This seemingly simple concept has led to a welter of both confusion and paperwork currently besieging both investigators and IRBs. Many trials of new drugs take place at 100 or more centers nationwide. Many trials involve new treatments for serious diseases such as advanced cancer or AIDS. In this context, the number of serious events reported is often staggering - a recent week brought 39 separate reports about adverse events from a single trial of an AIDS drug. Added to the volume of reports is the inconsistency between the requirements imposed by the National Institutes of Health and the FDA for reporting adverse events.

The notification requirements described in 45 CFR PART 46 "Protection of Human Subjects", followed by the NIH, 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 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

The criterion used by NIH is both broader and more variable than that used by FDA. In many cases, as when NIH funds a multi-center trial of a new drug, both rules apply. This means that in many cases, any and all reactions to the drug, whether serious or not, and whether unexpected or not, are reported individually to all investigators and all IRB's involved in the trial.

In a notice, NIH Guidance on Reporting Adverse Events to IRBs , published June 11, 1999, the National Institutes of Health seeks to reduce the burden on investigators and local IRBs for reviewing, interpreting and documenting the plethora of adverse event reports they receive from other sites. To do this, they will rely on summary reports of the trial's Data Safety Monitoring Board (DSMB). Most multi-center clinical trials have a DSMB that periodically reviews the developing outcome and safety data. DSMBs monitor toxicity and discuss any concern in this regard. They also review 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 DSMB makes recommendations based on those data regarding appropriate protocol and operational changes.

Under the new procedure, individual investigators will not be required to forward separate adverse event reports originating at other sites to their local IRBs. Instead, investigators are expected to forward periodic summary reports issued by the study's DSMB, which will incorporate adverse event information from all sites. The report will document that a review of data and outcomes across all centers took place on a given date, and will summarize the DSMB's review of the cumulative toxicities reported from all participating sites. It will also inform investigators about the DSMB's conclusion with respect to need for modification of the protocol. The investigator is required to transmit the report to the local IRB.

This streamlined process does not relieve the investigator of the duty to promptly report all serious and unexpected adverse events which take place at his/her own site to the local IRB as well as to the study sponsor. It will, however, give both investigator and the IRB a context in which to judge off-site adverse events and will relieve both of a growing paperwork burden.

See Also:
D-IV.b. Adverse Event Report Form