Orphans of the Storm

Trouble has been brewing for a long time in the choppy European waters around treatments for rare diseases, with patients’ demands for attention often going unheeded, drug firms buffeted by rising costs of research, and paying agencies creaking under the strains of austerity-and now the price tags attached to some recent treatments are turning stiff headwinds into a howling gale. 

Amid this maelstrom, the European Union’s (EU) 15-year-old scheme to incentivize orphan-drug development has become a victim of its own success, with ever more companies taking advantage of it, and the costs and consequences rising accordingly for the European and national authorities that operate it.

To date, the European Commission has already authorized 114 orphan medicines for the benefit of patients suffering from rare diseases, and has designated 1,243 products as orphans, entitling them to a range of incentives, including protocol assistance, fee waivers and market exclusivity. In mid- November, the Commission released a consultation document setting out how the scheme is to be “streamlined.” The consultation runs until February, and the Commission intends to introduce changes in the first half of 2016. The result could be that some potential treatments for rare diseases become orphans of the storm rather than orphan drugs.

Over recent years, the authorities have shown increasing signs of disquiet, and earlier this year, one of the senior EU committees on pharmaceutical policy formally noted “some weaknesses and challenges in the field of orphans that affect the reputation and the credibility of the system.” Top of the list of priorities for action was “to clarify the requirements to facilitate entry of innovative products with a significant benefit over existing products.”

Access to the scheme’s incentives is restricted to products that can show they are bringing something new. So, according to the Commission-which is responsible for the rules of the scheme-“we need to clarify what type of data the sponsors need to show to demonstrate the significant benefit over authorised medicines.”

This is tough love. A product may be designated as an orphan product even if a treatment exists for the intended condition, provided that it represents a significant benefit to those affected by that condition. But the proposed new rules insist that establishing significant benefit “cannot be limited to an assessment of the intrinsic qualities of the product in question without comparing them with the intrinsic qualities of the authorised methods”-and must deliver “a clinically relevant advantage or a major contribution to patient care.”

This implies, the text goes on to spell out, an investment in research and development that provides improved efficacy, a better safety profile or better tolerability, greater ease of self-administration, or an important and demonstrable improvement in adherence to treatment through a new form.

At the same time, it makes it clear that significant benefit should not be considered based on just a possible increase in supply when there are shortages (or non-availability) of existing authorized products, or mere enhancement of the pharmaceutical quality of a product or a simple alternative mechanism of action. And any assumptions made about benefit (since there may be little clinical experience with the product when an application is made) will be subject to assessment by the EU’s Committee on Orphan Medicinal Products.

The criteria must continue to be met when the designated orphan product comes up for marketing authorization, too-and the data requirements will be tougher by that stage. If not, the product will lose its orphan designation (and the advantages that go along with it). “The significant benefit should consider a quantitative element that allows the committee to measure the magnitude of the effect based on direct or, when not possible, indirect comparative clinical trials with already authorized medicinal products,” says the text.

The new version of the rules also underlines the risks a designated orphan faces if it fails to deliver. Removal of its status can take place “if there is evidence that the basis on which the original designation was granted has changed”-such as lack of data to support earlier assumptions.

The Commission also envisions closing a loophole that has been used by companies to circumvent the ban on getting a second orphan designation for a new form of the same active substance. To get around this, some companies have asked a third party to apply for the desired orphan designation, which is subsequently transferred back to the original applicant. “This practice can be considered as an attempt to circumvent the intention and the purpose of this provision,” says the Commission. It can also delay the marketing of generic rivals, it adds, indicating that it favors tightening up here, too.

One or two of the other elements in the consultation might make life a little easier for some applicants. For instance, in the wake of the Ebola crisis, the Commission suggests allowing access to assistance for products currently excluded from the scheme because they have zero incidence in the EU (such as diseases that have been declared eradicated by the World Health Organization). “An infectious disease with a very low prevalence in the EU can very rapidly become a serious threat to public health,” the Commission recognizes. Consequently, the scheme might be modified to apply a risk-based approach to eligibility, so as to encourage the development of orphan products for communicable diseases. And another possible easing of the conditions may be introduced in situations where two authorization application procedures are running in parallel-a situation that has occasionally led to harsh treatment of the second product to reach the authorization stage, since it is faced with the near-impossible task of demonstrating significant benefit over a product that may have been authorized only weeks or months before it.

But, overall, the effect of the envisioned changes is likely to be greater constraints on drug developers. Already under the existing rules, there has been some attrition of orphans. By the end of 2014, when the magic figure was reached of 100 marketing authorizations granted to products with an orphan indication, there had also been 80 failures, with 69 applications withdrawn and 11 refused. And 13 applications that had received marketing authorization then lost their orphan designation when they were reviewed. The new rules are intended to improve the performance of the scheme-but could do so at the cost of increasing the failure rate.

Some leading industry figures have suggested that protocol assistance might have prevented many of these failures, since the records show that where protocol assistance is used, chances of success in product registration are higher. Kerstin Westermark of Genzyme said earlier this year that protocol assistance is in fact the main incentive provided by the regulation. A clearer presentation of the available incentives and conditions might also help. An inventory of the incentives at EU and national level to support research, development, and availability of orphans, which the Commission is required to provide, has not been updated since 2005; the Commission is working on a new version, which may appear before the end of the year.

But the principal stumbling block remains the issue of patient access, even when orphan designation and marketing authorization runs smoothly. Yann Le Cam, head of the European rare patients’ organization Eurordis, has pointed out that even where rare disease treatments exist, 30% of patients across the EU are still unable to access them, because they are not reimbursed by national authorities, who are often deterred by the high price of individual products. He argues that the overall burden of treatments for rare disease is not high. Le Cam estimates that they account for only 1-2% of healthcare spending today, and might reach 5% by 2020.

That is an argument that appeals to the end users of orphan medicines, and to the companies developing them. But the authorities in the middle- responsible for designating orphans and for paying for them-are finding the argument less compelling, and orphans may still face neglect. 

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium