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Rheumatoid Arthritis, etanercept, post-marketing study, comparative study
There are fundamental differences in design between phase III clinical trials and phase IV post-marketing studies that involve patient characteristics, the clinical setting (environment) and the manner of drug use. As well, many phase IV studies are extensions of randomized clinical trials (RCTs) and suffer from selection bias.
To determine if the data obtained from RCTs of etanercept (Enbrel®) in the treatment of rheumatoid arthritis would be representative of the effects attainable in community practice.
An analysis was conducted comparing data from published RCTs of etanercept use in rheumatoid arthritis patients with data collected in a community based cohort study that was not an extension of an RCT.
Baseline clinical data, such as tender or painful joint count, patient’s global assessment, the heath assessment questionnaire, physical and mental component summary of the SF-36, and rheumatoid arthritis drug profile were significantly different between the patients receiving etanercept in the phase IV community cohort study and the patients enrolled in the RCTs. Differences in the baseline data for the control patients were also noted amongst the RCT studies. The treatment outcome, American College of Rheumatology (ACR) response rate of 20%, 50% and 70% at 6 month, was the same between the cohort study and the RCTs, but at 12 months the clinical response was less for the community based patients than for the RCT patients. At 6 months there were fewer withdrawals involving community-based patients than RCT patients due to less frequent withdrawals associated with lack of efficacy. At 12 months the withdrawal rate due to either a lack of efficacy or from adverse events was similar between data sets.
The data from the etanercept phase III RCTs may not reflect the characteristics of patients using etanercept in community practice, nor the clinical outcomes observed by RA patients at 12 months. These discrepancies may be derived from methodological differences in study design and patient selection. On the other hand, outcomes such as withdrawal rates at 12 months appear comparable between the two types of populations.
2. Peck CC, Barr WH, Benet LZ, Collins J, Desjardins RE, Furst DE et al. Opportunities for integration of pharmacokinetics, pharmacodynamics, and toxicokinetics in rational drug development. J Pharm Sci. 1992;81:605-10.
3. Weissinger J. Pharmacology and toxicology of novel drug delivery systems. Regulatory issues. Drug Saf. 1990;5:107-13.
4. Lexchin J. Drug withdrawals from the Canadian market for safety reasons, 1963-2004. CMAJ. 2005;172:765-67.
5. Streiner DL. The 2 "Es" of research: Efficacy and effectiveness trials. Canadian Journal of Psychiatry-Revue Canadienne de Psychiatrie 2002;47:552-56.
6. Wells KB. Treatment research at the crossroads: The scientific interface of clinical trials and effectiveness research. American Journal of Psychiatry 1999;156:5-10.
7. Corrigan OP. A risky business: the detection of adverse drug reactions in clinical trials and post- marketing exercises. Social Science & Medicine 2002;55:497-507.
8. Linden M. Controlled clinical trials and post marketing experience. Psychopharmako therapie 1997;4:26-31.
9. Linden M. Differences in adverse drug reactions in phase III and phase IV of the drug evaluation process. Psychopharmacol Bull. 1993;29:51-56.
10. Lawson DH. Postmarketing surveillance versus clinical trials: which benefits the patient? Cardiology 1994;85:18-23.
11. Linden M. Phase-IV research: specifics, objectives and methodology. Pharmacopsychiatry 1984;17:140-42.
12. Community-Based Evaluation of Etanercept in Rheumatoid Arthritis Patients. Farahani P, Levine M, Gaebel K, Wang E, Khalidi N. J Rheumatology (in press)
13. Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ et al. Etanercept therapy in rheumatoid arthritis - A randomized, controlled trial. Annals of Internal Medicine 1999;130:478-486.
14. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI et al. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. New England Journal of Medicine 1999;340:253-59.
15. Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. New England Journal of Medicine 2000;343:1586-93.
16. Ware J. SF-36 Health Survey. Manual and Interpretation Guide. The Health Institute, New England Medical Centre.Boston 1993.
17. Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthr Rheum 1980;23:137-45.
18. Felson DT, Anderson JJ, Boers M, Bombardier C, Chernoff M, Fried B et al. The American College of Rheumatology preliminary core set of disease
activity measures for rheumatoid arthritis clinical trials. The Committee on Outcome Measures in Rheumatoid Arthritis Clinical Trials. Arthritis Rheum. 1993;36:729-40.
19. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995;38:727-35.
20. Escalante A. What do self-administered joint counts tell us about patients with rheumatoid arthritis? Arthritis Care Res. 1998;11:280-90.
21. Pincus T, Callahan LF, Brooks RH, Fuchs HA, Olsen NJ, Kaye JJ. Self-report questionnaire scores in rheumatoid arthritis compared with traditional physical, radiographic, and laboratory measures. Ann.Intern.Med 1989;110:259-66.
22. Deyo RA, Inui TS, Leininger JD, Overman SS. Measuring functional outcomes in chronic disease: a comparison of traditional scales and a self- administered health status questionnaire in patients with rheumatoid arthritis. Med Care 1983;21:180- 92.
23. Pincus T, Sokka T, Kavanaugh A. Quantitative documentation of benefit/risk of new therapies for rheumatoid arthritis: patient questionnaires as an optimal measure in standard care. Clin Exp.Rheumatol. 2004;22:S26-S33.