Exploring Novel Clinical Trial Designs for Gene-Based Therapies Proceedings of a Workshop (2020) / Chapter Skim
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1 Introduction and Overview
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had approved four gene therapy products for use, including two genetically modified T-cell immunotherapies for different types of leukemia and lymphoma, one gene therapy for patients with mutation-associated retinal dystrophy, and one gene therapy for children less than 2 years old with spinal muscular atrophy.2 The design of clinical trials for gene therapy products is often complex and can present many translational, clinical, and ethical issues, including challenges with determining an optimal dosage, delivering the product effectively, and successfully recruiting patients and following them over the long term. Patients and clinicians may also face difficult decisions about enrolling in gene therapy trials because of uncertainty about 1The planning committee's role was limited to planning the workshop, and the Proceedings of a Workshop was prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop.
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For such therapies, it is important to identify ways to balance the potential clinical benefits with available safety data and to address when it would be appropriate to rely on data obtained from the preclinical program and natural history studies to support administering novel gene therapies to young children. Another type of challenge faces clinical trials with gene therapies aimed at treating or curing rare genetic diseases, as the number of patients who are eligible to receive an experimental therapy during a clinical trial may be very limited.
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In his introductory remarks to the workshop, Krishanu Saha, an associate professor and the Retina Research Foundation Kathryn and Latimer Murfee Chair in the Department of Biomedical Engineering at the University of Wisconsin–Madison, discussed the differences in how gene-based therapies move through clinical trials compared with most drugs in development. Typically, he explained, drug discovery and development entails screening thousands of compounds for the desired properties, conducting extensive preclinical studies, and enrolling hundreds if not thousands of patients in multiple clinical trials that can take 6 to 7 years to complete.
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The opening keynote lecture by Katherine High is covered later in this chapter, and Chapter 2 explores the early stages of development of gene-based therapies, including designing research questions and collecting preclinical data. Also included in BOX 1-1 Workshop Objectives • To gain a better understanding of the design complexities and ethical issues associated with clinical trials for gene-based therapies by considering topics such as: ∘ Transitioning to first-in-human trials ∘ Determining the optimal starting dose ∘ Optimizing therapeutic delivery ∘ Communicating risks and benefits to patients and families • To identify potential ways to improve the design of gene therapy clinical trials from the perspective of participants, product developers, regulators, and other key stakeholders 3See What Is Gene Therapy?
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LESSONS FROM THE DEVELOPMENT OF A GENE THERAPY TO TREAT CHILDREN AND ADULTS WITH INHERITED VISION LOSS There are several challenges that gene-based therapy developers face in bringing a product to market, according to Katherine High, the president and head of research and development at Spark Therapeutics. During her keynote lecture High shared examples of these challenges and spoke about her experience with obtaining FDA approval for the first gene therapy for a genetic disease, in this case a rare inherited retinal dystrophy that goes by several names, including Leber congenital amaurosis and retinitis pigmentosa (Russell et al., 2017)
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eyes of the 12 test subjects. Using Natural History Data in Clinical Trials In addition to the clinical trials of AAV2-RPE65, FDA encouraged the company to conduct a natural history study in patients with biallelic RPE65 mutation-associated retinal dystrophy; the data from such studies can be useful in interpreting safety and efficacy data generated from a trial.
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. Ethical Considerations with Pediatric Subjects Because the preclinical studies in dogs had demonstrated that the earlier the intervention, the better the eventual outcome, the research team wanted to include children in the clinical trials from the start.
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In the separate validation study, which compared performance in both sighted participants and those with inherited retinal dystrophies, the investigators found that no subjects with an inherited retinal dystrophy improved over the course of 1 year without treatment and that in 28 percent of these subjects the condition worsened. Points to Consider with Gene Therapy Trial Design A randomized controlled crossover trial design was used for the Phase 3 clinical trial of AAV2-RPE65.
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In closing, High said that understanding the pathophysiology and natural history of the disease played a critical role in developing the clinical endpoint because it led to measuring mobility at different levels of illumination, something that existing mobility tests did not do. High noted, too, that collecting clinical measurements repeatedly over time can yield important information, which is why the Spark clinical trial collected data at baseline, 30 days, 90 days, 180 days, and 365 days.
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