Design of clinical trials for new products in hemophilia: communication from the SSC of the ISTH

Abstract

This report presents an alternative approach to the clinical trial design of preauthorization trials for clotting factor products in previously treated patients (PTPs) with severe hemophilia. This approach is rooted in the overall regulatory goals for preregistration product safety and efficacy determination and incorporates both current immunological theories of neoantigenicity and consensus clinical efficacy end point definitions. All results and recommendations are further discussed in the online Supplementary Information (Appendix S1). The project group was constituted to include expertise in clinical care and investigation, immunology, clinical trial design and methodology, and regulatory science represented by the Food and Drug Administration (FDA) of the United States and the European Medicines Agency (EMA) (Table 1). We set out to review known clinical data on factor VIII (FVIII) and factor IX (FIX) product immunogenicity, as well as emerging data for novel therapeutics in PTPs and previously untreated patients (PUPs); explore the potential impact of alternative statistical approaches on the design of preauthorization regulatory trials for product safety and efficacy; examine the relevant scientific concepts of immunogenicity and neoantigenicity for potential influence on clinical trial design and approach to antibody surveillance; and formulate recommendations with input from all stakeholders. The statistical models derive from the well‐characterized epidemiology of inhibitor risk in severe hemophilia A and are applied to the rarer FIX inhibitor risk.Table 1Members of the project group on clinical trials for new products in hemophilia (affiliation/representation)Donna DiMichele (chair; former clinical investigator)Nisha Jain (regulatory representative, FDA)Anneliese Hilger (regulatory representative, EMA)Alok Srivastava (representative, FVIII/IX Subcommittee of ISTH; WFH liaison)Flora Peyvandi (chair, FVIII/IX Subcommittee of ISTH; clinical investigator)Sebastien Lacroix‐Desmazes (expert, immunology)Frits R. Rosendaal (expert, epidemiology and clinical trial design)John Scott (expert, statistics and small clinical trial design, FDA) Open table in a new tab Treatment efficacy has historically been ascertained with non‐standardized 4‐point‐scale patient‐reported hemostatic outcomes evaluated in single‐arm, open‐label preauthorization studies and reported with descriptive statistics. Recent efforts identified objective criteria, tested by prespecified statistical analyses to establish product efficacy for episodic treatment, prophylaxis, and surgery (Table S5 in Appendix S1) 1.Blanchette V.S. Key N.S. Ljung L.R. Manco‐Johnson M.J. van den Berg H.M. Srivastava A. Subcommittee on Factor VIII FIX, Rare Coagulation DDefinitions in hemophilia: communication from the SSC of the ISTH.J Thromb Haemost. 2014; 12: 1935-9Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar. The routine use of prespecified validated end points for clinical safety and efficacy is crucial to the standardization of outcomes in all clinical trials. Key aspects of regulatory agency guidance for preauthorization new product trials in severe hemophilia A are summarized in Table S2 in Appendix S1 2.Aledort L.M. Harmonization of clinical trial guidelines for assessing the risk of inhibitor development in hemophilia A treatment.J Thromb Haemost. 2011; 9: 423-7Crossref PubMed Scopus (18) Google Scholar, 3.Mannucci P.M. Evolution of the European guidelines for the clinical development of factor VIII products: little progress towards improved patient management.Haemophilia. 2013; 19: 344-8Crossref PubMed Scopus (8) Google Scholar, 4.Hilger A. Arras‐Reiter C. Keller‐Stanislawski B. Ljungberg B. Male C. Mentzer D. Seitz R. Silvester G. Comment on: Mannucci, P. M. Evolution of the European guidelines for the clinical development of factor VIII products.Haemophilia. 2013; 19: 349-50Crossref PubMed Scopus (2) Google Scholar, 5.European Medicines AgencyReport of Expert Meeting on Factor VIII Products and Inhibitor Development. European Medicines Agency, London2007Google Scholar, 6.US Food and Drug Administration (FDA)Office for Biologics Evaluation and Research and Office of Blood Research and Review and the International Association for Biologicals. The Factor VIII Inhibitor Workshop. US Food and Drug Administration (FDA), Bethesda, MD2003Google Scholar. Preauthorization trials are primarily sized to rule out a greater than acceptable risk of FVIII product immunogenicity in PTPs (defined by > 150 prior product exposure days [EDs], or ‘exposures’] 1.Blanchette V.S. Key N.S. Ljung L.R. Manco‐Johnson M.J. van den Berg H.M. Srivastava A. Subcommittee on Factor VIII FIX, Rare Coagulation DDefinitions in hemophilia: communication from the SSC of the ISTH.J Thromb Haemost. 2014; 12: 1935-9Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar. Currently, ≤ 1 inhibitor in 80 subjects is required to rule out a 6.8% inhibitor cumulative incidence over 50 EDs, based on the upper level of the 95% confidence interval in a Poisson distribution, the current upper bound of cumulative incidence 6.US Food and Drug Administration (FDA)Office for Biologics Evaluation and Research and Office of Blood Research and Review and the International Association for Biologicals. The Factor VIII Inhibitor Workshop. US Food and Drug Administration (FDA), Bethesda, MD2003Google Scholar. This report explores the boundaries of acceptable risk and how these boundaries might impact the design of preauthorization clinical trials through the interrelationship of acceptable maximum risk, event rate, and cohort size. Furthermore, the proposed statistical model for trial design exploits the known ‘biphasic’ nature of post FVIII exposure inhibitor incidence: an early exposure (15, IQR 10–20 EDs) high peak ‘epidemic’ rate of up to 30% in PUPs 7.Gouw S.C. van der Bom J.G. Ljung R. Escuriola C. Cid A.R. Claeyssens‐Donadel S. van Geet C. Kenet G. Makipernaa A. Molinari A.C. Muntean W. Kobelt R. Rivard G. Santagostino E. Thomas A. van den Berg H.M. Factor VIII products and inhibitor development in severe hemophilia A.N Engl J Med. 2013; 368: 231-9Crossref PubMed Scopus (339) Google Scholar is followed by a lifelong low ‘endemic’ incidence of 0.1–0.6% per patient‐year 8.McMillan C.W. Shapiro S.S. Whitehurst D. Hoyer L.W. Rao A.V. Lazerson J. The natural history of factor VIII: C inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII:C inhibitors.Blood. 1988; 71: 344-8Crossref PubMed Google Scholar, 9.Kempton C.L. Inhibitors in previously treated patients: a review of the literature.Haemophilia. 2010; 16: 61-5Crossref PubMed Scopus (16) Google Scholar, 10.Hay C.R. Palmer B. Chalmers E. Liesner R. Maclean R. Rangarajan S. Williams M. Collins P.W. Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom.Blood. 2011; 117: 6367-70Crossref PubMed Scopus (148) Google Scholar. Initial new product trials enroll PTPs who have successfully transited the ‘epidemic phase’ on previously used products. They aim to detect a higher than expected incidence of inhibitors that either augments the ‘endemic rate’ or constitutes another ‘epidemic’ peak of antibody development due to product‐related immunogenicity (Fig. S1A–C). Therefore, there will be two study phases. To detect a product‐related ‘epidemic’ elevation in inhibitor incidence 11.Rosendaal F.R. Nieuwenhuis H.K. van den Berg H.M. Heijboer H. Mauser‐Bunschoten E.P. van der Meer J. Smit C. Strengers P.F. Briët E. A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Dutch Hemophilia Study Group.Blood. 1993; 81: 2180-6Crossref PubMed Google Scholar, the first phase is confined to the early new product exposure period. This period would currently be defined by 50 EDs; however, a shorter period of 20 EDs may suffice and would considerably shorten the study 12.Gouw S.C. van den Berg H.M. Fischer K. Auerswald G. Carcao M. Chalmers E. Chambost H. Kurnik K. Liesner R. Petrini P. Platokouki H. Altisent C. Oldenburg J. Nolan B. Garrido R.P. Mancuso M.E. Rafowicz A. Williams M. Clausen N. Middelburg R.A. et al.Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study.Blood. 2013; 121: 4046-55Crossref PubMed Scopus (241) Google Scholar. The measured outcome is cumulative incidence (events/people), and the sample size is based on the predefined inhibitor risk to be excluded. This methodology is currently used in the design of PTP FVIII trials. The second phase serves to detect an elevated ‘endemic’ rate of inhibitor development. Here, the rate itself is the effect measure (events/person‐time), and the sample size is dependent on both the predefined rate of inhibitor development to be excluded and the person‐time accrued in the study. Following this rationale, our recommendation relaxes the upper bound of cumulative incidence to 8%/year in the first phase of a biphasic study and aims to exclude a rate of four per 100 person‐years in the second phase. These limits are in the range of elevated ‘epidemic’ 11.Rosendaal F.R. Nieuwenhuis H.K. van den Berg H.M. Heijboer H. Mauser‐Bunschoten E.P. van der Meer J. Smit C. Strengers P.F. Briët E. A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Dutch Hemophilia Study Group.Blood. 1993; 81: 2180-6Crossref PubMed Google Scholar and ‘endemic’ 7.Gouw S.C. van der Bom J.G. Ljung R. Escuriola C. Cid A.R. Claeyssens‐Donadel S. van Geet C. Kenet G. Makipernaa A. Molinari A.C. Muntean W. Kobelt R. Rivard G. Santagostino E. Thomas A. van den Berg H.M. Factor VIII products and inhibitor development in severe hemophilia A.N Engl J Med. 2013; 368: 231-9Crossref PubMed Scopus (339) Google Scholar rates reported in the literature. This would typically result in studies with < 100 subjects (representative of the target treatment population), to be completed in < 2 years. Sample size requirements (to be prespecified and unalterable for both phases of a registered protocol) are outlined in Table 2 and in Tables S3 and S4 in Appendix S1. To rule out a cumulative incidence of 8% in the first phase, one would observe zero events in 45, one or less in 68, or two or less in 88 subjects. In this model, once an ‘epidemic rate’ of product immunogenicity is excluded, the observation period for subjects who completed study phase 1 can be extended into phase 2. The biphasic study can also be designed to include more subjects in both phases to allow person‐years to accrue over a shorter time period. As Table 2 shows for phase 2, zero inhibitors observed among 93 person‐years, or one or less inhibitor over 140 person‐years, would rule out an incidence of four per 100 per year. To accrue 140 person‐years, one would have to follow 140 subjects for 1 year, or 70 for 2 years (or slightly more to account for censored subjects). To maintain the feasibility of phase 2 for the trial duration and to maintain sufficient interindividual variability, we propose to have no fewer than 50 subjects in this phase.Table 2Sample sizes for phases 1 and 2Phase 1Observed number of inhibitors allowed013Cumulative incidence ruled out1One‐sided α = .025; exact binomial model used according to current regulatory consensus.491137178572110142660911187517810184568889406078Phase 2Observed numbers of inhibitors allowed012Incidence rate (per 100 person‐yrs)2185 [16%]2Power assuming a true 1% inhibitor incidence.279 [23%]362 [30%]3123 [29%]186 [45%]241 [57%]493 [40%]140 [59%]181 [73%]574 [48%]112 [69%]145 [82%]662 [54%]93 [76%]121 [88%]753 [59%]80 [81%]104 [91%]847 [63%]70 [84%]91 [94%]1 One‐sided α = .025; exact binomial model used according to current regulatory consensus.2 Power assuming a true 1% inhibitor incidence. Open table in a new tab Available evidence suggests that virtually all inhibitors in PUPs develop within 20 EDs 12.Gouw S.C. van den Berg H.M. Fischer K. Auerswald G. Carcao M. Chalmers E. Chambost H. Kurnik K. Liesner R. Petrini P. Platokouki H. Altisent C. Oldenburg J. Nolan B. Garrido R.P. Mancuso M.E. Rafowicz A. Williams M. Clausen N. Middelburg R.A. et al.Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study.Blood. 2013; 121: 4046-55Crossref PubMed Scopus (241) Google Scholar. We recommend the use of postmarketing surveillance for the continued epidemiological study of inhibitor risk in the interval between 20 and 150 EDs to better define a ‘PTP.’ The proposed methodology is also recommended for severe hemophilia B trials. Since the frequency of inhibitor development is low, studies could be safely designed to observe zero events, reducing the subject requirements for each phase of the study such that 50 subjects followed for 2 years would suffice. The proposed study design is applicable to modified clotting factor preparations with a prolonged plasma half‐life; the concept of ‘exposure days’ requires additional consideration, since one infusion may result in several days of ‘exposure.’ Optimal design of preauthorization clinical trials is hampered by an incomplete understanding of the precise nature of interactions between an FVIII product and the recipient's immune system. Our limited knowledge derives in part from incomplete characterization of the PTP's immune status relative to pretrial therapeutic product exposure. Immunological ignorance is not routinely distinguished from active tolerance. Consequently, when a PTP develops an inhibitor during a new product trial, an immunological break in preexisting tolerance cannot be distinguished from product‐associated neoimmunogenicity. Systematic harmonized collection of clinical and biological data from subjects entering pre‐ and post‐authorization studies will be required to scientifically address these questions (Table S6 in Appendix S1). The regulatory intent of new product postmarketing surveillance is to expand the limited preauthorization dataset on product safety and hemostatic efficacy (including pharmacokinetics [PK]) in adults and children through well‐designed postauthorization studies. A dedicated project group will study the requirements for international harmonized postauthorization data collection. While specific data are sometimes needed to ensure the safety and efficacy of therapeutics in children, this requirement may not be necessary for all drugs and biologics. In the case of hemophilia, there is historical precedent for clotting factor concentrate (CFC) safety and efficacy in PTP children following product authorization based on adult‐generated data. Therefore, strong consideration should be given to a worldwide harmonized approach to CFC market authorization based on carefully evaluated adult PTP‐generated data supplemented with PK data from a limited number of PTP children. Recent data from the RODIN and both British and French national studies suggest that there may be product‐specific immune responses in PUPs who should be evaluated separately 7.Gouw S.C. van der Bom J.G. Ljung R. Escuriola C. Cid A.R. Claeyssens‐Donadel S. van Geet C. Kenet G. Makipernaa A. Molinari A.C. Muntean W. Kobelt R. Rivard G. Santagostino E. Thomas A. van den Berg H.M. Factor VIII products and inhibitor development in severe hemophilia A.N Engl J Med. 2013; 368: 231-9Crossref PubMed Scopus (339) Google Scholar, 13.Calvez T. Chambost H. Claeyssens‐Donadel S. d'Oiron R. Goulet V. Guillet B. Heritier V. Milien V. Rothschild C. Roussel‐Robert V. Vinciguerra C. Goudemand J. FranceCoag N. Recombinant factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A.Blood. 2014; 124: 3398-408Crossref PubMed Scopus (129) Google Scholar, 14.Collins P.W. Palmer B.P. Chalmers E.A. Hart D.P. Liesner R. Rangarajan S. Talks K. Williams M. Hay C.R. Organization UKHCD. Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe hemophilia A, 2000–2011.Blood. 2014; 124: 3389-97Crossref PubMed Scopus (101) Google Scholar. These data have been generated by long‐term postauthorization observational studies. Consequently, the creation of appropriate models for structured postmarketing surveillance of product safety and efficacy in both adults and children is a critical aspect of this consideration. In conclusion, innovative and evidence‐based approaches to pre‐ and post‐authorization studies in PTPs will increase the feasibility of studying multiple new products in rare disease populations without compromising assessment of product safety and efficacy and will lead to greater understanding of the immunology of inhibitor development.