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• Postmarketing surveillance for adverse drug effects
  Richard A. Deyo
  Published on: 1 April 2003
• Tracking adverse events in randomize control trials the lack of agreement among regulatory instituti
  Luis Manuel Santiago
  Published on: 26 March 2003

• Published on: 1 April 2003

  Postmarketing surveillance for adverse drug effects

  • Richard A. Deyo, Professor of Medicine

  Dear Editor

  Doctors Santiago, Debanne, and Neuhauser correctly point out the frequent deficiencies in post-marketing surveillance of newly marketed drugs.[1] Because of aggressive marketing to physicians and direct-to- consumer advertising in the US, a new drug can now have very rapid dissemination, exposing large populations in a short time. Passive surveillance with ambiguous definitions of adverse effects may ofte...

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  Dear Editor

  Doctors Santiago, Debanne, and Neuhauser correctly point out the frequent deficiencies in post-marketing surveillance of newly marketed drugs.[1] Because of aggressive marketing to physicians and direct-to- consumer advertising in the US, a new drug can now have very rapid dissemination, exposing large populations in a short time. Passive surveillance with ambiguous definitions of adverse effects may often impair early identification of serious problems. I agree with the recommendations of Santiago et al. for better and more consistent guidelines for drug surveillance.

  Santiago et al. also correctly note that drug trials with efficacy end points rarely have sufficient statistical power to identify unusual adverse drug effects. This may argue for wider use of observational study designs, such as the case-control method used by Psaty et al, to help identify important drug complications after marketing. As in the case of the calcium channel blockers, such observatonal designs may also help to estimate drug effects on important but infrequent end results of treatment (e.g. myocardial infarction or death), when the primary efficacy trials were focused on surrogate endpoints such as blood pressure.

  Reference

  (1) Santiago LM, Debanne SM, Neuhauser D. Tracking adverse events in randomize control trials the lack of agreement among regulatory instituti [electronic response to Deyo RA, Bruce Psaty and the risks of calcium channel blockers] qshc.com 2003 http://qhc.bmjjournals.com/cgi/eletters/11/3/294#25

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  Conflict of Interest:
  None declared.

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• Published on: 26 March 2003

  Tracking adverse events in randomize control trials the lack of agreement among regulatory instituti

  • Luis Manuel Santiago, Biostatistician
  • Other Contributors:
    • S M Debanne, D Neuhauser

  Dear Editor

  We need to do a better job of keeping track of potential side effects when designing randomized clinical trials (RCTs). Consider a 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, mortality in this case, a...

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  Dear Editor

  We need to do a better job of keeping track of potential side effects when designing randomized clinical trials (RCTs). Consider a 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, mortality in this case, 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 thus not necessarily sought out and consequently systematic data are not necessarily prospectively collected about them. This problem of falling to track such third order events is vividly shown in the recent article about Bruce Psaty and his recognition of the 3rd order side effects related to the use of calcium channel blockers [1].Although the United State of America 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 inherited 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 USA National Institutes of Health (NIH) and the World Health Organization (WHO) are aware of these issues. NIH guidelines appear to be focused on multi-center clinical trials. The definition of adverse events 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? See Table 1 for a summary of the NIH Institutes and their guidelines and their web sites.

  This lack of uniformity and clarity is not particular to the United States. Some international institutions rely on the World Health Organization (WHO) to establish their adverse reporting mechanism standards. The WHO in their Guidelines for good clinical practice (GCP) for trials on pharmaceutical products, 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, countries that have a comprehensive system of health care, information about adverse events, especially if observed after the trials and/or the medication is in the open market, is not easily accessible.

  We think there should be more clarity and uniformity in these guidelines and 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

  Agency 1	Procedure	Web site
  NIH	General guidelines for all Institutes and Centers (IC). Requires establishment of Data Safety Monitoring Boards (DSMB) for multi-site clinical trials. Gives each IC the ability to establish its own procedures.	http://grants1.nih.gov/grants/guide/index.hml/
  NCI	Follows general NIH guidelines. Additionally, defines" adverse events" and gives categories for severity and attribution of such events	http://ctep.info.nih.gov.
  NEI	Follows general NIH guidelines.	http://wwwt.nei.nih.gov/funding/policy6.htm.
  NHLBI	Follows general NIH guidelines. Specifies situations where PI submits safety monitoring plans.	http://rover2.nhlbi.nih.gov/policies
  NHGRI	Issue does not appear to be specifically addressed	http://www.nhgri.nih.gov/
  NIA	Follows general NIH guidelines.	http://www.nia.nih.gov/funding/policies/gfunding.html#data
  NIAAA	Issue does not appear to be specifically addressed	http://www.niaaa.nih.gov/
  NIAID	Gives guidelines for DSMBs	http://www.niaid.nih.gov/dmid/clinresearch/dsm.htm
  NIAMS	Follows general NIH guidelines.	http://www.niams.nih.gov/rtac/clinical/safe_monitoring_plan.htm
  NIBIB	Issue does not appear to be specifically addressed	http://www.nibib1.nih.gov/
  NICHD	Follows general NIH guidelines	http://www.nichd.nih.gov/funding/datasafety.htm
  NIDCD	Follows general NIH guidelines.	http://www.nidcd.nih.gov/funding/clinical/clin_policy.htm
  NIDCR	Follows general NIH guidelines.	http://www.nidr.nih.gov/research/
  NIDDK	Follows general NIH guidelines. Additionally, defines "adverse events" and gives categories for severity, attribution, action taken and outcome of such events.	http://www.niddk.nih.gov/patient/patient.htm#policy
  NIDA	Gives detailed guidelines for DSMBs	http://www.nida.nih.gov/Funding/DSMBSOP.html
  NIEHS	Follows general NIH guidelines.	http://www.niehs.nih.gov/dert/clinsafe.htm
  NIGMS	Follows general NIH guidelines	http://www.nigms.nih.gov/
  NIMH	Gives detailed guidelines for DSMBs	http://www.nimh.nih.gov/research/safetymonitoring.cfm
  NINDS	Institute appoints Performance and Safety Monitoring Boards	http://www.ninds.nih.gov/funding/ninds_patient_safety_guidelines.htm
  NINR	Issue does not appear to be specifically addressed	http://www.nih.gov/ninr/

  1: NIH: National Institutes of Health; NCI: National Cancer Institute; NEI: National Eye Institute; NHLBI: National Heart, Lung and Blood Institute; NHGRI: National Human Genome Research Institute; NIA: National Institute on Aging; NIAAA: National Institute on Alcohol Abuse and Alcoholism; NIAID: National Institute of Allergy and Infectious Diseases; NIAMS: National Institute of Arthritis and Musculoskeletal Diseases; NIBIB: National Institute of Biomedical Imaging and Bioengineering; NICHD: National Institute of Child Health and Human Development; NIDCD: National Institute on Deafness and Other Communication Disorders; NIDCR: National Institute of Dental and Craniofacial Research; NIDDK: National Institute of Diabetes and Digestive and Kidney Diseases; NIDA: National Institute on Drug Abuse; NIEHS: National Institute of Environmental Health Sciences; NIGMS: National Institute of General Medical Sciences; NIMH: National Institute of Mental Health; NINDS: National Institute of Neurological Diseases and Stroke; NINR: National Institute of Nursing Research.

  References (1) Deyo RA. Bruce Psaty and the risks of calcium channel blockers. Qual Saf Health Care 2002 11(3): 294-6.

  (2) WHO. Guidelines for good clinical practice (GCP) for trials on pharmaceutical products. 1995. p. Annex 3.

  (3) Begg C et al. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. .JAMA 1996. 276(8):637-9.

  (4) Tramer MR et al. Quantitative estimation of rare adverse events which follow a biological progression: a new model applied to chronic NSAID use. Pain 2000. 85(1-2):169-82.

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  Conflict of Interest:
  None declared.

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