived as a conflict of interest related to the study and associated with commercial interests). These nominations are subject to the approval by the Director of the NIGMS.
- Submit a proposed supplemental budget for travel and administrative expenses for monitoring. The NIGMS will reserve the right to appoint additional members to the monitoring body to include expertise in topic areas relevant to the trial such as biostatistics, ethics, or patient advocacy.
For awards that are to be funded, the Program Administrator will:
- Review and approve data and safety monitoring plans. This plan should be incorporated into the Terms and Conditions of Award.
- 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 the awardee's site cannot recruit participants until both NIGMS program staff and the awardee's IRB have approved the monitoring plan and that NIGMS program staff also have 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 Administrator 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.
- Upon receipt of noncompeting renewal applications (and more frequently if necessary), review rationale for continuation of study, and terminate award if recommended by the DSMB and/or the Director of NIGMS (e.g., inadequate recruitment, retention or compliance, or excessive adverse events).
For studies with DSMBs, the Program Administrator also will:
- Include (in the Notice of Grant Award) a condition stating the awardee cannot recruit participants until the NIGMS Program Administrator approves the protocol based on recommendations of the DSMB.
- Review DSMB reports.
- Request—as needed—that the DSMB provide advice to the study on trial protocol and safety issues arising during the study and continuation or termination of the study.
- Facilitate implementation of DSMB recommendations by the Institute.
Additional Requirements for Phase III Trials
Additional Requirements for Investigators for Phase III Trials
Applications for any intervention study should state whether the proposed study meets NIH's criteria for a NIH-defined Phase III trial in the "Research Plan section" of the PHS-398 form. Applicants also should provide justification for this opinion. After the IRG reviews the application, the NIGMS Program Administrator reviews this information. If the proposal for a study deemed by NIGMS to be a Phase III trial does not include the required information for such studies (described below), NIGMS will not fund the project until this information is received and reviewed by the Program Administrator. The Program Administrator may obtain additional consultation from IRG members (acting through the appropriate SRA), NIH staff, or National Advisory General Medical Sciences Council (NAGMSC) members, or other experts as necessary or appropriate.
Proposals for Phase III trials must include:
- Plans for the establishment of an independent DSMB.
- A data processing and analysis unit or function administered by a designated individual other than the PIs of the trial. (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 the Program Administrator is a member. In all cases, all data from this unit must be directly available to the Program Administrator and the DSMB on request.
- Protocols for quality assurance/quality control, data management, and analysis.
- 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.).
A detailed Manual of Procedures must be available for review and approval by the Program Administrator and the DSMB prior to entering subjects. Basic elements include:
- identification of the patient population;
- inclusion and exclusion criteria;
- adequate plans for recruitment and retention of participants;
- experimental design and protocols;
- clear definition of the research hypothesis and outcome measures;
- quality control/assurance procedures;
- data management and analytical techniques;
- sample size estimates with justification;
- administrative procedures (including regulatory approvals if necessary);
- collaborative arrangements;
- duties and responsibilities of study chairperson, clinical sites, coordinating center, and other central resources such as a central laboratory;
- monitoring plans to assure patient protection and data integrity.
Additional Requirements for the DSMB for Phase III Trials
- The DSMB's initial task is to review the entire study protocol, the Manual of Procedures, and the informed consent form with regard to recruitment, randomization, intervention, subject safety, data management, plans for auditing of primary subject records, and quality control and analysis, and to identify needed modifications. The DSMB will identify the relevant data parameters and the format of the information to be regularly reported. If the need for modifications to the protocol, Manual of Procedures, 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.
- Review masked or unmasked outcome data as needed and appropriate during the trial.
- 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.
- Provide advice on issues regarding data discrepancies found by the data auditing system or other sources. If this advice is requested by the Project Office/Program Administrator, it should be provided by the DSMB in writing within 2 weeks of the date of this request.
- Review manuscripts of trial results prior to submission for publication. (The NIGMS Program Administrator may require that the DSMB approval of the manuscript be obtained before submission.)
Additional Requirements for the Program Administrator for Phase III Trials
After an IRG reviews the application, the Program Administrator will determine whether the study is an NIH-defined Phase III trial. If the information required in applications for Phase III trials (described above) is not included in the application, the Program Administrator will notify the applicant of which items are missing and indicate NIGMS will not fund the project until this information is reviewed and approved by the Program Administrator. The Program Administrator may obtain additional consultation from NIH staff or National Advisory General Medical Sciences Council (NAGMSC) members, or other experts as necessary or appropriate.
The Program Administrator will:
- Institute any appropriate terms in the award needed for subject safety, satisfactory data management, quality, and analysis; recruitment and protocol adherence (e.g., data reporting formats and schedules, restrictions on expenditure of funds pending completion of particular activities, etc.).
- Review regular reports of relevant masked group data on treatment effects.
- Request additional data from investigators as needed on safety issues, data management, quality, and analysis; recruitment, retention, and protocol adherence issues arising during the study.
- Request—as needed—the DSMB provide advice to the study on trial protocol and safety issues; data management, quality, and analysis; recruitment, retention, and protocol adherence issues arising during the study and continuation or termination of the study.
- Acknowledge reports of serious data discrepancies found by the DSMB, or other sources within 2 weeks of the receipt of this information by the Project Officer/Program Administrator.
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 NIGMS.
- 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 NIGMS and be reimbursed directly by NIGMS (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]).
- The NIGMS Program Administrator may obtain prior review by the DSMB of manuscripts reporting major outcomes before submission of such manuscripts for publication.
Peer Review of Applications to NIGMS for Phase III Trials
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
NIGMS welcomes questions and comments from potential applicants. Inquiries are encouraged and may be directed to the NIGMS program staff member with whom the applicant/grantee has been in contact. For questions regarding policy issues, please contact:
Paul A. Sheehy, Ph.D.
Deputy Associate Director for Extramural Activities
National Institute of General Medical Sciences
45 Center Drive, Room 2AN24G
Bethesda, MD. 20892-6200
Phone: 301-594-4499
FAX: 301-480-1852
E-Mail: sheehyp@nigms.nih.gov
Policies last updated Sep 17, 2005
