FDA Guidance document for industry open for public comment
"Rare Diseases: Common Issues in Drug Development" a guidance document recently published by United States Food and Drug Administration (FDA) is now open for public comment
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 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
Read the document
Deadline for public comment: 30 September 2015
An article published in ACS Medicinal Chemistry Letters elucidates 2 bills currently being followed in the United States Congress and Senate to promote the development of orphan drugs. These bills are the 21st Century Cures Act (CCA) and Orphan Product Extension Now Accelerating Cures and Treatment Act of 2015 (The OPEN ACT) 1421). 
The TGA sought comments from interested parties on the Orphan drugs program discussion paper. A total of 30 submissions were received, of which 10 were from pharmaceutical companies, 7 from consumer organisations, 4 from industry organisations and 3 from Government bodies. The remaining 6 submissions were from regulatory affairs organisations, professional bodies and other miscellaneous organisations/individuals. 
APARDO is the new alliance for the Asia Pacific region and after several years of preliminary work it was formally launched at the Orphan Drugs Congress in Singapore in June 2015. There are many aspects of policy, culture, regulation and levels of development that make it vital for rare disease action plans to be sensitive to and responsive to local and regional issues. APARDO will work to boost rare disease policy and action plans in the region not by trying to “transplant” ideas from the developed health systems, but more by “translating” those ideas and actions into relevant themes for countries in this region. Though APARDO does not yet have a website active, you can read about its development in an article in “An Asia Pacific Alliance for Rare Diseases” published in The Patient. 
A study in the Orphanet Journal of Rare Diseases shows how the Canadian print media reports on issues of access to treatment. The authors demonstrate, through an exhaustive study of the articles published in major newspapers that journalists are more likely to take the view that access to treatment should be provided, sometimes at the expense of evidence. The authors provide compelling and interesting evidence on the nature of bias. Also revealing was that only 23 articles (4.3%) were judged to have a neutral perspective, demonstrating the extent of bias. Access to treatment is an important and often painful issue especially for rare disease patients, and being sympathetic to their cause is natural but this article shows the sizable breadth of this bias. 
Offlabel of drugs is particularly relevant to patients with a rare disease where sometimes it can be the only available treatment. The author of an article published in Perspectives in Clinical Research describes the risks and benefits to allowing offlabel use of drugs in India. The author asserts that an offlabel use may provide the best available intervention for a patient, especially rare disease patients but may also carry some risks for the patients in case inappropriately utilised, as often the case in India. According to the article, the drug controller general of India (DCGI) is the regulatory authority in India for granting approval for new drugs but, unfortunately, has not produced clearcut guidelines on the offlabel use of drugs. The author believes that the "good reprint practices guidance of FDA could be a good starting point" for DCGI. The authors describes the advantages of offlabel use of drugs making a case for the government, in close association with the DCGI, to look at ways and means to streamline the practice. 
The authors of a study published in PLOS One designed a "capture array for all the coding sequence of 2,181 genes associated with 561 Mendelian diseases and conducted next generation sequencing to detect mutations." Results of the evaluation showed that their method had high accuracy and stability in detecting disease causing mutations. The authors believe that this technology can be used for "diagnostic testing, providing effective basis for the clinical diagnosis or genetic counseling of 561 Mendelian diseases." The article provides a list of the Mendelian diseases analysed in this study in their supplementary materials. 
