Advanced therapies – referred to as advanced therapy medicinal products (ATMPs) in the EU and as cell and gene therapies (CGT) in the US – are a class of products based on genes, tissues or cells used to treat or deliver treatment to patients. Since the first gene therapy for a rare paediatric leukaemia was approved by the U.S. Food and Drug Administration (FDA) in 2017, there has been mounting excitement that advanced therapies could help manage, or even provide a durable solution for, rare diseases. These ‘living’ therapies are designed to have long-lasting or permanent effects that restore biological function and address the underlying cause of disease. This includes genetic causes, which account for the majority of rare diseases.

The excitement around advanced therapies for rare disease has been amplified by the overwhelming, unmet need for treatment options. At present, 90 percent of rare diseases have no FDA-approved therapies. While there is a great need for rare disease advanced therapies, clinical development and subsequent market authorisation remains challenging. This blog discusses common hurdles and considerations for the clinical development of rare disease advanced therapies.

Rare disease clinical development

The primary challenges of rare disease clinical development, regardless of therapeutic class, include a limited patient population, wide geographic distribution of these patients and minimal preclinical data. Rare diseases are often poorly characterised, and have only a few specialists with the expertise to run a clinical trial. In addition, clinical trials must recruit from an extremely small population, and this population is often paediatric patients with life threatening conditions. The limited number of participants, paired with an ethical obligation to treat as many as possible, means that controls are designed to be very small or external to the trial. Great unmet need also means that rare diseases are often eligible for expedited market authorisation. Most commonly, the development pipeline for a rare disease involves a phase 1/2 combined trial, a phase 3 trial and market approval followed by patient follow-up and phase 4 trials.

Advanced therapy clinical development

Development challenges specific to advanced therapy clinical development include stringent regulations during manufacturing and production, and limited preclinical information to guide clinical trial design. Establishing manufacturing and quality standards is also a major challenge for advanced therapies, because their biological nature can pose unique risks, including immunogenicity and variable efficacy. In addition, animal models are unsuitable for preclinical studies, limiting preclinical data before first-in-human trials. Many advanced therapies also should not be tested on healthy volunteers, limiting first-in-human studies to the target population.

Advanced therapies specifically for rare diseases must navigate the compounding challenges faced in rare disease and advanced therapy development. A strategic regulatory strategy will help ensure that these therapies get the appropriate resources during development and consideration during market authorisation.

For more information on unlocking the potential of advanced therapies developed for rare diseases, read our whitepaper and check out our regulatory strategy blog.