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Exploring Novel Clinical Trial Designs for Gene-Based Therapies: Proceedings of a Workshop (2020)

Chapter: 6 Reflections on the Workshop and Potential Opportunities for Next Steps

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Suggested Citation:"6 Reflections on the Workshop and Potential Opportunities for Next Steps." National Academies of Sciences, Engineering, and Medicine. 2020. Exploring Novel Clinical Trial Designs for Gene-Based Therapies: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25712.
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Page 69
Suggested Citation:"6 Reflections on the Workshop and Potential Opportunities for Next Steps." National Academies of Sciences, Engineering, and Medicine. 2020. Exploring Novel Clinical Trial Designs for Gene-Based Therapies: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25712.
×
Page 70
Suggested Citation:"6 Reflections on the Workshop and Potential Opportunities for Next Steps." National Academies of Sciences, Engineering, and Medicine. 2020. Exploring Novel Clinical Trial Designs for Gene-Based Therapies: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25712.
×
Page 71
Suggested Citation:"6 Reflections on the Workshop and Potential Opportunities for Next Steps." National Academies of Sciences, Engineering, and Medicine. 2020. Exploring Novel Clinical Trial Designs for Gene-Based Therapies: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25712.
×
Page 72
Suggested Citation:"6 Reflections on the Workshop and Potential Opportunities for Next Steps." National Academies of Sciences, Engineering, and Medicine. 2020. Exploring Novel Clinical Trial Designs for Gene-Based Therapies: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25712.
×
Page 73
Suggested Citation:"6 Reflections on the Workshop and Potential Opportunities for Next Steps." National Academies of Sciences, Engineering, and Medicine. 2020. Exploring Novel Clinical Trial Designs for Gene-Based Therapies: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25712.
×
Page 74
Suggested Citation:"6 Reflections on the Workshop and Potential Opportunities for Next Steps." National Academies of Sciences, Engineering, and Medicine. 2020. Exploring Novel Clinical Trial Designs for Gene-Based Therapies: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25712.
×
Page 75
Suggested Citation:"6 Reflections on the Workshop and Potential Opportunities for Next Steps." National Academies of Sciences, Engineering, and Medicine. 2020. Exploring Novel Clinical Trial Designs for Gene-Based Therapies: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25712.
×
Page 76

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6 Reflections on the Workshop and Potential Opportunities for Next Steps Celia Witten, the deputy director of the Center for Biologics Evalua- tion and Research at FDA, moderated a short panel session at the end of the day to discuss potential paths forward to support the clinical devel- opment of safe and effective gene-based therapies and to summarize the lessons learned and topics discussed through the day. The panelists were Ron Bartek, Mildred Cho, Richard Finkel, Pat Furlong, Katherine High, and Julie Kanter. Panelists were asked to consider ideas emerging from the workshop discussions and suggest specific changes that could improve the design of gene therapy clinical trials and the overall experience for partici- pants and their families. POSSIBLE NEXT STEPS FOR IMPROVING THE DESIGN OF GENE THERAPY CLINICAL TRIALS When asked to identify the important points that emerged during the workshop, High emphasized the benefits of understanding the natural his- tory of a disorder that is being treated with gene therapy, developing and validating novel endpoints, and improving the experience of patients who participate in clinical trials. The number of work streams and the expense required to mount a successful clinical trial for a gene therapy is staggering, she said, particularly for those diseases for which there are no existing ther- apies. However, the future is bright for the development of gene therapies for diseases where it is fairly straightforward to quantify outcomes, such as with hemophilia, thalassemia, and sickle cell disease, she said. 69 PREPUBLICATION COPY—Uncorrected Proofs

70 NOVEL CLINICAL TRIAL DESIGNS FOR GENE-BASED THERAPIES Possible Ways to Improve the Clinical Trial Experience for Patients and Families In terms of the next steps that product developers could take to improve the design of clinical trials for gene therapies, Furlong suggested standard- izing the inclusion criteria for trials and the methodology and parameters for testing patients for immunity to the vector virus being used in the gene therapy. In the case of DMD, she said, there are three companies conduct- ing gene therapy clinical trials, and each company has different methods for testing immunity to the vector virus. Patients would benefit from a clear explanation of the immunity testing parameters being used and the ratio- nale for doing so, Furlong said. In the same vein, she suggested standard- izing the sequence of outcome measures and data collection across trials for each disease. Doing so, she said, will require trial sponsors to work closely with FDA. Efforts should also be made to maximize the potential therapeutic ben- efit of the first-in-human dose, Bartek said, given that most gene therapies will involve a one-time treatment. Furthermore, he said, developers and regulators should maximize inclusiveness from the start of clinical research and include both adults and children in early research. This would require shifting the paradigm of demonstrating safety of a therapy in adults first, he said, but the treatment for certain conditions may be profoundly effective in younger patients. Learning from the Past and Scaling Up Another approach to improving gene therapy clinical trials, Cho said, involves developing the infrastructure needed to scale gene therapies so that they can be appropriately integrated into clinical practice. In the future there should be a focus on establishing a rationing strategy for these therapies, given that it will likely be necessary until full scale-up has been achieved. Another step forward, Cho said, will involve understanding why recent clinical trials with gene therapies have been successful whereas the previous 30 years of trials had little success. There are lessons to learn, she said, in terms of patient enrollment, setting endpoints, and patient selec- tion. Also of importance, Cho said, is the fact that the institutions that conduct these trials, the researchers involved, and the trial sponsors may all have interests that may be either competing or aligned with the interests of patients and families in terms of enrollment, retention, and access to treat- ment. Finally, she said, it will be critical to address the disparities that exist in the way that trials are conducted and the social justice issues that result from those disparities, such as who is offered long-term follow-up care and why, a point that had been previously mentioned by DeBaun. PREPUBLICATION COPY—Uncorrected Proofs

REFLECTIONS ON THE WORKSHOP AND POTENTIAL OPPORTUNITIES 71 Patient, Family, and Physician Education Improving education for patients and their families about trials, expec- tations, and risks is the most important change to make to improve the experience of participants in gene therapy clinical trials, Kanter said. More patients should be included in trials as evidence mounts that outcomes are good, she said, noting that she has more than 15 people on a wait list to participate in a trial at her center. Furlong agreed with the need for more education, noting that pediatric diseases are family diseases and that often children in trials are separated from their siblings and other relatives, who may have only a little understanding about what is happening. One way to address this is to bring the family into the clinic for at least one appoint- ment with the patient to give family members a better sense of what their loved one is going through and to provide them with an opportunity to ask questions. Physicians need additional education about gene therapies and related clinical trials too, High said. As investigational agents become products, she said, it can become apparent how limited the understanding of gene therapy is among some physicians. Finkel added that physician education needs to include ways to frame patient expectations for these treatments so as to avoid disappointment. Ideas for Developing Clinical Endpoints in Different Ways Panelists were asked by an audience member if they saw opportunities for groups to work together in the precompetitive space to develop new endpoints for gene-based therapy clinical trials. There is both the opportu- nity and the need to this type of work, Finkel said, but the challenge will be getting support for this type of effort from sponsors. Often a therapy will enter the preclinical pipeline without validated reliable outcome measures in place, he said, and noted that patient advocates can play an important role in getting resources and support for developing outcome measures and conducting natural history studies. A workshop participant suggested that NCATS be involved in supporting pre-competitive efforts aimed at devel- oping new endpoints for gene therapy trials. Another example of effective pre-competitive efforts, Lapteva said, involves the drug development tool (DDT) qualification programs at FDA.1 The aim of this set of programs is to qualify DDTs and make them available in order to expedite drug devel- opment and regulatory applications. 1More information about FDA’s Drug Development Tool Qualification Programs can be found at https://www.fda.gov/drugs/development-approval-process-drugs/drug-development- tool-ddt-qualification-programs (accessed January 27, 2020). PREPUBLICATION COPY—Uncorrected Proofs

72 NOVEL CLINICAL TRIAL DESIGNS FOR GENE-BASED THERAPIES ONGOING CHALLENGES FOR GENE THERAPY CLINICAL TRIALS Each disease area is faced with the issue of identifying the optimal population to study, Finkel said, and, in fact, children may be the ideal first population to study in certain situations. There are also challenges with producing enough vector to treat patients on a dose per kilogram basis, which again would argue for starting trials in children, he said. Jay Siegel, a former forum co-chair, added that another major chal- lenge is that many of the diseases amenable to gene-based therapies are quite rare, which makes it difficult to secure the funding to develop and test a novel therapy. His hope is that as technology improves and as the field gains experience with successful vectors, development and manufacturing costs will fall. FINAL REMARKS AND SUMMARY Witten provided an overview of points highlighted by individual speak- ers throughout the workshop. The first session, she recalled, involved a robust discussion around natural history data and its uses, about dose selection, and the importance of transparency and careful assessment (see Box 6-1). The second session explored issues of patient selection, enrollment, and consent both from the researchers’ point of view and from the patients’ perspective. The discussion, Witten said, focused on trial enrollment in the context of other available care, on burdens incurred by patients and their families during trial participation, and on eligibility criteria that can make trial enrollment difficult, Witten said (see Box 6-2). The third session at the workshop included a robust discussion centered on developing endpoints for gene therapy clinical trials, Witten recalled. Examples were provided by speakers, including one that centered on devel- oping a novel, clinically meaningful endpoint for assessing visual improve- ment in patients with retinal disorders. The workshop heard that patient registries can be valuable tools for developing clinical endpoints and that educational materials tailored to patients might be important to include in a given trial, Witten said. Additional points are provided in Box 6-3. The fourth session of the workshop examined long-term patient follow- up and management. There is general agreement that long-term follow-up is needed in certain cases to identify and mitigate delayed risk, Witten said. Other fields, including oncology and cystic fibrosis, can provide excellent examples and lessons learned about challenges to following clinical trial participants and the transition from being a participant in a clinical trial to PREPUBLICATION COPY—Uncorrected Proofs

REFLECTIONS ON THE WORKSHOP AND POTENTIAL OPPORTUNITIES 73 BOX 6-1 Key Points from Individual Speakers Related to Natural History Data and First-in-Human Gene Therapy Clinical Trials • Natural history data can be valuable for serving as a control and can inform the development of endpoints as well as the interpretation of safety and efficacy data. (Finkel, High, Kaufmann) • Natural history datasets can be made more robust with frequent visits, stan- dardized measures, and an effort to collect high-quality, patient-level data. (High, Kaufmann) • When selecting a starting dose, consideration should be given to selecting a potentially effective dose. (Bartek, Finkel) • When selecting the study population, it is important to identify the genetic diagnosis (if applicable) and to be aware of any effects on safety or efficacy with particular genotypes. (Finkel) • Pediatric populations (infants, children, adolescents) are all different and ex- hibit differences in drug metabolism, excretion, presentation, and off-target effects, factors that are important when testing experimental gene therapies. (Finkel) • Strong partnerships between patients, families, researchers, and clinicians are critical for collecting natural history data and moving the development of gene therapies forward. (Kaufmann) • Trial design will need to take into account the unique aspects of each disease/ condition, including what therapies are available, if any. (Finkel, Kimmelman) • Although some early trials in small groups or a single patient may be per- formed with the aim of treatment, transparency and rigorous data collection are critically important in these cases as well. (Kimmelman) surviving the disease and returning to standard clinical care, she said. The fourth session highlighted the need for strong infrastructure for long-term surveillance, Witten said, and there may be some exciting opportunities with mobile health applications. Summary points from the fourth session are provided in Box 6-4. Over the years, the regulatory process has evolved with regard to gene therapies, Siegel said, and FDA is much more flexible regarding novel designs and approaches to clinical trials and the use of registries and sur- rogate endpoints, all while trying to maintain high scientific standards and make all of this feasible. The field is better situated today than at any time in the past to answer the challenges identified over the course of the day, he continued. “We know a lot more about how to create and develop registries and use them in the drug development and regulatory setting than we did,” he said, “and we know a lot more about how to create endpoints and how to validate endpoints, whether surrogate or real endpoints.” PREPUBLICATION COPY—Uncorrected Proofs

74 NOVEL CLINICAL TRIAL DESIGNS FOR GENE-BASED THERAPIES BOX 6-2 Key Points from Individual Speakers Related to Patient Selection, Enrollment, and Consent • Patients and families should be team members or partners in the research and development process. (Furlong, Tisdale) • The informed consent process for gene therapy trials can be confusing for patients and their families. A summary or abstract of the informed consent would be helpful, as would providing additional time for patients and families to ask questions of the researchers. (Fitzhugh, Furlong) • Trust between patients, families, and those overseeing the clinical trials de- pends on open communication and must be developed over multiple interac- tions. (Samuels) • Earlier treatment with gene therapies often results in better patient outcomes, and newborn screening can help identify infants with rare, serious conditions. (Bartek, Puck) • Population-level newborn screening promotes fair access to treatment, includ- ing to cutting-edge trials. (Puck) • Certain eligibility criteria, such as geography or age, and the lack of a sibling protocol can be restrictive or extremely challenging for patients and families. (Contreras, Furlong) • Clinical trial participants and their families incur very high indirect financial costs. (Contreras, Furlong) • Patients with sickle cell disease often must account for the potential burdens on their families of other treatment options in decisions about undergoing gene therapy trials. (Fitzhugh, Samuels) • Many patients find value in having a support system available to them consist- ing of research nurses, physicians, and others who have gone through the trials. (Samuels) PREPUBLICATION COPY—Uncorrected Proofs

REFLECTIONS ON THE WORKSHOP AND POTENTIAL OPPORTUNITIES 75 BOX 6-3 Key Points from Individual Speakers Related to Developing Endpoints for Gene Therapy Clinical Trials • Clinically meaningful, reliable, and rigorous endpoints are especially important for gene therapy trials, where trials may be smaller and treatments are irre- versible. (Lapteva, Maguire) • Pompe disease and sickle cell disease are two examples of conditions that need improved clinical endpoints and predictors of disease severity. (Kanter, Koeberl) • The multi-luminance mobility test provides a quantifiable and reproducible measure of clinically meaningful vision performance, but it was an expensive and lengthy investment to develop that measure. (Maguire) • It is critical to define clinical trial “stopping points” for when a gene therapy is not working. (Kanter) • Vector copy number and transduction levels can provide a predictive measure- ment of gene therapy. (Kanter) • A collaborative, national sickle cell disease registry will be an important tool to help with development of reliable clinical endpoints. (Kanter) • Educational materials for patients are critical to help convey that each gene therapy approach is unique with regard to the materials used, potential risks, and benefits. (Kanter) • Investigators and sponsors working on rare disorders often find themselves defining novel endpoints midway through the development process. (Koeberl) • Investigators or researchers who want a discussion with the Food and Drug Administration about the acceptability of their endpoint in a disease can con- sider participating in the agency’s drug development tools program. (Lapteva) PREPUBLICATION COPY—Uncorrected Proofs

76 NOVEL CLINICAL TRIAL DESIGNS FOR GENE-BASED THERAPIES BOX 6-4 Key Points from Individual Speakers Related to Long-Term Patient Follow-Up • Long-term follow-up is critical to identifying and mitigating delayed risks to patients who receive investigational gene therapies. (Purohit-Sheth) • Retrospective follow-up presents several challenges, including the loss of contact with patients and patients’ refusal to sign medical release documents; prospective approaches are preferable. (Robison) • Mobile health applications may be useful tools to help with the collection of patient-reported outcomes over several years. (Robison) • There is a need for further clarity on monitoring for the off-target effects of genome editing and insertional mutagenesis. (Chonzi) • Harmonizing how long-term follow-up data are collected would help the field better understand potential risks. (Chonzi) • Patient registries with a strong infrastructure are a valuable tool to help with post-marketing follow-up studies. (Marshall) • Significant guidance on long-term follow-up is available from regulatory agen- cies around the world, including the Food and Drug Administration. (Chonzi, Purohit-Sheth) PREPUBLICATION COPY—Uncorrected Proofs

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Recognizing the potential design complexities and ethical issues associated with clinical trials for gene therapies, the Forum on Regenerative Medicine of the National Academies of Sciences, Engineering, and Medicine held a 1-day workshop in Washington, DC, on November 13, 2019. Speakers at the workshop discussed patient recruitment and selection for gene-based clinical trials, explored how the safety of new therapies is assessed, reviewed the challenges involving dose escalation, and spoke about ethical issues such as informed consent and the role of clinicians in recommending trials as options to their patients. The workshop also included discussions of topics related to gene therapies in the context of other available and potentially curative treatments, such as bone marrow transplantation for hemoglobinopathies. This publication summarizes the presentation and discussion of the workshop.

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