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• W1526931462 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 GS et al.Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation.J Am Soc Nephrol. 2010; 21: 1398-1406Crossref PubMed Scopus (643) Google Scholar,4Burns JM Cornell LD Perry DK et al.Alloantibody levels and acute humoral rejection early after positive crossmatch kidney transplantation.Am J Transplant. 2008; 8: 2684-2694Crossref PubMed Scopus (181) Google Scholar) and for serial monitoring during and after AMR therapy (5Everly MJ Everly JJ Arend LJ et al.Reducing de novo donor-specific antibody levels during acute rejection diminishes renal allograft loss.Am J Transplant. 2009; 9: 1063-1071Crossref PubMed Scopus (177) Google Scholar). Such data suggest the feasibility to use semiquantitative data from solid phase HLA antibody detection assays as endpoints in clinical trials of antihumoral agents. One of the major barriers to regulatory approval of single HLA antigen bead assays is the inter- and intra-laboratory variability in results. In fact, this has been recognized by the NIH which recently funded a project wherein seven histocompatibility laboratories will collaborate with each other and with manufacturers of solid phase HLA antibody detection assays to systematically address the issue of standardization, including the use of robotics to reduce technician-related variability. Of course, there are additional variables, including inconsistent densities of HLA antigens on individual beads, lot-to-lot bead variability and bead saturation (i.e. a plateau effect which occurs in a substantial proportion of highly sensitized wait list patients) that will also be addressed. The willingness of the FDA to consider assay validation within the context of a regulatory trial is noteworthy and a critical step toward facilitating drug development in this area. Histological assessment of the allograft is another area in which progress may contribute significantly toward the regulatory process and clinical trial design. Although histological diagnostic criteria for AMR have been developed, more sensitive and objective methods are still needed to demonstrate active complement involvement. Similarly, improved methods for objective assessment of AMR severity are important for patient stratification and therapeutic endpoints. Molecular techniques may also provide a means to enhance pathologic diagnosis and grading in AMR. One area not addressed in the workshop report involves the issue of compassionate therapy in antihumoral drug development. This is an important issue for patients and treating physicians, as sponsors are reluctant to allow compassionate release use of new agents, primarily because such use cannot aid in achieving regulatory approval, but adverse reactions with compassionate treatment can have negative effects on the approval process. Development of new immunosuppressive agents arguably impacts the field of transplantation more than any other type of innovation. The remarkable growth and improvement in outcomes in solid organ transplantation in the 1980s and 1990s was primarily the result of regulatory approval of several new T cell focused immunosuppressive agents. However, as graft loss and episodes of acute rejection diminished, they became irrelevant as endpoints for superiority trial designs. The lack of defined endpoints that were acceptable for superiority trial designs for regulatory approval, combined with the great difficulties associated with inferiority trial designs, led to immunosuppressive agents being developed in autoimmune diseases, greatly limiting development of such drugs for new indications in transplantation. In fact, development of new, potent and more specific immunosuppressive agents in transplantation were relegated to post-approval (i.e. phase 4) studies. Current evidence suggests that elimination of humorally mediated allograft injury will provide a great advance in solid organ transplantation, and a number of new agents available for testing in registration-targeted trials appear quite promising. However, if the barriers noted above are not addressed, these agents will likely be developed for indications outside of transplantation, or not at all. Careful consideration must be given to new trial designs and alternative endpoints, especially development of endpoints within the context of regulatory trials. Regulatory consideration and acceptance of statistical approaches that facilitate trial conduct in small patient populations will have substantial influence on success in these efforts." @default.
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• W1526931462 title "Regulatory Approval for New Antihumoral Therapies: Addressing the Barriers" @default.
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