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Orphan drug development: the increasing role of clinical pharmacology

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Abstract

Over the last few decades there has been a paradigm shift in orphan drug research and development. The development of the regulatory framework, establishment of rare disease global networks that support drug developments, and advances in technology, has resulted in tremendous growth in orphan drug development. Nevertheless, several challenges during orphan drug development such as economic constraints; insufficient clinical information; fewer patients and thus inadequate power; etc. still exist. While the standard regulatory requirements for drug approval stays the same, applications of scientific judgment and regulatory flexibility is significantly important to help meeting some of the immense unmet medical need in rare diseases. Clinical pharmacology presents a vital role in accelerating orphan drug development and overcoming some of these challenges. This review highlights the critical contributions of clinical pharmacology in orphan drug development; for example, dose finding, optimizing clinical trial design, indication expansion, and population extrapolation. Examples of such applications are reviewed in this article.

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References

  1. FDA Final Rule. CFR 316. Orphan Drug Regulations 57 FR 62076 December 29, 1992

  2. European Commission (2008) Communication from the commission to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions on Rare Diseases: Europe’s challenges. http://ec.europa.eu/health/ph_threats/non_com/docs/rare_com_en.pdf. Accessed 2 Dec 2018

  3. U.S. Department of Health and Human Services. National Institute of Health. NCATS and rare diseases research (updated 12 Feb 2018). https://ncats.nih.gov/rdd. Accessed 2 Dec 2018

  4. Report: complex issues in developing drugs and biological products for rare diseases and accelerating the development of therapies for pediatric rare diseases including strategic plan: accelerating the development of therapies for pediatric rare diseases. https://www.fda.gov/downloads/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/FDASIA/UCM404104.pdf. Accessed 2 Dec 2018

  5. Augustine EF, Adams HR, Mink JW (2013) Clinical trials in rare disease: challenges and opportunities. J Child Neurol 28(9):1142–1150

    PubMed  PubMed Central  Google Scholar 

  6. U.S. Food and Drug Administration (2015) Rare diseases: common issues in drug development. Guidance for industry. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM458485.pdf. Accessed 2 Dec 2018

  7. Orphan Drug Act: Public Law 97-414 (1983)

  8. Rinaldi A (2005) Adopting an orphan: incentives to develop drugs for rare disorders raise hopes and controversy. EMBO Rep 6(6):507–510

    CAS  PubMed  PubMed Central  Google Scholar 

  9. U.S. Food and Drug Administration (2017) Pediatric rare diseases—a collaborative approach for drug development using gaucher disease as a model: guidance for industry

  10. Committee for Medicinal Products for Human Use. Guideline on clinical trials in small populations 2006. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003615.pdf. Accessed 2 Dec 2018

  11. U.S. Food and Drug Administration (2018) Duchenne muscular dystrophy and related dystrophinopathies: developing drugs for treatment. Guidance for industry. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM450229.pdf. Accessed 2 Dec 2018

  12. U.S. Food and Drug Administration (2018) Amyotrophic lateral sclerosis: developing drugs for treatment: guidance for industry. https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm596718.pdf. Accessed 2 Dec 2018

  13. Drug Approval Package: Bavencio® (avelumab) Application No. 761049. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761049Orig1s000MultidisciplineR.pdf. Accessed 2 Dec 2018

  14. Drug Approval Package: Ilaris® (canakinumab) Application No. 125319. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125319Orig1s085,086,087ClinPharmR.pdf. Accessed 2 Dec 2018

  15. Drug Approval Package: Xenazine® tablets (tetrabenazine) Application No. 021894. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/021894s000TOC.cfm. Accessed 2 Dec 2018

  16. XENAZINE® (tetrabenazine) tablet: prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021894s010lbl.pdf. Accessed 2 Dec 2018

  17. Wagner C, Zhao P, Pan Y, Hsu V, Grillo J, Huang S et al (2015) Application of physiologically based pharmacokinetic (PBPK) modeling to support dose selection: report of an FDA public workshop on PBPK. CPT Pharmacomet Syst Pharmacol 4(4):226–230

    CAS  Google Scholar 

  18. Zhao P, Zhang L, Grillo J, Liu Q, Bullock J, Moon Y et al (2011) Applications of physiologically based pharmacokinetic (PBPK) modeling and simulation during regulatory review. Clin Pharmacol Ther 89(2):259–267

    CAS  PubMed  Google Scholar 

  19. Garnett CE, Lee JY, Gobburu JV (2011) Contribution of modeling and simulation in the regulatory review and decision-making: US FDA perspective. Clinical trial simulations. Springer, New York, pp 37–57

    Google Scholar 

  20. Bhattaram V, Bonapace C, Chilukuri D, Duan J, Garnett C, Gobburu J et al (2007) Impact of pharmacometric reviews on new drug approval and labeling decisions—a survey of 31 new drug applications submitted between 2005 and 2006. Clin Pharmacol Ther 81(2):213–221

    CAS  PubMed  Google Scholar 

  21. Bhattaram VA, Booth BP, Ramchandani RP, Beasley BN, Wang Y, Tandon V et al (2005) Impact of pharmacometrics on drug approval and labeling decisions: a survey of 42 new drug applications. AAPS J 7(3):E503–E512

    PubMed  PubMed Central  Google Scholar 

  22. Lee JY, Garnett CE, Gobburu JV, Bhattaram VA, Brar S, Earp JC et al (2011) Impact of pharmacometric analyses on new drug approval and labelling decisions. Clin Pharmacokinet 50(10):627–635

    PubMed  Google Scholar 

  23. Brooke MH, Fenichel GM, Griggs RC, Mendell JR, Moxley R, Miller JP et al (1983) Clinical investigation in Duchenne dystrophy: 2. Determination of the “power” of therapeutic trials based on the natural history. Muscle Nerve Off J Am Assoc Electrodiagn Med 6(2):91–103

    CAS  Google Scholar 

  24. Schuelke M, Wagner KR, Stolz LE, Hübner C, Riebel T, Kömen W et al (2004) Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med 350(26):2682–2688

    CAS  PubMed  Google Scholar 

  25. Bhattacharya I, Manukyan Z, Chan P, Harnisch L, Heatherington A (2016) Making every subject count: a case study of drug development path for medication in a pediatric rare disease. Clin Pharmacol Ther 100(4):330–332

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Pfizer terminates domagrozumab (pf-06252616) clinical studies for the treatment of Duchenne muscular dystrophy. https://www.pfizer.com/news/press-release/press-release-detail/pfizer_terminates_domagrozumab_pf_06252616_clinical_studies_for_the_treatment_of_duchenne_muscular_dystrophy. Accessed 2 Dec 2018

  27. Yoneyama K, Schmitt C, Kotani N, Levy GG, Kasai R, Iida S et al (2017) A pharmacometric approach to substitute for a conventional dose-finding study in rare diseases: example of Phase III dose selection for emicizumab in hemophilia A. Clin Pharmacokinet. https://doi.org/10.1007/s40262-017-0616-3

    Article  PubMed Central  Google Scholar 

  28. Rosendaal F (2001) Definitions in hemophilia, Recommendation of the Scientific Subcommittee on Factor VIII and Factor IX of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis Factor VII and Factor IX Subcommittee

  29. Biggs R, Macfarlane R (1958) Haemophilia and related conditions: a survey of 187 cases. Br J Haematol 4(1):1–27

    CAS  PubMed  Google Scholar 

  30. Ahmed MA, Kartha RV, Brundage RC, Cloyd J, Basu C, Carlin BP et al (2016) A model-based approach to assess the exposure–response relationship of Lorenzo’s oil in adrenoleukodystrophy. Br J Clin Pharmacol 81(6):1058–1066

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Basu C, Ahmed MA, Kartha RV, Brundage RC, Raymond GV, Cloyd JC et al (2016) A hierarchical Bayesian approach for combining pharmacokinetic/pharmacodynamic modeling and Phase IIa trial design in orphan drugs: treating adrenoleukodystrophy with Lorenzo’s oil. J Biopharm Stat 26(6):1025–1039

    PubMed  PubMed Central  Google Scholar 

  32. U.S. Food and Drug Administration (2007) FDA approves first-of-its-kind drug to treat rare blood disorder. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108869.htm. Accessed 2 Dec 2018

  33. SOLIRIS® (eculizumab): prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/125166lbl.pdf. Accessed 2 Dec 2018

  34. Lathia C, Kassir N, Mouksassi M, Jayaraman B, Marier J, Bedrosian C (eds) (2014) Modeling and simulation of eculizumab in paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) patients: learning from one indication to the next. In: Presented at the American Society for Clinical Pharmacology and Therapeutics (ASCPT) annual meeting

  35. Lathia C, Kassir N, Mouksassi M, Jayaraman B, Marier J, Bedrosian C (2014) PK/PD modeling of eculizumab and free complement component protein C5 in pediatric and adult patients with atypical hemolytic uremic syndrome (aHUS). Clin Pharmacol Ther 95(1):S97

    Google Scholar 

  36. Drug Approval Package: Soliris® (eculizumab) Application No. 125166s172 (2011). https://www.accessdata.fda.gov/drugsatfda_docs/bla/2011/125166Orig1s172-2.pdf. Accessed 2 Dec 2018

  37. U.S. Food and Drug Administration. Fast track, breakthrough therapy, accelerated approval and priority review 2013. https://www.fda.gov/forpatients/approvals/fast/default.htm. Accessed 2 Dec 2018

  38. BLA 125166/368 and 125166/380: supplement approval. Fulfillment of postmarketing requirement (2014). https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/125166Orig1s368,125166Orig1s380ltr.pdf. Accessed 2 Dec 2018

  39. The Clinical and Functional TRanslation of CFTR (CFTR2) (updated 12/08/2017). https://www.cftr2.org/mutations_history. Accessed 2 Dec 2018

  40. Yu H, Burton B, Huang C-J, Worley J, Cao D, Johnson JP et al (2012) Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros 11(3):237–245

    CAS  PubMed  Google Scholar 

  41. Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T et al (2009) Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci USA 106(44):18825–18830

    PubMed  PubMed Central  Google Scholar 

  42. U.S. Food and Drug Administration. Drugs@FDA: FDA approved drug products. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=203188. Accessed 2 Dec 2018

  43. Drug Approval Package: Kalydeco® (ivacaftor). Application No. 203188 (updated 13 March 2012). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203188s000TOC.cfm. Accessed 2 Dec 2018

  44. Durmowicz AG, Lim R, Rogers H, Rosebraugh CJ, Chowdhury BA (2018) The US Food and Drug Administration’s experience with ivacaftor in cystic fibrosis. Establishing efficacy using in vitro data in lieu of a clinical trial. Ann Am Thorac Soc 15(1):1–2

    PubMed  Google Scholar 

  45. U.S. Food and Drug Administration. FDA News Release: FDA expands approved use of Kalydeco to treat additional mutations of cystic fibrosis (updated 28 March 2018). https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm559212.htm. Accessed 2 Dec 2018

  46. U.S. Food and Drug Administration. Novel approach allows expansion of indication for cystic fibrosis drug (updated 18 May 2017). https://www.fda.gov/Drugs/NewsEvents/ucm559051.htm. Accessed 2 Dec 2018

  47. ICH. Addendum to ICH E11: clinical investigation of medicinal products in the pediatric population (Addendum). ICH. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E11/E11-R1EWG_Step4_Addendum_2017_0818.pdf. Accessed 2 Dec 2018

  48. European Medicine Agency (2018) Reflection paper on the use of extrapolation in the development of medicines for paediatrics. https://www.ema.europa.eu/documents/scientific-guideline/adopted-reflection-paper-use-extrapolation-development-medicines-paediatrics-revision-1_en.pdf. Accessed 2 Dec 2018

  49. Labrecque G, Bureau JP, Reinberg AE (1995) Biological rhythms in the inflammatory response and in the effects of non-steroidal anti-inflammatory drugs. Pharmacol Ther 66(2):285–300

    CAS  PubMed  Google Scholar 

  50. Kramer A, Yang FC, Snodgrass P, Li X, Scammell TE, Davis FC et al (2001) Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science 294(5551):2511–2515

    CAS  PubMed  Google Scholar 

  51. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J et al (2005) Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 353(23):2462–2476

    CAS  PubMed  Google Scholar 

  52. Hyams J, Crandall W, Kugathasan S, Griffiths A, Olson A, Johanns J et al (2007) Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology 132(3):863–873

    CAS  PubMed  Google Scholar 

  53. Hyams J, Damaraju L, Blank M, Johanns J, Guzzo C, Winter HS et al (2012) Induction and maintenance therapy with infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol 10(4):391–399.e1

    CAS  PubMed  Google Scholar 

  54. Sauer CG, Kugathasan S (2010) Pediatric inflammatory bowel disease: highlighting pediatric differences in IBD. Med Clin 94(1):35–52

    CAS  Google Scholar 

  55. Hyams JS, Lerer T, Griffiths A, Pfefferkorn M, Stephens M, Evans J et al (2010) Outcome following infliximab therapy in children with ulcerative colitis. Am J Gastroenterol 105(6):1430

    CAS  PubMed  Google Scholar 

  56. Gamalo-Siebers M, Savic J, Basu C, Zhao X, Gopalakrishnan M, Gao A et al (2017) Statistical modeling for Bayesian extrapolation of adult clinical trial information in pediatric drug evaluation. Pharm Stat 16(4):232–249

    PubMed  Google Scholar 

  57. Fleming TR, Powers JH (2012) Biomarkers and surrogate endpoints in clinical trials. Stat Med 31(25):2973–2984

    PubMed  PubMed Central  Google Scholar 

  58. Simonneau G, Galiè N, Rubin LJ, Langleben D, Seeger W, Domenighetti G et al (2004) Clinical classification of pulmonary hypertension. J Am Coll Cardiol 43(12 Supplement):S5–S12

    Google Scholar 

  59. Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H et al (2004) Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 43(12 Supplement):S40–S47

    Google Scholar 

  60. Barst RJ (2001) Medical therapy of pulmonary hypertension: an overview of treatment and goals. Clin Chest Med 22(3):509–515

    CAS  PubMed  Google Scholar 

  61. Rubin LJ (1997) Primary pulmonary hypertension. N Engl J Med 336(2):111–117

    CAS  PubMed  Google Scholar 

  62. Mehta S, McCormack DG (2002) Pathophysiology of pulmonary vascular disease. In: Drugs for the treatment of respiratory diseases. Cambridge University Press, Cambridge, pp 453–472

  63. Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D et al (2005) Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353(20):2148–2157

    PubMed  Google Scholar 

  64. Division of Cardio-Renal Products. Medical review. Revatio® (sildenafil) tablets. Application No. 21845. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021845s000_Revatio_medr.pdf. Accessed 2 Dec 2018

  65. Office of Clinical Pharmacology Review. Revatio® (sildenafil citrate) powder for oral suspension. Application No. 203109. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM320473.pdf. Accessed 2 Dec 2018

  66. Barst RJ, Ivy DD, Gaitan G, Szatmari A, Rudzinski A, Garcia AE et al (2012) A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension clinical perspective. Circulation 125(2):324–334

    CAS  PubMed  Google Scholar 

  67. Holford NH (1996) A size standard for pharmacokinetics. Clin Pharmacokinet 30(5):329–332

    CAS  PubMed  Google Scholar 

  68. West GB, Brown JH, Enquist BJ (1997) A general model for the origin of allometric scaling laws in biology. Science 276(5309):122–126

    CAS  PubMed  Google Scholar 

  69. Barst RJ, Beghetti M, Pulido T, Layton G, Konourina I, Zhang M et al (2014) STARTS-2 clinical perspective: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension. Circulation 129(19):1914–1923

    CAS  PubMed  Google Scholar 

  70. Harnisch L. Revatio in paediatric pulmonary arterial hypertension (PAH), an orphan indication. Pfizer. http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2011/11/WC500118284.pdf. Accessed 2 Dec 2018

  71. Briefing Information for the July 29, 2010 Meeting of the Cardiovascular and Renal Drugs Advisory Committee. https://wayback.archive-it.org/7993/20170404150601/https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ucm220249.htm. Accessed 2 Dec 2018

  72. Chanu P, Gao X, Smith M, Bruno R, Harnisch L (2011) A dose selection rationale based on hemodynamics for sildenafil in pediatric patients with pulmonary arterial hypertension (PAH). Pediatrics 80(10):20

    Google Scholar 

  73. Chanu P, Gao X, Smith M, Bruno R, Harnisch L (2011) Hemodynamics as an additional measure to prove efficacy and to provide a dose rationale for sildenafil in pediatric patients with pulmonary arterial hypertension (PAH). Am J Respir Crit Care Med 183:A6281

    Google Scholar 

  74. Center of Drug Evaluation and Research. Administrative and correspondence documents. Revatio (sildenafil). Application No. 203109. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203109Orig1s000AdminCorres.pdf. Accessed 2 Dec 2018

  75. Galiè N, Humbert M, Vachiery J-L, Gibbs S, Lang I, Torbicki A et al (2015) 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 37(1):67–119

    PubMed  Google Scholar 

  76. Kenyon KW, Nappi JM (2003) Bosentan for the treatment of pulmonary arterial hypertension. Ann Pharmacother 37(7–8):1055–1062

    CAS  PubMed  Google Scholar 

  77. Macp F (2008) Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland. Heart 94:i1–i41

    Google Scholar 

  78. Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF et al (2001) Effects of the dual endothelin-receptor antagonist Bosentan in patients with pulmonary hypertension: a randomised placebo controlled study. Lancet 358(9288):1119–1123

    CAS  PubMed  Google Scholar 

  79. Rubin LJ, Badesch DB, Barst RJ, Galiè N, Black CM, Keogh A et al (2002) Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 346(12):896–903

    CAS  PubMed  Google Scholar 

  80. TRACLEER® (bosentan) film-coated tablets: prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2001/21290lbl.pdf. Accessed 2 Dec 2018

  81. Barst RJ, Ivy D, Dingemanse J, Widlitz A, Schmitt K, Doran A et al (2003) Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther 73(4):372–382

    CAS  PubMed  Google Scholar 

  82. Beghetti M, Haworth SG, Bonnet D, Barst RJ, Acar P, Fraisse A et al (2009) Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: the FUTURE-1 study. Br J Clin Pharmacol 68(6):948–955

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Berger RM, Haworth SG, Bonnet D, Dulac Y, Fraisse A, Galiè N et al (2016) FUTURE-2: results from an open-label, long-term safety and tolerability extension study using the pediatric FormUlation of bosenTan in pUlmonary arterial hypeRtEnsion. Int J Cardiol 202:52–58

    PubMed  Google Scholar 

  84. Berger RM, Gehin M, Beghetti M, Ivy D, Kusic-Pajic A, Cornelisse P et al (2017) A bosentan pharmacokinetic study to investigate dosing regimens in paediatric patients with pulmonary arterial hypertension: FUTURE-3. Br J Clin Pharmacol 83(8):1734–1744

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Clinical/clinical pharmacology efficacy review: Tracleer (bosentan) dispersible tablets. Application No. 0209279. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209279Orig1s000MedR.pdf. Accessed 2 Dec 2018

  86. Prentice RL (1989) Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med 8(4):431–440

    CAS  PubMed  Google Scholar 

  87. Bell SA, Smith CT (2014) A comparison of interventional clinical trials in rare versus non-rare diseases: an analysis of ClinicalTrials.gov. Orphanet J Rare Dis 9(1):170

    PubMed  PubMed Central  Google Scholar 

  88. Kesselheim AS, Myers JA, Avorn J (2011) Characteristics of clinical trials to support approval of orphan vs nonorphan drugs for cancer. JAMA 305(22):2320–2326

    CAS  PubMed  Google Scholar 

  89. Mitsumoto J, Dorsey E, Beck CA, Kieburtz K, Griggs RC (2009) Pivotal studies of orphan drugs approved for neurological diseases. Ann Neurol 66(2):184–190

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Joppi R, Garattini S (2013) Orphan drugs, orphan diseases. The first decade of orphan drug legislation in the EU. Eur J Clin Pharmacol 69(4):1009–1024

    PubMed  Google Scholar 

  91. Evaluate Pharma. Orphan drug report 2014. http://info.evaluategroup.com/rs/evaluatepharmaltd/images/2014OD.pdf. Accessed 2 Dec 2018

  92. Cornu C, Kassai B, Fisch R, Chiron C, Alberti C, Guerrini R et al (2013) Experimental designs for small randomised clinical trials: an algorithm for choice. Orphanet J Rare Dis 8(1):48

    PubMed  PubMed Central  Google Scholar 

  93. Abrahamyan L, Feldman BM, Tomlinson G, Faughnan ME, Johnson SR, Diamond IR et al (2016) Alternative designs for clinical trials in rare diseases. Am J Med Genet C. https://doi.org/10.1002/ajmg.c.31533

    Article  Google Scholar 

  94. Bogaerts J, Sydes MR, Keat N, McConnell A, Benson A, Ho A et al (2015) Clinical trial designs for rare diseases: studies developed and discussed by the International Rare Cancers Initiative. Eur J Cancer 51(3):271–281

    PubMed  PubMed Central  Google Scholar 

  95. Viceconti M, Henney A, Morley-Fletcher E (2016) In silico clinical trials: how computer simulation will transform the biomedical industry. Int J Clin Trials 3(2):37–46

    Google Scholar 

  96. Nony P, Kurbatova P, Bajard A, Malik S, Castellan C, Chabaud S et al (2014) A methodological framework for drug development in rare diseases. Orphanet J Rare Dis 9(1):164

    PubMed  PubMed Central  Google Scholar 

  97. Kurbatova P, Bajard A, Tiddens H, Volpert V, Cornu C, Bessonov N et al (2014) Modelling and simulation of experimental designs to find the best design of randomized clinical trials in a rare disease: cystic fibrosis. Eur Respir J 44(Suppl 58):P1220

    Google Scholar 

  98. Rare disease use of clinical trial simulation for the choice and optimization of study designs/Priomedchild Call/ER (updated 05/30/2018). http://gtr.ukri.org/projects?ref=MC_G1100157. Accessed 2 Dec 2018

  99. Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW et al (1994) Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med 331(10):637–642

    CAS  PubMed  Google Scholar 

  100. PULMOZYME® (dornase alfa) inhalation solution: prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/103532s5175lbl.pdf. Accessed 2 Dec 2018

  101. Yeh H-C, Schum G (1980) Models of human lung airways and their application to inhaled particle deposition. Bull Math Biol 42(3):461–480

    CAS  PubMed  Google Scholar 

  102. Shak S, Capon DJ, Hellmiss R, Marsters SA, Baker CL (1990) Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. Proc Natl Acad Sci USA 87(23):9188–9192

    CAS  PubMed  PubMed Central  Google Scholar 

  103. International Rare Diseases Research Consortium (2016) Small Population Clinical Trials Task Force workshop report and recommendations. http://www.irdirc.org/wp-content/uploads/2017/12/SPCT_Report.pdf. Accessed 2 Dec 2018

  104. Yero T, Rey JA (2008) Tetrabenazine (Xenazine), an FDA-approved treatment option for Huntington’s disease-related chorea. Pharm Ther 33(12):690

    Google Scholar 

  105. Walker FO (2007) Huntington’s disease. Lancet 369(9557):218–228

    CAS  PubMed  Google Scholar 

  106. Vonsattel JPG, DiFiglia M (1998) Huntington disease. J Neuropathol Exp Neurol 57(5):369

    CAS  PubMed  Google Scholar 

  107. Hayden M (1991) Huntington disease: a disorder of families. Am J Hum Genet 48(1):171

    PubMed Central  Google Scholar 

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  1. Mariam A. Ahmed

    Present address: , 10903 New Hampshire Ave, Silver Spring, MD, 20993, USA

Authors and Affiliations

  1. Department of Experimental and Clinical Pharmacology, University of Minnesota, Twin Cities, MN, USA

    Mariam A. Ahmed, Richard Brundage & Reena V. Kartha

  2. Clinical Pharmacology Modeling and Simulation (CPMS), GlaxoSmithKline, Upper Providence, PA, USA

    Malek Okour

  3. Center for Orphan Drug Research, University of Minnesota, Twin Cities, MN, USA

    Richard Brundage & Reena V. Kartha

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Ahmed, M.A., Okour, M., Brundage, R. et al. Orphan drug development: the increasing role of clinical pharmacology. J Pharmacokinet Pharmacodyn 46, 395–409 (2019). https://doi.org/10.1007/s10928-019-09646-3

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