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 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 the 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:

• Identify and mitigate long-term risks
• Gain an understanding of the persistence of gene editing products
• Improve the ability to capture adverse events

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

• Developers must capture, at minimum, the safety and agency requirements. It’s recommended they identify the ‘nice to have’ requirements to allow for cost savings since long-term data capture is costly
• The possibility of remote and decentralized follow-up is unclear, which if not feasible, the need for in-person visits and sample collection may drive costs and increase patient burden

Unclear Data Capture Best Practices

• There is no ‘gold standard’ for tools to capture the long-term follow-up data and best databases for hosting the data
  • To maximize the impact of these complex studies, data needs to be shared openly and rapidly with the scientific community. Sharing clinical data enhance the safety and efficacy of gene therapies by reducing the exposure of participants in future trials to avoid harms, risks, and avoidable costs

When to Interact with the FDA

• There needs to be a balance of planning vs. overpromising in the IND submission. It’s recommended to have early interactions with the FDA, be very clear and feasible on the long-term follow-up plan, and include the plan in the IND based on the FDA recommendations
• There is uncertainty around the right timing of interacting with the FDA on findings from the long-term follow-up. For example, ‘when is it appropriate to share the data and on what revolving schedule?’

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.

• Gain accesses to shared patient databases as this will help to inform product development and long-term follow-up strategies
• Hold a pre-IND meeting with the FDA and discuss long-term follow-up strategies to align on critical decisions as early as possible
• Include language in the protocol from the 2020 guidance on follow-up and capture the minimum requirements indicated in the guidance; for example, telephone check-ins are allowed after year five, so that patients consent to this follow-up and costs are reduced on behalf of the product developer

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.