Written by Susan Schneider, MD
The clinical case for an ophthalmic gene or cell therapy candidate is often an exciting and cutting-edge discussion within an organization’s development program. However, what a Sponsor might underestimate is the potential gap between the clinical trial(s) that was/were conceptualized in the clinical development plan and the clinical trial(s) that actually has/have to execute on according to that plan, including identifying, enrolling, and dosing study participants as well as short and long term follow-up, encompassing many years, after receiving an investigational gene or cell therapy. In my two decades of clinical development experience, including a more recent focus on the important and emerging field of gene therapy, some consistent patterns representing gaps, or potential blind spots, in clinical development, continue to surface.
Patient identification is more challenging than the prevalence number suggests
In most ocular gene and cell therapy clinical trials, the published prevalence for the indication under study represents only a starting point for enrollment planning. Several components serve to shrink that pool of potential patients. A gene therapy program that targets rare conditions such as inherited retinal disease, must consider that not every patient with that disorder has been genetically tested. This might limit or impede overall numbers of potential participants to enroll. Even if patients with the disorder of interest for a clinical study have been tested, they may not be captured in relevant registries that the Sponsor and/or clinical research sites have access to. Within the genetically confirmed patient pool, key study protocol features such as inclusion/exclusion criteria with respect to age, baseline best corrected visual acuity, retinal anatomic findings, and having received prior therapeutic modalities, by example, can further impact the ability to recruit and enroll appropriate participants for a given clinical trial. By the time one accounts for, in addition, informed consent, ability to travel to a qualifying site, and screening activities, programs aiming to enroll and eventually file for registration may struggle to reach an appropriate number of patients for their indication of interest and to realistically address an unmet need in the community.
Therefore, Sponsors who plan a clinical trial based solely on prevalence of disease, rather than an addressable enrollable population can fall quite far behind target recruitment rates and timelines by trying to fill study cohorts with participants that, realistically, may not be available. Building an enrichment strategy through community outreach, specific patient advocacy groups, and other targeted patient organizations, plus access to registries for the disease under study, as well as genetic testing partners are key to recruitment success.
However, this important strategic piece takes longer than Sponsors typically anticipate and plan for. Therefore, starting as early as possible, and not later than protocol finalization would be instrumental in study execution timelines not potentially slipping by a quarter, or more. Vigilance, flexibility, strategic planning, and remaining open to novel approaches, are important components in successfully operationalizing a gene therapy trial.
Manufacturing and CMC planning incorporated into clinical design decisions as an integrated program
For some programs, such as with small molecules, manufacturing and clinical execution can run largely in parallel tracks, but for gene and cell or gene therapy they are too tightly coupled to be siloed in any way. Key activities such as vector lot production schedules, lot-to-lot comparability tasks, and any process change during the course of clinical development, create direct dependencies on the trial and thus the overall clinical development plan timeline. This concept is laid out explicitly in the FDA’s CMC guidance for gene therapy INDs. A planned process change for scale-up often triggers comparability work and, from time to time, an Agency request for additional data, such as for bridging purposes. Such necessary interactions can result in a delays such as for first-patient-in and/or extended dosing windows in a trial. Sponsors who approach CMC clinical strategy as a parallel workstream, working in a siloed fashion, and without strong cross-functional communication and alignment are often surprised when a seemingly technical manufacturing decision becomes a strategic clinical timeline decision overnight that might heavily impact the ability to move a program forward. A better approach would be to plan CMC and clinical objectives and strategies together, tightly coupled, under the same governance where possible, so that leaders and key stakeholders can make informed, timely decisions. Keeping lines of communication open both internally across core functions as well as externally with regulatory agencies represents an additional key to success in gene and cell therapy programs.
As an exclusively ophthalmic CRO, iuvo is set up to support Sponsors in the gene and cell therapy space, starting at protocol ideation and in carrying that through to protocol finalization, operational execution, and core cross functional alignment as delineated with examples above. I believe that, from initiation of a protocol concept through important conversations incorporating risks and mitigation strategies for a Sponsor that this perspective, on gene therapy trial design, is a key element of what I bring to iuvo’s Clinical Advisory Board.
About the Author
Dr. Susan Schneider is a biopharmaceutical executive leader and ophthalmologist with two decades of clinical development experience. With her extensive background, she provides hands-on global support for development pipelines across a spectrum of indications, including the important and emerging field of inherited retinal disorders. Dr. Schneider has held a number of director level and higher management positions and has served various leadership and executive roles in a host of pharmaceutical and biotechnology organizations. She has also been involved in multiple product launches. Her contributions span the breadth of work and multiple phases of activity required for the planning, strategy, and execution of pre-clinical and clinical studies that are integral for the successful research and development of viable drug therapies from IND through product approval. Dr. Schneider currently is a clinical consultant, providing support for clinical development execution and strategic planning for clients.
Footnote: U.S. Food and Drug Administration, Center for Biologics Evaluation and Research (CBER). Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs): Guidance for Industry. January 2020.