The potential investment impact of improved access to accelerated approval on the development of treatments for low prevalence rare diseases

Orphanet Journal of Rare Diseases

Emil D Kakkis¹  Brigitta E Miyamoto¹ 

[1] Kakkis EveryLife Foundation For Rare Diseases, 77 Digital Drive, Suite 210, Novato, CA 94949, USA

关键词: Clinical trials;    Surrogate endpoint;    Drug development;    Rare diseases;    Accelerated approval;   

Others  :  866829
DOI  :  10.1186/1750-1172-6-49

 received in 2011-05-19, accepted in 2011-07-06,  发布年份 2011

【 摘 要 】

Background

Over 95% of rare diseases lack treatments despite many successful treatment studies in animal models. To improve access to treatments, the Accelerated Approval (AA) regulations were implemented allowing the use of surrogate endpoints to achieve drug approval and accelerate development of life-saving therapies. Many rare diseases have not utilized AA due to the difficulty in gaining acceptance of novel surrogate endpoints in untreated rare diseases.

Methods

To assess the potential impact of improved AA accessibility, we devised clinical development programs using proposed clinical or surrogate endpoints for fifteen rare disease treatments.

Results

We demonstrate that better AA access could reduce development costs by approximately 60%, increase investment value, and foster development of three times as many rare disease drugs for the same investment.

Conclusion

Our research brings attention to the need for well-defined and practical qualification criteria for the use of surrogate endpoints to allow more access to the AA approval pathway in clinical trials for rare diseases.

【 授权许可】

   
2011 Miyamoto and Kakkis; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Braun MM, Farag-El-Massah S, Xu K, Cote TR: Emergence of orphan drugs in the United States: a quantitative assessment of the first 25 years. Nat Rev Drug Discov 2010, 9:519-522.
• [2]Temple R: Are surrogate markers adequate to assess cardiovascular disease drugs? JAMA - J Am Med Assn 1999, 282:790-795.
• [3]Code of Federal Regulations, Title 21 [http:/ / www.accessdata.fda.gov/ scripts/ cdrh/ cfdocs/ cfcfr/ CFRSearch.cfm?fr = 314.510] webcite 5
• [4]Accelerated and Restricted Approvals Under Subpart H (drugs) and Subpart E (biologics) [http:/ / www.fda.gov/ Drugs/ DevelopmentApprovalProcess/ HowDrugsareDevelopedandApproved/ DrugandBiologicApprovalReports/ ucm121597.htm] webcite
• [5]Waisbren SE, Noel K, Fahrbach K, Cella C, Frame D, Dorenbaum A, Levy H: Phenylalanine blood levels and clinical outcomes in phenylketonuria: A systematic literature review and meta-analysis. Mol Genet Metab 2007, 92:63-70.
• [6]Brusilow SW, Horwich AL: Urea Cycle Enzymes. In Metabolic and Molecular Bases of Inherited Disease -- OMMBID. Edited by Scriver CR, Childs B, Sly WS, Valle D, Beaudet AL, Vogelstein B, Kinsler KW. New York: McGraw-Hill; 2010.
• [7]Kakkis ED, Muenzer J, Tiller GE, Waber L, Belmont J, Passage M, Izykowski B, Phillips J, Doroshow R, Walot I, Hoft R, Yu KT, Okazaki S, Lewis D, Lachman R, Thompson JN: Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med 2001, 344:182-188.
• [8]Kakkis ED: Enzyme replacement therapy for the mucopolysaccharide storage disorders. Expert Opin Investig Drugs 2002, 11:675-685.
• [9]Barton G: Surrogate end-points for use in phase III clinical trials: their development and role in MAA approval: EFPIA Position Paper Proposals. EMEA/EFPIA Workshop on Biomarkers 2006. London
• [10]Ormarsdottir S, Reginster JY, Abadie E: European regulatory perspectives for innovative therapies. Osteoporosis Int 2008, 19:725-731.
• [11]Heemstra HE, van Weely S, Buller HA, Leufkens HGM, de Vrueh RLA: Translation of rare disease research into orphan drug development: disease matters. Drug Discov Today 2009, 14:1166-1173.
• [12]Worgall S, Sondhi D, Hackett NR, Kosofsky B, Kekatpure MV, Neyzi N, Dyke JP, Ballon D, Heier L, Greenwald BM, Christos P, Mazumdar M, Souweidane MM, Kaplitt MG, Crystal RG: Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum Gene Ther 2008, 19:463-474.
• [13]Wraith JE, Clarke LA, Beck M, Kolodny EH, Pastores GM, Muenzer J, Rapoport DM, Berger KI, Swiedler SJ, Kakkis ED, Braakman T, Chadbourne E, Walton-Bowen K, Cox GF: Enzyme replacement therapy for mucopolysaccharidosis I: A randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (Laronidase). J Pediat 2004, 144:581-588.
• [14]Harmatz P, Giugliani R, Schwariz I, Guffon N, Teles EL, Miranda MCS, Wraith JE, Beck M, Arash L, Scarpa M, Yu ZF, Wittes J, Berger KI, Newman MS, Lowe AM, Kakkis E, Swiedler SJ: Enzyme replacement therapy for mucopolysaccharidosis VI: A Phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (recombinant human arylsulfatase B or rhASB) and follow-on, open-label extension study. J Pediat 2006, 148:533-539.
• [15]Peelen GOH, Dejong JGN, Wevers RA: Hplc Analysis of Oligosaccharides in Urine from Oligosaccharidosis Patients. Clin Chem 1994, 40:914-921.
• [16]Warner TG, Mock AK, Nyhan WL, Obrien JS: Alpha-Mannosidosis - Analysis of Urinary Oligosaccharides with High-Performance Liquid-Chromatography and Diagnosis of A Case with Unusually Mild Presentation. Clin Genet 1984, 25:248-255.
• [17]Mononen I, Kaartinen V, Mononen T: Laboratory Detection of Aspartylglycosaminuria. Scand J Clin Lab Invest 1988, 48:7-11.
• [18]Takahashi Y, Nakamura Y, Yamaguchi S, Orii T: Urinary Oligosaccharide Excretion and Severity of Galactosialidosis and Sialidosis. Clin Chim Acta 1991, 203:199-210.
• [19]Tomatsu S, Okamura K, Taketani T, Orii KO, Nishioka T, Gutierrez MA, Velez-Castrillon S, Fachel AA, Grubb JH, Cooper A, Thornley M, Wraith E, Barrera LA, Giugliani R, Schwartz IV, Frenking GS, Beck M, Kircher SG, Paschke E, Yamaguchi S, Ullrich K, Isogai K, Suzuki Y, Orii T, Kondo N, Creer M, Noguchi A: Development and testing of new screening method for keratan sulfate in mucopolysaccharidosis IVA. Pediat Res 2004, 55:592-597.
• [20]Kaye EM, Ullman MD, Kolodny EH, Krivit W, Rischert JC: Possible Use of Csf Glycosphingolipids for the Diagnosis and Therapeutic Monitoring of Lysosomal Storage Diseases. Neurology 1992, 42:2290-2294.
• [21]Muenzer J, Wraith JE, Beck M, Giugliani R, Harmatz P, Eng CM, Vellodi A, Martin R, Ramaswami U, Gucsavas-Calikoglu M, Vijayaraghavan S, Wendt S, Puga A, Ulbrich B, Shinawi M, Cleary M, Piper D, Conway AM, Kimura A: A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet Med 2006, 8:465-473.
• [22]Assmann G, Seedorf U: Acid Lipase Deficiency: Wolman Disease and Cholesteryl Ester Storage Disease. In Metabolic and Molecular Bases of Inherited Disease -- OMMBID. Edited by Scriver CR, Childs B, Sly WS, Valle D, Beaudet AL, Vogelstein B, Kinsler KW. New York: McGraw-Hill; 2010.
• [23]Lieske JC, Monico CG, Holmes WS, Bergstralh EJ, Slezak JM, Rohlinger AL, Olson JB, Milliner DS: International registry for primary Hyperoxaluria. Amer J Nephrol 2005, 25:290-296.
• [24]Tabolli S, Sampogna F, Di Pietro C, Paradisi A, Uras C, Zotti P, Castiglia D, Zambruno G, Abeni D: Quality of life in patients with epidermolysis bullosa. Brit J Dermatol 2009, 161:869-877.
• [25]Clarke A, Phillips DIM, Brown R, Harper PS: Clinical Aspects of X-Linked Hypohidrotic Ectodermal Dysplasia. Arch Dis Child 1987, 62:989-996.
• [26]Niehues R, Hasilik M, Alton G, Korner C, Schiebe-Sukumar M, Koch HG, Zimmer KP, Wu RR, Harms E, Reiter K, von Figura K, Freeze HH, Harms HK, Marquardt T: Carbohydrate-deficient glycoprotein syndrome type Ib - Phosphomannose isomerase deficiency and mannose therapy. J Clin Invest 1998, 101:1414-1420.
• [27]Babovic-Vuksanovic D, Patterson MC, Schwenk WF, O'Brien JF, Vockley J, Freeze HH, Mehta DP, Michels VV: Severe hypoglycemia as a presenting symptom of carbohydrate-deficient glycoprotein syndrome. J Pediat 1999, 135:775-781.
• [28]de Lonlay P, Cuer M, Vuillaumier-Barrot S, Beaune G, Castelnau P, Kretz M, Durand G, Saudubray JM, Seta N: Hypersulinemic hypoglycemia as a presenting sign in phosphomannose isomerase deficiency: A new manifestation of carbohydrate-deficient glycoprotein syndrome treatable with mannose. J Pediat 1999, 135:379-383.
• [29]Tamminga RYJ, Lefeber DJ, Kamps WA, van Spronsen FJ: Recurrent Thrombo-Embolism in A Child with A Congenital Disorder of Glycosylation (Cdg) Type Ib and Treatment with Mannose. Pediatr Hematol Oncol 2008, 25:762-768.
• [30]Westphal V, Kjaergaard S, Davis JA, Peterson SM, Skovby F, Freeze HH: Genetic and metabolic analysis of the first adult with congenital disorder of glycosylation type Ib: Long-term outcome and effects of mannose supplementation. Mol Genet Metab 2001, 73:77-85.
• [31]Milliner DS, Wilson DM, Smith LH: Clinical expression and long-term outcomes of primary hyperoxaluria types 1 and 2. J Nephrology 1998, 11:56-59.
• [32]Latta K, Brodehl J: Primary Hyperoxaluria Type-I. Eur J Pediat 1990, 149:518-522.
• [33]Damen G, de Klerk H, Huijmans J, den Hollander J, Sinaasappel M: Gastrointestinal and other clinical manifestations in 17 children with congenital disorders of glycosylation type IA, Ib, and Ic. J Pediat Gastroenterol Nutr 2004, 38:282-287.
• [34]Harms HK, Zimmer KP, Kurnik K, Bertele-Harms RM, Weidinger S, Reiter K: Oral mannose therapy persistently corrects the severe clinical symptoms and biochemical abnormalities of phosphomannose isomerase deficiency. Acta Paediat 2002, 91:1065-1072.
• [35]Mention K, Lacaille F, Valayannopoulos V, Romano S, Kuster A, Cretz M, Zaidan H, Galmiche L, Jaubert F, de Keyzer Y, Seta N, de Lonlay P: Development of liver disease despite mannose treatment in two patients with CDG-Ib. Mol Genet Metab 2008, 93:40-43.
• [36]Penel-Capelle D, Dobbelaere D, Jaeken J, Klein A, Cartigny M, Weill J: Congenital disorder of glycosylation Ib (CDG-Ib) without gastrointestinal symptoms. J Inherit Metab Dis 2003, 26:83-85.
• [37]Wong T, Gammon L, Liu L, Mellerio JE, Dopping-Hepenstal PJC, Pacy J, Elia G, Jeffery R, Leigh IM, Navsaria H, McGrath JA: Potential of fibroblast cell therapy for recessive dystrophic epidermolysis bullosa. J Invest Dermatol 2008, 128:2179-2189.
• [38]Lexner MO, Bardow A, Hertz JM, Nielsen LA, Kreiborg S: Anomalies of tooth formation in hypohidrotic ectodermal dysplasia. Int J Paediatr Dent 2007, 17:10-18.
• [39]Casal ML, Lewis JR, Mauldin EA, Tardivel A, Ingold K, Favre M, Paradies F, Demotz S, Gaide O, Schneider P: Significant correction of disease after postnatal administration of recombinant ectodysplasin a in canine x-linked ectodermal dysplasia. Amer J Hum Genet 2007, 81:1050-1056.
• [40]Stewart JJ, Allison PN, Johnson RS: Putting a price on biotechnology - Many bioentrepreneurs incorrectly estimate the value of their technology by failing to account adequately for the cost, risk, and time inherent in product development. Nat Biotechnol 2001, 19:813-817.
• [41]Java applets for power and sample size [http://www.stat.uiowa.edu/~rlenth/Power/index.html] webcite
• [42]Sample size for comparing Event Rates between two Independent Cohorts [http://department.obg.cuhk.edu.hk/researchsupport/Sample_size_Comp2Prop.asp] webcite
• [43]Bonten EJ, Wang DN, Toy JN, Mann L, Mignardot A, Yogalingam G, d'Azzo A: Targeting macrophages with baculovirus-produced lysosomal enzymes: implications for enzyme replacement therapy of the glycoprotein storage disorder galactosialidosis. FASEB J 2004, 18:971-992.
• [44]Chang M, Cooper JD, Sleat DE, Cheng SH, Dodge JC, Passini MA, Lobel P, Davidson BL: Intraventricular enzyme replacement improves disease phenotypes in a mouse model of late infantile neuronal ceroid lipofuscinosis. Mol Ther 2008, 16:649-656.
• [45]Du H, Schiavi S, Levine M, Mishra J, Heur M, Grabowski GA: Enzyme therapy for lysosomal acid lipase deficiency in the mouse. Hum Mol Genet 2001, 10:1639-1648.
• [46]Dunder U, Kaartinen V, Valtonen P, Vaananen E, Kosma VM, Heisterkamp N, Groffen J, Mononen I: Enzyme replacement therapy in a mouse model of aspartylglycosaminuria. FASEB J 2000, 14:361-367.
• [47]Gaide O, Schneider P: Permanent correction of an inherited ectodermal dysplasia with recombinant EDA. Nature Med 2003, 9:614-618.
• [48]Matsuda J, Suzuki O, Oshima A, Yamamoto Y, Noguchi A, Takimoto K, Itoh M, Matsuzaki Y, Yasuda Y, Ogawa S, Sakata Y, Nanba E, Higaki K, Ogawa Y, Tominaga L, Ohno K, Iwasaki H, Watanabe H, Brady RO, Suzuki Y: Chemical chaperone therapy for brain pathology in G(M1)-gangliosidosis. Proc Nat Acad Sci USA 2003, 100:15912-15917.
• [49]Matzner U, Herbst E, Hedayati KK, Lullmann-Rauch R, Wessig C, Schroder S, Eistrup C, Moller C, Fogh J, Gieselmann V: Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy. Hum Mol Genet 2005, 14:1139-1152.
• [50]Miranda SRP, He XX, Simonaro CM, Gatt S, Dagan A, Desnick RJ, Schuchman EH: Infusion of recombinant human acid sphingomyelinase into Niemann-Pick disease mice leads to visceral, but not neurological, correction of the pathophysiology. FASEB J 2000, 14:1988-1995.
• [51]Roces DP, Lullmann-Rauch R, Peng JH, Balducci C, Andersson C, Tollersrud O, Fogh J, Orlacchio A, Beccari T, Saftig P, von Figura K: Efficacy of enzyme replacement therapy in alpha-mannosidosis mice: a preclinical animal study. Hum Mol Genet 2004, 13:1979-1988.
• [52]Sands MS, Vogler C, Kyle JW, Grubb JH, Levy B, Galvin N, Sly WS, Birkenmeier EH: Enzyme Replacement Therapy for Murine Mucopolysaccharidosis Type-Vii. J Clin Invest 1994, 93:2324-2331.
• [53]Savas PS, Hemsley KM, Hopwood JJ: Intracerebral injection of sulfamidase delays neuropathology in murine MPS-IIIA. Mol Genet Metab 2004, 82:273-285.
• [54]Sidhu H, Schmidt ME, Cornelius JG, Thamilselvan S, Khan SR, Hesse A, Peck AB: Direct correlation between hyperoxaluria/oxalate stone disease-and the absence of the gastrointestinal tract-dwelling bacterium Oxalobacter formigenes: Possible prevention by gut recolonization or enzyme replacement therapy. J Amer Soc Nephrol 1999, 10:S334-S340.
• [55]Tomatsu S, Montano AM, Ohashi A, Gutierrez MA, Oikawa H, Oguma T, Dung VC, Nishioka T, Orii T, Sly WS: Enzyme replacement therapy in a murine model of Morquio A syndrome. Hum Mol Genet 2008, 17:815-824.
• [56]Woodley DT, Keene DR, Atha T, Huang Y, Lipman K, Li W, Chen M: Injection of recombinant human type VII collagen restores collagen function in dystrophic epidermolysis bullosa. Nature Med 2004, 10:693-695.
• [57]Grujic D, Salido EC, Shenoy BC, Langman CB, McGrath ME, Patel RJ, Rashid A, Mandapati S, Jung CW, Margolin AL: Hyperoxaluria Is Reduced and Nephrocalcinosis Prevented with an Oxalate-Degrading Enzyme in Mice with Hyperoxaluria. Amer J Nephrol 2009, 29:86-93.
• [58]Remington J, Wang XY, Hou YP, Zhou H, Burnett J, Muirhead T, Uitto J, Keene DR, Woodley DT, Chen M: Injection of Recombinant Human Type VII Collagen Corrects the Disease Phenotype in a Murine Model of Dystrophic Epidermolysis Bullosa. Mol Ther 2009, 17:26-33.
• [59]Endocrinologic and Metabolic Advisory Committee Meeting Tuesday, January 14, 2003 [http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3917T2.htm] webcite
• [60]Fleming TR, Demets DL: Surrogate end points in clinical trials: Are we being misled? Ann Intern Med 1996, 125:605-613.
• [61]Fleming TR: Surrogate endpoints and FDA's accelerated approval process. Health Affair 2005, 24:67-78.
• [62]Health Council of the Netherlands: Neonatal Screening. The Hague 2005.