A New Toolkit for Conducting Clinical Trials in Rare Disorders
Main Article Content
Keywords
Evidence-based medicine, observational studies, rare disorders, NNT, adaptive trial design, Bayesian analysis
Abstract
Evidence based medicine requires strong scientific evidence upon which to base treatment. Because the available study populations for rare diseases are small, this evidence is difficult to accrue. Investigators need to consider a flexible toolkit of methods to deal with the problems inherent in the study of rare disease. We present some potential solutions in this paper.
References
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13. Behera M, Kumar A, Soares HP, Sokol L, Djulbegovic B. Evidence - based medicine for rare diseases: implications for data interpretation and clinical trial design. Cancer C ontrol 2007;14(2):160 - 6.
14. Gallin JI, Alling DW, Malech HL, et al. Itraconazole to prevent fungal infections in chronic granulomatous disease. N Engl J Med 2003;348(24):2416 - 22.
15. Wilcken B. Rare diseases and the assessment of intervention: what sorts of clini cal trials can we use? J Inherit Metab Dis 2001;24(2):291 - 8.
16. Abrahamyan L, Johnson SR, Beyene J, Shah PS, Feldman BM. Quality of randomized clinical trials in juvenile idiopathic arthritis. Rheumatology (Oxford) 2008;47(5):640 - 5.
17. Laupacis A, Sackett DL, Ro berts RS. An assessment of clinically useful measures of the consequences of treatment. N Engl J Med 1988;318(26):1728 - 33.
18. Halpern SD, Karlawish JH, Casarett D, Berlin JA, Townsend RR, Asch DA. Hypertensive patients' willingness to participate in placebo - c ontrolled trials: implications for recruitment efficiency. Am Heart J 2003;146(6):985 - 92.
19. Halpern SD, Ubel PA, Berlin JA, Townsend RR, Asch DA. Physicians' preferences for active - controlled versus placebo - controlled trials of new antihypertensive drugs. J Gen Intern Med 2002;17(9):689 - 95.
20. Makuch RW, Johnson MF. Dilemmas in the use of active control groups in clinical research. IRB 1989;11(1):1 - 5.
21. Manco - Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007;357(6):535 - 44.
22. The World Medical Association Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. 59th WMA General Assembly. Seoul: 2008 October. Report No.
23. Zong Z. Sho uld post - trial provision of beneficial experimental interventions be mandatory in developing countries? J Med Ethics 2008;34(3):188 - 92.
24. Grady C. The challenge of assuring continued post - trial access to beneficial treatment. Yale J Health Policy Law Ethics 2005;5(1):425 - 35.
25. Senn S. The AB/BA crossover: past, present and future? Stat Methods Med Res 1994;3(4):303 - 24.
26. Elbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV, Vail A. Meta - analyses involving cross - over trials: methodological issues. Int J Ep idemiol 2002;31(1):140 - 9.
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28. Reed JF, 3rd. Analysis of two - treatment, two - period crossover tr ials in emergency medicine. Ann Emerg Med 2004;43(1):54 - 8.
29. Straube S, Derry S, McQuay HJ, Moore RA. Enriched enrollment: definition and effects of enrichment and dose in trials of pregabalin and gabapentin in neuropathic pain. A systematic review. Br J Cli n Pharmacol 2008;66(2):266 - 75.
30. Katz N. Enriched enrollment randomized withdrawal trial designs of analgesics: focus on methodology. Clin J Pain 2009;25(9):797 - 807.
31. Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. The New England journal of medicine 2000;342(11):763 - 9.
32. Feldman B, Wang E, Willan A, Szalai JP. The randomized placebo - phase design for clinical trials. J Clin Epidemiol 2001;54(6):550 - 7.
33. Abrahamyan L, Li CS, Beyene J, Willan AR, Feldman BM. Survival distributions impact the power of randomized placebo - phase design and parallel groups randomized clinical trials. J Clin Epidem iol 2010;64(3):286 - 92.
34. Shook S. Randomized placebo - phase design: evaluation, interim monitoring and analysis. Diss: University of Pittsburgh; 2010.
35. Abrahamyan L, Beyene J, Feng J, et al. Response times follow lognormal or gamma distribution in arthritis pa tients. J Clin Epidemiol 2010;63(12):1363 - 9.
36. Goodman SN. Toward evidence - based medical statistics. 1: The P value fallacy. Ann Intern Med 1999;130(12):995 - 1004.
37. Sterne JA, Davey Smith G. Sifting the evidence - what's wrong with significance tests? BMJ 2001;3 22(7280):226 - 31.
38. Lilford RJ, Thornton JG, Braunholtz D. Clinical trials and rare diseases: a way out of a conundrum. BMJ 1995;311(7020):1621 - 5.
39. Diamond GA, Kaul S. Prior convictions: Bayesian approaches to the analysis and interpretation of clinical mega t rials. J Am Coll Cardiol 2004;43(11):1929 - 39.
40. Spiegelhalter DJ, Myles JP, Jones DR, Abrams KR. Bayesian methods in health technology assessment: a review. Health Technol Assess 2000;4(38):1 - 130.
41. Johnson SR, Tomlinson GA, Hawker GA, Granton JT, Feldman BM. Methods to elicit beliefs for Bayesian priors: a systematic review. J Clin Epidemiol 2010;63(4):355 - 69.
42. Howard G, Coffey CS, Cutter GR. Is Bayesian analysis ready for use in phase III randomized clinical trials? Beware the sound of the sirens. Stroke 2005; 36(7):1622 - 3.
43. Goodman SN. Toward evidence - based medical statistics. 2: The Bayes factor. Ann Intern Med 1999;130(12):1005 - 13.
44. Johnson SR, Feldman BM, Pope JE, Tomlinson GA. Shifting our thinking about uncommon disease trials: the case of methotrexate in sc leroderma. J Rheumatol 2009;36(2):323 - 9.
45. Menzies D, Popa J, Hanley JA, Rand T, Milton DK. Effect of ultraviolet germicidal lights installed in office ventilation systems on workers' health and wellbeing: double - blind multiple crossover trial. Lancet 2003;3 62(9398):1785 - 91.
46. Gilron I, Booher SL, Rowan JS, Max MB. Topiramate in trigeminal neuralgia: a randomized, placebo - controlled multiple crossover pilot study. Clin Neuropharmacol 2001;24(2):109 - 12.
47. Zucker D, Schmid C, McIntosh M, D'Agostino R, Selker H, Lau J. Combining single patient (N - of - 1) trials to estimate population treatment effects and to evaluate individual patient responses to treatment. J Clin Epidemiol 1997;50(4):401 - 10.
48. Guyatt G, Sackett D, Adachi J, et al. A clinician's guide for conducting ra ndomized trials in individual patients. CMAJ 1988;139(6):497 - 503.
49. Guyatt GH, Heyting A, Jaeschke R, Keller J, Adachi JD, Roberts RS. N of 1 randomized trials for investigating new drugs. Control Clin Trials 1990;11(2):88 - 100.
50. Nathan PC, Tomlinson G, Dupuis LL, et al. A pilot study of ondansetron plus metopimazine vs. ondansetron monotherapy in children receiving highly emetogenic chemotherapy: a Bayesian randomized serial N - of - 1 trials design. Support Care Cancer 2006;14(3):268 - 76.
51. Huber AM, Tomlinson GA, K oren G, Feldman BM. Amitriptyline to relieve pain in juvenile idiopathic arthritis: a pilot study using Bayesian meta - analysis of multiple N - of - 1 clinical trials. J Rheumatol 2007;34(5):1125 - 32.
52. Sung L, Tomlinson GA, Greenberg ML, et al. Serial controlled N - of - 1 trials of topical vitamin E as prophylaxis for chemotherapy - induced oral mucositis in paediatric patients. Eur J Cancer 2007;43(8):1269 - 75.
53. Zucker DR, Ruthazer R, Schmid CH. Individual (N - of - 1) trials can be combined to give population comparative treatment effect estimates: methodologic considerations. J Clin Epidemiol 2010;63(12):1312 - 23.
54. Rubin DB. Estimating causal effects from large data sets using propensity scores. Ann Intern Med 1997;127(8 Pt 2):757 - 63.
55. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika 1983;70(1):41 - 55.
56. D'Agostino RB. Tutorial in biostatistics. Propensity score methods for bias reduction in the comparison of a treatment to a non - randomized control group. Statist Med 1998;17:2265 - 81.
57. Rosenbaum PR, Rubin DB. Reducing bias in observational studies using subclassificat ion on the propensity score. JAMA 1984;79(387):516 - 24.
58. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity - score matched samples. Statist Med 2009;28:3083 - 107.
59. Johnson SR, Granton JT, Tomlinson GA, et al. Warfarin in scleroderma - associated and idiopathic pulmonary arterial hypertension. A Bayesian approach to evaluating treatment in uncommon disease. Submitted 2011.
60. Condliffe R, Kiely DG, Peacock AJ, et al. Connective tissue disease - ass ociated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med 2009;179(2):151 - 7.
61. Koh ET, Lee P, Gladman DD, Abu - Shakra M. Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients. Br J Rheumatol 1996;35(10): 989 - 93.
62. Seshadri R, Feldman BM, Ilowite N, Cawkwell G, Pachman LM. The role of aggressive corticosteroid therapy in patients with juvenile dermatomyositis: a propensity score analysis. Arthritis Rheum 2008;59(7):989 - 95.
63. Robins JM, Hernan MA, Brumback B. Ma rginal structural models and causal inference in epidemiology. Epidemiology 2000;11(5):550 - 60.
64. Stukel TA, Fisher ES, Wennberg DE, Alter DA, Gottlieb DJ, Vermeulen MJ. Analysis of observational studies in the presence of treatment selection bias: effects of invasive cardiac management on AMI survival using propensity score and instrumental variable methods. JAMA 2007;297(3):278 - 85.
65. Pullenayegum EM, Lam C, Manlhiot C, Feldman BM. Fitting marginal structural models: estimating covariate - treatment associations in the reweighted data set can guide model fitting. J Clin Epidemiol 2008;61(9):875 - 81.
2. Gustason W. Reasoning from evidence. Inductive logic. New York: Macmillan College Publishing Company. 1994;318.
3. Morabia APCA. Louis and the birth of clinical epidemiology. J Clin Epidemiol 1996;49(12):1327 - 33.
4. Wikipedia contributors. Evidence - based medicine: Wikipedia, The Free Encyclopedia.; 2011 [updated 27 April 2011 08:08 UTC; cited 2011 12 May]. Available from: http://en.wikipedia.org/w/index.php?title=Evide nce - based_medicine&oldid=426171031 .
5. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn't. BMJ 1996;312(7023):71 - 2.
6. Savitz DA. Interpreting Epidemiologic Evidence. Strategies for study design and analysis. Oxford: Oxford University Press, Inc.; 2003.
7. Feinstein AR. Clinical Epidemiology. The Architecture of clinical research. Philadelphia: W. B. Saunders Company; 1985.
8. Bosco JL, Silliman RA, Thwin SS, et al. A most stubborn bias: no adjustment method fully resolves confounding by indication in observational studies. J Clin Epidemiol. 2010;63(1):64 - 74.
9. Kaplan W, Laing R. Priority medicines for Europe and the World. World Health Organization, Department of Essential Drugs and Medicines Policy. 2004. Available: http://mednet3.who.int/prioritymeds/repo?rt/fina l18october.pdf . Accessed 23 April, 2011.
10. Hughes DA, Tunnage B, Yeo ST. Drugs for exceptionally rare diseases: do they deserve special status for funding? QJM 2005;98(11):829 - 36.
11. European Organisation for Rare Diseases (EURORDIS). Rare diseases: understanding this public health priority. 2005. Available: http://www.eurordis.org/IMG/pdf/princeps_docu ment - EN.pdf . Accessed 23 April, 2011.
12. Ger ss JWO, Kopcke W. Clinical trials and rare diseases. Adv Exp Med Biol 2010;686:173 - 90.
13. Behera M, Kumar A, Soares HP, Sokol L, Djulbegovic B. Evidence - based medicine for rare diseases: implications for data interpretation and clinical trial design. Cancer C ontrol 2007;14(2):160 - 6.
14. Gallin JI, Alling DW, Malech HL, et al. Itraconazole to prevent fungal infections in chronic granulomatous disease. N Engl J Med 2003;348(24):2416 - 22.
15. Wilcken B. Rare diseases and the assessment of intervention: what sorts of clini cal trials can we use? J Inherit Metab Dis 2001;24(2):291 - 8.
16. Abrahamyan L, Johnson SR, Beyene J, Shah PS, Feldman BM. Quality of randomized clinical trials in juvenile idiopathic arthritis. Rheumatology (Oxford) 2008;47(5):640 - 5.
17. Laupacis A, Sackett DL, Ro berts RS. An assessment of clinically useful measures of the consequences of treatment. N Engl J Med 1988;318(26):1728 - 33.
18. Halpern SD, Karlawish JH, Casarett D, Berlin JA, Townsend RR, Asch DA. Hypertensive patients' willingness to participate in placebo - c ontrolled trials: implications for recruitment efficiency. Am Heart J 2003;146(6):985 - 92.
19. Halpern SD, Ubel PA, Berlin JA, Townsend RR, Asch DA. Physicians' preferences for active - controlled versus placebo - controlled trials of new antihypertensive drugs. J Gen Intern Med 2002;17(9):689 - 95.
20. Makuch RW, Johnson MF. Dilemmas in the use of active control groups in clinical research. IRB 1989;11(1):1 - 5.
21. Manco - Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007;357(6):535 - 44.
22. The World Medical Association Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. 59th WMA General Assembly. Seoul: 2008 October. Report No.
23. Zong Z. Sho uld post - trial provision of beneficial experimental interventions be mandatory in developing countries? J Med Ethics 2008;34(3):188 - 92.
24. Grady C. The challenge of assuring continued post - trial access to beneficial treatment. Yale J Health Policy Law Ethics 2005;5(1):425 - 35.
25. Senn S. The AB/BA crossover: past, present and future? Stat Methods Med Res 1994;3(4):303 - 24.
26. Elbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV, Vail A. Meta - analyses involving cross - over trials: methodological issues. Int J Ep idemiol 2002;31(1):140 - 9.
27. Campbell H, Surry SA, Royle EM. A review of randomised controlled trials published in Archives of Disease in Childhood from 1982 - 96. Arch Dis Child 1998;79(2):192 - 7.
28. Reed JF, 3rd. Analysis of two - treatment, two - period crossover tr ials in emergency medicine. Ann Emerg Med 2004;43(1):54 - 8.
29. Straube S, Derry S, McQuay HJ, Moore RA. Enriched enrollment: definition and effects of enrichment and dose in trials of pregabalin and gabapentin in neuropathic pain. A systematic review. Br J Cli n Pharmacol 2008;66(2):266 - 75.
30. Katz N. Enriched enrollment randomized withdrawal trial designs of analgesics: focus on methodology. Clin J Pain 2009;25(9):797 - 807.
31. Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. The New England journal of medicine 2000;342(11):763 - 9.
32. Feldman B, Wang E, Willan A, Szalai JP. The randomized placebo - phase design for clinical trials. J Clin Epidemiol 2001;54(6):550 - 7.
33. Abrahamyan L, Li CS, Beyene J, Willan AR, Feldman BM. Survival distributions impact the power of randomized placebo - phase design and parallel groups randomized clinical trials. J Clin Epidem iol 2010;64(3):286 - 92.
34. Shook S. Randomized placebo - phase design: evaluation, interim monitoring and analysis. Diss: University of Pittsburgh; 2010.
35. Abrahamyan L, Beyene J, Feng J, et al. Response times follow lognormal or gamma distribution in arthritis pa tients. J Clin Epidemiol 2010;63(12):1363 - 9.
36. Goodman SN. Toward evidence - based medical statistics. 1: The P value fallacy. Ann Intern Med 1999;130(12):995 - 1004.
37. Sterne JA, Davey Smith G. Sifting the evidence - what's wrong with significance tests? BMJ 2001;3 22(7280):226 - 31.
38. Lilford RJ, Thornton JG, Braunholtz D. Clinical trials and rare diseases: a way out of a conundrum. BMJ 1995;311(7020):1621 - 5.
39. Diamond GA, Kaul S. Prior convictions: Bayesian approaches to the analysis and interpretation of clinical mega t rials. J Am Coll Cardiol 2004;43(11):1929 - 39.
40. Spiegelhalter DJ, Myles JP, Jones DR, Abrams KR. Bayesian methods in health technology assessment: a review. Health Technol Assess 2000;4(38):1 - 130.
41. Johnson SR, Tomlinson GA, Hawker GA, Granton JT, Feldman BM. Methods to elicit beliefs for Bayesian priors: a systematic review. J Clin Epidemiol 2010;63(4):355 - 69.
42. Howard G, Coffey CS, Cutter GR. Is Bayesian analysis ready for use in phase III randomized clinical trials? Beware the sound of the sirens. Stroke 2005; 36(7):1622 - 3.
43. Goodman SN. Toward evidence - based medical statistics. 2: The Bayes factor. Ann Intern Med 1999;130(12):1005 - 13.
44. Johnson SR, Feldman BM, Pope JE, Tomlinson GA. Shifting our thinking about uncommon disease trials: the case of methotrexate in sc leroderma. J Rheumatol 2009;36(2):323 - 9.
45. Menzies D, Popa J, Hanley JA, Rand T, Milton DK. Effect of ultraviolet germicidal lights installed in office ventilation systems on workers' health and wellbeing: double - blind multiple crossover trial. Lancet 2003;3 62(9398):1785 - 91.
46. Gilron I, Booher SL, Rowan JS, Max MB. Topiramate in trigeminal neuralgia: a randomized, placebo - controlled multiple crossover pilot study. Clin Neuropharmacol 2001;24(2):109 - 12.
47. Zucker D, Schmid C, McIntosh M, D'Agostino R, Selker H, Lau J. Combining single patient (N - of - 1) trials to estimate population treatment effects and to evaluate individual patient responses to treatment. J Clin Epidemiol 1997;50(4):401 - 10.
48. Guyatt G, Sackett D, Adachi J, et al. A clinician's guide for conducting ra ndomized trials in individual patients. CMAJ 1988;139(6):497 - 503.
49. Guyatt GH, Heyting A, Jaeschke R, Keller J, Adachi JD, Roberts RS. N of 1 randomized trials for investigating new drugs. Control Clin Trials 1990;11(2):88 - 100.
50. Nathan PC, Tomlinson G, Dupuis LL, et al. A pilot study of ondansetron plus metopimazine vs. ondansetron monotherapy in children receiving highly emetogenic chemotherapy: a Bayesian randomized serial N - of - 1 trials design. Support Care Cancer 2006;14(3):268 - 76.
51. Huber AM, Tomlinson GA, K oren G, Feldman BM. Amitriptyline to relieve pain in juvenile idiopathic arthritis: a pilot study using Bayesian meta - analysis of multiple N - of - 1 clinical trials. J Rheumatol 2007;34(5):1125 - 32.
52. Sung L, Tomlinson GA, Greenberg ML, et al. Serial controlled N - of - 1 trials of topical vitamin E as prophylaxis for chemotherapy - induced oral mucositis in paediatric patients. Eur J Cancer 2007;43(8):1269 - 75.
53. Zucker DR, Ruthazer R, Schmid CH. Individual (N - of - 1) trials can be combined to give population comparative treatment effect estimates: methodologic considerations. J Clin Epidemiol 2010;63(12):1312 - 23.
54. Rubin DB. Estimating causal effects from large data sets using propensity scores. Ann Intern Med 1997;127(8 Pt 2):757 - 63.
55. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika 1983;70(1):41 - 55.
56. D'Agostino RB. Tutorial in biostatistics. Propensity score methods for bias reduction in the comparison of a treatment to a non - randomized control group. Statist Med 1998;17:2265 - 81.
57. Rosenbaum PR, Rubin DB. Reducing bias in observational studies using subclassificat ion on the propensity score. JAMA 1984;79(387):516 - 24.
58. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity - score matched samples. Statist Med 2009;28:3083 - 107.
59. Johnson SR, Granton JT, Tomlinson GA, et al. Warfarin in scleroderma - associated and idiopathic pulmonary arterial hypertension. A Bayesian approach to evaluating treatment in uncommon disease. Submitted 2011.
60. Condliffe R, Kiely DG, Peacock AJ, et al. Connective tissue disease - ass ociated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med 2009;179(2):151 - 7.
61. Koh ET, Lee P, Gladman DD, Abu - Shakra M. Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients. Br J Rheumatol 1996;35(10): 989 - 93.
62. Seshadri R, Feldman BM, Ilowite N, Cawkwell G, Pachman LM. The role of aggressive corticosteroid therapy in patients with juvenile dermatomyositis: a propensity score analysis. Arthritis Rheum 2008;59(7):989 - 95.
63. Robins JM, Hernan MA, Brumback B. Ma rginal structural models and causal inference in epidemiology. Epidemiology 2000;11(5):550 - 60.
64. Stukel TA, Fisher ES, Wennberg DE, Alter DA, Gottlieb DJ, Vermeulen MJ. Analysis of observational studies in the presence of treatment selection bias: effects of invasive cardiac management on AMI survival using propensity score and instrumental variable methods. JAMA 2007;297(3):278 - 85.
65. Pullenayegum EM, Lam C, Manlhiot C, Feldman BM. Fitting marginal structural models: estimating covariate - treatment associations in the reweighted data set can guide model fitting. J Clin Epidemiol 2008;61(9):875 - 81.