Global Health Risk Framework Research and Development of Medical Products: Workshop Summary (2016) / Chapter Skim
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4 Development
4 Development
Pages 39-54
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• The core issue for robust clinical trial design is appropriate controls or comparators.
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o vaccine trials, there could be more flexibility for novel For clinical trial designs (e.g., the Ebola ring vaccination trial with the 21-day vaccination delay control group)
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Discussion focused on the methodological design considerations for both vaccine and therapeutic clinical trials and the practical challenges encountered by those conducting trials in West Africa during that time. METHODOLOGICAL DESIGN CONSIDERATIONS In his presentation, Andre Kalil, Director of the Transplant ID Program at the University of Nebraska Medical Center, noted that the most optimal and ethical study design for evaluating experimental drugs with low availability, in diseases affecting low-resource areas, is the one that offers the highest probability of detecting true success or true failure with the
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Moreover, the addition of an adaptive Bayesian design makes randomized trials even more cost effective. Another argument is that randomized studies are unnecessary if a drug has demonstrated very high survival success in small animals and nonhuman primate models.
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Peter Kilmarx, Deputy Director of the Fogarty International Center at NIH, elaborated on the challenges of clinical trials in the face of extremely limited infrastructure and inadequate capacity (e.g., limited physical infrastructure and human resources; lack of training; lack of laboratory capacity, systems, and quality assurance; lack of data management capacity and data; and lack of systems of ethical review)
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Dull contended that observational studies could be useful in that context and especially for identifying highly efficacious or kill products. Myron Levine, Associate Dean for Global Health, Vaccinology, and Infectious Diseases at the University of Maryland School of Medicine, offered another perspective on ways of conducting clinical trials in a crisis, calling for more flexibility in trial design.
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For therapeutic trials of emerging infectious diseases, options are limited, despite our best creative efforts, Borio said, and historical controls are simply unreliable, she reiterated. The best approach for therapeutics would be to use Bayesian designs and adaptive clinical trials.
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Analyses of the accumulating study data are performed at prospectively planned timepoints within the study, can be performed in a fully blinded manner or in an unblinded manner, and can occur with or without formal statistical hypothesis testing." See Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics at http://www.fda.gov/ downloads/drugs/guidancecomplian-%20ceregulatoryinformation/guidances/ucm201790.pdf (accessed October 30, 2015)
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is pursuing regulatory reform. This group, established in 2007, is a platform for information sharing by product developers on vaccine candidates, target countries, and timelines for clinical trials.
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Moreover, the disease processes for cancer and for acute infectious diseases are very different. Borio said that FDA needs to see interpretable data coming out of clinical studies, and generally speaking, that means randomized trials where the test product is evaluated against an appropriate control.
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PRACTICAL CONSIDERATIONS AND COMMUNITY ENGAGEMENT Samba Sow, Director General of the Center for Vaccine Development– Mali (CVD–Mali) ,4 discussed practical considerations and community engagement in the context of the Ebola clinical trials conducted in Mali.
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Any effort involving public health, including research, must start and end with the community, Sow said. One must understand the situation in the field, and Western textbook science and academic center trial designs do not apply necessarily to West Africa.
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To be successful, a global risk framework must engage the community and community systems, including religious leaders, traditional leaders, and peer groups. She urged product developers also to keep the challenges for frontline workers on the ground in mind (e.g., terrain, temperature, and limited infrastructure)
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Bell reminded participants that research conducted in the context of an outbreak must be done in coordination with public health, so that the research supports the outbreak response and does not interfere with public health efforts to control the outbreak. In addition, research capacity is connected to basic public health capacity, which is built on surveillance, early detection, and fundamental laboratory capacities, as well as training and response.
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Yamada suggested that many clinical trial participants who have given informed consent may not have really given educated consent. They have been informed of the risks and benefits but do not necessarily understand what the trial is about, or about clinical trials in general and that their purpose is to test new medicines that might not work as expected, and might cause harm.
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. Hall observed that communication and social mobilization in crisis situations such as the Ebola outbreak are often one-directional, with no feedback from the community.
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