The US Food and Drug Administration  (FDA) has published six guidances focused on gene therapy, including one specific for rare diseases.The six guidances are:

  1. Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)
  2. Testing of Retroviral Vector-Based Gene Therapy Products for Replication Competent Retrovirus (RCR) during Product Manufacture and Patient Follow-up
  3. Long Term Follow-Up After Administration of Human Gene Therapy Products
  4. Human Gene Therapy for Hemophilia
  5. Human Gene Therapy for Retinal Disorders
  6. Human Gene Therapy for Rare Diseases

The guidances provide recommendations to companies that are developing human gene therapy products. It should be noted that these guidances are recommendations only and that companies and other gene therapy developers are free to adhere to them or not. However, it is likely in the best interest of companies/developers to heed the recommendations of the FDA.

The guidance includes suggestions on best practices for:

  • General chemistry, manufacturing and controls (CMC) that includes addressing product-related variation, potency assays, as well as the ability to develop commercial-scale production and demonstrating product comparability prior to the initiation of clinical trials.
  • Preclinical studies that 1) identify a biologically active dose range; 2) provide recommendations for an initial clinical dose level, dose-escalation schedule, and dosing regimen; 3) establish the feasibility and reasonable safety of the proposed clinical route of administration (ROA); 4) support patient eligibility criteria; and 5) identify potential toxicities and physiologic parameters that help guide clinical monitoring for a particular investigational product.
  • Clinical studies, such as addressing the study population so that they include persons that are properly diagnosed and exclude those with pre-existing antibodies to the gene therapy product. The clinical studies should also strive to choose persons as young as possible with the least severe symptoms. Persons with more severe symptoms of a disease, or a more advanced disease progression, may experience confounding adverse events that are related to the underlying disease rather than to the gene therapy. The clinical trial design should be a randomized and where appropriate, placebo control groups should be used. Healthy volunteers should not receive gene therapy.

Some of the other study design suggestion by the FDA include:

  • Sponsors should consider designing their first-in-human study to be an adequate and well-controlled investigation that has the potential, depending on the study results, to provide evidence of effectiveness to support a marketing application.
  • It is important for sponsors, when applicable, to consider stratified randomization based on disease stage/severity.
  • For some genetically targeted indications (e.g., a genetic skin disease), the use of an intra-subject control design may be useful.
  • A single-arm trial using historical controls may be considered if there are feasibility issues with conducting a randomized, controlled trial.
  • If a single-arm trial design with a historical control is necessary, then knowledge of the natural history of disease is critical.
  • A small sample size, together with high inter-subject variability in clinical course, diminishes a study’s power to detect treatment-related effects. Therefore, alternative trial designs and statistical techniques that maximize data from a small and potentially heterogeneous group of subjects should be considered.
  • Clinical protocols should include adequate measures to minimize bias.
  • Efforts should be made early in the development program to identify relevant biomarkers. Some biomarkers or endpoints are very closely linked to the underlying pathophysiology of the disease.
  • Regarding concomitant medication, the dose should be stable over a specific time period (e.g., until measurement of the primary endpoint), and justified in the clinical protocol.

Regarding safety, the FDA recommends:

  • Clinical trials should include a monitoring plan that is adequate to protect the safety of clinical trial subjects.
  • Monitoring of neutralizing and non-neutralizing immune responses that are directed against the product throughout the clinical trial.
  • Early-phase clinical trial protocols should include study stopping rules, which are criteria for halting the study based on an observed incidence of adverse events.
  • The potential for viral shedding should be addressed early in product development.
  • Pharmacovigilance systems should actively monitor each recipient of a GT product.

Finally, the FDA strongly encourages all companies/developers to be in regular communications with the FDA’s Office of Tissues and Advanced Therapies (OTAT) to discuss the planning of their gene therapy program well before submitting an investigational new drug (IND) application. Subsequent meeting with OTAT, as well as other FDA departments, are also encouraged to make sure that the gene therapy program is developed in a way that will be beneficial to all parties involved.

To download the full guidance, click here.



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