Regulatory Approval for New Antihumoral Therapies: Addressing the Barriers

Abstract

The regulatory framework guiding the approval of therapies for antibody-mediated rejection is complex, and collaboration between the scientific community and the FDA will be required to facilitate registration trials for this indication. See meeting report by Archdeacon et al on page 896. The regulatory framework guiding the approval of therapies for antibody-mediated rejection is complex, and collaboration between the scientific community and the FDA will be required to facilitate registration trials for this indication. See meeting report by Archdeacon et al on page 896. The role of alloantibody in solid organ allograft injury has been and remains an area of intense focus. Presently, several agents are being considered for clinical development as antihumoral therapies that will require a series of well designed clinical trials to achieve requisite regulatory approval from the Food and Drug Administration (FDA). Recognition of these important issues resulted in an FDA-sponsored workshop on antihumoral therapies in June, 2010, the results of which are summarized by Archdeacon and his FDA colleagues in this issue of AJT (1Archdeacon P Chan M Neuland C et al.Summary of FDA antibody mediated rejection workshop.Am J Transplant. 2011; 11: 896-906Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). Four clinical settings were considered in the workshop: acute antibody-mediated rejection (AMR), desensitization, induction (prevention beginning at the time of transplant) and chronic AMR. Several issues that influence drug development in each of these settings were identified. First and foremost was the recognition of the paucity of controlled clinical trials in this area that significantly complicates selection of appropriate controls, as well as definition of inferiority margins, thereby requiring superiority designs. Second, at least for certain clinical settings, patient populations eligible for study are quite (perhaps too) small. Third, potential endpoints are complicated by the lack of (i) assays that reliably quantify HLA alloantibody levels and (ii) reliable histologic markers for AMR diagnosis and assessment. Finally, it was clear that more reliable surrogate endpoints need to be identified and validated. Collectively, these are formidable barriers to regulatory approval of new and promising agents as antihumoral therapies. Overcoming these obstacles will require effective collaborations among the scientific community, the FDA, the NIH and industry. Multicenter cooperative trials will be required to address the lack of controlled trials, particularly with historically used IVIG-based protocols. Several innovative strategies such as adaptive, iterative and Bayesian trial designs can be employed to address the real problem of small study populations. Recent acceptance of Bayesian trial designs for FDA device approval provides an important regulatory precedent for adoption of this position (2Guidance for the use of Bayesian statistics in medical device clinical trials. Available at: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidance/default.htm. Accessed March 24, 2011.Google Scholar). Adaptive trial designs are important for industry in drug development as they offer the advantage of early identification of subpopulations likely to be responsive (or resistant) to the effects of innovator drugs, as well as abandonment of individual study limbs shown to be inferior, without halting the entire study. Iterative trial designs allow the use of previous study groups as both control and comparator groups. Development of reliable and reproducible assays to quantify donor specific HLA alloantibodies are essential to facilitate clinical trials of antihumoral therapies. Recent single center experiences suggest that single HLA antigen coated beads provide a semiquantitative platform that can be used to predict AMR in sensitized kidney transplant recipients (3Lefaucheur C Loupy A Hill G