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Orphans under the spotlight

It's time to bring drugs for rare diseases out of the shadows

Man in red standing out from the crowdDeveloping and bringing to market drugs for rare disease is not economically viable under normal market conditions; nevertheless, patients with rare conditions should be entitled to the same quality of treatment as other patients. This was the impetus for the introduction of legislation offering a package of economic incentives for the R&D and marketing of orphan medicinal products (OMPs) by the EU ten years ago.

EU legislation
A drug can only be granted orphan status in the EU if it is intended to treat a condition that is life-threatening/chronically debilitating and for which there is an unmet need. There is considered to be an unmet need if there is no satisfactory method of diagnosis, prevention or treatment currently authorised, or if the product will be of significant benefit. Additionally the drug must either target a condition that is rare (defined as affecting not more than 500 per million people in the EU) or be unlikely to generate sufficient return on investment to justify the expenditure without incentives (although this criterion has rarely been invoked).

The term 'ultra orphan' has also come into common use to designate drugs targeted at very rare conditions (defined by the National Institute for Health and Clinical Excellent (NICE) as conditions with a prevalence of less than 20 per million) but this term is not recognised in the EU legislation and no special arrangements for ultra orphan drugs exist.

The package of incentives for manufacturing OMPs in the EU consists of protocol assistance, direct access to the centralised regulatory procedure, fee reduction, EU-funded research and 10 years' market exclusivity (although this may be reduced to six years in certain circumstances).

Since the legislation was introduced, over 600 drugs have been granted orphan designation, of which (at the time of writing) 60 have progressed to gaining European marketing authorisation. But how successful has this legislation been in increasing the availability of medicines for patients with rare disease in the UK?

Procurement in the UK
In England, most treatable non-cancer rare diseases are defined in the National Specialised Services Definition Set (NSSDS), meaning that treatments for these conditions — in other words, OMPs — are commissioned by specialised commissioners. This commissioning can be either regional, in Specialised Commissioning Groups (SCGs), or national, by the National Commissioning Group (NCG), though the NCG only commissions services that generally impact fewer than 500 patients. Where medicines are used as part of a service commissioned by the NCG (for example, Genzyme's Cerezyme in the treatment of the inherited metabolic disease Gaucher's), the medicine is paid for centrally. In contrast, where the medicine is used to treat a condition that is commissioned by SCGs (for example, Actelion's Tracleer for pulmonary arterial hypertension), Primary Care Trusts (PCTs) remain the ultimate payers.

NICE's position is that OMPs should be appraised in the same way as medicines for more prevalent diseases, although NICE does not appraise ultra orphan drugs. However, since only technologies chosen through a topic selection process are referred to NICE, only three OMPs have been appraised and recommended to date. The unintended consequence of the topic selection process has been 'NICE blight' for many OMPs in England. In the absence of NICE guidance, the decision of whether or not to pay for OMPs often falls to Individual Funding Request (IFR) panels, which consider case-by-case applications in individual PCTs. This can lead to inconsistency in decision making and geographic health inequalities.

By contrast, the Scottish Medicines Consortium (SMC) appraises all new medicines, although it applies 'modifiers' to the cost per QALY (quality-adjusted life year) approach. Despite the use of these 'modifiers', of the 46 OMPs appraised by the SMC by May 2010, 18 were recommended, 11 recommended for restricted use and 17 rejected.

This demonstrates that, where a QALY-based approach to health technology assessment (HTA) is applied to OMPs, there is a high rate of rejection.

Specific challenges
The use of the QALY or ICER (incremental cost-effectiveness ratio) approach to determining the 'value' of OMPs is challenging for a number of reasons: firstly, that of inadequate data. Often it is difficult to enrol high enough numbers of patients in clinical trials to be able to achieve sufficient statistical power to demonstrate the clinical effectiveness that is needed to fulfil the requirements of HTA. This phenomenon is well recognised; indeed, it formed the rationale for the previous Government's (subsequently abandoned) 'innovation pass', the stated aim of which was to give 'earlier access to innovative drugs for patients with the greatest need, and at the same time facilitate the collection of further information to support a subsequent NICE appraisal

Another reason the QALY approach is challenging is the issue of pricing. It is perhaps no surprise that the cost of orphan drugs is often high. The reason most often cited for their high costs is the need to recoup the substantial financial outlay of R&D from a small number of patients, which inevitably results in a high drug acquisition cost per patient. A cynical view may be that certain manufacturers have taken advantage of the monopoly of marketing exclusivity given to OMPs.

Finally, the challenge of generating an ICER that is deemed cost effective is frequently compounded by the absence of an appropriate (approved) comparator treatment. This is unsurprising given that an absence of a satisfactory treatment forms the basis of orphan designation. In many instances, the comparator is best supportive care.

Holistic assessment
So, if a QALY-based evaluation fails to recognise the special nature of OMPs and fails to consider all the aspects of value provided by them, what's the alternative? One recent development that represents a step in the right direction is the publication by the Advisory Group for National Specialised Services (AGNSS) of a decision-making framework. This model has been designed to support decisions around which products, services or technologies should be commissioned and paid for nationally. It evaluates the product against 12 core criteria organised into four domains, with a holistic view taken across all criteria. (See Figure 1)


Figure 1: Core criteria for national commissioning
Taken from AGNSS's Decision Making Framework:

Core criteria for national commissioning


Although as yet untested, this approach does at least appear to represent a more considered manner of evaluating drugs for rare disease. Unfortunately its application will be restricted to OMPs that treat not more than 500 patients in England; that is, ultra orphan drugs only.

The future
So what does the future hold for rare disease and OMPs in the UK? Is there any cause for optimism?

Some observers are optimistic.

The Specialised Healthcare Alliance (SHCA) believes that these changes represent an important opportunity for the pharmaceutical sector to improve market access for innovative products that deliver real clinical value.

The issues surrounding rare disease are also achieving increasing prominence, helped in part by the activities of umbrella coalitions such as Rare Disease UK and the SHCA.

Additionally, in June 2009, the UK, in common with other EU member states, adopted the European Council's recommendation to develop a national strategy for the treatment of rare disease by 2013. In his most recent annual report, Sir Liam Donaldson, the chief medical officer, dedicated a chapter to the issue of rare disease and made a number of recommendations, including one to 'strengthen research, including translational research with economic incentives, to develop and market medicines for orphan diseases.'

Sound familiar? I would suggest that research into a more appropriate mechanism to appraise the value of medicines that evolve from this research (as well as those already marketed for orphan diseases) would be equally useful.

Although not specifically referred to in Equity and Excellence: Liberating the NHS, the NHS reforms White Paper published in July, it's inevitable that the proposed healthcare reforms will impact access to OMPs. The two proposals with potentially the greatest impact are the transition of specialised services commissioning to the new NHS Commissioning Board and the introduction of value-based pricing from January 2013. What the likely impact of these initiatives is, for the moment at least, anyone's guess.

There is little doubt that the attractiveness of the orphan disease market has increased in recent years, as manufacturers change their focus from discovery of the next mass market 'blockbuster' to more specialist 'niche busters'. Unquestionably the OMP legislation enacted 10 years ago has provided a stimulus for this: this is borne out in the statistics, with a doubling of the number of OMPs receiving EU marketing authorisation in the last five years (there were 22 up to 2005 and a further 40 in the following five years). In 2006, for example, orphan drugs accounted for 23 per cent of all new marketing applications.

It is also equally evident that in the UK patients with rare diseases will continue to be denied access to innovative and effective treatments for rare and neglected diseases, treatment that can make a difference to what are, by definition, life threatening or chronically debilitating illnesses, until the current methods of evaluating and paying for orphan drugs are overhauled.

The Author
John Irwin is head of market access at Actelion UK & Ireland

To comment on this article, email

19th October 2010


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