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Open-Label Extension Studies

Do They Provide Meaningful Information on the Safety of New Drugs?


The number of open-label extension studies being performed has increased enormously in recent years. Often it is difficult to differentiate between these extension studies and the double-blind, controlled studies that preceded them. If undertaken primarily to gather more patient-years of exposure to the new drug in order to understand and gain confidence in its safety profile, open-label extension studies can play a useful and legitimate role in drug development and therapeutics. However, this can only occur if the open-label extension study is designed, executed, analysed and reported competently. Most of the value accrued in open-label extension studies is gained from a refinement in the perception of the expected incidence of adverse effects that have most likely already been identified as part of the preclinical and clinical trial programme. We still have to rely heavily on post-marketing safety surveillance systems to alert us to type B (unpredictable) adverse reactions because open-label extension studies are unlikely to provide useful information about these types of often serious and relatively rare adverse reactions.

Random allocation into test and control groups is needed to produce precise incidence data on pharmacologically expected, or type A, adverse effects. Some increased confidence about incidence rates might result from the open-label extension study; however, as these studies are essentially uncontrolled and biased, the data are not of great value.

Other benefits have been proposed to be gained from open-label extension studies. These include ongoing access to an effective but otherwise unobtainable medicine by the volunteers who participated in the phase III pivotal trials. However, there are unappreciated ethical issues about the appropriateness of enrolling patients whose response to previous treatment is uncertain, largely because treatment allocation in the preceding randomised, double-blind, controlled trial has not been revealed at the time of entry into the open-label extension study.

Negative aspects of open-label extension studies revolve around their use as a marketing tool, as they build a market for the drug and generate pressure for subsidised access to the drug from consumers and their physicians. Consumers, institutions where these studies are conducted and research ethics committees need to be convinced of the motives, as well as the quality, of the open-label extension study and its execution before supporting such studies.

Open-label extension studies do have a legitimate but limited place in the clinical development of new medicines. The negative perceptions about these studies have arisen because of perversion of acceptable rationales for this type of study and a failure to recognise (or disclose) the limitations resulting from the inherent weaknesses in their design. Increased human exposure to a new medicine under reasonably controlled circumstances to increase confidence in the safety of the medicine is an acceptable rationale for an open-label extension study, and a useful activity to increase the knowledge of the safety profile of a new medicine. However, this goal is increasingly being achieved by means other than open-label extension studies.

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Table I
Table II


  1. 1.

    Schneider LS. Open label extension studies and misinformation [letter]. Arch Neurol 2006; 63: 1036

    PubMed  Article  Google Scholar 

  2. 2.

    Taylor WJ, Weatherall M. What are open-label extension studies for? J Rheumatol 2006; 33(4): 642–3

    PubMed  Google Scholar 

  3. 3.

    Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000; 343(22): 1586–93

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Taylor GJ, Wainwright P. Open label extension studies: research or marketing? BMJ 2005; 331: 572–4

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Adverse drug reactions. BMJ 1989; 282: 1819–20

    Google Scholar 

  6. 6.

    Inman WHW. Editor’s introduction and commentary. In: Inman WHW, editor. Monitoring for drug safety. 2nd ed. Lancaster: Springer, 1986: 4

    Google Scholar 

  7. 7.

    Fung M, Thornton A, Mybeck K, et al. Evaluation of the characteristics of safety withdrawal of prescription drugs from worldwide pharmaceutical markets: 1960 to 1999. Drug Inf J 2001; 35: 293–317

    Article  Google Scholar 

  8. 8.

    Johnsen SP, Larsson H, Tarone RE, et al. Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case-control study. Arch Intern Med 2005; 165: 978–84

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    de Klerk E, van der Heijde D, Landewe R, et al. Patient compliance in rheumatoid arthritis, polymyalgia and gout. J Rhematology 2003; 30(1): 44–54

    Google Scholar 

  10. 10.

    Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343(21): 1520–30

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004; 351(17): 1709–10

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352(11): 1092–102

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Ray WA, Stein M, Daugherty JR, et al. Cox-2 selective nonsteroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet 2002; 360: 1072–3

    Google Scholar 

  14. 14.

    Schnitzer TJ, Truitt K, Fleishmann R, et al. The safety profile, tolerability, and effective dose range of rofecoxib in the treatment of rheumatoid arthritis. Clin Ther 1999; 21(10): 1688–702

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Ehrich EW, Schnitzer TJ, McIlwain H, et al. Effect of specific COX-2 inhibition in osteoarthritis of the knee: a 6 week double blind, placebo controlled pilot study of rofecoxib. J Rheumatol 1999; 26(11): 2438–47

    PubMed  CAS  Google Scholar 

  16. 16.

    Reicin AS, Shapiro D, Sperling RS, et al. Comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with rofecoxib versus nonselective nonsteroidal anti-inflammatory drugs (ibuprofen, diclofenac, and nabumetone) [comment]. Am J Cardiol 2002; 89(2): 204–9

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    US Food and Drug Administration. Guidance for industry. Premarketing risk assessment. In: Services USDoHaH, Administration FaD, (CDER) CfDEaR, (CBER) CfBEaR, editors. Office of Training and Communication, Division of Drug Information, HFD-240, Center for Drug Evaluation and Research, Food and Drug 2005 [online]. Available from URL: [Accessed 2006 Dec 27]

  18. 18.

    Silman A, Symmons D. Reporting requirements for longitudinal observational studies in rheumatology. J Rhematol 1999; 26: 481–3

    CAS  Google Scholar 

  19. 19.

    Wolfe F, Hassere M, van der Heijde D, et al. Preliminary core set of domains and reporting requirements for longitudinal observation studies in rheumatology. J Rheumatol 1999; 26: 484–9

    PubMed  CAS  Google Scholar 

  20. 20.

    Donofrio PD, Raskin P, Rosenthal NR, et al. Safety and effectiveness of topiramate for the management of painful diabetic peripheral neuropathy in an open-label extension study. Clinical Ther 2005; 27(9): 1420–31

    Article  CAS  Google Scholar 

  21. 21.

    Davidson MH. Rosuvastatin safety: lessons from the FDA review and post-approval surveillance. Expert Opin Drug Saf 2004; 3(6): 547–57

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. General Considerations for Clinical Trials E8. 17 July 1997. Available from URL: [Accessed 2007 Jan 3]

  23. 23.

    International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(RI). 10 June 1996. Available from URL: [Accessed 2007 Jan 3]

  24. 24.

    De Angelis C, Drazen JM, Frizelle FA, et al. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. N Engl J Med 2004; 351(12): 1250–1

    PubMed  Article  Google Scholar 

  25. 25.

    Ray WA, Stein CM. Reform of drug regulation: beyond an independent drug-safety board. N Engl J Med 2006; 354(2): 194–201

    PubMed  Article  CAS  Google Scholar 

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The authors would like to thank Ms Leonie Snowden, Librarian at the NSW Medicines Information Centre, New South Wales, Australia, for assistance with the literature review. No sources of funding were used in the preparation of this article. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.

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Correspondence to Richard O. Day.

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Day, R.O., Williams, K.M. Open-Label Extension Studies. Drug-Safety 30, 93–105 (2007).

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