Journal of Thrombosis and Haemostasis, 13: 876–879
DOI: 10.1111/jth.12882
RECOMMENDATIONS AND GUIDELINES
Design of clinical trials for new products in hemophilia: communication from the SSC of the ISTH D. M. DIMICHELE,* S. LACROIX-DESMAZES,† F. PEYVANDI,‡ A. SRIVASTAVA§ and F. R. ROSENDAAL,¶** FOR THE SUBCOMMITTEE ON FACTOR VIII, FACTOR IX AND RARE COAGULATION DISORDERS *Division of Blood Diseases and Resources, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA; †Centre de Recherche des Cordeliers, Universite Pierre et Marie Curie-Paris 6, Universite Paris Descartes, INSERM, UMR S 1138, Paris, France; ‡Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Fondazione Luigi Villa and Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Milan, Italy; §Department of Hematology, Christian Medical College, Vellore, India; ¶Department of Clinical Epidemiology, Leiden University Medical Center, and **Department of Thrombosis and Haemostasis, Leiden University Medical Center, Leiden, the Netherlands
To cite this article: DiMichele DM, Lacroix-Desmazes S, Peyvandi F, Srivastava A, Rosendaal FR, for the Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders. Design of clinical trials for new products in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13: 876–9.
Introduction 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).
peutics 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. Results Clinical trial design for preauthorization trials
Methods 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 theraCorrespondence: Donna M. DiMichele, Division of Blood Diseases and Resources, NHLBI, 6701 Rockledge Drive, Bethesda, MD 20892, USA. Tel.: +1 301 435 0080; fax: +1 301 480 0867. E-mail: [email protected] Received 24 September 2014 Manuscript handled by: W. Ageno Final decision: W. Ageno, 10 February 2015
Critical elements of clinical trial design: Clinical efficacy end points 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]. The routine use of prespecified validated end points for clinical safety and efficacy is crucial to the standardization of outcomes in all clinical trials. Critical elements of clinical trial design: safety end points Key aspects of regulatory agency guidance for preauthorization new product trials in severe hemophilia A are summarized in Table S2 in Appendix S1 [2–6]. Preauthorization trials are primarily sized to rule out a greater than acceptable risk of FVIII product immunoge© 2015 International Society on Thrombosis and Haemostasis
Clinical trials in hemophilia 877 Table 1 Members 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)
nicity in PTPs (defined by > 150 prior product exposure days [EDs], or ‘exposures’] [1]. 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]. 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] is followed by a lifelong low ‘endemic’ incidence of 0.1–0.6% per patient-year [8–10]. 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 productrelated immunogenicity (Fig. S1A–C). Therefore, there will be two study phases. To detect a product-related ‘epidemic’ elevation in inhibitor incidence [11], 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]. 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] and ‘endemic’ [7] rates reported in the literature. This would typically © 2015 International Society on Thrombosis and Haemostasis
Table 2 Sample sizes for phases 1 and 2 Phase 1 Observed number of inhibitors allowed 0 Cumulative incidence ruled out* 4 91 5 72 6 60 7 51 8 45 9 40
1
3
137 110 91 78 68 60
178 142 118 101 88 78
Phase 2 Observed numbers of inhibitors allowed 0 Incidence rate (per 100 person-yrs) 2 185 [16%]† 3 123 [29%] 4 93 [40%] 5 74 [48%] 6 62 [54%] 7 53 [59%] 8 47 [63%]
1
279 186 140 112 93 80 70
2
[23%] [45%] [59%] [69%] [76%] [81%] [84%]
362 241 181 145 121 104 91
[30%] [57%] [73%] [82%] [88%] [91%] [94%]
*One-sided a = .025; exact binomial model used according to current regulatory consensus. †Power assuming a true 1% inhibitor incidence.
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 personyears, 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. Additional considerations in study design
Reexamining the definition of PTP Available evidence suggests that virtually all inhibitors in PUPs develop
878 D. M. DiMichele et al
within 20 EDs [12]. 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.’ Application to FIX products 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. Application to long-acting products 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.’ The immunology of product neoantigenicity 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 postauthorization studies will be required to scientifically address these questions (Table S6 in Appendix S1). Role of postauthorization studies
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. Product authorization in children
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 care-
fully 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 [7,13,14]. 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. Conclusions 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. Addendum D. M. DiMichele S. Lacroix-Desmazes, F. Peyvandi, A. Srivastava, and F. R. Rosendaal contributed to scientific content and direction, revised intellectual content, and approved the current version of this report. D. M. DiMichele and F. R. Rosendaal wrote the manuscript. Acknowledgements The group acknowledges the contribution, discussion, and comments of Drs. Jain and Scott, members of this project group, and is indebted to Dr. Anneliese Hilger for critical discussion. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the National Institutes of Health. Disclosure of Conflict of Interests F. Peyvandi reports grants and personal fees from Novo Nordisk, Biotest, and Kedrion Biopharma and personal fees from CSL Behring, LFB, Grifols, Bayer, Baxter, Biokit, Alnylam and Octapharma outside the submitted work. All other authors state that they have no conflict of interest. Supporting Information Additional Supporting Information may be found in the online version of this article: Data S1. Full length manuscript that includes additional documentation of the project group’s deliberations and further details about the group’s recommendations. © 2015 International Society on Thrombosis and Haemostasis
Clinical trials in hemophilia 879
Fig. S1. (A) Early exposure high peak ‘epidemic’ rate in previously untreated patients (PUPs) is followed by a lifelong low ‘endemic’ incidence of inhibitors, particularly after the > 150 EDs that define. (B) and (C) Initial new product trials enroll PTPs who have already successfully transited the ‘epidemic phase’ without apparent inhibitor development. They aim to detect a higher than expected incidence of inhibitors that could either augment the ‘endemic rate’ (Fig. 1B), or, alternatively, constitute another epidemic peak of antibody development due to product immunogenicity (Fig. 1C). References 1 Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A, Subcommittee on Factor VIII FIX, Rare Coagulation D. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12: 1935–9. 2 Aledort LM. Harmonization of clinical trial guidelines for assessing the risk of inhibitor development in hemophilia A treatment. J Thromb Haemost 2011; 9: 423–7. 3 Mannucci PM. Evolution of the European guidelines for the clinical development of factor VIII products: little progress towards improved patient management. Haemophilia 2013; 19: 344–8. 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– 50. 5 European Medicines Agency. Report of Expert Meeting on Factor VIII Products and Inhibitor Development. London: European Medicines Agency, 2007. 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. Bethesda, MD: US Food and Drug Administration (FDA), 2003.
© 2015 International Society on Thrombosis and Haemostasis
7 Gouw SC, van der Bom JG, Ljung R, Escuriola C, Cid AR, Claeyssens-Donadel S, van Geet C, Kenet G, Makipernaa A, Molinari AC, Muntean W, Kobelt R, Rivard G, Santagostino E, Thomas A, van den Berg HM. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med 2013; 368: 231–9. 8 McMillan CW, Shapiro SS, Whitehurst D, Hoyer LW, Rao AV, 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: 344–8. 9 Kempton CL. Inhibitors in previously treated patients: a review of the literature. Haemophilia 2010; 16: 61–5. 10 Hay CR, Palmer B, Chalmers E, Liesner R, Maclean R, Rangarajan S, Williams M, Collins PW. Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom. Blood 2011; 117: 6367–70. 11 Rosendaal FR, Nieuwenhuis HK, van den Berg HM, Heijboer H, Mauser-Bunschoten EP, van der Meer J, Smit C, Strengers PF, Bri€et E. A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Dutch Hemophilia Study Group. Blood 1993; 81: 2180–6. 12 Gouw SC, van den Berg HM, 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 RP, Mancuso ME, Rafowicz A, Williams M, Clausen N, Middelburg RA, et al. Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study. Blood 2013; 121: 4046–55. 13 Calvez T, Chambost H, Claeyssens-Donadel S, d’Oiron R, Goulet V, Guillet B, Heritier V, Milien V, Rothschild C, RousselRobert 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: 3398–408. 14 Collins PW, Palmer BP, Chalmers EA, Hart DP, Liesner R, Rangarajan S, Talks K, Williams M, Hay CR. 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: 3389–97.
DOI: 10.1111/jth.12882
RECOMMENDATIONS AND GUIDELINES
Design of clinical trials for new products in hemophilia: communication from the SSC of the ISTH D. M. DIMICHELE,* S. LACROIX-DESMAZES,† F. PEYVANDI,‡ A. SRIVASTAVA§ and F. R. ROSENDAAL,¶** FOR THE SUBCOMMITTEE ON FACTOR VIII, FACTOR IX AND RARE COAGULATION DISORDERS *Division of Blood Diseases and Resources, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA; †Centre de Recherche des Cordeliers, Universite Pierre et Marie Curie-Paris 6, Universite Paris Descartes, INSERM, UMR S 1138, Paris, France; ‡Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Fondazione Luigi Villa and Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Milan, Italy; §Department of Hematology, Christian Medical College, Vellore, India; ¶Department of Clinical Epidemiology, Leiden University Medical Center, and **Department of Thrombosis and Haemostasis, Leiden University Medical Center, Leiden, the Netherlands
To cite this article: DiMichele DM, Lacroix-Desmazes S, Peyvandi F, Srivastava A, Rosendaal FR, for the Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders. Design of clinical trials for new products in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13: 876–9.
Introduction 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).
peutics 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. Results Clinical trial design for preauthorization trials
Methods 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 theraCorrespondence: Donna M. DiMichele, Division of Blood Diseases and Resources, NHLBI, 6701 Rockledge Drive, Bethesda, MD 20892, USA. Tel.: +1 301 435 0080; fax: +1 301 480 0867. E-mail: [email protected] Received 24 September 2014 Manuscript handled by: W. Ageno Final decision: W. Ageno, 10 February 2015
Critical elements of clinical trial design: Clinical efficacy end points 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]. The routine use of prespecified validated end points for clinical safety and efficacy is crucial to the standardization of outcomes in all clinical trials. Critical elements of clinical trial design: safety end points Key aspects of regulatory agency guidance for preauthorization new product trials in severe hemophilia A are summarized in Table S2 in Appendix S1 [2–6]. Preauthorization trials are primarily sized to rule out a greater than acceptable risk of FVIII product immunoge© 2015 International Society on Thrombosis and Haemostasis
Clinical trials in hemophilia 877 Table 1 Members 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)
nicity in PTPs (defined by > 150 prior product exposure days [EDs], or ‘exposures’] [1]. 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]. 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] is followed by a lifelong low ‘endemic’ incidence of 0.1–0.6% per patient-year [8–10]. 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 productrelated immunogenicity (Fig. S1A–C). Therefore, there will be two study phases. To detect a product-related ‘epidemic’ elevation in inhibitor incidence [11], 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]. 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] and ‘endemic’ [7] rates reported in the literature. This would typically © 2015 International Society on Thrombosis and Haemostasis
Table 2 Sample sizes for phases 1 and 2 Phase 1 Observed number of inhibitors allowed 0 Cumulative incidence ruled out* 4 91 5 72 6 60 7 51 8 45 9 40
1
3
137 110 91 78 68 60
178 142 118 101 88 78
Phase 2 Observed numbers of inhibitors allowed 0 Incidence rate (per 100 person-yrs) 2 185 [16%]† 3 123 [29%] 4 93 [40%] 5 74 [48%] 6 62 [54%] 7 53 [59%] 8 47 [63%]
1
279 186 140 112 93 80 70
2
[23%] [45%] [59%] [69%] [76%] [81%] [84%]
362 241 181 145 121 104 91
[30%] [57%] [73%] [82%] [88%] [91%] [94%]
*One-sided a = .025; exact binomial model used according to current regulatory consensus. †Power assuming a true 1% inhibitor incidence.
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 personyears, 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. Additional considerations in study design
Reexamining the definition of PTP Available evidence suggests that virtually all inhibitors in PUPs develop
878 D. M. DiMichele et al
within 20 EDs [12]. 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.’ Application to FIX products 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. Application to long-acting products 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.’ The immunology of product neoantigenicity 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 postauthorization studies will be required to scientifically address these questions (Table S6 in Appendix S1). Role of postauthorization studies
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. Product authorization in children
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 care-
fully 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 [7,13,14]. 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. Conclusions 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. Addendum D. M. DiMichele S. Lacroix-Desmazes, F. Peyvandi, A. Srivastava, and F. R. Rosendaal contributed to scientific content and direction, revised intellectual content, and approved the current version of this report. D. M. DiMichele and F. R. Rosendaal wrote the manuscript. Acknowledgements The group acknowledges the contribution, discussion, and comments of Drs. Jain and Scott, members of this project group, and is indebted to Dr. Anneliese Hilger for critical discussion. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the National Institutes of Health. Disclosure of Conflict of Interests F. Peyvandi reports grants and personal fees from Novo Nordisk, Biotest, and Kedrion Biopharma and personal fees from CSL Behring, LFB, Grifols, Bayer, Baxter, Biokit, Alnylam and Octapharma outside the submitted work. All other authors state that they have no conflict of interest. Supporting Information Additional Supporting Information may be found in the online version of this article: Data S1. Full length manuscript that includes additional documentation of the project group’s deliberations and further details about the group’s recommendations. © 2015 International Society on Thrombosis and Haemostasis
Clinical trials in hemophilia 879
Fig. S1. (A) Early exposure high peak ‘epidemic’ rate in previously untreated patients (PUPs) is followed by a lifelong low ‘endemic’ incidence of inhibitors, particularly after the > 150 EDs that define. (B) and (C) Initial new product trials enroll PTPs who have already successfully transited the ‘epidemic phase’ without apparent inhibitor development. They aim to detect a higher than expected incidence of inhibitors that could either augment the ‘endemic rate’ (Fig. 1B), or, alternatively, constitute another epidemic peak of antibody development due to product immunogenicity (Fig. 1C). References 1 Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A, Subcommittee on Factor VIII FIX, Rare Coagulation D. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12: 1935–9. 2 Aledort LM. Harmonization of clinical trial guidelines for assessing the risk of inhibitor development in hemophilia A treatment. J Thromb Haemost 2011; 9: 423–7. 3 Mannucci PM. Evolution of the European guidelines for the clinical development of factor VIII products: little progress towards improved patient management. Haemophilia 2013; 19: 344–8. 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– 50. 5 European Medicines Agency. Report of Expert Meeting on Factor VIII Products and Inhibitor Development. London: European Medicines Agency, 2007. 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. Bethesda, MD: US Food and Drug Administration (FDA), 2003.
© 2015 International Society on Thrombosis and Haemostasis
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