Small Population, Huge Impact


Navigating European Market Access With an Orphan Disease Product

Deriving its name from the belief that no manufacturer would care to adopt them, "orphan disease" molecule development was traditionally eschewed by companies for the chance to develop medicines in larger and more profitable markets. Due to the significant incentives available for rare conditions, more and more manufacturers are focusing on developing and marketing molecules for orphan conditions. 

EMA FDA Requirements

The European Union (EU) and United States (US) differ slightly in their definitions of what constitutes an orphan drug, but both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) provide significant incentives for manufacturers to develop products in this space. In the EU, orphan drug designation conveys access to the centralized authorization procedure, ten years of market exclusivity, and reduced fees for regulatory activities (including a form of scientific advice specific to orphan medicines called protocol assistance). The US provides similar incentives, such as a fast-track procedure through the FDA, a 50% tax credit on the cost of US-based clinical trials, and a seven-year marketing exclusivity.

While the regulatory incentives are substantial, the most critical factor for success of a given orphan disease therapy is achieving and retaining access in the major European markets. Each country takes a different approach in how it assesses rare disease treatments compared to traditional therapies, but if there is one theme that unites the nations of Europe, it is that the appraisal of orphan disease therapies is in a state of constant evolution. The United Kingdom (UK) illustrates perfectly how uncertain and evolving the orphan disease technology assessment process can be-the National Institute for Health and Care Excellence (NICE) Highly Specialised Technology (HST) Programme, which took responsibility for evaluating very rare conditions in April 2013, just released its only guidance in late January 2015, and only three other technologies are under review. As such, there is a severe lack of real-world evidence for manufacturers to discern the HST decision processes. In Scotland, following a governmental review on access to new medicines, the Scottish introduced a Patient and Clinician Engagement (PACE) group into the appraisal process for orphan disease medicines in May 2014, hoping to better highlight the added benefits that may not be fully captured within the conventional clinical and economic assessment process. Because of the continuous flux of rare disease health technology assessment (HTA) processes, it may appear difficult to draw any concrete conclusions around clinical and/or cost-effectiveness evidence requirements-and, as a result, it may seem daunting to navigate the road to market access.

NICE HST CriteriaCountries differ considerably when assessing therapies for orphan diseases. Several states have alternative pathways or evaluation structures for medicines targeting orphan diseases. Germany is a particularly attractive destination for rare disease molecules, as official orphan designation by the EMA automatically conveys a rating of added benefit and leads to pricing negotiations, reducing the high evidence hurdle associated with conventional drugs. The Netherlands also highly values technologies indicated for rare diseases, as inclusion on the Orphan Drugs List provides exemption from pharmacoeconomic evaluation and four years of conditional approval. Furthermore, England has a separate process to evaluate very rare conditions-but the criteria to participate in the HST process are very specific and are applied strictly, forcing a number of therapies that treat rare diseases to go through the standard technology appraisal. Conversely, France, Italy, Spain, and Sweden have no alternative process specific to orphan disease medicines. As a case example, the French National Authority for Health (HAS) maintains that the innovation and unmet medical need orphan drugs fill is already reflected in their SMR (Medical Benefit) and ASMR (Improvement in Medical Benefit) score; therefore, no supplementary procedure is considered necessary. Orphan drugs do automatically receive a proven Medical Benefit rating, but the total budget impact of the molecule cannot exceed €30 million to qualify for this benefit. This is not the only instance of a country attempting to limit overall exposure to orphan disease products-the proven additional benefit grade in Germany is only given if the total budget impact is less than €50 million per year. Even though orphan disease technology-specific pathways (or a lack thereof) differ across Europe, nearly every HTA body has policies that provide an advantage to rare disease treatments seeking reimbursement. 

Drugs treating orphan diseases often benefit from policies that traditional technologies do not, in part due to addressing a high unmet need, having a relatively low budget impact, and/or treating a rare condition. These advantages take many forms, but most commonly orphan disease products have a more relaxed standard when it comes to cost-effectiveness and evidence requirements. Sweden, for example, accepts a higher level of uncertainty in the evidence submission and has tolerated cost per quality-adjusted life year (QALY) ratios up to €100,000 for medications treating severe rare conditions. Scotland also has a history of recommending orphan disease medicines above £20,000 per QALY.

Another common benefit is an accelerated timeline or early access to a particular market. Beyond its Authorization for Temporary Use (ATU) program that allows access to drugs for life-threatening rare diseases before EMA marketing authorization, France offers a "fast track" assessment for any treatment that is a new therapeutic modality, has demonstrated efficacy/safety, and addresses a high unmet need. Likewise, as of 2012, the Italian Medicines Agency (AIFA) facilitates orphan disease technology pricing negotiations prior to regulatory approval. Lastly, cancer drugs often have additional incentives compared to other orphan conditions-most famously the contentious Cancer Drug Funds in the UK, which provide funding to selected oncology treatments regardless of NICE recommendation. Because interventions for rare conditions often meet a high unmet need and tend to have a relatively low overall budget impact, unique opportunities are available to ease the route to market access.

So where is the best place to start the journey to European market access for an orphan disease product? The answer will largely depend on the resources dedicated to seeking access, as obtaining and retaining reimbursement is no easy task in any European country. For this reason, many smaller manufacturers choose to take a step-wise approach to Europe, prioritizing regions such as Germany, the Netherlands, and the UK based on a comparatively good chance of success and ability to retain a higher international reference price. When pursuing access in a given nation, the most critical element is support from a high-quality market access specialist familiar with the evolving orphan disease assessment landscape. Though a general knowledge of European technology assessments is valuable, the processes and policies for rare disease treatments are constantly fluctuating, making it vital to keep abreast of the changes (particularly as some benefits and/or pitfalls may not be explicitly stated). While there is typically less scrutiny surrounding the evidence package required for orphan disease molecules, a strong base of data that supports the product's level of innovation and how it addresses an unmet need will widen the path to access considerably. Finally, as with any disease state, a clinical expert knowledgeable of the orphan condition who has relationships with local practitioners can be invaluable. Clinical experts are crucial in researching country-specific incidence and prevalence figures, galvanizing the medical community (or identifying where the treatment may meet resistance), and providing input on cost-effectiveness inputs and outputs. Ultimately, with the right team, expertise, and approach, the route to market access for an orphan disease is not as overwhelming as it first appears. 

Summary Of Orphan Market Access Across Europe


This article is an excerpt from HTA Quarterly - the e-newsletter with insights to bridge science and policy. As a strategic consulting partner for hundreds of brands, we've learned what insights HEOR and Market Access teams find most useful. And we've designed an e-newsletter specifically with your needs in mind. From at-a-glance updates on important HTA decisions, to reviews that shine a spotlight on what those decisions mean for specific therapeutic areas, each edition of the HTA Quarterly provides insight into the evolving perspectives and priorities for HTAs; as well as Xcenda's unique perspective so you are more prepared to address the challenges of an uncertain and rapidly changing healthcare environment. Subscribe today to HTA Quarterly.




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