Bayesian analysis; Centronuclear myopathy; Complex innovative clinical trial design; Disease progression model; Natural history data
Abstract :
[en] BACKGROUND: Centronuclear myopathies are severe rare congenital diseases. The clinical variability and genetic heterogeneity of these myopathies result in major challenges in clinical trial design. Alternative strategies to large placebo-controlled trials that have been used in other rare diseases (e.g., the use of surrogate markers or of historical controls) have limitations that Bayesian statistics may address. Here we present a Bayesian model that uses each patient's own natural history study data to predict progression in the absence of treatment. This prospective multicentre natural history evaluated 4-year follow-up data from 59 patients carrying mutations in the MTM1 or DNM2 genes. METHODS: Our approach focused on evaluation of forced expiratory volume in 1 s (FEV1) in 6- to 18-year-old children. A patient was defined as a responder if an improvement was observed after treatment and the predictive probability of such improvement in absence of intervention was less than 0.01. An FEV1 response was considered clinically relevant if it corresponded to an increase of more than 8%. RESULTS: The key endpoint of a clinical trial using this model is the rate of response. The power of the study is based on the posterior probability that the rate of response observed is greater than the rate of response that would be observed in the absence of treatment predicted based on the individual patient's previous natural history. In order to appropriately control for Type 1 error, the threshold probability by which the difference in response rates exceeds zero was adapted to 91%, ensuring a 5% overall Type 1 error rate for the trial. CONCLUSIONS: Bayesian statistical analysis of natural history data allowed us to reliably simulate the evolution of symptoms for individual patients over time and to probabilistically compare these simulated trajectories to actual observed post-treatment outcomes. The proposed model adequately predicted the natural evolution of patients over the duration of the study and will facilitate a sufficiently powerful trial design that can cope with the disease's rarity. Further research and ongoing dialog with regulatory authorities are needed to allow for more applications of Bayesian statistics in orphan disease research.
Aitken M, Mercer EJ, McKemey A. Understanding neuromuscular disease care: current state and future prospects. IQVIA Institute for Human Data Science. 2018. https://www.iqvia.com/insights/the-iqvia-institute/reports/understanding-neuromuscular-disease-care. Accessed 09 June 2020.
Mendell JR, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L, Lowes LP, et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013. 10.1002/ana.23982. DOI: 10.1002/ana.23982
Desnick RJ. Enzyme replacement therapy for Fabry disease: Lessons from two α-galactosidase A orphan products and one FDA approval. Expert Opin Biol Ther. 2004;4(7):1167–76. 10.1517/14712598.4.7.1167. DOI: 10.1517/14712598.4.7.1167
Al-Zaidy SA, Kolb SJ, Lowes L, Alfano LN, Shell R, Church KR, et al. AVXS-101 (Onasemnogene Abeparvovec) for SMA1: comparative study with a prospective natural history cohort. J Neuromuscul Dis. 2019;6(3):307–17. 10.3233/JND-190403. DOI: 10.3233/JND-190403
European Medicines Agency. Myozyme EPAR - Scientific discussion. 2006. https://www.ema.europa.eu/en/documents/scientific-discussion/myozyme-epar-scientific-discussion_en.pdf. Accessed 22 May 2020.
Chabanon A, Seferian AM, Daron A, Péréon Y, Cances C, Vuillerot C, et al. Prospective and longitudinal natural history study of patients with Type 2 and 3 spinal muscular atrophy: Baseline data NatHis-SMA study. PLoS ONE. 2018;13(7):e0201004. 10.1371/journal.pone.0201004. DOI: 10.1371/journal.pone.0201004
Food and Drug Administration. Surrogate Endpoint Resources for Drug and Biologic Development. https://www.fda.gov/drugs/development-resources/surrogate-endpoint-resources-drug-and-biologic-development. Accessed 26 October 2019.
Charleston JS, Schnell FJ, Dworzak J, Donoghue C, Lewis S, Chen L, et al. Eteplirsen treatment for Duchenne muscular dystrophy. Neurology. 2018;90(24):e2146–54. 10.1212/WNL.0000000000005680. DOI: 10.1212/WNL.0000000000005680
Frank DE, Schnell FJ, Akana C, El-Husayni SH, Desjardins CA, Morgan J, et al. Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. Neurology. 2020;94:e2270–82. 10.1212/WNL.0000000000009233. DOI: 10.1212/WNL.0000000000009233
Aartsma-Rus A, Goemans N. A Sequel to the Eteplirsen Saga: Eteplirsen is approved in the United States but was not approved in Europe. Nucleic Acid Ther. 2019;29(1):13–5. 10.1089/nat.2018.0756. DOI: 10.1089/nat.2018.0756
Goldman AI, Carlin BP, Crane LR, Launer C, Korvick JA, Deyton L, et al. Response of CD4 lymphocytes and clinical consequences of treatment using ddI or ddC in patients with advanced HIV infection. J Acquir Immune Defic Syndr Hum Retrovirol. 1996;11(2):161–9. 10.1097/00042560-199602010-00007. DOI: 10.1097/00042560-199602010-00007
European Medicines Agency. Myozyme. https://www.ema.europa.eu/en/medicines/human/EPAR/myozyme. Accessed 26 October 2019.
Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377:1713–22. 10.1056/NEJMoa1706198. DOI: 10.1056/NEJMoa1706198
Food and Drug Administration. Rare Diseases: Common Issues in Drug Development Guidance for Industry Draft Guidance. Cent Drug Eval Res Cent Biol Eval Res. 2019; Revision 1:1–27. https://www.fda.gov/media/119757/download. Accessed 22 May 2020.
Carlin BP, Louis TA. Bayesian Methods for Data Analysis. 3rd ed. Boca Raton, FL: Chapman and Hall/CRC Press; 2009.
European Medicines Agency. Concept paper on extrapolation of efficacy and safety in medicine development; London; EMA/129698/2012. 2013;44. 2013. https://www.ema.europa.eu/en/documents/scientific-guideline/concept-paper-extrapolation-efficacy-safety-medicine-development_en.pdf. Accessed 22 May 2020.
European Medicines Agency. Regulatory Science Strategy to 2025 Human Stakeholder Workshop. Foster Innovation in clinical trials. Slide presentation, 19 November 2019. https://www.ema.europa.eu/en/documents/presentation/presentation-ema-regulatory-science-2025-foster-innovation-clinical-trials_en.pdf. Accessed 22 May 2020.
Food and Drug Administration. Adaptive Designs for Clinical Trials of Drugs and Biologics FDA Guidance for Industry. Cent Drug Eval Res Cent Biol Eval Res. 2019; https://www.fda.gov/media/78495/download. Accessed 22 May 2020.
Food and Drug Administration. Interacting with the FDA on Complex Innovative Trial Designs for Drugs and Biological Products: Guidance for Industry. Cent Drug Eval Res Cent Biol Eval Res. 2019; https://www.fda.gov/media/130897/download. Accessed 22 May 2020.
Food and Drug Administration. Leveraging Existing Clinical Data for Extrapolation to Pediatric Uses of Medical Devices Draft Guidance for Industry and Food and Drug Administration Staff. Cent Devices Radiol Heal Cent Biol Eval Res. 2016; 1–37. https://www.fda.gov/media/91889/download. Accessed 22 May 2020.
Annoussamy M, Lilien C, Gidaro T, Gargaun E, Chê V, Schara U, et al. X-linked myotubular myopathy: a prospective international natural history study. Neurology. 2019;92(16):e1852–67. 10.1212/WNL.0000000000007319. DOI: 10.1212/WNL.0000000000007319
Vandersmissen I, Biancalana V, Servais L, Dowling JJ, Vander Stichele G, Van Rooijen S, et al. An integrated modelling methodology for estimating the prevalence of centronuclear myopathy. Neuromuscul Disord. 2018;28(9):766–77. 10.1016/j.nmd.2018.06.012. DOI: 10.1016/j.nmd.2018.06.012
Laporte J, Hu LJ, Kretz C, Mandel JL, Kioschis P, Coy JF, et al. A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast. Nat Genet. 1996;13(2):175–82. 10.1038/ng0696-175. DOI: 10.1038/ng0696-175
Bitoun M, Maugenre S, Jeannet PY, Lacène E, Ferrer X, Laforêt P, et al. Mutations in dynamin 2 cause dominant centronuclear myopathy. Nat Genet. 2005;37(11):1207–9. 10.1038/ng1657. DOI: 10.1038/ng1657
Böhm J, Biancalana V, Malfatti E, Dondaine N, Koch C, Vasli N, et al. Adult-onset autosomal dominant centronuclear myopathy due to BIN1 mutations. Brain. 2014;137(12):3160–70. 10.1093/brain/awu272. DOI: 10.1093/brain/awu272
Nicot AS, Toussaint A, Tosch V, Kretz C, Wallgren-Pettersson C, Iwarsson E, et al. Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy. Nat Genet. 2007;39(9):1134–9. 10.1038/ng2086. DOI: 10.1038/ng2086
Amburgey K, Tsuchiya E, Chastonay SD, Glueck M, Alverez R, Nguyen C-T, et al. A natural history study of X-linked myotubular myopathy. Neurology. 2017;89(13):1355–64. 10.1212/wnl.0000000000004415. DOI: 10.1212/wnl.0000000000004415
Graham RJ, Muntoni F, Hughes I, Yum SW, Kuntz NL, Yang ML, et al. Mortality and respiratory support in X-linked myotubular myopathy: a RECENSUS retrospective analysis. Arch Dis Child. 2019;105(4):332–8. 10.1136/archdischild-2019-317910. DOI: 10.1136/archdischild-2019-317910
Tasfaout H, Cowling BS, Laporte J. Centronuclear myopathies under attack: a plethora of therapeutic targets. J Neuromuscul Dis. 2018;5(4):387–406. 10.3233/JND-180309. DOI: 10.3233/JND-180309
Goemans N, van den Hauwe M, Wilson R, van Impe A, Klingels K, Buyse G. Ambulatory capacity and disease progression as measured by the 6-minute-walk-distance in Duchenne muscular dystrophy subjects on daily corticosteroids. Neuromuscul Disord. 2013;23:618–23. 10.1016/j.nmd.2013.05.006. DOI: 10.1016/j.nmd.2013.05.006
Buyse GM, Voit T, Schara U, Straathof CSM, D’Angelo MG, Bernert G, et al. Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids (DELOS): a double-blind randomised placebo-controlled phase 3 trial. Lancet. 2015;385(9979):1748–57. 10.1016/S0140-6736(15)60025-3. DOI: 10.1016/S0140-6736(15)60025-3
Quintana M, Shrader J, Slota C, Joe G, McKew JC, Fitzgerald M, et al. Bayesian model of disease progression in GNE myopathy. Stat Med. 2019;38(8):1459–74. 10.1002/sim.8050. DOI: 10.1002/sim.8050
Ramanan AV, Hampson LV, Lythgoe H, Jones AP, Hardwick B, Hind H, et al. Defining consensus opinion to develop randomised controlled trials in rare diseases using Bayesian design: an example of a proposed trial of adalimumab versus pamidronate for children with CNO/CRMO. PLoS ONE. 2019;14(6):1–16. 10.1371/journal.pone.0215739. DOI: 10.1371/journal.pone.0215739
Brard C, Piperno-Neumann S, Delaye J, Brugières L, Hampson LV, Le Teuff G, et al. Sarcome-13/OS2016 trial protocol: a multicentre, randomised, open-label, phase II trial of mifamurtide combined with postoperative chemotherapy for patients with newly diagnosed high-risk osteosarcoma. BMJ Open. 2019;9(5):1–9. 10.1186/s12874-019-0714-z. DOI: 10.1186/s12874-019-0714-z
Cooner F, Williamson F, Carlin BP. Bayesian frameworks for rare disease clinical development programs. In: Lesaffre E, Boulanger B, Baio G, editors. Bayesian methods in pharmaceutical research. Boca Raton: Taylor and Francis/CRC Press; 2020. p. 243–57. DOI: 10.1201/9781315180212-12
Chow S-C, Chang Y-W. Statistical considerations for rare diseases drug development. J Biopharm Stat. 2019;29(5):874–86. 10.1080/10543406.2019.1657441. DOI: 10.1080/10543406.2019.1657441
Berry SM, Carlin BP, Lee JJ, Muller P. Bayesian adaptive methods for clinical trials. Boca Raton: Chapman and Hall/CRC Press; 2011.
McEntagart M, Parsons G, Buj-Bello A, Biancalana V, Fenton I, Little M, et al. Genotype-phenotype correlations in X-linked myotubular myopathy. Neuromuscul Disord. 2002;12(10):939–46. 10.1016/S0960-8966(02)00153-0. DOI: 10.1016/S0960-8966(02)00153-0
Beggs AH, Byrne BJ, De CS, Hughes I, James ES, Kuntz NL, et al. A multicenter, retrospective medical record review of X-linked myotubular myopathy: the RECENSUS study. Muscle Nerve. 2017;57(4):1–37. 10.1002/mus.26018. DOI: 10.1002/mus.26018
Biancalana V, Caron O, Gallati S, Baas F, Kress W, Novelli G, et al. Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with a very mild phenotype. Hum Genet. 2003;112(2):135–42. 10.1007/s00439-002-0869-1. DOI: 10.1007/s00439-002-0869-1
Monseur A, Boulanger B, Thielemans L, Khazal P, Freitag C, Carlin B, Seferian A et al. Hierarchical Bayesian model of disease progression in centronuclear myopathy for demonstrating treatment efficacy with a small sample size. Poster Presented at WMS Conference 2020.
Goemans N, Signorovitch J, Sajeev G, Yao Z, Gordish-Dressman H, McDonald CM, et al. Suitability of external controls for drug evaluation in Duchenne muscular dystrophy. Neurology. 2020;95(10):1381–91. 10.1212/WNL.0000000000010170. DOI: 10.1212/WNL.0000000000010170
Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C, Connolly AM, et al. Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med. 2018;378:625–35. 10.1056/NEJMoa1702752. DOI: 10.1056/NEJMoa1702752
Dangouloff T, Servais L. Clinical evidence supporting early treatment of patients with spinal muscular atrophy: Current perspectives. Ther Clin Risk Manag. 2019;15:1153–61. 10.2147/TCRM.S172291. DOI: 10.2147/TCRM.S172291
Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377:1723–32. 10.1056/NEJMoa1702752. DOI: 10.1056/NEJMoa1702752
De Vivo DC, Bertini E, Swoboda KJ, Hwu WL, Crawford TO, Finkel RS, et al. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study. Neuromuscul Disord. 2019;29(11):842–56. 10.1016/j.nmd.2019.09.007. DOI: 10.1016/j.nmd.2019.09.007
Dangouloff T, Burghes A, Tizzano EF, Servais L, NBS SMA Study Group. 244th ENMC international workshop: newborn screening in spinal muscular atrophy May 10–12, 2019, Hoofdorp, The Netherlands. Neuromuscul Disord. 2020;30(1):93–103. 10.1016/j.nmd.2019.11.002. DOI: 10.1016/j.nmd.2019.11.002
Jalali A, Rothwell E, Botkin JR, Anderson RA, Butterfield RJ, Nelson RE. Cost-effectiveness of Nusinersen and universal newborn screening for spinal muscular atrophy. J Pediatr. 2020;11:S0022-3476(20)30876-3. 10.1016/j.jpeds.2020.07.033. DOI: 10.1016/j.jpeds.2020.07.033
