Notice Number: NOT-HS-10-019
Key Dates
Release Date: June 16, 2010
Comment Due Date: September 30, 2010
Issued by
Agency for Healthcare Research and Quality (AHRQ) www.ahrq.com
Background and Purpose
AHRQ’s mission is to enhance the quality, safety, efficiency, and effectiveness of health services, and access to such services, for all Americans. AHRQ conducts, supports, and disseminates a broad program of health services research related to its mission through the establishment of a broad base of scientific research.
AHRQ-conducted or supported research programs are intended to improve clinical practice, improve the health care system's ability to provide access to and deliver high quality, high-value health care, and provide policymakers with the ability to assess the impact of system changes on outcomes, quality, access to, cost, and use of health care services.
The spectrum of AHRQ-funded human subjects research ranges from research utilizing administrative data sets and observational studies to research studies with human subjects designed to answer specific questions about healthcare interventions, including the determination of safety, efficacy, or effectiveness. This encompasses comparative effectiveness research (CER), research to identify what works for which patients under what circumstances. CER includes health research to generate and synthesize evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition or to improve the delivery of care, and the knowledge base upon which patient-centered care can be given. CER can take the form of systematic evidence reviews, large established databases to capture health care practices and outcomes, prospective registries and cohort studies to understand the natural course of disease and factors influencing clinical outcomes, as well as randomized controlled trials (IOM, 2009).
The purpose of this notice is to announce a proposed AHRQ policy on the requirements for data and safety monitoring plans for AHRQ-conducted or supported research involving interventions with human subjects.
The Agency for Healthcare Quality and Research (AHRQ) invites comments on its draft policy on the requirements for a data and safety monitoring plan in AHRQ-conducted or supported research involving interventions with human subjects. Studies that are exempt under the Department of Health and Human Services (HHS) human subjects protection regulations (45 CFR Part 46) are not subject to this policy. If research falls under Food and Drug Administration (FDA) regulatory requirements (21 CFR 50; 21 CFR 56), the researcher must follow both HHS and FDA human subjects protection regulations, as well as this policy. The draft policy specifies that a data and safety monitoring plan must be submitted as part of the research grant application prior to the conduct of research involving interventions with human subjects. Effective with its publication, this policy will be incorporated as part of the terms and conditions for all new awards. Release of funds for research activities will be contingent upon compliance with AHRQ’s data and safety monitoring policy.
AHRQ plans to publish a policy on Data and Safety Monitoring in the NIH Guide during the fall of 2010.
Policy
AHRQ is committed to the protection of human subjects and their data in its research programs. HHS regulations define a human subject as a living individual about whom an investigator conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information (45 CFR Part 46). As such, all human subjects research must be approved by an institutional review board (IRB) for compliance with safety, privacy, and other requirements and such research monitored at least annually as part of continuing review by IRBs.It is AHRQ’s policy that data and safety monitoring should be an essential component of all AHRQ-conducted or supported research involving interventions with human subjects, to ensure the safety of participants and the validity and integrity of the data. In this context, a data and safety monitoring plan must be submitted as part of the research grant application, prior to the conduct of research involving interventions with human subjects. The data and safety monitoring plan should describe the method and degree of oversight and monitoring that are commensurate with the degree of risk involved for participating subjects, and the size and complexity of the proposed research.
General considerations for implementing the appropriate level of data and safety monitoring in AHRQ-funded research that the data and safety monitoring plan should address are:
- Potential harm from study procedures and interventions
- Level of vulnerability of study participants (e.g., children, pregnant women, frail elderly, extremely sick patients, prisoners, and others incapable of providing true informed consent)
- Size, complexity, and cost of the study
- Complexity of the monitoring itself (e.g., difficult statistical questions)
Additional independent monitoring is generally expected for human subjects research involving greater than minimal risk of harm as a direct result of an intervention or as an indirect result of withholding an intervention. AHRQ policy specifies that for interventional studies with a known or anticipated risk of major events as a direct result of an intervention or as an indirect result of withholding an intervention, the data and safety monitoring plan should include the constitution of an independent, external monitoring board, generally in the form of a Data and Safety Monitoring Board (DSMB) or Data Monitoring Committee (DMC).
Principles of Monitoring Data and Safety
The principles of data and safety monitoring require that all AHRQ conducted and supported non-exempt human subjects interventional research be monitored to ensure the safe and effective conduct of human subjects research, and to recommend changes to the protocol or study termination when significant benefits or risks are identified or if it is unlikely that the research can be concluded successfully. Risks associated with participation in research must be minimized and the method and degree of monitoring should be commensurate with the degree of risk involved in participation, and the size, scope, and complexity of the research. Data and safety monitoring exists on a continuum and may be conducted in various ways using a range of monitoring options, depending on the risks, the complexity, and the nature of the human subjects interventional research.Data and Safety Monitoring Plan
A data and safety monitoring plan is a general plan contained in the research application which delineates how participant safety and data integrity will be monitored in order to ensure the safety of the subjects and the validity and integrity of the data. Monitoring the ongoing study plays an essential role in protecting the safety of participants and assuring the integrity of research. A data and safety monitoring plan articulates the procedures for the frequency of assessing study performance, subject safety, and where applicable, intervention effectiveness. Safety monitoring involves the review of accumulated outcome data for groups of study participants to determine if any of the treatment procedures and practices should be altered or stopped. A data and safety monitoring plan serves to ensure that eligible AHRQ-conducted or supported interventional research involving human subjects has a level of monitoring commensurate with its risk, and that study monitoring is an integral part of the research plan.
As noted, it is AHRQ’s policy that data and safety monitoring plans are required in all non-exempt research applications when support is sought to study the effect of a health-related intervention on outcomes in human subjects. The requirement of a data and safety monitoring plan covers career and training awards in which the trainee has direct responsibility for conducting human subjects research or in which award funds directly support a research project.
Prior to the conduct of human subjects interventional research, a detailed data and safety monitoring plan must be submitted as part of the research grant application, including a budget where applicable. This plan will undergo review at peer review and any concerns will be included as an administrative note in the peer review summary. When modifications to the data and safety monitoring plan are made before the study begins, a final monitoring plan must also be submitted to AHRQ and the local IRB.
The essential elements of a data and safety monitoring plan that should be described are:
- Entity responsible for monitoring e.g., principal investigator or a formal DSMB or DMC
- The type of data or events to be captured under the monitoring plan
- Procedures for monitoring study progress including the specifics of how monitoring the data and safety of participants will occur (addressing procedures for responding to recommendations that emanate from monitoring activities)
- Procedures for minimizing research-associated risk
- Policies and procedures for reporting unanticipated problems involving risks to subjects or others, as well as adverse events if applicable; and
- How data accuracy and protocol compliance will be assured; (For multi-site studies, procedures to ensure compliance with the monitoring plan and reporting requirements across study sites).
Monitoring plans may propose a range of monitoring options that can include the project director/principal investigator and institution; independent individual/safety officer; designated medical monitor; internal committee or board with explicit guidelines; data monitoring committee or board, with a hybrid of members external and internal to the study, or a DSMB or DMC, the latter consisting of a formal, full chartered data and safety monitoring observational committee or board external to the study wherein the members and the analysis statistician are independent of the trial.
Monitoring activities must be conducted by experts in all scientific disciplines needed to interpret the data and ensure patient safety. Interventional research (e.g., clinical trial) experts, biostatisticians, bioethicists, and clinicians knowledgeable about the disease/condition and treatment under study should be part of the monitoring group or be available if warranted.
Considerations such as who shall perform the monitoring activities, the composition of the monitoring group (if a group is to be used), details of the appointment and membership, the frequency and character of monitoring meetings (e.g., open or closed, public or private), and the frequency, content, and distribution of meeting reports, should be a part of the monitoring plans. Unanticipated problems and adverse events (if applicable), reporting forms and process, should be articulated in the data and safety monitoring plan for a DSMB (or DMC).
Roles and Responsibilities
Applicants
It is the applicants responsibility to propose and implement appropriate data and safety monitoring. Applicants must describe the data and safety monitoring plan for the proposed research involving interventions with human subjects, by providing a detailed data and safety monitoring plan in the research application, as specified in the policy.
Peer Review Groups
Scientific peer reviewers will review the data and safety monitoring plan for the proposed research and indicate its adequacy or the need for additional safeguards related to data and safety monitoring. The AHRQ scientific review officer will document the recommendations made by the scientific peer reviewers, related to data and safety monitoring.
AHRQ
AHRQ program officials will communicate with the applicant about data and safety monitoring requirements identified at the time of scientific peer review. The AHRQ program official has the responsibility of informing study investigators about the data and safety monitoring policy and procedures.
Once the research grant has been funded, the AHRQ program official will serve as a liaison between the principal investigator and AHRQ, on the implementation of the data and safety monitoring plan. The program official monitors the progress of the data and safety monitoring plan, and communicates with the principal investigator, on issues and recommendations that emanate from data monitoring activities.
How to Submit Comments
All comments on this proposed policy from the extramural community of researchers and users of AHRQ-sponsored research should be sent by e-mail to: DSMPolicyComments@ahrq.hhs.gov by 5:00 p.m. (EDT) on Thursday, September 30, 2010.
Reference:
Institute of Medicine of the National Academies. Initial National Priorities for Comparative Effectiveness Research. Report Brief. June 2009. (see http://www.iom.edu/~/media/Files/Report%20Files/2009/ComparativeEffectivenessResearchPriorities/CER%20report%20brief%2008-13-09.ashx.
and Human Services (HHS)
