Orphan drugs: overcoming HTA barriers to access

How can orphan drug manufacturers demonstrate value and improve access to drugs? In this first of two articles on the subject, Ewan Bennett outlines ways to achieve reimbursement in countries where health technology assessment (HTA) approval is required.

Historically there were few incentives for the pharmaceutical industry to invest in orphan drug development, which was expensive, given the small numbers of patients who would benefit from such treatments and high development costs. However, over time, governments have enacted legislation to encourage orphan drug development and improve patient care.

The first of these was the US Orphan Drug Act of 1983, which granted tax credits, an accelerated approval process, and an additional two years’ market exclusivity over non-orphan drugs.1,2 Similarly, in 2000, the European Medicines Agency enacted regulations granting 10 years’ market exclusivity.1 This legislation stimulated the market for orphan drugs and, while only 34 orphan products were marketed in the decade prior to 1983, 275 orphan drugs were approved by the FDA between 1983 and 2009.1

Orphan drug market share has subsequently grown steadily and was estimated at 16.4% of overall worldwide prescriptions in 2016, with growth to 20.2% anticipated by 2020.3 However, while orphan drug development has vastly increased treatment options for patients, their increased market share and high price has alarmed payers, who now often seek to restrict access.1

In the current price-sensitive market, how does a manufacturer with an orphan drug overcome the high price and demonstrate value? This challenge is increasingly recognised by stakeholders, resulting in the trend to go beyond simple cost-based coverage decisions and seek to understand the broader value of a treatment to the healthcare system.4-6

Health technology assessment

In some countries, once a drug is approved by the relevant regulatory agency the company is free to negotiate a price, at a national or regional level. However, many countries have Health Technology Assessment (HTA) processes in place that require cost-effectiveness to established as well, before it can be approved.

Owing to their high cost, this will always be more challenging for orphan drugs, although this is recognised by HTA bodies in many countries.7 However, other countries have no specific systems for evaluation of these drugs, and they are assessed using the same criteria as other drugs.

Therefore, when developing a submission strategy for a drug it is vital to understand the needs of each country; ideally, this means early mapping of country-specific processes, followed by payer research, either via interviews or advisory boards with ex-payers. These can provide invaluable insight into the thought processes of each agency: What data do they want to see? What do they think of the existing data? What are their recommendations based on this data? These questions can help determine how best to present the clinical and economic case for a drug.

Presenting a strong case for the efficacy of a drug is the first challenge in every HTA; inevitably, this is more difficult for orphan drugs. There is a small patient population, so recruitment for clinical trials is hard, and as payers may know very little about the disease, they may not appreciate the burden on patients or understand the outcome measures used to demonstrate efficacy. This is a particular problem when quality of life (QoL) has to be considered, as clinical trials for rare disease may not capture such data or, if they do, may use specific or adapted QoL scales unfamiliar to payers. Any submission must therefore carefully set out both the relevance to patients of the outcomes used, and the relevance of the differences in these outcomes between the product and the comparator.

Issues with QoL data are linked to the second challenge in HTAs: demonstrating cost-effectiveness. This typically requires data from clinical trials to be mapped to a scale that payers recognise (e.g. EQ-5D). Even if this is possible, the high cost of the drug is still likely to produce a measure of cost-effectiveness (e.g. an incremental cost-effectiveness ratio) that will make payers wince. Consequently, a traditional economic evaluation may be inappropriate in demonstrating the value of a drug, and alternative approaches should be considered. For such an alternative approach to be successful, it is necessary to understand what other manufacturers in a similar position have done before, what their submissions were criticised for, and then pressure-test the new approach with ex-payers to identify areas of weakness or concern.

Whatever economic evaluation is presented, the fundamental question for payers is how much of their budget it will use. Here the small patient population works in their favour, as there may be just a handful of patients eligible for the drug. The submission must therefore clearly define the type of patient needing the drug, how many there are likely to be, and the total annual cost. This may be easier where a comparator exists, as market research can identify how many patients currently receive that drug.

If no comparator exists there may be uncertainty in the population, and epidemiological data for orphan diseases in the literature typically have wide ranges. Engagement with patient advocacy groups to define the population based on data they hold can, consequently, be a valuable strategy and help to demonstrate that there is a limited and predictable budget impact associated with the drug.

Population data are not the only way in which advocacy groups can be important in securing access to orphan drugs. The patient voice for orphan diseases is often drowned out by those for more prevalent conditions and the appraisal committee may not fully understand the disease burden. Encouraging these groups to be involved in the HTA process wherever possible can introduce a powerful and independent voice for the human impact of the disease.

Appraisal meetings can be a pivotal step in the HTA process and can make or break a submission. Manufacturers must, therefore, prepare diligently for such meetings. While many of the questions can be predicted and prepared for, industry representatives can often be too close to the data to think of everything they may be asked. These meetings can also be intimidating and high-pressure experiences. Holding a rehearsal meeting, with external clinical and economic experts taking on the role of the evaluating committee can be invaluable in preparing for the crucible of the assessment meeting, allowing preparation of answers and an insight into the meeting process.


Obtaining a recommendation from a HTA body for an orphan drug can be a long and arduous process but, with proper preparation and planning, many of the risks associated with these submissions can be avoided. However, gaining a recommendation is only the first step in demonstrating the value of a drug and securing a market position. The second step, market access, will be discussed in the second article in this two-part series.


Cohen, J P, Felix A. Are payers treating orphan drugs differently? J Mark Access Health Policy. 2014;2.

Orphan Drug Regulations (57 FR 62076), December 29, 1992 and 21 CFR Part 316 et seq.

Evaluate Pharma. 30 September 2015.

Neumann P J, Cohen J T. Measuring the Value of Prescription Drugs. N Engl J Med. 2015. Dec 31;373(27):2595-7.

Schoonveld E. Can Payers and Drug Industry Agree on Real Value? Pharmexec.com. Available from http://www.pharmexec.com/can-payers-and-drug-industry-agree-real-value (accessed December 2016). 2015.

The Parliamentary Office of Science and Technology. Value Based Assessment of Drugs. POSTnote 487 January. 2015.

Decision Resources Group Consulting. Orphan drugs: Considerations for market access and reimbursement. 2015.

The second article in this two-part series considers market access following reimbursement approval. Read it here.

About the author:

Ewan Bennett is Principal Medical Writer at DRG Abacus. He joined the company in 2011, and works with pharma companies on value demonstration and market access for their products. He has extensive experience in rare diseases, helping develop materials to support global market access and health technology assessments in the UK.

He holds an EngD in Medical Devices from the University of Strathclyde and an MSci in Medicinal Chemistry from the University of Glasgow.