This document aims to assists sponsors of in conducting an efficient and successful developmental programme for orphan drugs and biologics. The document discusses selected issues commonly encountered in rare disease drug development. The United States Food and Drug Administration (FDA) addresses the following important aspects of drug development:
Adequate description and understanding of the disease’s natural history
FDA advises sponsors to evaluate existing natural history knowledge of the disease in question early in drug development, to guide clinical development. They recommend that additional data should be collected, preferably prospective data, for a sufficient duration in order to capture “clinically meaningful outcomes and determine variability in the course of the disease.”
Adequate understanding of the pathophysiology of the disease and the drug’s proposed mechanism of action
The FDA does not require sponsors to study the biochemical basis of a disease, but necessitates the sponsors to seek an adequate understanding of the pathophysiology at the outset of drug development. The document delineates the aspects of drug development the knowledge will help understand many aspects that is helpful towards drug development which are delineated in the document.
Nonclinical pharmacotoxicology considerations to support the proposed clinical investigation or investigations
FDA stipulated the requirement of “toxicology information from in-vitro studies, animal studies or both before first-in-human use of an investigational drug.” Toxicology study design should be based on the biology of the disease, expected pharmacology of the drug, existing Proof-of-Concept (POC) data, clinical trial design or designs to be proposed, and the indication being sought. They ask the sponsors to follow internationally accepted, general guidance’s for the timing and nature of nonclinical safety studies relative to clinical trials in drug development. They instruct drug developers to thoroughly understand the biological relevance and limitations of the animal model of disease if used in nonclinical studies.
Reliable endpoints and outcome assessment
Another important aspect of clinical studies for orphan drugs is the selection of appropriate endpoints. They suggest early development of new assessment tools, or modification of existing ones, before relying upon it as the basis of an endpoint in a clinical trial. Endpoint selection for a clinical trial entails multiple considerations including: an understanding of the disease, including the likelihood, range, and course of clinical manifestations associated with the disease (disease definition). They document also describes the favourable characteristics of the assessment tool to measure suitable endpoints.
Standard of evidence to establish safety and effectiveness
The statutory requirement for marketing approval is “substantial evidence” that the drug will have its claimed effect. To establish this, the sponsors must have an adequate and well-controlled study design, which the FDA has described in the document. FDA stipulates that the sponsor should use “all tests reasonably applicable” and a monitoring plan to establish the safety of the drug for its intended use. According to the document there is no specific minimum number of patients to establish effectiveness and safety of a treatment for any rare disease as it is determined on a case-by-case basis.
Drug manufacturing considerations during drug development
Finally, the document provides guidance on the final facet of drug development as it proceeds to later-phase studies, such as increasing experience with manufacture of the drug, changes in available technology, and the need for larger amounts of the drug in later phases of clinical development which may lead to manufacturing changes that include manufacturing procedures, purification methods, and increased scale. FDA recognises that, especially in the case of orphan drugs, transfer of manufacturing responsibilities could occur after initial testing, which may lead to unanticipated changes to drug characteristics. If significant differences are identified in drug, FDA require these to be addressed and necessary changes be made. To avoid delays, FDA advocate addressing these issues as early as possible.
In all cases the guidance document strongly recommends the sponsors of treatments for rare diseases to start an early dialogue with the FDA in order to avail valuable and productive information to carry forward their trials.
OrphaNews 15 September 2015
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Deadline for public comment: 30 September 2015