Enabling Precision Medicine The Role of Genetics in Clinical Drug Development: Proceedings of a Workshop (2017) / Chapter Skim
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2 Overarching Considerations for Implementing Successful Genetics-Enabled Drug Development
2 Overarching Considerations for Implementing Successful Genetics-Enabled Drug Development
Pages 9-22
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• Accurate, reliable, clinically useful, and appropriately imple mented biomarker tests for molecularly targeted therapies are key to realizing the full potential of precision medicine. (Nussbaum)
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Biomarker tests can therefore be applied within the drug development process, and the workshop planning committee agreed that it is important to discuss the challenges and opportunities associated with developing, validating, regulating, and integrating biomarker tests for molecularly targeted therapies. Therefore, a brief overview of the recent National Academies consensus study report Biomarker Tests for Molecularly Targeted Therapies: Key to Unlocking Precision Medicine was provided by Nussbaum, who was a member of the study committee (NASEM, 2016b)
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Nussbaum also reviewed the ten main goals identified by the report committee, which were crafted around three main topic areas that the committee identified as forming the key components of a rapid learning system framework for biomarker tests for molecularly targeted therapies. The three topic areas were developing a more supportive policy and regulatory environment, advancing clinical practice processes to improve patient care, and supporting a data infrastructure to better integrate and analyze data (see Figure 2-1)
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Perlmutter went on to share her perspectives on genetics-enabled drug development from her experiences as a patient, a patient advocate, and a scientist. Patient Concerns: Data Privacy and Security Principle concerns for patients, particularly in the context of genetics and genomics, are data privacy and security and the timely return of their genetic testing results.2 While much attention is paid to privacy and security in medicine (for example, the protections afforded by the Health Insurance 2 Perlmutter referred workshop participants to recent guidelines from the Multi-Regional Clinical Trials initiative at Harvard University, which describe the principles for returning aggregate and individual results to trial participants.
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Educating and Engaging Potential Clinical Trial Participants To better engage patients and encourage participation in clinical trials, Perlmutter noted that patients could be more effectively educated on the trial process before they are acutely in need of a clinical trial. She noted that more effective education could help people understand the genetic underpinnings of disease and also the medical research and development processes, including protections afforded to patients involved in clinical t rials.
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NAVIGATING THE REGULATORY PATHWAY FOR IN VITRO DIAGNOSTIC TESTS AND BIOMARKERS IN CLINICAL DRUG DEVELOPMENT Pacanowski provided an overview of key regulatory issues associated with the identification of biomarkers and the development of companion IVDs. The use of genomics in drug development, he said, can be preemptive (e.g., to validate molecular targets, predict adverse events or toxicities, or define target population)
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The first insight was that relying on retrospective data analysis to identify potential biomarkers depends highly on context and could be affected by incomplete biospecimen sampling. Instead, he said, a better approach could entail using prospectively planned biomarker analysis accompanied by a more complete biospecimen collection.
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Finally, trials in marker-negative patients, who may not have met the eligibility criteria for a molecularly defined cohort of a genetics-enabled trial, can be conducted in the postmarket setting, he said, adding that such trials can provide a better sense of risks and benefits in the broader, real-world population. Over the years, FDA has drafted and released a number of guidance documents for industry related to the collection of biospecimens in clinical trials for biomarker development, the use of enrichment strategies in clinical trials, and, recently, the codevelopment of companion diagnostics in the context of a therapeutic trial.3 Pacanowski highlighted select key points from the recent draft codevelopment guidance (see Pacanowski presentation, March 8, 2017)
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and the epistatic interactions at play.4 The potential molecular complexity presented by genetic diseases also raises the question of how trial eligibility criteria should be defined to enroll molecularly defined subsets of patients in confirmatory trials, Pacanowski 4 Epistasisis a circumstance where the expression of one gene is affected by the expression of one or more independently inherited genes. For more information on reduced penetrance and variable expressivity, see https://ghr.nlm.nih.gov/primer/inheritance/penetranceexpressivity (accessed May 6, 2017)
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Targeted Drug Development in Common Complex Diseases In general, genetically enabled drug development for common complex diseases remains infrequent and, when pursued, tends to focus on the stratification of patient populations using well-established markers of drug metabolism and disease, such as the association between the polipoprotein E gene (APOE) and the progression of Alzheimer's disease, a Pacanowski said.
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. While targeted drug development has been relatively uncommon outside of oncology, a variety of issues arise during the review of drugs and IVDs for common, complex medical diseases to which FDA attends closely, Pacanowski said.
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documents released for public comment in 2016 related to the qualification process for biomarkers.5 Regulatory Issues to Consider In summary, Pacanowski said that there are three key regulatory issues to be considered in precision drug development: 1. The strength of the evidence provided to support biomarker directed precision drug development.
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Finally, when moving from a GWAS finding to a Phase 3 trial, using robust methods, performing supportive experiments, and addressing ethnic diversity are all important considerations, he said.
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