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Tracking adverse events in RCTs: lack of agreement among regulatory institutions
  1. L M Santiago,
  2. S M Debanne,
  3. D Neuhauser
  1. Department of Epidemiology and Biostatistics, Medical School, Case Western Reserve University, Cleveland, Ohio 44106-4945, USA
  1. Correspondence to:
 Dr L M Santiago, Epidemiology and Biostatistics, Medical School, Case Western Reserve University, Cleveland, Ohio 44106-4945, USA;

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We need to do a better job of keeping track of potential side effects when designing randomized clinical trials (RCTs). Consider an RCT for a new drug tested for the main or first order effect—the reduction of hypertension. Power calculations are carried out so that meaningful differences between the drug users and the controls can be detected on this effect. Second order effects—in this case, mortality—are those adverse events that are prospectively tracked, recorded, planned for in advance and, if sufficiently serious, may bring the trial to a halt through review conducted by a Data Safety Monitoring Board. Too rarely are there systematic prospective efforts to collect information on other unpredicted effects of the drug being tested. These third order effects may be important but are rare and unexpected and are not therefore necessarily sought out, so systematic data on them are not prospectively collected. This problem of failing to track such third order events is vividly shown in the recent article about Bruce Psaty and his recognition of the third order side effects related to the use of calcium channel blockers.1

Although the US Food and Drug Administration (FDA) and other Government agencies have systems in place for the post-marketing reporting of possible side effects, this surveillance is passive in nature and relies mainly on the judgment of practitioners to suggest whether or not a patient's complaint is related to the drug in question. This creates an inherent underreporting of side effects. It also assumes that everyone has the same access to health care or that, by the time the complaint is reported, there is enough time to avoid serious complications in other patients.

The US National Institutes of Health (NIH) and the World Health Organization (WHO) are aware of these issues. NIH guidelines appear to be focused on multicenter clinical trials; the definition of adverse events is less well characterized for single center trials. Furthermore, the definition of an adverse event, while in compliance with the FDA regulations, is somewhat broad or vague. For example, the federal regulation requires the reporting of adverse events that are “serious and unexpected”. This term could be interpreted differently. Does the event in question need to be both serious and unanticipated by the investigator? What about unanticipated effects regardless of the seriousness? How serious? Are events that are costly to a patient in terms of productive time, money, or psychological damage considered serious? A summary of the NIH Institutes and their guidelines and websites is shown in table 1.

This lack of uniformity and clarity is not peculiar to the USA. Some international institutions rely on the WHO to establish their adverse reporting mechanism standards. In their guidelines for good clinical practice (GCP) for trials on pharmaceutical products the WHO states that the investigator is “ . . .responsible for notifying (with documentation) the relevant health authorities, the sponsor and, when applicable, the ethics committee immediately in the case of serious adverse events or reactions, as governed by national regulations . . .”. This statement contains little guidance as to who is the relevant authority, what documentation to use, and under what circumstances the established ethical committee should be involved. Furthermore, the statement “as governed by national regulations” does not clearly assign responsibility for the reporting of adverse events, especially in situations when one nation is conducting medical trials in another country. Moreover, the WHO falls short in suggesting any type of analyses for the examination of possible population wide repercussions.2

Countries in Central and South America basically follow the guidance of the WHO through the Pan-American Health Organization (PAHO). In England and Australia, information about adverse events, especially if observed after the trials and/or the medication is on the open market, is not easily accessible.

We think there should be more clarity and uniformity in these guidelines and that all guidelines should be accessible through the internet or some other form of common global communication to the scientific community. Furthermore, investigators and agencies alike should be aware of studies reporting adverse events. These reporting mechanisms should have direct relationship with post marketing surveillance efforts.3,4

Table 1

Procedures for monitoring adverse events for USA NIH Institutes


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