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Rare diseases impact more than 25 million people across the United States and 350 million worldwide. Among the 7,000 known rare diseases, roughly 80% are caused by a single-gene defect. What’s more, nearly 95% of these diseases have no approved treatment option. This leaves many rare disease patients without viable care for their condition.

Key Highlights

In Part Three of our Decoding FDA Gene Therapy Guidances series, we discuss the need for thorough long-term follow-up studies for these products, as well as recommendations set forth by the FDA to help drug developers ensure the long-term safety of their patients.

Rare Disease Gene Therapy Working Group
Rare Disease Gene Therapy Working Group

In a recent installment of our Decoding FDA Gene Therapy Guidances series, we discussed the promise of gene therapy drug development for rare disease patients and outlined the latest FDA Guidances surrounding gene therapy development for these conditions. Below, we’ll discuss the need for thorough long-term follow-up studies for these products, as well as recommendations set forth by the FDA to help drug developers ensure the long-term safety of their patients.

Long-term safety of rare disease patients

Gene therapy products intend to enact permanent or long-acting changes in the human body.

“A single-dose, durable treatment is a tantalizing possibility for rare disease patients—especially for the majority of rare disease patient communities who have no FDA-approved treatments today,” explains PRA’s Amy Raymond, PhD, Director of Therapeutic Expertise at the Center for Rare Diseases. “Just as the potential durability of gene therapy is part of what makes it so attractive, that same durability could conceivably be a nightmare if treatment has unintended and unforeseen consequences.”

Similar to their use in other treatment modalities, long-term follow-up studies are used to monitor the potential long-term effects of gene therapy products, and provide sponsors with data about how a treatment or drug could affect patients over time. For gene therapy in particular, these are essential in understanding the totality of the treatment effect.

After participating in a clinical trial and being administered an investigational gene-therapy product, patients will be offered to participate in a long-term follow-up study. This extension trial, in which patients will enter immediately after they complete the main study, will allow for long-term monitoring of the patients in a clinical trial setting.

Extension studies are essential for observing any unpredictable outcomes, such as delayed adverse events, and ensuring the long-term safety of rare disease patients participating in human gene therapy studies.

Adverse events are any undesirable experiences associated with the use of a medical product in a patient. Delayed adverse events are typically defined as any adverse event that occurs more than a year after exposure to a drug or treatment. Delayed adverse events can occur with any human gene therapy product, and specific characteristics unique to these products might increase the potential risk. The biological activity of retroviral vectors whose integration is not directed to particular human genome sites can result in an increased risk for potential gene disruption at the integration site. Genome editing activity might also produce undesirable genomic changes, either ex vivo or in vivo, including malignancies or gene function impairment. Additionally, prolonged-expression and latency might lead to unregulated cell growth or reactivation, respectively—both of which are delayed adverse events.

Long-term follow-up protocols allow sponsors to assess the long-term clinical efficacy and durability of their products. Clinical experiences in monitoring and improvements in analytical approaches have led to a better understanding of the risks associated with gene therapy, however concerns remain on potential delayed adverse events. Long-term consequences are a key consideration for any durable treatment, particularly in the case of novel products like transposon-based gene insertion and genome editing.

The FDA recommends that trial sponsors use all available preclinical and clinical evidence to conduct a thorough risk assessment to address these concerns. Sponsors should reassess risks on an ongoing basis. As data accumulates, sponsors can revise existing long-term follow-up study protocols or initiate a new protocol for the first time.

FDA recommendations for long-term follow-up studies

It is imperative to identify and mitigate the long-term risks to patients receiving gene therapy products at any stage of drug development. However, the FDA cautions that when the study population includes high numbers of patients with conditions that may confound observations—short life expectancy, multiple comorbidities, or exposure to radiation or chemotherapy—long-term follow-up studies may have limited utility. Sponsors may find greater value in patients with few comorbidities or limited disease when assessing long-term outcomes and delayed adverse events.

To determine the right duration for long-term follow-up studies, sponsors should consider the type of exposure, the characteristics of the product, and the anticipated time to adverse events. Current FDA recommendations are up to 15 years for integrating vectors, herpes virus vectors, microbial vectors, and genome editing products, and up to five years for adeno-associated virus vectors. To reduce participant burden, sponsors can modify the long-term follow-up study’s duration based on an ongoing evaluation of product persistence, transgene expression, and clinical findings.

FDA recommendations encourage trial sponsors to establish a dedicated clinical protocol for long-term safety follow-up studies. The protocol should include:

  • Details on patient visit schedules
  • A plan for patient test samples
  • Monitoring test methods
  • A list of which clinical events of interest will be monitored during the long-term follow-up observation

Sponsors should also keep strong patient case histories, including baseline history and data from scheduled healthcare provider visits.

Investigators must keep a detailed record of mutagenic agent exposures for at least the first five years, with easy access to adverse event profiles. Careful record keeping is also key to document new malignancies, new or exacerbated neurologic or autoimmune disorders, new hematologic disorders, or new infections among study participants. After the initial five-year period, sponsors should contact participants at least once a year for screening.

Design protocols with the patient at the center

Without long-term follow-up data, sponsors will never get market approval for their gene therapy products. However, maintaining long-term observation can be challenging for even the most straightforward clinical trials.

Participating in a clinical trial is already burdensome for rare disease patients. Getting these same patients to then participate in a long-term follow-up trial can be tricky. Often patients and their families are expected to travel long distances for frequent onsite visits, which interrupts their daily lives and can take a toll on their physical and emotional wellbeing. This can lead to non-compliance and retention issues as the study continues.

In order to enroll, retain, and ensure the safety of patients, sponsors must design long-term follow-up studies that fit into the lives that rare disease patients are living post-treatment.

The first important step is to separate the long-term follow-up protocol from the initial gene therapy protocol. When combined from the start, sponsors must determine all the details of their protocol design for 15 years out. Designing a long-term follow-up protocol before starting the initial study is incredibly challenging and omits the patient voice from the process. Separating the two protocols allows sponsors to design a more lightweight long-term follow-up study based on feedback from all stakeholders—ensuring the protocol is designed first and foremost with the needs of the patient in mind.

Incorporating mobile health technologies into a long-term follow-up protocol helps bring the study to the patients—in their own homes, using their own devices, on their own time. Combined with our Real World Evidence team’s expertise, PRA’s Mobile Health Platform (MHP) reaches patients where they already are, improving enrollment and retention while ensuring more accurate and timely data collection.

“Having long-term follow-up data collected as needed gives all stakeholders—patients, their families, regulators, and physicians—confidence that decisions will be made on the totality of treatment effects,” says Dr. Raymond. “Long-term follow-up data is the single best way to demystify the risk/benefit ratio unique to gene therapy treatments.”

Learn how PRA’s Real World Solutions team designs long-term follow-up studies that work for real patients in the real world


Sandra Bihary-Waltz, DBA, MSN—Senior Director, Global Regulatory Affairs, Regulatory Strategy and Agency Liaison

Maxime Thomas, Manager of Global Regulatory Affairs, Global Regulatory Clinical Services, Country Consultant for France

Amy Raymond, PhD, PMP—Director of Therapeutic Expertise, Center for Rare Diseases

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