Drug Safety

, Volume 25, Issue 2, pp 77–84 | Cite as

Improving Safety Reporting from Randomised Trials

Current Opinion


Randomised clinical trials offer a unique opportunity for capturing safety information under a controlled setting that minimises biases in the comparison of different therapeutic options. Nevertheless, empirical evidence across diverse medical fields suggests that the reporting of safety information in clinical trials is largely neglected and receives less attention compared with efficacy outcomes. An analysis of 192 randomised trials has shown that reasons for withdrawals due to toxicity were specified per study arm in only 46% of the trial reports. Adequate reporting of clinical adverse effects and laboratory-determined toxicity occurred in only 39 and 29% of the trials, respectively, even with lenient definitions of what constitutes adequate reporting. The use of standardised scales for adverse effects is a prerequisite for improved reporting on safety in randomised trials. Safety data need to be collected and analysed in a systematic fashion and active surveillance for toxicity during the conduct of a randomised trial is preferable to passive surveillance. Standardised reporting of safety data does not necessarily require extensive space to accomplish. It is essential to provide numerical data per study arm on each type of adverse effect along with a categorisation of the severity of the adverse effects with an emphasis on severe and life-threatening reactions. The severity grading must be referred to well-known standardised scales and new scales need to be carefully defined. Information on withdrawals due to toxicity is also important to report, along with the specific reasons leading to discontinuation. Tabulation of information may be helpful and rare or not previously reported adverse effects should be described in detail. The availability of newer options such as electronic publication, publication of raw databases, large database research, meta-analytic approaches, and prospective registration of clinical trials and of their databases may further improve the safety insights we can gain from randomised clinical trials.


Safety Data Active Surveillance Safety Outcome Safety Information Standardise Scale 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Glasziou P, Irwig LM. An evidence-based approach to individualizing treatment. BMJ 1995; 311: 1356–9PubMedCrossRefGoogle Scholar
  2. 2.
    Ziegler DK, Mosier MC, Buenaver M, et al. How much information about adverse effects of medications do patients want from physicians? Arch Intern Med 2001; 161: 706–13PubMedCrossRefGoogle Scholar
  3. 3.
    Ioannidis JPA, Contopoulos-Ioannidis DG. Reporting of safety data from randomised trials. Lancet 1998; 352: 1752–3PubMedCrossRefGoogle Scholar
  4. 4.
    Ioannidis JPA, Lau J. Completeness of safety reporting in randomized trials: an evaluation of 7 medical areas. JAMA 2001; 285: 437–43PubMedCrossRefGoogle Scholar
  5. 5.
    Edwards JE, McQuay HJ, Moore AR, et al. Reporting of adverse effects in clinical trials should be improved: lessons from postoperative pain. J Pain Symptom Manage 1999; 18: 427–37PubMedCrossRefGoogle Scholar
  6. 6.
    Lau J, Ioannidis JP, Schmid CH. Summing up evidence: one answer is not always enough. Lancet 1998; 351: 123–7PubMedCrossRefGoogle Scholar
  7. 7.
    Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med 1997; 127: 820–6PubMedGoogle Scholar
  8. 8.
    Chalmers TC, Berrier J, Hewitt P, et al. Meta-analysis of randomized controlled trials as a method of estimating rare complications of non-steroidal anti-inflammatory drug therapy. Aliment Pharmacol Ther 1988; 2Suppl. 1: 9–26PubMedGoogle Scholar
  9. 9.
    Mehta SR, Eikelboom JW, Yusuf S. Risk of intracranial haemorrhage with bolus versus infusion thrombolytic therapy: a meta-analysis. Lancet 2000; 356: 449–54PubMedCrossRefGoogle Scholar
  10. 10.
    Schoenfeld P. Gastrointestinal safety profile of meloxicam: a meta-analysis and systematic review of randomised controlled trials. Am J Med 1999; 107: 48S–54SPubMedCrossRefGoogle Scholar
  11. 11.
    Shah MB, Martin JE, Schroeder TJ, et al. The evaluation of the safety and tolerability of two formulations of cyclosporine: neural and sandimmune. A meta-analysis. Transplantation. 1999; 67: 1411–7PubMedCrossRefGoogle Scholar
  12. 12.
    Stason WB, Schmid CH, Niedzwiecki D, et al. Safety of nifedipine in angina pectoris: a meta-analysis. Hypertension 1999; 33: 24–31PubMedCrossRefGoogle Scholar
  13. 13.
    Eikelboom JW, Mehta SR, Pogue J, et al. Safety outcomes in meta-analyses of phase 2 vs phase 3 randomized trials: intracranial hemorrhage in trials of bolus thrombolytic therapy. JAMA 2001; 285: 444–50PubMedCrossRefGoogle Scholar
  14. 14.
    Ernst E, Pittler MH. Systematic reviews neglect safety issues. Arch Intern Med 2001; 161: 125–6PubMedCrossRefGoogle Scholar
  15. 15.
    Li wan Po A, Herxheimer A, Poolsup N, et al. How do Cochrane reviewers address adverse effects of drug therapy? In: Abstracts of the 8th International Cochrane Colloquium: 2000 Oct 25-29: Capetown. Capetown: International Cochrane Collaboration, 2000Google Scholar
  16. 16.
    National Cancer Institute. Common toxicity criteria (CTC). Version 2.0 [online]. Available from URL: http://ctep.info.nih.gov/CTC3/default.htm [Accessed 1999 Apr 30]
  17. 17.
    World Health Organization (WHO). Cancer treatment: WHO recommendations for grading of acute and subacute toxicity. Cancer 1981; 47: 207–14Google Scholar
  18. 18.
    Sanders C, Egger M, Donovan J, et al. Reporting on quality of life in randomized controlled trials. BMJ 1998; 317: 1191–4PubMedCrossRefGoogle Scholar
  19. 19.
    Peloso PM, Wright JG, Bombardier C. A critical appraisal of toxicity indexes in rheumatology. J Rheumatol 1995; 22: 989–94PubMedGoogle Scholar
  20. 20.
    Thornley B, Adams C. Content and quality of 2000 controlled trials in schizophrenia over 50 years. BMJ 1998; 317: 1181–4PubMedCrossRefGoogle Scholar
  21. 21.
    Stephens MD, Routledge PA, Talbot JCC, editors. Detection of new adverse drug reactions. 4th ed. London: Grove’s Dictionaries Inc., 1998Google Scholar
  22. 22.
    Stephens MD. The diagnosis of adverse medical events associated with drug treatment. Adverse Drug React Acute Poisoning Rev 1987; 6: 1–35PubMedGoogle Scholar
  23. 23.
    Corso DM, Pucino F, DeLeo JM, et al. Development of a questionnaire for detecting potential adverse drug reactions. Ann Pharmacother 1992; 26: 890–6PubMedGoogle Scholar
  24. 24.
    Chuang-Stein C. Laboratory data in clinical trials: a statistician’s perspective. Control Clin Trials 1998; 19: 167–77PubMedCrossRefGoogle Scholar
  25. 25.
    Rochon PA, Binns MA, Litner JA, et al. Are randomized control trial outcomes influenced by the inclusion of a placebo group? A systematic review of nonsteroidal anti-inflammatory drug trials for arthritis treatment. J Clin Epidemiol 1999; 52: 113–22PubMedCrossRefGoogle Scholar
  26. 26.
    Hayashi K, Walker AM. Japanese and American reports of randomized trials: differences in the reporting of adverse effects. Control Clin Trials 1996; 17: 99–110PubMedCrossRefGoogle Scholar
  27. 27.
    Begg C, Cho M, Eastwood S, et al. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA 1996; 276: 637–9PubMedCrossRefGoogle Scholar
  28. 28.
    Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel group randomized trials. BMC Med Res Methodol 2001; 1(1): 2PubMedCrossRefGoogle Scholar
  29. 29.
    Moher D, Schulz KF, Altman DG, et al. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 2001; 357: 1191–4PubMedCrossRefGoogle Scholar
  30. 30.
    Shapiro SH, Weijer C, Freedman B. Reporting the study populations of clinical trials. Clear transmission or static on the line? J Clin Epidemiol 2000; 53: 973–9PubMedCrossRefGoogle Scholar
  31. 31.
    Smith R. Electronic publishing in science. BMJ 2001; 322: 627–9PubMedCrossRefGoogle Scholar
  32. 32.
    Hutchon DJ. Publishing raw data and real time statistical analyses on e-journals. BMJ 2001; 322: 530PubMedCrossRefGoogle Scholar
  33. 33.
    Easterbrook P, Berlin JA, Gopalan R, Matthews DR. Publication bias in clinical research. Lancet 1991; 337: 867–72PubMedCrossRefGoogle Scholar
  34. 34.
    Ioannidis JPA. Effect of the statistical significance of results on the time to completion and publication of randomized efficacy trials. JAMA 1998, 279: 281–6PubMedCrossRefGoogle Scholar
  35. 35.
    Bero L, Rennie D. The Cochrane Collaboration. JAMA 1995; 274: 1935–8PubMedCrossRefGoogle Scholar
  36. 36.
    Simes RJ. Publication bias: the case for an international registry of clinical trials. J Clin Oncol 1986; 4: 1529–41PubMedGoogle Scholar
  37. 37.
    McCray AT, Ide NC. Design and implementation of a national clinical trials registry. J Am Med Inform Assoc 2000; 7: 313–23PubMedCrossRefGoogle Scholar
  38. 38.
    Irl C, Hasford J. Assessing the safety of drugs in pregnancy: the role of prospective cohort studies. Drug Saf 2000; 22: 169–77PubMedCrossRefGoogle Scholar
  39. 39.
    Cohen JS. Dose discrepancies between the Physicians’ Desk Reference and the medical literature, and their possible role in the high incidence of dose-related adverse drug events. Arch Intern Med 2001; 161: 957–64PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  1. 1.Clinical Trials and Evidence-Based Medicine Unit, Department of Hygiene and EpidemiologyUniversity of Ioannina School of MedicineIoanninaGreece
  2. 2.Division of Clinical Care Research, New England Medical Center, and the Department of MedicineTufts University School of MedicineBostonUSA

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