Gene Therapy Clinical Trials for Rare Diseases: 5 Key Takeaways from FDA’s Recent Town Hall

Gene Therapy Clinical Trials for Rare Diseases: 5 Key Takeaways from FDA’s Recent Town Hall

Involving pediatric patients in gene therapy clinical trials for rare diseases is one of the challenges addressed by the FDA in their recent town hall.

The US Food and Drug Administration’s (FDA) Office of Tissues and Advanced Therapies (OTAT) held a recent town hall where three experts from the regulator provided guidance on how to design and conduct gene therapy clinical trials for rare diseases. These types of studies present researchers with unique challenges, including small patient pools, limited natural history data and heterogeneity within rare diseases.

“It’s a very exciting time in gene therapy. We are seeing one or two new applications coming in every week for new gene therapies for different diseases,” said Dr. Melanie Blank, clinical team leader for General Medicine Branch 1 at FDA’s Division of Clinical Evaluation and Pharmacology/Toxicology (DCEPT), at the beginning of the town hall.

For many years, it was thought that there were around 5,000 to 8,000 different rare diseases; however, a new report by RARE-X, a rare disease technology non-profit organization, indicated that there may be as many as 10,867 rare diseases. There are around 300 million people worldwide living with a rare disease. Over 70 percent of rare diseases are genetic, and of those, 70 percent begin in childhood.

Since most rare diseases are genetically driven, gene therapies strive to fix the root cause of a disease instead of just treating a patient’s symptoms. For this reason, rare disease patient communities are hopeful for a new gene therapy that may result in long-term benefits to their quality of life and survival.

Last year, the FDA approved four new gene therapies: Zynteglo (betibeglogene autotemcel, beti-cel), Skysona (elivaldogene autotemcel, eli-cel), Hemgenix (etranacogene dezaparvovecfor) and Adstiladrin (nadofaragene firadenovec-vncg).

Here are five key takeaways from the 90-minute FDA town hall that rare disease clinical research professionals need to know.

1. Suitability of External Controls in Clinical Trials for Rare Diseases

Considering that some rare diseases are ultra-rare, have rapid onset or are life-threatening, many clinical research professionals are wondering when it is acceptable to run a single-arm, externally controlled gene therapy trial.

An external control usually consists of data that was gathered from patients outside of the clinical study, like data from a natural history study.

On the other hand, a concurrent control involves participants who are enrolled at the same time as the treatment group from the same source population. Concurrent controls are monitored for the same study period as the treatment group.

According to Dr. Lei Xu, chief of DCEPT’s General Medicine Branch 2, the FDA prefers these three types of concurrent controls:

  • The placebo or sham concurrent control
  • The active concurrent control where an acceptable alternative treatment is used as the control
  • The dose-ranging, concurrent control

The above-mentioned concurrent controls allow for both randomization and blinding, and so they help ensure that study results are more understandable and mostly free of bias.

The next best control according to Dr. Xu is the no-treatment concurrent control because even though participants are aware if they are or are not receiving the investigational drug, they will be assessed according to the same study protocol as those receiving the gene therapy.

Dr. Xu emphasized that an external control may be appropriate for gene therapy trials under certain circumstances — for instance, if the pathogenesis of the disease is well understood, or if the disease course is well documented and very predictable. In addition, external controls should be comparable to the clinical study population, and the expected treatment effect of the gene therapy needs to be large and self-evident.

Dr. Xu mentioned how the FDA’s approval of Zolgensma in May 2019 was based on substantial evidence of effectiveness from two single-arm, externally controlled trials in patients with infantile-onset spinal muscular atrophy.

However, Dr. Xu’s key takeaway is that the chance of reliably showing the effectiveness of a drug with an external control is low. Dr. Xu said that regardless of the prevalence of a disease, the FDA recommends that sponsors choose a more suitable trial design, including the use of a concurrent control.

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2. Study Populations for Early-Phase Trials

Since the main objectives of early-phase gene therapy trials are to evaluate safety, tolerability and dose, there are a few factors to consider when determining the study population. Dr. Blank said the two main principles are the benefit-risk consideration and the ability to give informed consent.

“In terms of benefit-risk, we want to enroll a patient population who is most likely to benefit,” said Dr. Blank. “We also like to ensure that they are otherwise healthy because of the concerns about toxicity.”

While adults can give consent, the pediatric population can, at most, provide assent and the youngest children cannot even meet this criterion.

“When possible, if the disease affects an adult population we like to go first in adults and ensure that there is some preliminary safety data before going to children. And then, if there are children affected, it’s best to go first into the ones who can assent before those who cannot assent,” explained Dr. Blank.

In addition, Dr. Xu stressed that the benefit-risk profile of most gene therapy trials makes it unacceptable to enroll healthy volunteers.

“It’s usually prudent to enroll subjects with more severe or advanced diseases into these early-phase studies, essentially patients who are out of options,” said Dr. Elizabeth Hart, chief of DCEPT’s General Medicine Branch 1.

However, Dr. Hart added that there are cases where the product in development is thought to mostly help patients with early or more moderate disease. In such cases, it would be more appropriate to enroll that population in these early-phase studies.

3. Safety Monitoring in Gene Therapy Clinical Trials

A thorough evaluation of safety is needed for gene therapy products in both early and late-phase clinical trials. Dr. Xu said the FDA recommends general safety monitoring and specific tests to look for both expected and unexpected safety issues.

General safety monitoring usually involves recording symptoms and common clinical measurements, like routine labs and physical exams.

“Specific safety monitoring depends on multiple different factors, such as the nature and the mechanism of action of the gene therapy product, the study population, the results of the animal studies, and any related human experience of the same or similar gene therapy products,” explained Dr. Xu.

Another thing Dr. Xu recommended is to monitor the immune response to gene therapy products. Immune assays were recommended to measure both cellular and human immune responses to the viral vector and the transgene, as applicable.

To minimize immune responses, Dr. Xu said that immunosuppressants like corticosteroids may be used before or after the gene therapy’s administration. Dr. Xu noted that the immune-suppressing regimen needs to be justified because use of immunosuppressants carries its own risks.

4. Best Ways to Use Biomarker Endpoints

Biomarkers are important for a clinical development program as they can be used to help assess efficacy and safety, as well as pharmacodynamic effects to help with dose finding. Dr. Blank emphasized the importance of starting a natural history study early while the gene therapy clinical development program is still in the planning stages.

“Scientific data are needed to provide confidence in the utility of a biomarker, and understanding the natural history of the disease through a natural history study is the best way to explore the clinical utility of biomarkers,” said Dr. Blank.

Validated and established biomarkers could support a traditional approval pathway; however, Dr. Blank explained how an accelerated approval can occur when sponsors have established an improvement on a biomarker that is likely to predict a subsequent improvement in the way a patient feels, functions or survives.

An accelerated approval is especially helpful because some diseases progress slowly, and it could take a very long time to show that a gene therapy has an irreversible effect on morbidity and mortality.

Dr. Blank also gave the example of how the FDA’s accelerated approval of Bluebird Bio’s Skysona (elivaldogene autotemcel, eli-cel) was based on an intermediate clinical endpoint that was reasonably likely to predict a long-term clinical benefit.

5. Involving Pediatric Patients in Clinical Trials for Rare Diseases

Researchers often want to know when it may be appropriate to evaluate a gene therapy in pediatric patients first, before assessing it in adults. This is of great importance to innovator biotechs since many rare diseases begin in childhood and some can be life-threatening.

Children are a highly vulnerable population, and Dr. Blank explained how federal regulations (specifically Title 21 CFR50 Subpart D) are in place to provide additional safeguards for children in clinical investigations.

Before an investigational product with more than minimal risk to study subjects — like a gene therapy — is tested in children, its potential to treat the disease needs to be first established through non-clinical or animal studies, or through clinical studies involving adults.

“Once the prospect of direct benefit is established, children may be studied; however, adult safety should be established first, if feasible,” said Dr. Blank. “If there is no suitable adult population to test the product first for safety, and the prospect of benefit is solely reliant upon animal data, children may need to be the first early-phase study subjects,” explained Dr. Blank.

In such cases, the oldest pediatric population with the prospect of direct benefit is usually enrolled first because they can provide assent.

As of March 10th, 2023, there are 1,038 studies on ClinicalTrials.gov that list gene therapy as an intervention. Since the number of gene therapy clinical trials is increasing substantially, the FDA is holding another OTP Town Hall on April 25 to speak about gene therapy chemistry, manufacturing and controls (CMC).