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Rare diseases affect an estimated 25 to 30 million Americans, with single-gene defects causing 80% of the 7,000 known rare diseases. Approximately half of all rare diseases affect children. Despite these staggering numbers, approximately 95% of rare diseases—often severe or life-threatening conditions—have no approved treatments.

Key Highlights

In Part Two of Decoding FDA Gene Therapy Guidances, we discuss three separate guidances that provide further insight into how sponsors can safely and effectively develop gene therapy products for rare disease patients.

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

How can drug developers meet this high unmet medical need and provide rare disease patients with the care and treatments they require? Stakeholders have raised a number of questions about the process of gene therapy product development in this space. Although gene therapy is a promising avenue, specific questions addressing regulation and oversight must be answered, making guidance for the industry more necessary than ever. Recent FDA guidance, published in early 2020, outlines key considerations for sponsors designing gene therapy clinical trials for rare diseases.

“Because most of the 7,000 rare diseases are caused by genetic mutation, gene therapy represents an exciting source of hope for durable and meaningful treatment for these patient communities,” says Amy Raymond, PhD, Director of Therapeutic Expertise at the Center for Rare Diseases. “Finalization of this important guidance creates a shared understanding of expectations between regulators and drug developers very early in the process, an efficiency that we all hope translates to bringing safe and effective treatments to the clinic sooner.”

In this installment of Decoding FDA Gene Therapy Guidances, we discuss three separate guidances that provide further insight into how sponsors can safely and effectively develop gene therapy products for rare disease patients.

Clinical challenges and considerations of rare disease gene therapy

The first guidance we’ll discuss here lays a foundation for sponsors developing gene therapy products intended to treat a rare disease in adult and pediatric patients. Developing any type of treatment for a rare disease is challenging, but human gene therapy presents its own unique set of challenges, one of which is natural history data.

FDA guidance encourages sponsors seeking to enroll patients to obtain pertinent information from a natural history study first. This information can help guide all stages of drug development, from discovery to safety and efficacy evaluation. Unfortunately, gathering accurate and robust natural history data can be a stumbling block for rare disease studies, as many clinical manifestations often occur early in life. This can present both ethical and regulatory issues surrounding the enrollment of children into clinical trials.

Sponsors should consider the following when developing their early and late-phase trials:

Study Populations

Sponsors must consider existing preclinical and clinical data to develop a risk-benefit profile for study participants. Rethinking trial design may be necessary if a study is not likely to result in informative safety or efficacy data.

Enrolling children in any type of clinical trial presents several challenges, both logistically and ethically. Gene therapy studies require even more considerations when it comes to pediatric patients as the risk-benefit ratio is significantly higher in gene therapy products than it is in other products. Sponsors must be very thoughtful about protecting this vulnerable population—especially considering gene therapy products could affect pediatric patients for the rest of their lives.

Study Design

Enrolling participants across all study phases is often challenging, so collecting pertinent study data—adverse events, efficacy outcomes, and biomarkers, for example—must begin with the first-in-human study. This information should provide evidence of effectiveness to support a marketing application.

FDA trial guidelines suggest using a randomized, concurrent-controlled trial as the so-called “ideal standard” for establishing safety and efficacy. The FDA also recommends using placebo controls to facilitate the interpretability of safety and efficacy results. Understanding the value of the intervention is important, as is determining if—or how much—improvement a treatment offers.

To do this, sponsors can consider stratified randomization based on disease stage and severity when possible. When studying genetically targeted indications, intra-subject control designs can be useful. Finally, sponsors should consider conducting a single-arm trial utilizing historical controls and an initial observation period when a randomized, controlled design is not possible.

Alternative trial designs and statistical techniques are critical in maximizing data from a small, potentially heterogeneous group of participants, as is often the case for rare diseases.

Dose Selection

Looking back at non-human data obtained from animal models is the only way to estimate an appropriate starting dose in humans for some products. In these cases, sponsors should use predictive models based on the current understanding of in vitro enzyme kinetics and allometric scaling.

In early phase studies focused on patients with serious or life-threatening conditions, trials can start treating patients with a therapeutic dose. If the consequent treatment effect decreases over time, investigators should repeat the administration of the gene therapy product.

Prioritizing Patient Safety

Although any clinical trial poses risks to patient safety, gene therapy has the potential to be associated with very serious health risks, including toxicity, inflammation, and cancer. However, the benefits of developing these products may ultimately outweigh the risks for patients with an unmet treatment need.

Gene therapy trials need to include a monitoring plan to ensure participant safety. Monitoring plans should be based on the disease in question and known information about the gene therapy product, including:

  • Dosing frequency
  • Preclinical toxicology
  • Chemistry, manufacturing, and controls (CMC) information
  • Previous human experiences

Immune responses may occur and could affect product safety and efficacy. Sponsors can mitigate these responses by developing the appropriate assays to measure the immune response.

Long-term safety is important in gene therapy development, but due to the nature of the mechanism of action, long-term safety for many of these products is unknown. Developing appropriate long-term follow-up observation protocols to monitor delayed adverse events is key.

Finally, it’s crucial for sponsors to acknowledge the reality that some early phase gene therapy trials may need to be terminated early. Protocols for termination should include study stopping rules, based on the observed incidence of adverse events.


Sponsors must follow the same principles as for any other product when demonstrating the clinical benefit of a gene therapy product. However, some gene therapy products might express unique characteristics that warrant consideration in preapproval and post-marketing settings. The FDA urges trial sponsors to discuss the proposed primary efficacy endpoints with the organization, as well-established, disease-specific efficacy endpoints are not available for many rare diseases.

Disease-specific recommendations

The considerations for generalized gene therapy also apply to sponsors developing trials for disease-specific gene therapies. However, due to rapid advancements in the field for retinal disorders and hemophilia, the FDA also released disease-specific recommendations for both of these target areas.

Inherited retinal diseases are primary targets in this space, particularly RPE65 gene mutations leading to retinal degeneration or retinal dystrophy. Clinical trials focused on the RPE65 gene demonstrated improvement in functional vision for trial participants. With the approval of voretigene neparvovec-rzyl (Luxturna), research has expanded into other inherited retinal diseases including choroideremia, X-linked juvenile retinoschisis, Stargardt disease, achromatopsia, and several others.

Several experimental gene therapies are also underway for hemophilia. These focus mainly on using a modified virus to insert a copy of the clotting factor gene into patients’ DNA. Two early phase clinical trials showed promising results and other trials are in various recruitment stages or are being investigated in phase I or phase II clinical trials.

Retinal Diseases

Fundamental considerations are similar to those for other biological products, per the FDA. Early phase trials can evaluate safety and feasibility, as well as gauge bioactivity and preliminary efficacy. Later phase trials should be well-controlled studies that provide substantial-effectiveness evidence.

When designing studies, it’s important to address the ethical considerations of intravitreal injection, including potential risks. Both intravitreal and subretinal injections and vehicles might be unacceptable under certain circumstances, both without a prospect of direct benefit.

Because visual acuity is subjective, patient effort may influence results, which introduces potential bias. Trial design should incorporate concurrent parallel-group or groups as a control to decrease this bias. Adequately designed masking procedures can also reduce bias in outcome measure assessments.


The severity levels of hemophilia are determined by the level of residual clotting factor (factor VIII or factor IX) activity in a patient’s blood. This is denoted by the percentage of factor activity in the blood, or international units per ml of blood (IU/ml).

The FDA recommends that trial sponsors consider taking several steps to better interpret factor activity due to discrepancies in factor activity measurements between one-stage clotting and chromogenic substrate assays. In vitro or ex vivo studies can compare assay performance, followed by the use of various clinical factor activity laboratory assays in preclinical animal studies. Analytical studies can clarify biochemical root causes for any observed discrepancies. These steps should be taken before considering whether to pursue accelerated approval.

Bring safe and effective treatments to the rare disease patients who need them most

Gene therapy product development provides options to meet the unmet needs of millions of rare disease patients around the world. However, we still have much to learn. These FDA guidance documents provide the first of many steps down the path to potentially successful treatments.

Another important component of gene therapy clinical development for rare diseases is the long-term follow-up, which allows sponsors to collect the necessary long-term data needed to ensure the safety of their patients and receive market approval for their product. We discuss FDA recommendations for these studies here.

Learn how PRA is designing rare disease clinical trials that work better for patients and sponsors


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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