BIOCHEMISTRY, BIOMEDICINE & PHARMACEUTICS

Human Gene Therapy for Rare Diseases  CONSIDERATIONS FOR PRECLINICAL STUDIES  A preclinical program that is tailored to the investigational product and the planned early-phase clinical trial contributes to the characterization of the product’s benefit/risk profile for the intended patient population. The overall objectives of a preclinical program for a GT product include:  identification of a biologically active dose range;  recommendations for an initial clinical dose level, dose-escalation schedule, and dosing regimen; establishment of feasibility and reasonable safety of the proposed clinical route of administration (ROA);  support of patient eligibility criteria; and  identification of potential toxicities and physiologic parameters that help guide clinical monitoring for a particular investigational product.  In addition, to justify conducting a pediatric first-in-human clinical trial that is associated with more than a minor increase over minima...

FDA Guidance on Human Gene Therapy for Rare Diseases CONSIDERATIONS FOR CHEMISTRY, MANUFACTURING, AND CONTROLS  The general chemistry, manufacturing, and controls (CMC) considerations for product manufacturing, testing, and release of GT products for rare diseases are the same as those described for other GT products.  However, 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. In traditional product development, critical quality attributes (CQAs) of the product are evaluated during each phase of clinical development, and characterization data from many drug product lots are correlated to clinical outcomes.  Smaller study populations may result in the need for fewer manufacturing runs, which can make it difficult to establish the critical process parameters (CPP) necessary for ensuring CQAs. In addition, GT products may have C...

 Immune responses to therapeutic protein products may pose problems for both patient safety and product efficacy. Immunologically based adverse events, such as anaphylaxis, cytokine release syndrome, and cross-reactive neutralization of endogenous proteins mediating critical functions, have caused sponsors to terminate the development of what otherwise may have been efficacious therapeutic protein products. Unwanted immune responses to therapeutic protein products may also neutralize their biological activities and result in adverse events not only by inhibiting the efficacy of the therapeutic protein product but also by cross-reacting to an endogenous protein counterpart, leading to loss of its physiological function (e.g., neutralizing antibodies to therapeutic erythropoietin cause pure red cell aplasia by also neutralizing the endogenous protein).  The regulatory agencies including FDA& EMA have outlined and recommended the risk-based approach to evaluating and mitigati...