Advancing Regulatory Science for Medical Countermeasure Development Workshop Summary (2011) / Chapter Skim
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3 Cutting-Edge Efforts to Advance MCM Regulatory Science
3 Cutting-Edge Efforts to Advance MCM Regulatory Science
Pages 29-64
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From page 29... ...
In addition to animal models, other nonclinical tools such as in silico biology and biomarkers can be employed to inform and advance MCM development. In Silico Approaches to Efficacy Assessment of MCMs A systems biology approach to health and disease acknowledges that there are likely complex molecular mechanisms, with groups of molecules, genes, proteins, and metabolites working in a coordinated fashion, that differ in healthy versus diseased states, explained Ramon Felciano, founder of Ingenuity Systems.
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2011. Presentation at IOM workshop; Advancing Regulatory Science for Medical Countermeasure Development.
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From page 31... ...
In summary discussion, participants discussed clinical trial simula tions, in which virtual patients are put through in silico trials, a process that allows a company to model a wide range of trial designs and analysis methods, with the goal of reaching programmatic decisions more quickly, more cheaply, and with greater certainty. To leverage in silico modeling, there is a need for more complete, shared databases of human and animal study data (e.g., genome-to-phenome information; data on human and animal model immunity in normal, vaccinated, and infected individuals)
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This rate, he said, is insufficient to meet broad clinical needs, without even considering MCM development. Part of this dearth of new biomarkers is caused by the lack of a real pipeline for systematic discovery, development, and marketing of bio markers.
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that animal models are critical to MCM development; however, most animal models
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The primary regulatory science tool for animal models is, of course, the FDA Animal Rule. There is a relatively new draft guidance published to support the Animal Rule, entitled "Qualification Process for Drug Development Tools." This guidance, Leffel clarified, is not a mechanism to discuss product-specific tools or assays; rather, it is meant to address how animal models can be applied broadly to more than one drug.
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From page 35... ...
Animal models were developed, she said, that were thought to be appropriately reflective of human disease. It was demonstrated that an immune marker, anthrax toxin neutralization antibodies, correlated with protection in the animals, and the protective level of antibody was 1 A participant from FDA clarified the status of the draft Animal Rule guidance.
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From page 36... ...
Patel of FDA suggested having a control animal dataset in a national database to which sponsors could compare their animal test data. Leffel commented that organizations such as the Alliance for Biosecurity, a public-private partnership, have taken steps to pursue development of a shared database of anthrax animal model data; unfortunately, that effort was underfunded.
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From page 37... ...
Another participant suggested that an alternative approach could be to conduct a new animal study with a current, approved drug or vaccine, in an appropriate model, and base the predictions on that data. Key Messages: Nonclinical Approaches to Assessing Efficacy In Silico Approaches and Biomarkers • Clinical trial simulations hold promise for modeling a wide range of trial designs and analysis methods and could facilitate reaching programmatic decisions more quickly, more cheaply, and with greater certainty.
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From page 38... ...
could allow for assessment of concordance between existing "well-characterized animal models" and in silico links between molecular systems and animal study endpoints. • A control animal dataset in a national database would permit comparisons by sponsors of their animal test data.
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-- pain upon injection, fever, headache and malaise, and injection site reactions -- are often considered to be rather subjective and can be difficult assess in animal models. Electronic Monitoring of Adverse Events Kenneth Mandl of the Harvard Medical School Center for Biomedical Informatics characterized four main sources of clinical electronic health data:
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Discussion Richard Forshee of CBER explained that voluntary reporting of data (e.g., to the Vaccine Adverse Event Reporting System or VAERS) is a key component of FDA's activities in near real-time safety surveillance in the
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Mendrick cautioned that it can be very difficult to discriminate between drug-related postmarket adverse events and disease-related processes in humans. Key Messages: Safety and Real-Time Monitoring • Collaborative working groups should be convened to share data and experi ences with respect to safety biomarkers.
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. As later-stage clinical trials with threat agents are impossible, it is necessary to rely on civilian indications for clinical trials.
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Judice emphasized the need to enroll more patients with resistant organisms into clinical trials and suggested a superiority trial design in which patients are enrolled but are not randomized until after culture and sensitivity results are known. To facilitate this, he added, rapid diag nostic tests are needed.
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He suggested there should be a way to de-identify and share those data for reference by researchers. Key Messages: Antimicrobials • There is a need to enroll more patients with resistant organisms into clinical trials through superiority trial design, with randomization after sensitivity re sults are available.
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From page 45... ...
In reality, Magill said, it should assist in culling down selection of candidates; clinical trials will likely always be needed. Human tissue engineering is another area that DARPA is aggressively moving into as a potential tool for testing medicines in lieu of animal models (Figure 3-2)
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2011. Presentation at IOM workshop; Advancing Regula tory Science for Medical Countermeasure Development.
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In closing points, Magill reminded participants that technology will not solve all of the problems of drug development and MCM development in particular. There is a need for better understanding of natural history and pathogenesis of disease and of immunology.
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With regard to vaccine development, Frucht emphasized that vaccine potency is a critical product quality characteristic, and the potency assay used should reflect the presumed mechanism of action of the product in humans. This is especially relevant, he said, when the Animal Rule is being used to establish clinical efficacy.
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From page 49... ...
He also suggested a viral structure consortium that would develop common databases of structural information characterizing the different classes of virus that are likely to emerge as human pathogens. Ed Nuzum of NIAID noted that there are numerous challenges for MCM sponsors beyond the Animal Rule: process development, manufacturing, product characterization, and potency assays are just examples.
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This capacity to synthesize DNA is changing the field of biological research, he said. Glass described six examples of how synthetic biology can be used to advance MCM development.
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2011. Presentation at IOM workshop; Advancing Regulatory Science for Medical Countermeasure Development.
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2011. Presentation at IOM workshop; Advancing Regulatory Science for Medical Countermeasure Development.
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These new tools and technologies are important to virologists because they aid the study of the global impact of virus infection on host gene expression; and they can be used to discover cellular regulatory pathways targeted by viruses, identify new cellular targets for antiviral therapies, and develop new vaccines. Katze proposed an integrated approach to infectious disease, combining traditional histopathological, virological, and biochemical approaches with functional genomics, pro teomics, and computational biology.
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• ncreased interdisciplinary crosstalk between computational scien I tists and bench scientists to define standards for study designs. In discussion, a participant raised the issue of training the next gen eration of the workforce to advance regulatory science outside the context of a particular product.
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Iversen also questioned whether the use of healthy volunteers for safety assessment is necessary for MCM development. He noted that in normal healthy volunteers, the dose limiting toxicity may fall below the anticipated therapeutic dose.
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Additionally, if diagnostic tests are not already in place before an emergency, it is very difficult to get physicians to employ them in a crisis if they do not have prior experience with the test or have not been shown evidence of
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In this regard, Wattendorf suggested that a role for regulatory science would be the development of new formats for simple, self-collected biospecimens, formats that would be optimized for specimen source (blood, urine, etc.) and analyte class (specific proteins, types of RNA, etc.)
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Participants discussed the potential for commercial assays on multiplex platforms to be used as epidemiological surveillance tools (as opposed to diagnostic tests where results are reported back to the patient)
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He noted that the FDA draft guidance on adaptive designs3 is a substantial step forward in helping the industry understand how best to move forward with innovative trial designs. Another topic for consideration is the simulation of the 3 See Guidance for Industry Adaptive Design Clinical Trials for Drugs and Biologics (Draft Guidance)
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From a regulatory science perspective, Ruberg said that the use of Bayesian approaches for phase III confirmatory trials would require in-depth sponsor-agency discussions at the endof-phase-II meeting or sooner. Important to the use of Bayesian approaches is the development of a comprehensive data element dictionary.
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report on how to handle missing data in clinical trials (NRC, 2010) , and he suggested that the National Academies conduct a study to evaluate the use of Bayesian methods in clinical trials, with particular emphasis on phase III confirmatory trials.
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A participant noted that CDISC is approaching standards development disease by disease. In response, Ruberg suggested that there could be a working group of experts in MCMs to define what generally needs to be measured and start discussing standard data elements.
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• here was also interest in platform approaches to health data soft T ware design, for which many applications or "apps" could be developed. These could be used for collection, management, and analysis of electronic health data, specifically for monitoring of adverse events.
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