By Rebecca Mayo, J.D.
To assist stakeholders developing a human gene therapy (GT) product intended to treat a rare disease in adult and/or pediatric patients, the FDA issued a draft guidance providing recommendations regarding the manufacturing, preclinical, and clinical trial design issues for all phases of the clinical development program. Due to the unique nature of GT products and the rare diseases they may be used to treat, the FDA noted in the draft guidance that there may be limited study population size and potential feasibility and safety issues as well as issues relating to the interoperability of bioactivity/efficacy outcomes (Notice, 83 FR 32303, July 12, 2018).
Product development. Some aspects of the development programs for rare diseases, such as limited population size and fewer lots manufactured, may make it challenging to follow traditional product development strategies. Some product-specific considerations may arise including product-related variations, potency assays, and limited availability of starting materials or reference materials.
Preclinical studies. The objectives of a preclinical program should include: 1) identification of a biologically active dosage range; 2) recommendations for an initial clinical dose level, dose-escalation schedule, and dosing regimen; 3) establishment of feasibility and reasonable safety of the proposed clinical route of administration; 4) support of patient eligibility criteria; and, 5) identification of potential toxicities and physiological parameters that help guide clinical monitoring for a particular investigational product. Preclinical in vitro and in vivid proof-of-concept (POC) studies, biodistribution studies, toxicology studies, and additional nonclinical studies that may still be necessary should be considered in developing a preclinical program.
Clinical trials. Selection of the study population should consider existing preclinical or clinical data to determine the potential risks and benefits for the study subjects. In addition, the sponsor should perform genetic tests for the specific defects of interest if the disease is caused by a genetic defect. A companion diagnostic may be considered to detect potential pre-existing antibodies to the GT product. The severity of the disease should be considered as well as the anticipated risk and potential benefits to subjects. Since most rare diseases are pediatric diseases or have onset of manifestation in childhood, pediatric studies are critical to drug development but risks and benefits should be weighed heavily. Additionally, the risks of most GT products include the possibility of unintended effects that may be permanent, which should be considered.
For rare diseases, there may be a limited number of patients who may qualify for enrollment into a clinical study, which may restrict the way the study is designed. The guidance recommends that sponsors consider the best way to achieve randomization, the potential use of an intra-subject control design, the potential use of a single-arm trial using historical controls, as well as alternative trial designs and statistical techniques that maximize data. Clinical trials should include a monitoring plan that is adequate to protect the safety of clinical trial subjects. The guidance provides a list of safety considerations for sponsors as well as considerations in selecting an efficient endpoint.
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