6

Reflections on the Workshop and Potential Opportunities for Next Steps

Celia Witten, the deputy director of the Center for Biologics Evaluation and Research at FDA, moderated a short panel session at the end of the day to discuss potential paths forward to support the clinical development 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 participants 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 history 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 therapies. 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.

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 standardizing 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 Duchenne muscular dystrophy (DMD), she said, there are three companies conducting 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 rationale for doing so, Furlong said. In the same vein, she suggested standardizing 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 benefit 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 selection. 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 treatment. 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.

Patient, Family, and Physician Education

Improving education for patients and their families about trials, expectations, 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 appointment 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 opportunity and the need to do 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 developing 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 development and regulatory applications.

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¹ More 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).

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 challenge 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 speakers 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 developing a novel, clinically meaningful endpoint for assessing visual improvement 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 followup 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

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 surrogate 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.”