NOT-99-107: GUIDANCE ON REPORTING ADVERSE EVENTS TO INSTITUTIONAL REVIEW BOARDS FOR NIH-SUPPORTED MULTICENTER CLINICAL TRIALS

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GUIDANCE ON REPORTING ADVERSE EVENTS TO INSTITUTIONAL REVIEW BOARDS FOR NIH-SUPPORTED MULTICENTER CLINICAL TRIALS Release Date: June 11, 1999 National Institutes of Health Effective July 1, all multi-site trials with data safety monitoring boards are expected to forward summary reports of adverse events to each IRB involved in the study. This action in no way reduces the responsibilities of individual IRBs to address such reports coming to them from the site over which they have responsibility. NIH program staff will ensure that this language appears in new solicitations for clinical trials and is broadly disseminated to current principal investigators with appropriate follow-up. This National Institutes of Health (NIH) document provides guidance to investigators engaged in NIH-supported multi-center clinical trials to promote effective reporting of adverse events to the appropriate IRBs. The mechanism for reporting should be optimized to protect study participants from research risks, while at the same time reducing the regulatory burden on these committees. It is recognized that multiple parties, e.g., NIH, Food and Drug Administration (FDA), or industrial sponsors, must be notified of adverse events. However, this document provides guidance specifically for IRB notification. The NIH is directing principal investigators to report adverse events by identifying the DSMB to the IRB and ensuring reports of assessments of adverse events are transmitted from the DSMB to each IRB. Background In response to a congressional request to streamline and reduce unnecessary Federal regulations that govern the conduct of extramural scientific research, the NIH recently published a report NIH Initiative to Reduce Regulatory Burden following extensive interviews and focus group meetings with the research community (http://grants.nih.gov/grants/policy/regulatoryburden/index.htm). Among the five major areas of focus, the report identified the reporting of adverse events to the IRB for multicenter clinical trials as burdensome and confusing. Some of the confusion stems from the different regulations governing the NIH and the FDA in this area. Federal regulations (45 CFR Part 46, Subpart A), shared by 17 Departments and Agencies as the Common Rule, require written procedures and policies for ensuring reporting of unanticipated problems involving risks to participants to the IRB, appropriate institutional officials, and the Department or Agency Head. Under a different set of regulations, 21 CFR 312, the FDA requires the sponsor to notify the FDA and participating investigators of any adverse event associated with the use of a test article that is both serious and unexpected. The reporting of adverse events is in addition to, and does not supplant, periodic reports to the IRB at intervals appropriate to the degree of risk in the study, generally, an annual report. Definitions The definitions and reporting requirements for adverse events differ between the two Federal regulations. The notification requirements described in the Common Rule define adverse events as unanticipated problems involving risks to study participants or others. Generally, the funding Institutes and Centers establish operational definitions of adverse events that apply to the particular trial. The National Cancer Institute (NCI), for example, defines adverse drug reactions in its clinical trials involving antineoplastic agents, as: (1) previously unknown toxicities, and (2) life-threatening or fatal toxicities regardless of whether or not previously unknown. Toxicity criteria are generally included in the protocols. The FDA, in Federal regulations 21 CFR Part 312, defines adverse events as any untoward medical occurrence that may present itself during treatment or administration with a pharmaceutical product, and which may or may not have a causal relationship with the treatment. In the guideline entitled Clinical Safety Data Management: Definitions and Standards for Expedited Reporting , the Agency further clarifies and defines serious adverse events stemming from a drug study as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, creates persistent or significant disability/incapacity, or a congenital anomaly/birth defects (http://www.fda.gov/cder/guidance/iche3.pdf). Issues For multicenter clinical trials, an IRB may receive individual adverse event reports from sites other than its own. Such off-site reports may not be presented in a useful format and duplicate reports are received, sometimes, months apart. The receipt of reports that are not aggregated (no numerators or denominators are included) and that come from disparate sources contributes to confusion and added workload of the IRB. More importantly, the format of the reports jeopardizes the IRB’s ability to make an informed judgement on the appropriate action, if any, to be taken. Investigator Responsibility An investigator is responsible for knowing the policies of the local IRB, adhering to these policies, and maintaining a copy of the policies in the study file. An investigator is also responsible for the accurate documentation, investigation and follow-up of all possible study-related adverse events. For NIH-supported multicenter clinical trials, investigators do not necessarily report these events to off- site IRBs as long as the local IRB has been notified. In lieu of receiving individual adverse event reports from each of the clinical sites, the IRBs should receive from the investigator a written summary report whenever a data safety monitoring board (DSMB) review has taken place (see below). It should be noted that these summary reports do not replace other reporting requirements to the local IRBs, e.g., annual reports. Any protocol submitted for IRB approval should both identify the DSMB (not members names), if any, that will be reviewing interim results, and include a brief description of the monitoring plan as well as procedures for transmitting the DSMB’s summary reports to the IRB. Communication between Data Safety Monitoring Board and IRB DSMBs play an essential role in protecting the safety of participants, and assuring integrity of the study. They accomplish the former by being familiar with the protocol, proposing appropriate analyses, and periodically reviewing the developing outcome and safety data. They accomplish the latter by reviewing data on such aspects as participant enrollment, site visits, study procedures, forms completion, data quality, losses to follow-up, and other measures of adherence to protocol. The Board makes recommendations based on those data, regarding appropriate protocol and operational changes. DSMBs (and the investigators) monitor toxicity and discuss any concern in this regard. The DSMB monitoring function is above and beyond the oversight traditionally provided by IRBs and as such is particularly important for multicenter trials. Typically, the study statisticians and the investigators, along with the DSMB, develop monitoring guidelines. However, for some trials, the study statisticians and the investigators develop interim monitoring guidelines that are reviewed as part of the protocol review process by the Institutes and Centers. In the recent re-issuance of the policy for data and safety monitoring (NIH Guide for Grants and Contracts, June 12, 1998), the NIH clearly addressed the need for communication between the DSMB and IRB. Once a DSMB is established, each IRB should be informed of the operating procedures with regard to data and safety monitoring (e.g., who, what, when, and how monitoring will take place). This information will serve to assure the IRB that the safety of the research participants is appropriately monitored. If the IRB is not satisfied with the monitoring procedures, it should request modifications. While it is recognized that it may not be possible to satisfy every IRB completely, IRB comments should be considered seriously. The DSMB’s summary report should provide feedback at regular and defined intervals to the IRBs. The Institutes and Centers should assure that there is a mechanism in place to distribute the report to all participating investigators for submission to their local IRB. For example, after each meeting of the DSMB, the executive secretary should send a brief summary report to each investigator. The report should document that a review of data and outcomes across all centers took place on a given date. It should summarize the Board’s review of the cumulative toxicities reported from all participating sites without specific disclosure by treatment arm. It should also inform investigators of the study the Board’s conclusion with respect to progress or need for modification of the protocol. The investigator is required to transmit the report to the local IRB. IRB Responsibilities An IRB has the authority to suspend or terminate approval of research at its site that has been associated with unexpected serious harm to participants. When an IRB takes such action, it is required to provide a statement of reasons for the action and to promptly report this action to the investigator, appropriate institutional officials, the Department or Agency head, Office for Protection from Research Risks (OPRR), and the FDA if an investigational new drug or device is involved. For studies that have a DSMB, the investigator should forward summary reports to the IRB as soon as they are received, it is within the purview of the IRB to request this information. IRBs could make reporting contingent on IRB approval for specific studies that are deemed appropriate. An IRB should communicate concerns to the DSMB and/or the Institute sponsoring the study if it believes that the safety of study participants is in jeopardy. Implementation: The NIH program staff will review multicenter clinical trials with the following expectations: A. Investigators submitting a protocol for IRB review must identify the DSMB involved, if any. They must describe plans for monitoring adverse events. B. Investigators must submit a written summary of DSMB periodic review to their IRB. C. When a study is conducted in multiple sites, the funding Institutes and Centers must assure that there is a mechanism in place to distribute the report to all participating investigators for submission to their local IRBs.

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