Notice Number: NOT-HS-11-015
Key Dates
Release Date: May 6, 2011
Issued by
Agency for Healthcare Research and Quality (see http://www.ahrq.gov)
Purpose
BackgroundAHRQ’s mission is to improve the quality, safety, efficiency, and effectiveness of health care 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 patient-centered outcomes research to identify what works for which patients under which circumstances, and behavioral and social sciences research involving interventions with human subjects.
Purpose and Scope
This policy notice sets forth the requirements for data and safety monitoring (DSM) for Agency for Healthcare Research and Quality (AHRQ)-conducted or -supported research involving interventions with human subjects where there is a greater than minimal risk (45 CFR 46.102), to ensure the safety of participants and the validity and integrity of the data. 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.
AHRQ policy specifies that a proposed DSM plan must be submitted as part of the research strategy section in the grant application or the technical approach for a contract application. Further the DSM plan must be approved by the institutional review board (IRB) prior to the conduct of research involving interventions with human subjects where there is a greater than minimal risk. Effective with its publication, this policy is incorporated as part of the terms and conditions for all new awards. Release of funds for research activities is contingent upon compliance with AHRQ’s DSM policy.
In developing this policy, AHRQ solicited public comment by publishing the draft policy in the National Institutes of Health (NIH) Guide (see https://grants.nih.gov/grants/guide/notice-files/NOT-HS-10-019.html). This policy notice is informed by the comments the Agency received.
AHRQ Data and Safety Monitoring 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 (Refer to the revised definition of human subjects, 45 CFR Part 46 at https://www.hhs.gov/ohrp/regulations-and-policy/regulations/revised-common-rule-regulatory-text/index.html). As such, all human subjects research must be approved by an institutional review board (IRB) for compliance with safety, privacy, and other requirements relevant to the review and reporting of unanticipated problems and adverse events (see http://www.hhs.gov/ohrp/policy/AdvEvntGuid.pdf). Such research must be monitored at least annually as part of continuing review by IRBs.
It is AHRQ’s policy that DSM should be an essential component of all AHRQ-conducted or supported non-exempt research involving interventions with human subjects where there is a greater than minimal risk, to ensure the safety of participants and the validity and integrity of the data. In this context, a DSM plan must be described as part of the research strategy in the research grant application or the technical approach for a contract application. The DSM plan should address the potential for harm as a direct result of the proposed intervention, or as an indirect result of withholding the intervention. 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. The plan should further specify the method and degree of oversight and monitoring that are commensurate with the risk of harm for participating subjects, as described by the applicant.
Data and Safety Monitoring Plan
It is AHRQ’s policy that DSM 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 where there is greater than minimal risk.
A DSM plan is a general plan described in the research strategy section of the research application that 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 DSM plan articulates the procedures for the frequency of assessing study performance, subject safety, and where applicable, intervention effectiveness. Safety monitoring then 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 DSM 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.
Review and comment on the adequacy of the research application’s DSM plan will be a component of the scientific peer review and any concerns will be included as an administrative note in the peer review summary.
Considerations such as who shall perform the monitoring activities, the composition and independence of the monitoring entity (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 any DSM plan.
Examples of monitoring options that may be proposed in the plan include the project director/principal investigator and institution; independent individual/safety officer; designated medical monitor; internal data monitoring committee, or a data and safety monitoring board (DSMB).
Monitoring entities must include expertise in relevant scientific disciplines needed to interpret the data and ensure participant 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 entity or be available if needed.
Applicants should describe the following elements of a DSM plan as part of the research strategy:
- The monitoring entity or individual(s) responsible for monitoring the study;
- 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, e.g., study stopping rules );
- Procedures for mitigating research-associated risk;
- Policies and procedures for identifying, reviewing, and reporting unanticipated problems involving risks to subjects or others, and adverse events, if applicable (http://www.hhs.gov/ohrp/policy/AdvEvntGuid.pdf);
- Investigators on AHRQ-conducted or supported health services research are required to report unanticipated problems involving risks to subjects or others, to the Institutional Review Board (IRB), appropriate institutional officials, AHRQ, and the HHS Office for Human Research Protections (OHRP), see 45 CFR Part 46.
- 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. The reporting of adverse events will be done per FDA regulations; and
- 45 CFR part 46, which applies to all AHRQ-conducted or -supported health services research, does not require that HHS be informed of adverse events but instead requires the reporting of unanticipated problems to the IRB and the department or agency head (and OHRP). The reporting of adverse events is referenced in FDA regulations, but not all AHRQ studies will be FDA regulated (DHHS-Office of General Counsel, 2009). For further information please refer to guidance provided by the Office for Human Research protections at http://www.hhs.gov/ohrp/policy/advevntguid.html.
- How protocol compliance will be assured; (For multi-site studies, procedures to ensure compliance with the monitoring plan and reporting requirements across study sites).
A DSM plan must be submitted to the applicant’s IRB for approval prior to the accrual of human subjects. When modifications to the DSM plan are made before the study begins, a final monitoring plan must also be submitted to the IRB of record and to AHRQ.
Inquiries
Questions regarding this Notice should be directed to: Hope Hongzhu He
Office of Extramural Research, Education, and Priority Populations (OEREP)
Agency for Healthcare Research and Quality (AHRQ)
301-427-1905
Hopehongzhu.he@ahrq.hhs.gov
References
DeMets DL, Furberg CD, Friedman LM, Monitoring Committees: Why and How. In Data Monitoring in Clinical Trials. A Case Studies Approach. Eds: David L. DeMets, Curt D. Furberg, Lawrence M. Friedman, 2006 Springer Science+Business Media, Inc.
Ellenberg SS, Fleming TR, DeMets DL. Data monitoring committees in clinical trials: a practical perspective. John Wiley & Sons, 2002.
Healthcare Research and Quality Act of 1999, http://www.ahrq.gov/hrqa99a.htm.
SCT Working Group on Data Monitoring: Dixon DO, Freedman RS, Jay Herson J, Hughes M, Kyung Mann Kim, Silverman MH, and Tangen CM. Guidelines for data and safety monitoring for clinical trials not requiring traditional data monitoring committees. Clinical Trials 2006; 3: 314 319.
U.S. Department of Health and Human Services Public Health ServiceSF424 (R&R) Application Guide for NIH and Other PHS Agencies. PART II Supplemental Instructions for Preparing the Human Subjects Section of the Research Plan Updated November 24, 2010; (see https://grants.nih.gov/grants/funding/424/SF424_RR_Guide_General_Adobe_VerB.pdf. Accessed February 7, 2011.
U.S. Department of Health and Human Services, Office for Human Research Protections (OHRP) Federal Policy for the Protection of Human Subjects Code of Federal Regulations, TITLE 45 PUBLIC WELFARE; (see http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html. Accessed February 7, 2011.
Definitions
Adverse Event: As defined by the Office for Human Research Protections (see OHRP), an adverse event is any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research. Adverse events encompass both physical and psychological harms.
Data and Safety Monitoring Board: A DSMB is a board that is external to the study wherein the members and the analysis statistician are independent of the research.
Minimal Risk: As defined in 45 CFR 46.102, minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered by the research population in daily life or during the performance of routine physical or psychological examinations or tests.
Program Official: The AHRQ staff member responsible for the programmatic, scientific, and/or technical aspects of a grant. Note that this title is most frequently used to refer to the scientific or technical representative for grants, but the generic program official term also may refer to a Project Officer if the funding mechanism is a contract.
Project Officer: The AHRQ staff member designated as a Contracting Officer’s technical representative to coordinate the substantive aspects of an acquisition from its development through to contract award and administration.
Unanticipated Problem: According to OHRP, unanticipated problems generally include any incident, experience, or outcome that meets all of the following criteria:
1. unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied;
2. related or possibly related to participation in the research (in this guidance document, possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and
3. suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.
and Human Services (HHS)
