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Implementing the FDA Guidance on Long-Term Follow-Up for Gene Editing

Gene editing offers new and unique approaches to treating previously intractable diseases. Rather than treating disease symptoms, gene therapy can address the root causes of diseases by modifying gene expression or by repairing or replacing abnormal genes. They’re still considered to be a paradigm-shifting class of treatments. Because of the complexity of these clinical trials, the Food and Drug Administration (FDA) has approximately thirty-five guidelines on various aspects of gene (and cell) editing therapy.

There are challenging dynamics for product developers to navigate as they develop gene editing therapies. One dynamic, in particular, is the proper long-term follow-up design. In January 2020, the FDA released a guidance on “Long-Term Follow-Up After Administration of Human Gene Therapy Products,” to share recommendations regarding the design of long-term follow-up studies for the collection of data on delayed adverse events following administration of a gene therapy product. Often, gene editing products are designed to achieve a therapeutic effect through permanent or long-acting changes in the body – and as a result – an investigational gene editing therapy product may pose a potential unique adverse events profile over small molecules.

Therefore, product approvals must be matched by the development of new clinical frameworks for adequately assessing and managing the potential long-term effects of these new therapies. But many gene editing developers are still left with questions and concerns on how to implement the guidance and design their long-term follow-up plan.

In this blog post, we’ll summarize the guidance, and share potential challenges and successful strategies to provide suggestions for developers on how to align with the FDA before submitting an Investigational New Drug (IND) application.

Goals of Long-Term Follow-Up

The recommendations for the long-term follow-up monitoring date back to the 2006 “Delayed Adverse Events” guidance that was based on discussions among gene therapy stakeholders, and cumulative preclinical and clinical experience with gene therapy products. After many discussions and forums, the FDA advised developers to observe patients for delayed adverse events for up to 15 years, depending on the vector, and specified that the follow-up includes a minimum of five years of annual examinations, followed by up to ten years of annual patient queries either in person or by questionnaire.

The 2020 guidance is an update with new recommendations and goals based on clinical experience and insights gained on delayed adverse events. The main goal of long-term follow-up is to capture the right amount of follow-up data to examine the following:

Not all gene editing products require long-term follow-up, but all require an ongoing risk assessment. All follow-up studies should have a dedicated clinical trial protocol that specifies patient-visitation schedules, a sampling plan, the methodology that will be used to assess the biologic persistence of the editing, the clinical events that will be monitored, and the means for collecting these case histories.

This information needs to be reported to the regulatory authorities, and keep in mind, there are differences in the expectations per regulatory authority. For example, the European Medicines Agency (EMA) has similar recommendations to the FDA but differs on the tools to capture follow-up data. In addition to patient diaries, phone, electronic surveys, and in-person visits, they recommend disease registries and an integration of studies that pool patients across similar therapies to explore long-term safety effects.

Current Challenges

We’ve seen gene editing developers grapple with three main themes. Here are a few of our assessments.

Increased Costs

Unclear Data Capture Best Practices

When to Interact with the FDA

Successful Strategies

As we continue to learn as an industry, here are successful strategies we’ve witnessed so far as developers approach their clinical trial protocol development.

Such guidelines are not a means to serve as another regulatory obstacle for clinical approval, but to consider life expectancy and safety based on the particular studied disease and the possible exposure to other comorbidities that may have long-term adverse effects. These are fascinating, complex products that warrant complex monitoring.

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From strategic development plans and study design to vendor selection and oversight, Halloran Consulting Group’s clinical team helps their clients map the path, identify and mitigate risks, and keep their clinical programs on track. For more information, please contact us.