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 stimulate the development of medical devices that are intended for use in the treatment or diagnosis of a rare disease.

The Orphan Drug Act is widely accepted as having been hugely successful in driving R&D into rare diseases. In Figure 1.1, the number of orphan drug designations made by the OOPD since the adoption of the Orphan Drug Act in 1983 in the USA is illustrated, along with the number of orphan drugs that received market authorisation. The number of designations has increased markedly in the last decade to an average of well over 100 per year, reflective of generally increased interest from R&D companies in rare diseases. However, one can also see that the number of market authorisation approvals in the same period has remained relatively constant, and in fact relatively constant going back to the previous decade also, which at first glance may look like diminished, or at best flat, productivity.

Using the data set charted in Figure 1.1, over the entire period 1984-2013, 15% of all designations resulted in an approved product. Year on year, overall approval rates as a proportion of designations was plotted in Figure 1.2 and is relatively flat, with a peak towards the end of the last decade.

This picture is of course atypical in a period where overall drug approval rates have fallen, and therefore the proportion of orphan drugs being approved as a percentage of overall drug approvals is actually rising and appear to have higher approval rates than more mainstream drug applications in recent years.

1.5 Outside of the USA

In the European Union, the Committee for Orphan Medicinal Products (COMP) is responsible for reviewing requests for drug products being given an orphan medicinal product (OMP) designation that are being developed for the purpose of treating a rare disease. Compounds that are given this designation are then assessed by the Committee for Medicinal Products for Human Use (CHMP) to receive formal market authorisation should they have demonstrable efficacy and safety. In Europe, the incentives for drugs that have been designated as having orphan status include 10 years of market exclusivity, grants for conducting clinical trials and fee reductions for requests made to the European Medicines Agency (EMA). The OMP legislation came into force in 2000, the same year the COMP was established. Several other countries also now have dedicated legislation, development incentives and approvals procedures for rare disease treatments, including Japan, Australia and Singapore.

1.6 Thirty Years on from the Orphan Drug Act

Since these regulations were established, the number of licensed therapies for rare diseases has increased markedly. Since 1983, there have been some 400 orphan product approvals in the USA now available for use by patients around the world, compared to just 10 orphan drugs approved in the previous decade. Focusing on the last decade only, the number of drug approvals has been both high (in total more than 180) and consistent and appears set to continue this trend into the future (Figure 1.3).

In Europe, within the same period of time, more than 65 orphan drug products have been granted market authorisation since the EU orphan drug legislation was enacted (Figure 1.4).

These regulatory guidelines can therefore be described as very successfully stimulating orphan drug development. However, the Orphan Drug Act and its sister regulations in other regions have sparked some controversy, not least through the advent of blockbuster orphans. These are drugs that generate annual revenues of at least several hundred million dollars through high per unit cost, sometimes in excess of $100 000 per patient per year or by widespread use of the drug outside of its primary orphan indication. Some studies have identified orphan drugs that generate significantly more revenue through off-label use than for any orphan indication.

Most orphan drugs are approved for a single indication only, but now almost 50 drugs have been approved for multiple rare diseases. One of the most commercially successful orphan drugs is imatinib (Gleevec), with sales in excess of $4.5 billion in 2011 and seven separate orphan drug approvals. Indeed, in 2006–2008, no less than 16 orphan drugs made the top 200 list of best-selling drugs in the USA with annual sales in the range $200 million to $2 billion, and fuels the perception that orphan drugs can be economically viable and offer attractive business opportunities for biomedical drug development organisations. It should be borne in mind, however, that each market authorisation requires separate clinical trials for each additional indication added to a product, which needs to be paid for by the sponsor. It is also clear that for small market sizes and first-in-class medicines, a sponsor needs to embark on a R&D programme in the knowledge that their investment can be recouped, which does imply higher drug pricing, without which many of the products invented to date may never have come to market. It should also be highlighted that the legislation as it applies to orphan drug development makes no explicit provision for enhancing basic research into rare diseases, their diagnosis or which diseases receive drug development attention in which order.

1.7 Drug Repurposing

A crucial aspect of drug development activity for rare diseases has been the repurposing of existing drugs that had previously received marketing approval for a more common disease. This is particularly important as previously approved compounds will already have completed pre-clinical toxicity testing and been deemed to have demonstrated pharmacological activity in another disease indication. The OOPD has recently published data on the FDA website that details all 97 drugs that have an orphan designation and have previously been approved for a more mainstream indication. In addition, the same resource details the 71 drugs that are orphan-designated and have received previous market authorisation for another rare disease, and the 36 drugs that have an orphan designation and have been previously approved for both orphan and mainstream indications. Taken together, all drugs that have been previously approved for any disease indication by a regulatory authority offers a significant resource for rare disease research, having cleared many of the hurdles that often lead to attrition in the drug development process. There are more than 200 drugs that have a current orphan drug designation and benefit from market authorisation for some disease indication, but of course this is but a small fraction of the totality of approved drugs that could have some utility against a rare disease.

An example of a drug that was approved for a mainstream indication and subsequently approved for a rare disease is sildenafil from Pfizer (as Viagra, approved for the treatment of male erectile dysfunction in 1998), which was approved for the treatment of pulmonary arterial hypertension in 2005 as Revatio. Examples of drugs that were initially launched as orphan drugs and then were repurposed for broader indications include rituximab from Genentech (as Rituxan, initially approved for the treatment of non-Hodgkin lymphomas in 1997) and epoetin alpha from Amgen (as Epogen initially approved for the treatment of anaemia in 1989).

An interesting example of a drug that was never intended for use as a human therapeutic is nitisinone, which was developed originally as a herbicide. Nitisinone is a 4-hydroxyphenyl pyruvate oxidase inhibitor that interrupts the formation of excess tyrosine in the blood and helps to prevent liver damage in children with hereditary tyrosinemia.

1.8 Treatments and Modalities

The breadth and diversity of rare diseases makes all therapeutic modalities potentially applicable. Of the currently approved orphan drugs, many are small molecules, but others include, for example, monoclonal antibodies or enzyme replacement therapy (ERT) that at the time of approval were considered to be highly innovative. A wide range of experimental therapies based on the next generation of novel and innovative technologies that are especially well suited to gene defects include anti-sense oligonucleotides, RNA interference and stem cell-based therapies. Applications of all of these technologies to the treatment of rare diseases are illustrated below.

1.8.1 Small Molecules

The vast majority of rare disease treatments available today are small molecules, and mirrors the research focus of most mainstream disease indications across the industry. It seems likely that this trend will continue, particularly where a specific distribution feature of a rare disease (a neurological disease, for example) or an intolerance to other modalities (for example the use of the small molecule miglustat for the treatment of metabolic disorders where ERTs are poorly tolerated) dictates that small molecule options are best suited. The origins of the small molecule agents that are currently approved as a rare disease treatment again mirrors those of more mainstream small molecule drugs, and include phenotypic screens, high-throughput single target screens and natural product semi-synthesis as well as drug repurposing.