Clinical Research: Phase 1 - Phase 4

Where Biomarkers and Gene Therapy Trials Intersect: Benefits Abound

We’re currently experiencing breakthrough times for clinical research in gene therapies. These complex treatments offer much-needed hope to more than 30 million U.S. patients affected by over 10,000 rare diseases1, many of which are life-threatening and the vast majority of which have no available treatment.  

Gene therapy products must meet the same key regulatory standards as other biologics or pharmaceuticals to receive approval: substantial evidence of safety & efficacy based on clinical investigations. Because gene therapies are long-lasting interventions, regulators want to see a measurable decrease in irreversible morbidity or mortality during clinical studies. The effect of the therapy on a biomarker carefully selected for a trial can be useful in determining the product’s efficacy.  

To provide regulatory insights for sponsors navigating the complex path to approval, the U.S. FDA’s Office of Tissues and Advanced Therapies (OTAT) at the Center for Biologics Evaluation Research launched a virtual Town Hall series to discuss OTAT-regulated products. The town hall session held on February 7, 2023, focused on gene therapy clinical development for rare diseases, and included guidance from OTAT on how best to utilize biomarker endpoints in early-phase studies. In this post we highlight several important insights on this topic: how to choose the right biomarker, pursuing Accelerated Approval, use of biomarkers for dose finding, and the potential for reducing the length of a trial.  

Choosing the right biomarker early in clinical development

Biomarkers, whether in the form of laboratory/imaging tests or other clinical measures, provide intel about the state or severity of a disease process. They can also potentially provide insight into the effect of an investigational product on the disease process.

To assess the suitability of a biomarker and how best to utilize it in a gene therapy trial, researchers should be able to answer these questions:

  • How well does the biomarker track with the disease process?
  • Will a pharmaceutical effect on the biomarker predict a clinically meaningful improvement on irreversible morbidity and mortality?
  • Are we confident in the assay or imaging technique etc., used to measure the biomarker?

Conducting a natural history study of the disorder being treated, is one of the best ways to explore the clinical utility of biomarkers. This study should ideally commence early in a clinical development program, and should aim to identify relevant biomarkers that track with disease activity and indicate the effect of the investigative product on that activity.

A number of validated and established biomarkers have been used as the basis for many drug approvals. An example of this is blood pressure measurement, which is predictive of future heart attack or stroke. If clinical data fully support the biomarker’s predictive ability for the disease process of interest, it is deemed a validated biomarker and can support a traditional approval.   

Biomarkers and the path to Accelerated Approval  

Since some rare diseases progress very slowly, it may take years to demonstrate a gene therapy’s effect on irreversible morbidity and mortality. For a therapeutic addressing a serious condition with an unmet medical need, the sponsor can utilize biomarker endpoint data from a trial to request Accelerated Approval from the FDA, which can bring the product to market faster. To pursue this pathway, researchers must establish that the therapy improves a biomarker which is reasonably likely to predict a subsequent improvement in the way a patient feels, functions, or survives—the standard for traditional approval.

While the Accelerated Approval pathway can shorten the regulatory timeline, a product approved under this expedited program still requires a confirmatory trial post-approval to show that it actually delivers a clinical benefit. Product efficacy can be further established during the post-marketing period.

How biomarkers can assist the dose finding process

Biomarkers can be used not only as a basis for drug approval, but also to assess important safety and pharmacodynamic effects, which are valuable for dose finding. Dose exploration is critical and should be conducted as soon as feasible in early-phase gene therapy studies. Specific plans for clinical dose escalation should reflect the risks and activity associated with each change in dosage. During the trial, researchers should identify the maximum tolerated dose within the therapeutic target range. Since clinical outcomes are usually delayed, toxicity and biomarker data can be helpful for dose selection in subsequent product development.

When time is of the essence, biomarkers offer hope

FDA guidelines on the length of clinical trials, including gene therapy trials, posit that studies should be planned for a time frame adequate to demonstrate a clinically meaningful effect on how patients feel, function, or survive in order to establish a treatment’s efficacy.   

In general, producing evidence of efficacy takes less time for gene therapies that have a faster onset of response and for conditions that progress quickly. If a disease is more heterogeneous, evolves more slowly, or there is a lag between product administration and development of the specific symptoms that the therapy is intended to treat, the clinical trial will of necessity be longer.

As noted previously, however, the FDA offers flexibility to speed drug development for rare diseases. Under the Accelerated Approval program, sponsors can obtain therapy approval by documenting a clinically meaningful effect on a validated biomarker in a shorter period of time, with plans for post-marketing studies to demonstrate a clinically meaningful benefit.

When in doubt, seek out the guidance

The effect of an investigational gene therapy on a carefully chosen biomarker used in a clinical trial can help determine product efficacy, aid in dose finding, reduce study length, and expedite regulatory approval. The FDA offers valuable guidance for product development stakeholders and researchers on how best to utilize biomarker endpoints in gene therapy clinical trials. Sponsors are well-advised to take advantage of this guidance and seek it out throughout the development process.

Partnering with a CRO who has experience in the end-to-end development of both rare diseases and cell and gene therapy (CGT) products can give biotech innovators a head start in clinical trial planning. At Premier Research, our expertise encompasses more than 240 rare disease and more than 95 CGT projects across multiple indications and treatment modalities in just the past 5 years. To learn more about how we can help at every stage of CGT product development, click here.

[1] National Institutes of Health (NIH) Genetic and Rare Diseases (GARD) Information Center. Accessed August 14, 2023. Available at