Identifying and Addressing Safety Signals in Clinical Trials: Some Issues and Challenges

  • Thomas R. FlemingEmail author
Conference paper
Part of the Lecture Notes in Statistics book series (LNS, volume 1205)


Reliable evidence is needed from clinical research about whether the interventions used in clinical practice are safe as well as effective. Regarding risk, safety is not established by failure to establish excess risk, such as obtaining confidence intervals for the relative risk of safety events that include unity. Absence of evidence is not evidence of absence. Rather, safety is established if available data about safety are sufficiently favorable and reliable to rule out the threshold for unacceptable risk, where this threshold should be determined by considering the strength of the evidence for efficacy.

Important insights about safety usually will be provided before marketing through Phase 1, 2, and 3 clinical trials. These insights, especially regarding risks associated with long-term use of the intervention and risks of rare but clinically compelling events, are enhanced by post-marketing active and passive surveillance, and especially by large, long-term randomized trials that provide the most reliable approach for identifying and addressing safety signals. The integrity of these randomized trials is enhanced by preventing irregularities in the quality of trial conduct that would reduce their sensitivity to detecting clinically meaningful safety risks caused by the experimental regimen.

After considering approaches to identifying and addressing safety risks and discussing performance standards to improve the quality of conduct of safety trials, we will consider further the vulnerability to undetected safety risks when evidence for efficacy has been limited to documentation of effects on surrogate endpoints such as biomarkers, and then discuss important considerations regarding cardiovascular safety trials conducted in the setting of type 2 diabetes mellitus.


Composite Endpoint Progressive Multifocal Leukoencephalopathy Safety Risk Expand Disability Status Scale Score Safety Event 
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.



The source of financial support for research described in this article is an NIH/NIAID grant entitled “Statistical Issues in AIDS Research” (R37 AI 29168). The author acknowledges New England Journal of Medicine as the source for Fig. 9.4. The author also acknowledges Jennifer Clark Nelson and Daniel L. Gillen for providing important insights.


  1. 1.
    Meeting Transcript of the joint Advisory Committee meeting of FDA's Arthritis and Drug Safety and Risk Management Advisory Committees, February 16–18, 2005.
  2. 2.
    Nelson HS, Weiss ST, Bleecker ER, Yancey MS, Dorinsky PM, SMART Study Group (2006) The Salmeterol Multicenter Asthma Research Trial. Chest 129:15–26CrossRefGoogle Scholar
  3. 3.
    Strom BL, Faich GA, Reynolds RF, Eng SM, D'Agostino RB, Ruskin JN, Kane JM (2008) The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC): design and baseline subject characteristics. J Clin Psychiatry 69(1):114–121CrossRefGoogle Scholar
  4. 4.
    Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, Feyzi JM, Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill JB, McMurray JJ, Parfrey P, Parving HH, Remuzzi G, Singh AK, Solomon SD, Toto R, for the TREAT Investigators (2009) A trial of darbepoetin alfa in type II diabetes and chronic kidney disease. N Engl J Med 361:2019–2032Google Scholar
  5. 5.
    Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D, for the CHOIR Investigators (2006) Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 355:2085–2098Google Scholar
  6. 6.
    Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A, for the CREATE Investigators (2006) Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 355:2071–2084Google Scholar
  7. 7.
    Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin DA (1998) The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 339:584–590CrossRefGoogle Scholar
  8. 8.
    Center for Drug Evaluation and Research. Approval package: Avandia (rosiglitazone maleate) tablets. Company: SmithKline Beecham Pharmaceuticals. Application no. 21–071. Approval date: 5/25/1999. (Accessed 15 May 2007, at
  9. 9.
    The Action to Control Cardiovascular Risk in Diabetes Study Group (2008) Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358:2545–2559CrossRefGoogle Scholar
  10. 10.
    Ettinger B, Black DM, Mitlak BH et al (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 282(7):637–645CrossRefGoogle Scholar
  11. 11.
    Wooltorton E (2006) Osteoporosis treatment: raloxifene (Evista) and stroke mortality. CMAJ 175(2):147–148CrossRefGoogle Scholar
  12. 12.
    Stefanick ML (2006) Risk–benefit profiles of raloxifene for women. N Engl J Med 355:190–192CrossRefGoogle Scholar
  13. 13.
    Mosca L, Grady D, Barrett-Connor E, Collins P, Wenger N, Abramson BL, Paganini-Hill A, Geiger MJ, Dowsett SA, Amewou-Atisso M, Kornitzer M (2009) Effect of raloxifene on stroke and venous thromboembolism according to subgroups in postmenopausal women at increased risk of coronary heart disease. Stroke 40:147–155CrossRefGoogle Scholar
  14. 14.
    Nissen SE, Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356:2457–2471CrossRefGoogle Scholar
  15. 15.
    Baggs J, Gee J, Lewis E et al (2011) The Vaccine Safety Datalink: a model for monitoring immunization safety. Pediatrics 127:S45–S53CrossRefGoogle Scholar
  16. 16.
    Behrman RE, Benner JS, Brown JS et al (2011) Developing the sentinel system — a national resource for evidence development. N Engl J Med 364(6):498–499CrossRefGoogle Scholar
  17. 17.
    Murphy TM, Gargiullo PM, Massoudi MS, Nelson DB, Jumaan AO, Okoro CA, Zanardi LR, Setia S, Fair E, LeBaron CW, Schwartz B, Wharton M, Livingood JR, for the Rotavirus Intussusception Investigation Team (2001) Intussusception among infants given an oral rotavirus vaccine. N Engl J Med 344:564–572Google Scholar
  18. 18.
    Assche GV, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M, Verbeeck J, Geboes K, Robberecht W, Rutgeerts P (2005) Progressive multifocal leukoencephalopathy after Natalizumab therapy for Crohn’s Disease. N Engl J Med 353:362–368CrossRefGoogle Scholar
  19. 19.
    Emerson S, Kittelson J, Gillen D (2007) Frequentist evaluation of group sequential clinical trial designs. Stat Med 26(28):5047–5080MathSciNetCrossRefGoogle Scholar
  20. 20.
    Rossebo AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, Gerdts E, Gohlke-Bärwolf C, Holme I, Kesäniemi YA, Malbecq W, Nienaber CA, Ray S, Skjærpe T, Wachtell K, Willenheimer R, for the SEAS Investigators (2008) Intensive lipid lowering with Simvastatin and Ezetimibe in aortic stenosis. N Engl J Med 359:1343–1356Google Scholar
  21. 21.
    Fleming TR (2010) Clinical trials: discerning hype from substance. Ann Intern Med 153:400–406Google Scholar
  22. 22.
    Bradford PG, Awad AB (2007) Phytosterols as anticancer compounds. Mol Nutr Food Res 51:161–170CrossRefGoogle Scholar
  23. 23.
    Assmann G, Kannenbert F, Ramey DR, Musliner TA, Gutkin SW, Veltri EP (2008) Effects of ezetimibe, simvastatin, atorvastatin, and ezetimibe-statin therapies on non-cholesterol sterols in patients with primary hypercholesterolemia. Curr Med Res Opin 24:249–259CrossRefGoogle Scholar
  24. 24.
    Imanaka H, Koide H, Shimizu S et al (2008) Chemoprevention of tumor metastasis by liposomal β-sitosterol intake. Biol Pharm Bull 31:400–404CrossRefGoogle Scholar
  25. 25.
    Cannon CP, Guigliano RP, Blaxing MA et al (2005) Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndrome. Am Heart J 149:464–473CrossRefGoogle Scholar
  26. 26.
    Baigent C, Landry M (2003) Study of heart and renal protection (SHARP). Kidney Int 63(Suppl 84):S207–S210CrossRefGoogle Scholar
  27. 27.
    Peto R, Emberson J, Landray M et al (2008) Analyses of cancer data from three ezetimibe trials. N Engl J Med 359(13):1357–1366. doi: 10.1056/NEJMsa0806603 CrossRefGoogle Scholar
  28. 28.
    Fleming TR (2008) Identifying and addressing safety signals in clinical trials. N Engl J Med 359:1400–1402CrossRefGoogle Scholar
  29. 29.
    Becker MC, Wang TH, Wisniewski L, Wolski K, Libby P, Lu¨scher TF, Borer JS, Mascette AM, Husni ME, Solomon DH, Graham DY, Yeomans ND, Krum H, Ruschitzka F, Lincoff AM, Nissen SE, for the PRECISION Investigators (2009) Rationale, design, and governance of Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION), a cardiovascular end point trial of nonsteroidal antiinflammatory agents in patients with arthritis. Am Heart J 157:606–612Google Scholar
  30. 30.
    Fleming TR (2011) Addressing missing data in clinical trials. Ann Intern Med 154:113–117Google Scholar
  31. 31.
    Fleming TR, Odem-Davis K, Rothmann MD, Shen YL (2011) Some essential considerations in the design and conduct of non-inferiority trials. Clin Trials 8:432–439CrossRefGoogle Scholar
  32. 32.
    ICH E-9—International conference on harmonisation: statistical principles for clinical trials, published in the Federal Register of May 9, 1997, (62 FR 25712)Google Scholar
  33. 33.
    Fleming TR, DeMets DL (1996) Surrogate end points in clinical trials: are we being misled? Ann Intern Med 125(7):605–613Google Scholar
  34. 34.
    Fleming TR (2005) Surrogate endpoints and FDA's accelerated approval process. Health Aff 24(1):67–78CrossRefGoogle Scholar
  35. 35.
    Temple RJ (1995) A regulatory authority's opinion about surrogate endpoints. In: Nimmo WS, Tucker GT (eds) Clinical measurement in drug evaluation. Wiley, New YorkGoogle Scholar
  36. 36.
    IOM (2010) Evaluation of biomarkers and surrogate endpoints in chronic disease. Washington DC, National Academies Press.
  37. 37.
    Fleming TR, Powers JH (2012) Biomarkers and surrogate endpoints in clinical trials. Stat Med doi: 10.1002/sim.5403, 2012
  38. 38.
    Dormandy JA, Charbonnel B, Eckland EJA et al (2005) Secondary prevention of macrovascular events in patients with type 2 diabetes: a randomized trial of pioglitazone. The PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events). Lancet 366:1279–1289CrossRefGoogle Scholar
  39. 39.
    The DCCT Research Group (1993) 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 329:977–986CrossRefGoogle Scholar
  40. 40.
    UKPDS Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853CrossRefGoogle Scholar
  41. 41.
    Nissen SE, Wolski K, Topol EJ (2005) Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 294:2581–2586CrossRefGoogle Scholar
  42. 42.
    Meeting Transcript of the FDA Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, September 24, 2012/ MetabolicDrugsAdvisoryCommittee/UCM 222628.pdf and UCM222629.pdf
  43. 43.
    Guidance for industry. diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes.
  44. 44.
    O'Brien PC, Fleming TR (1979) A multi-stage procedure for clinical trials. Biometrics 35:549–556CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of BiostatisticsUniversity of WashingtonSeattleUSA

Personalised recommendations