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Fundamentals of Clinical Trials pp 215–231Cite as

Assessing and Reporting Adverse Events

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Abstract

There is no perfectly safe intervention. All treatments result in some adverse events. Their severity ranges from mild symptoms to life-threatening events. Collection of adverse event data in randomized clinical trials is a regulatory requirement and additionally, clinically and scientifically important. The challenge is to know what and how to collect these data, the frequency of collection, and how to deal with small numbers of serious events. There are also potential legal issues to consider, which tend to lead to an over-collection of safety data. On the other hand, there is a marked underreporting of safety information in the published literature. A review of 192 large clinical trials from seven therapeutic areas revealed that the safety reporting was considered adequate in only 39% of the articles [1].

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References

  1. Ioannidis JPA, Lau J. Completeness of safety reporting in randomized trials: an evaluation of 7 medical areas. JAMA 2001;285:437–443.

    Article  Google Scholar 

  2. Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 1971;284:878–881.

    Article  Google Scholar 

  3. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton: PSG Publishing Company, 1977, pp. 1–7.

    Google Scholar 

  4. Meador KJ, Baker GA, Browning N, et al. for the NEAD Study Group. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009;360:1597–1605.

    Article  Google Scholar 

  5. McBride WG: Thalidomide and congenital malformations. Lancet 1961;ii:1358.

    Article  Google Scholar 

  6. Bombardier C, Laine L, Reicin A, et al. for the VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520–1528.

    Article  Google Scholar 

  7. Bresalier RS, Sandler RS, Quan H, et al. for the Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352:1092–1102.

    Article  Google Scholar 

  8. Solomon SD, McMurray JJV, Pfeffer MA, et al. for the Adenoma Prevention with Celecoxib (APC) Study Investigators. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1071–1080.

    Article  Google Scholar 

  9. Psaty BM, Furberg CD. COX-2 inhibitors – lessons in drug safety. N Engl J Med 2005;352:1133–1135.

    Article  Google Scholar 

  10. Fergusson D, Doucette S, Glass KC, et al. Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials. Br Med J 2005;330: 396–399. doi:10.1136/bmj.330.7488.396 (published 19 February 2005).

    Article  Google Scholar 

  11. US General Accounting Office. FDA Drug Review: Postapproval Risks, 1976–85. Washington, DC: US General Accounting Office, April 26, 1990, GAO/PEMD-90-15.

    Google Scholar 

  12. Singh S, Loke YK, Furberg CD. Thiazolidinediones and heart failure. Diabetes Care 2007;30:2141–2153.

    Article  Google Scholar 

  13. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007;298:1189–1195.

    Article  Google Scholar 

  14. Loke YK, Singh S, Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ 2009;180:32–39.

    Article  Google Scholar 

  15. Fong DS, Contreras R. Glitazone use associated with diabetic macular edema. Am J Ophthalmol 2009;147:583–586.

    Article  Google Scholar 

  16. Furberg BD, Furberg CD. Evaluating Clinical Research. All that Glitters is Not Gold (2nd edition). New York, NY: Springer, 2007, pp. 17–18.

    Book  MATH  Google Scholar 

  17. Venning GR. Identification of adverse reactions to new drugs. II: How were 18 important adverse reactions discovered and with what delays? Br Med J 1983;286:289–292 and 365–368.

    Article  Google Scholar 

  18. Aronson JK, Derry S, Loke YK. Adverse drug reactions: keeping up to date. Fundam Clin Pharmacol 2002;16:49–56.

    Article  Google Scholar 

  19. Vandenbroucke JP, Psaty BP. Benefits and risks of drug treatments. How to combine the best evidence on benefits with the best data about adverse effects. JAMA 2008;300:2417–2419.

    Article  Google Scholar 

  20. Committee on the Assessment of the US Drug Safety System. Baciu A, Stratton K, Burke SP (eds.). The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press, 2006.

    Google Scholar 

  21. Furberg CD, Levin AA, Gross PA, et al. The FDA and drug safety. A proposal for sweeping changes. Arch Intern Med 2006;166:1938–1942.

    Article  Google Scholar 

  22. MedDRA and the MSSO. http://www.meddramsso.com/MSSOWeb/index.htm.

  23. Aspirin Myocardial Infarction Study Research Group. A randomized, controlled trial of aspirin in persons recovered from myocardial infarction. JAMA 1980;243:661–669.

    Article  Google Scholar 

  24. Downing RW, Rickels K, Meyers F. Side reactions in neurotics: 1. A comparison of two methods of assessment. J Clin Pharmacol 1970;10:289–297.

    Google Scholar 

  25. Romanowski B, Gourlie B, Gynp P. Biased adverse effects? N Engl J Med 1988;319:1157–1158.

    Google Scholar 

  26. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986.

    Article  Google Scholar 

  27. Baron JA, Sandler RS, Bresalier RS, et al. Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial. Lancet 2008;372:1756–1764.

    Article  Google Scholar 

  28. Ioannidis JPA. Adverse events in randomized trials. Neglected, restricted, distorted, and silenced. Arch Intern Med 2009;169:1737–1739.

    Article  Google Scholar 

  29. Ioannidis JPA, Evans SJ, Gøtzsche PC, et al. for the CONSORT Group. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med 2004;141:781–788.

    Article  Google Scholar 

  30. Pitrou I, Boutron I, Ahmad N, Ravaud P. Reporting of safety results in published reports of randomized controlled trials. Arch Intern Med 2009;169:1756–1761.

    Article  Google Scholar 

  31. Department of Health and Human Services, Food and Drug Administration: International Conference on Harmonisation; Guideline on clinical safety data management: Definitions and standards for expedited reporting, Notice. Federal Register 60 (1 March 1995):11284–11287.

    Google Scholar 

  32. Department of Health and Human Services, Food and Drug Administration. International Conference on Harmonisation; Draft guidance on E2D postapproval safety data management: Definitions and standards for expedited reporting, Notice. Federal Register 68 (15 September 2003):53983–53984.

    Google Scholar 

  33. U.S. Department of Health and Human Services. Food and Drug Administration. Guidance for Industry. Premarketing risk assessment. March 2005. www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm126958.pdf.

  34. U.S. Department of Health and Human Services. Food and Drug Administration. Guidance for Industry. Good pharmacovigilance practices and pharmacoepidemiologic assessment. March 2005. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126834.pdf.

  35. U.S. Department of Health and Human Services. Food and Drug Administration. Reviewer Guidance. Conducting a clinical safety review of a new product application and preparing a report on the review. March 2005. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072974.pdf.

  36. Papanikolaou PN, Christidi GD, Ioannidis JPA. Comparison of evidence on harms of medical interventions in randomized and nonrandomized studies. CMAJ 2006;174:635–641.

    Article  Google Scholar 

  37. Multiple Risk Factor Intervention Trial Research Group. Baseline rest electrocardiographic abnormalities, antihypertensive treatment, and mortality in the Multiple Risk Factor Intervention Trial. Am J Cardiol 1985;55:1–15.

    Article  Google Scholar 

  38. Siscovick DS, Raghunathan TE, Psaty BM, et al. Diuretic therapy for hypertension and the risk of primary cardiac arrest. N Engl J Med 1994;330:1852–1857.

    Article  Google Scholar 

  39. Psaty BM, Furberg CD, Ray WA, Weiss NS. Potential for conflict of interest in the evaluation of suspected adverse drug reactions: use of cerivastatin and risk of rhabdomyolysis. JAMA 2004;292:2622–2631.

    Article  Google Scholar 

  40. Golder S, Loke YK. Is there evidence for biased reporting of published adverse effects data in pharmaceutical industry-funded studies? Br J Clin Pharmacol 2008;66:767–773.

    Article  Google Scholar 

  41. Ross JS, Madigan D, Hill KP, et al. Pooled analysis of rofecoxib placebo-controlled clinical trial data. Lessons for postmarket pharmaceutical safety surveillance. Arch Intern Med 2009;169:1976–1984.

    Article  Google Scholar 

  42. Hennekens CH, DeMets D. The need for large-scale randomized evidence without undue emphasis on small trials, meta-analyses, or subgroup analyses. JAMA 2009;302:2361–2362.

    Article  Google Scholar 

  43. Balkrishnan R, Furberg CD. Developing an optimal approach to global drug safety. J Intern Med 2001;250:271–279.

    Article  Google Scholar 

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Author information

Authors and Affiliations

  1. Bethesda, MD, USA

    Lawrence M. Friedman

  2. School of Medicine, Wake Forest University, Winston-Salem, NC, USA

    Curt D. Furberg

  3. Department of Biostatistics & Medical Informatics, University of Wisconsin, Madison, WI, USA

    David L. DeMets

Authors
  1. Lawrence M. Friedman
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  2. Curt D. Furberg
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  3. David L. DeMets
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Correspondence to Lawrence M. Friedman .

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© 2010 Springer New York

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Friedman, L.M., Furberg, C.D., DeMets, D.L. (2010). Assessing and Reporting Adverse Events. In: Fundamentals of Clinical Trials. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1586-3_12

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