There are several different paths that companies have followed to develop orphan drugs. And, in some cases, the pricing of the resulting drugs has led to the perception that unreasonably high prices are being paid for some, not leaving enough space for truly innovative drugs with high value. This can lead to the situation where orphan drugs are not effectively differentiated.
Formally and informally, governments are looking at how they are going to handle orphan drugs in the future. The question is a crucial one, since the health benefits of an orphan drug can only be realised if patients get access to them.
In recent years  there has been increasing criticism of behaviours in the orphan drug field, mainly centring on two perceptions of the system. The first is the high prices of orphan drugs and their resulting inability to meet standard cost-effectiveness thresholds. The second is the construct of the system itself and the ability of companies to “game” the system in order to secure the benefits that accrue from being badged as an orphan drug, which may, in turn, allow them to request a higher price point.
These two perceptions, or a combination of them, has led to an increasing questioning of the value of the orphan system in Europe, or pushed some governments to refuse reimbursement.
The authors hypothesise that by examining these criticisms individually, one might be able to turn these different “behaviours” into criteria. These criteria could then be at the basis of a new system for review and assessment of individual orphan drugs, at the time of pricing and reimbursement.
The authors provide below specific, non-exhaustive examples of “behaviours” that can be grouped into two main categories of dynamics: drug indication dynamics (1–3) and regulatory / market dynamics (4–5).
Multiple indications as opposed to a single, orphan indication
Imatinib, initially authorised for the treatment of Chronic Myeloid Leukaemia (CML) on 27 August 2001, has been repeatedly criticised for having more than one indication; and its subsequent authorisations for GIST (gastrointestinal stromal tumours), ALL (acute lymphoblastic leukaemia), myelodysplastic / myeloproliferative diseases, chronic eosinophilic leukaemia, and dermatofibrosarcoma protuberans have led to questions (so-called “indication creep”) about the system that allowed it. On the one hand, for each indication, there needs to be a separate clinical development programme and a separate request for, and granting of a European Marketing Authorisation – the new indications do not simply accrue from the original. On the other hand, the substance is already known, so some studies do not need to be repeated. There is an apparent expectation from the payers that, as the size of the market for an individual compound increases, the compound ceases to be truly orphan in its applications and, therefore, an expectation that the orphan incentives might no longer be as applicable as at the time of the first authorised orphan indication . Moreover, as indications increase, economies of scale may come into play. In this respect, the literature has consistently found an inverse relationship between orphan drug prices and the prevalence of rare diseases .
The current marketing authorisation pathway appears to oblige companies to follow a sequential approach when the mode of action for an active ingredient proves useful in multiple indications, which might undermine this ability. In the context of other initiatives, such as the IRDiRC , the need for regulatory approaches to address “repurposing” might be considered.
Rare into Common – similar questions being raised
A drug approved as an orphan for a specific indication may go on to seek and be granted a Marketing Authorisation for a non-orphan indication. Such a situation could turn a therapy intended initially for a small, well-defined, orphan population into a blockbuster. For example, Bosentan, an orphan medicine for the treatment of Pulmonary Arterial Hypertension (PAH), may also be effective to treat heart failure .
Authorisation first for a non-orphan indication and then for an orphan indication – common into rare
Sildenafil, initially authorised for erectile dysfunction, has become one of the world’s largest-selling drugs. On 28 October 2005, it received a separate Marketing Authorisation as an orphan drug for pulmonary arterial hypertension, a rare condition. Another example is ibuprofen, which is widely used and which has later been shown to be effective in treating patent ductus arteriosis, a rare condition, for which it has received marketing authorisation as an orphan .
Gaining orphan marketing authorisation of an existing therapy – formulation from “magistral” / hospital formula to approved orphan drug for the same condition
Several rare diseases can be treated by existing compounds and, indeed, may have been so for many years. The orphan legislation allows that a company seeking to create standardised production of pharmaceutical-quality versions of such compounds for treating the same condition may receive orphan designation for their version of the drug being approved. Recently, in the EU, amifampridine was granted a marketing authorisation as a designated orphan drug. The branded product is a slight modification of an unlicensed and low-priced compound that has been available for several decades. The price-point requested for the new product was 50-to 70-fold higher compared to the unlicensed formulation. The move caused a group of physicians to write an open letter  to the Prime Minister of the UK. Another example from the USA is 17-alpha hydroxyprogesterone caproate (17P), against preterm labour, a drug that had originally received FDA approval in the 1950s for multiple indications and that came off the market in 2000 because of a manufacturing issue. After a publicly funded 2003 study of 463 women, the drug gained widespread use, even though practitioners had to order it from compounding pharmacies . In 2011, the FDA approved 17P under its orphan drug programme, guaranteeing market exclusivity and the drug has been marketed for more than 100 times the price of the compounded product, a price that the company was forced to review after all the criticism received. In Belgium, similar findings have been documented .
The existence of other treatments for the same condition
Although the term “market exclusivity” in the EU’s Orphan Regulation might give rise to the impression that it is not possible to have more than one treatment for the same orphan indication approved within a given period, this is not the case. EU legislation allows for the prohibition of entry of another “similar” medicinal product for the same indication; however, a non-similar product that offers a significant benefit to patients suffering from the rare disease may indeed seek and be granted a marketing authorisation for the same therapeutic indication as an existing orphan product.
There is a perception of “clustering” of multiple treatments for the same indication. For example, currently in Europe there are five treatments for Pulmonary Arterial Hypertension (PAH), authorised at different times. For certain conditions, more than one product have been approved at the same time, such as rilonacept and canakinumab for Cryopyrin-Associated Periodic Syndromes (CAPS), both of which were granted marketing authorisation on the same day. Indeed, the first two approved orphan drugs in the EU were approved on the same day, for the same indication.
Summary of criticisms and issues arising
These examples threaten to create a climate of increasing uncertainty in an already uncertain field. This could undermine the willingness of companies to invest in the development of orphan drugs. Additionally, the increased uncertainty around successful pricing and reimbursement decisions creates a challenge for companies that face the prospect – at the end of a lengthy and expensive development process – of discovering that their proposed price-point is unacceptable to the payers in a given or multiple markets, resulting in rejections at the time of reimbursement negotiations. This wastes time and money, but also deprives patients of the treatment that they had been expecting.
The issue does not stop there, however. Subsequent evaluations and re-evaluations following public outcries or media campaigns consume resources and loud, public battles call into question the reputation of all stakeholders: industry, which may be accused of “sharp practices”; patients, who may be accused of demanding unreasonable shares of limited resources and, thereby, depriving others from those same resources; and governments, who are called upon to justify their decisions and, often, their reversals of decisions.