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Fundamentals of Clinical Trials pp 255–277Cite as

Assessment and Reporting of Harm

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Abstract

Assessment of harm is more complex than the assessment of benefit of an intervention. The measures of favorable effects are or should be prespecified in the protocol and they are limited in number. In contrast, the number of adverse events is typically very large and they are rarely prespecified in the protocol. Some may not even be known at the time of trial initiation. These facts introduce analytic challenges.

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References

  1. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Clinical Safety Data Management: Definition and Standards for Expedited Reporting E2A, October 27, 1994.

    Google Scholar 

  2. United States Code, Code of Federal Regulations 21 CFR 314.80(a) Postmarketing reporting of adverse drug experiences. Definitions.

    Google Scholar 

  3. 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 

  4. 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 

  5. 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 

  6. 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 

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

    Article  Google Scholar 

  8. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-2471.

    Article  Google Scholar 

  9. Food and Drug Administration. FDA briefing document: advisory committee meeting for NDA 21071 Avandia (rosiglitazone maleate) tablet July 13 and 14, 2010. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetEndocrinologicandMetabolicDr/UCM218493.pdf.

  10. Nissen SE. Rosiglitazone: a case of regulatory hubris. The FDA’s defensiveness over its decisions means further drug safety disasters may occur. BMJ 2013;347:f7428.

    Google Scholar 

  11. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-1151.

    Article  Google Scholar 

  12. Moore TJ, Cohen MR, Furberg CD. Quarterwatch 2012 Quarter 2. www.ismp.org/quarterwatch/pdfs/2012Q2.pdf

  13. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013;369:1206-1214.

    Article  Google Scholar 

  14. Frank C, Himmelstein DU, Woolhandler S, et al. Era of faster FDA drug approval has also been increased black-box warnings and market withdrawal. Health Affair 2014;33:1453-1459.

    Article  Google Scholar 

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

    Google Scholar 

  16. 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.

    Google Scholar 

  17. Moore TJ, Singh S, Furberg CD. The FDA and new safety warnings. Arch Intern Med 2012;172:78-80.

    Article  Google Scholar 

  18. 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 

  19. Guideline for Industry: The extent of population exposure to assess clinical safety for drugs intended for long-term treatment of non-life-threatening conditions. International Conference on Harmonization, Geneva, March 1995.

    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. 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 

  23. 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 

  24. 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 

  25. 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 

  26. www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm

  27. Introductory Guide MedDRA Version 16.1. Maintenance and Support Services Organization, Chantilly (MSSO), VA, 2013.

    Google Scholar 

  28. Introductory Guide for Standardised MedDRA Queries (SMQs) Version 16.1. MedDRA Maintenance and Support Services Organization (MMSSO), Chantilly, VA, 2013.

    Google Scholar 

  29. NCI Guidelines for Investigators. http://ctep.cancer.gov.

  30. 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 

  31. Lee K, Lee Y, Nam J, et al. Antidepressant-induced sexual dysfunction among newer antidepressants in a naturalistic setting. Psychiatry Investig 2010;7:55-59.

    Article  Google Scholar 

  32. Dalle Vedove C, Simon JC, Girolomoni G. Drug-induced lupus erythematosus with emphasis on skin manifestations and the role of anti-TNFα agents. J Dtsch Dermatol Ges 2012;10:889-897.

    Google Scholar 

  33. 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 

  34. Beasley N, Thompson, A. Clinical Review of NDA 022-512 Dabigatran (Pradaxa), August 24, 2010. (Amended October 17, 2010). US Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD, page 42.

    Google Scholar 

  35. Ahmed I, Dalmasso C, Haramburu F, et al. False discovery rate estimation for frequentist pharmacovigilance signal detection methods. Biometrics 2010;66:301-309.

    Article  MathSciNet  Google Scholar 

  36. Singh S, Loke YK, Furberg C. Thiazolidinediones and heart failure: A teleo-analysis. Diabetes Care 2007;30:2148-2153.

    Article  Google Scholar 

  37. Loke YK, Singh S, Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a systematic review and meta-analysis. CMAJ 2009;180:32-29

    Article  Google Scholar 

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

    Article  Google Scholar 

  39. 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 

  40. 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 

  41. Moher D, Schulz KF, Altman DG, for the CONSORT Group. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 2001;357:1191-1194.

    Google Scholar 

  42. 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.

    Google Scholar 

  43. 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 

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

    Article  Google Scholar 

  45. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c332.

    Article  Google Scholar 

  46. 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 

  47. 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 

  48. 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.

  49. 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.

  50. 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.

  51. European Medicines Agency, ICH Topic E 2 A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. European Medicines Agency, London, UK. June 1995.

    Google Scholar 

  52. Gøtzsche PC. Why we need easy access to all data from all clinical trials and how to accomplish it. Trials 2011;12:249.

    Article  Google Scholar 

  53. Boulton G, Rawlins M, Vallance P, Walport M. Science as a public enterprise: the case for open data. Lancet 2011;377:1633-1635.

    Article  Google Scholar 

  54. Loder E. Sharing data from clinical trials. Where we are and what lies ahead. BMJ 2013;347:f4794.

    Google Scholar 

  55. Mello MM, Francer JK, Wilenzick M, et al. Preparing for responsible sharing of clinical trial data. N Engl J Med 2013;369:1651-1658.

    Article  Google Scholar 

  56. Zarin DA. Participant-level data and the new frontier in trial transparency. N Engl J Med 2013;369:468-469.

    Article  Google Scholar 

  57. Eichler H-G, Pétavy F, Pignatti F, Rasi G. Access to patient-level data—a boon to drug developers. N Engl J Med 2013;369:1577-1579

    Article  Google Scholar 

  58. Krumholz HM, Peterson ED. Open access to clinical trials data. JAMA 2014;312:1002-1003.

    Article  Google Scholar 

  59. Wellcome Trust. Sharing research data to improve public health: full joint statement by funders of health research. 2011. http://www.wellcome.ac.uk/About-us/Policy/Spotlight-issues/Data-sharing/Public-health-and-epidemiology/WTDV030690.htm.

  60. PhRMA (Pharmaceutical Research and Manufacturers of America) and EFPIA (European Federation of Pharmaceutical Industries and Associations). Principles for responsible clinical trial data sharing: Our commitment to patients and researchers. 2013. http://phrma.org/sites/default/files/pdf/PhRMA PrinciplesForResponsibleClinicalTrialDataSharing.pdf.

  61. Nisen P, Rockhold F. Access to patient-level data from GlaxoSmithKline clinical trials. N Engl J Med 2013;369:475-478.

    Article  Google Scholar 

  62. NIH (National Institutes of Health). Final NIH statement on sharing research data. 2003. http://grants.nih.gov/grants/policy/data_sharing.

  63. IOM. Sharing clinical research data: Workshop summary. 2013. Washington, DC: The National Academies Press.

    Google Scholar 

  64. Godlee, F, Groves T. The new BMJ policy on sharing data from drug and device trials. BMJ 2012;345:1-3.

    Article  Google Scholar 

  65. Institute of Medicine Committee on Strategies for Responsible Sharing of Clinical Trial Data. Sharing clinical trial data: maximizing benefits, minimizing risk. Washington, D.C.: The National Academies Press, 2015.

    Google Scholar 

  66. Lester J, Neyarapally GA, Lipowski E, et al. Evaluation of FDA safety-related drug label changes in 2010. Pharmacoepidemiol Drug Saf 2013;22:302-305.

    Article  Google Scholar 

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Author information

Authors and Affiliations

  1. North Bethesda, MD, USA

    Lawrence M. Friedman

  2. Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Curt D. Furberg

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

    David L. DeMets

  4. Department of Biostatistics, Wake Forest School of Medicine, Winston-Salem, NC, USA

    David M. Reboussin

  5. Department of Medicine, Duke University, Durham, NC, USA

    Christopher B. Granger

  6. Institute for Safe Medication Practices, Alexandria, Virginia, USA

    Thomas J. Moore (Senior scientist)

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  1. Lawrence M. Friedman
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  2. Curt D. Furberg
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  4. David M. Reboussin
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  5. Christopher B. Granger
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  6. Thomas J. Moore
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Friedman, L.M., Furberg, C.D., DeMets, D.L., Reboussin, D.M., Granger, C.B., Moore, T.J. (2015). Assessment and Reporting of Harm. In: Fundamentals of Clinical Trials. Springer, Cham. https://doi.org/10.1007/978-3-319-18539-2_12

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