Definitions, History and Regulatory Framework for Rare Diseases and Orphan Drugs

DAVID C. PRYDE AND STEPHEN C. GROFT

1.1 Orphan Drugs

An orphan drug or orphan medicine is a formal regulatory term used to describe a drug product that has been granted orphan status by a regulatory agency. Orphan designation is reserved for medicines that will treat diseases with prevalence below the threshold set for rare diseases, and may have additional factors such as the lack of availability of alternative treatments. The word 'orphan', from the Greek word orphanus for a child that has lost a parent, is taken from the ground-breaking legislation in the USA enshrined in the Orphan Drug Act of 1983," designed to stimulate the development of pharmaceutical products that target rare diseases, which were at the time largely neglected as they affected relatively few people.

1.2 Rare Diseases

There is considerable diversity among conditions that are defined as rare diseases and include neurological conditions, infectious diseases, rare cancers, autoimmune disorders, respiratory disorders, muscle disorders, blood disorders and a wide range of inherited genetic disorders. It has been estimated that there are more than 7000 rare diseases known, but only around 5% of these have therapies available and the unmet medical need across the breadth of rare diseases remains high. Over 80% of rare diseases are genetic in origin. Most of these are caused by defects in a single gene (that may be dominant or recessive), but some rare diseases are caused by multiple gene defects or a multitude of factors. Fifty percent of all rare diseases affect children and 85% are classified as serious or life-threatening. Some rare diseases may only affect literally a handful of individuals around the world, while others may affect hundreds of thousands of patients. In the developed world alone, rare diseases are thought to affect some 6% of the population, with estimates of more than 25 million North Americans and more than 30 million Europeans affected by a rare disease. Across the thousands of highly heterogeneous rare diseases that are known, there is no unifying classification that links them all, with the exception that they affect a relatively small number of people.

There is no single, widely accepted definition for rare diseases. In the USA, rare diseases are denned as any disease or condition affecting fewer than 200 000 people. In Europe, a condition is considered rare if it affects fewer than 1 in 2000 people and in Japan 1 in 50 000. There are a few diseases that affect more than 200 000 people where certain subpopulations that carry a particular disease fall below the prevalence threshold for a rare disease.

1.3 Developing an Orphan Drug

Developing drugs to treat rare diseases poses many unique challenges. Designing and conducting clinical trials is constrained, as there is usually little understanding or information about the natural progression of the disease to inform end point selection. Many rare diseases do not have clearly identifiable symptoms and investigators often have difficulty identifying and enrolling a large number of patients. Basic tools, such as validated animal models, may not exist. Small sample sizes pose statistical hurdles. These challenges increase the uncertainty that a research programme will lead to a new therapy, resulting in historically less investment into these therapies. An interesting example was raised by Tambuyzer, who highlighted that for Gaucher disease patients in Germany, only around 5% of all possible patients are being treated despite treatments being available for more than 15 years. This example also highlights the difficulties of obtaining accurate prevalence data for rare diseases, and how variable different sources of these data are. Certain rare diseases are also known to have very different prevalence rates in different populations and geographical regions, for example the glycogen storage disease Pompe disease, which can range in prevalence from 1 in 200 000 in Caucasians to as much as 1 in 14 000 in African Americans.

In recognition of these specific issues facing drug development for rare diseases, many governments around the world have developed orphan drug regulations to support those working to develop new products intended for the diagnosis, prevention or treatment of rare conditions. While provisions vary from country to country, the key incentives created under various orphan drug regulations generally include marketing exclusivity, which prevents similars from competing with the original approved product during the exclusive period but is in no way intended to create a monopoly if clinical differentiation can be demonstrated. For example, several small molecule treatments (imatinib, dasatinib and nilotinib) have been approved in parallel for chronic myeloid leukaemia. There is also support for sponsors taking their orphan drug through the regulatory approval process in the form of fee waivers, additional scientific advice and expedited review. Some regulations also include research grants or R&D tax credits.

These incentives have successfully increased drug development activities within the orphan drug space. Orphan drugs can offer faster development timelines, lower R&D costs, lower marketing costs and lower risk of generic competition. An analysis has suggested that orphan drug approval rates were greater than those of mainstream drugs, and the proportion of overall new drug approvals in recent years that are orphan drugs has steadily grown.

1.4 The Orphan Drug Act

The USA passed the first legislation of this type when the Orphan Drug Act of 1983 was signed into law. Similar legislation has been created in Australia, Europe, Japan and Singapore, with Canada and Russia set to introduce their own regulatory frameworks in the near future. The Orphan Drug Act sought to encourage development of drugs, diagnostics and vaccines intended to improve the treatment options for rare diseases by designating them as an orphan drug.

Orphan drug designation does not imply that a medicine is safe, effective or legal to develop and manufacture, but simply that the sponsor qualifies for certain benefits in the course of the drug development process.

In the USA, the Office of Orphan Products Development (OOPD) within the Food and Drug Administration (FDA) grants an orphan designation to any product that is indicated for a rare disease as per the above definition. Orphan designation may be granted at any point through the drug development process. An orphan-designated product may subsequently gain market approval only if data derived from clinical trials demonstrate the safety and efficacy of the product. Orphan designation confers certain benefits to a sponsor; 50% tax credits for clinical development costs, exemption from application user fees, subsidies for conducting clinical trials and market exclusivity for 7 years. These incentives have clearly made a significant impact on rare disease drug development. In the decade leading up to the Orphan Drug Act being passed, only 10 products for rare diseases received marketing approved while in the period since, more than 10 products have received marketing approval every year, and to date some 430 orphan products for rare diseases have been approved. The OOPD also administers a related programme that is intended to...