Patient Reported Outcomes in Orphan Drug Submissions: Do They Make a Difference?

Under the European Medicines Agency (EMA), for a drug to obtain an orphan designation:

  1. It must be indicated for a life-threatening or “chronically debilitating” condition;
  2. The condition it is intended to treat must have a prevalence of no higher than 5 in 10,000 in the EU or there must be other evidence that marketing the drug is unlikely to result in sufficient financial returns to justify the initial investment; and
  3. “No satisfactory method of diagnosis, prevention or treatment of the condition concerned can be authorised, or, if such a method exists, the medicine must be of significant benefit to those affected by the condition.”

In the United States, the FDA considered an orphan disease condition a disease with a prevalence of fewer than 200,000 people affected in the United States.

Orphan drugs pose a challenge to Health Technology Assessment (HTA) agencies for a number of reasons.

Uncertain Efficacy and Cost-effectiveness

Orphan drugs are intended to treat conditions that affect relatively few people. As such, it is often difficult, if not impossible, to run a clinical trial with a population of sufficient size to guarantee statistical rigor. Trials must often rely on surrogate outcomes that are likely to predict a more meaningful clinical benefit, as it may be too costly or time consuming to obtain a more clinically-meaningful endpoint. The small patient population could also mean that only a small number of patients will achieve a clinically meaningful outcome during the trial time.

These difficulties often result in uncertainties around the cost-effectiveness of orphan drugs. Economic models concerning orphan drugs must generally rely on surrogate outcomes. Furthermore, orphan drugs usually represent entirely new therapeutic areas, so finding valid comparators can be very difficult, if it is possible at all.

Most HTA agencies have an official or unofficial ICER threshold above which they will generally not recommend a drug for reimbursement. Orphan drugs, however, tend to be very costly and their clinical outcomes are generally less certain than those of non-orphan drugs. For this reason orphan drugs often fall beyond the range of normally-acceptable ICERs.

Finally, cost-effectiveness measurements generally do not consider the social benefits or ethical concerns that comes with treating a condition that affects only a small population.

Proposed Strategies: Patient-Reported Outcomes and Real-World Evidence

Various approaches have been proposed to address the challenges in evaluating and reimbursing orphan drugs. According to a study by Georgi Iskrov and Rumen Stefanov, “Post-marketing access to orphan drugs: a critical analysis of health technology assessment and reimbursement decision-making considerations,” one approach is to submit real-world evidence (RWE) in cases when information from randomized controlled trials (RCTs) may not be sufficient. RWE provides data about the orphan drug and the condition it is intended to treat in the “real world,” not just in controlled trial situations. RWE is a way for the manufacturers to demonstrate the clinical effectiveness of the drug, which is a point of contention if efficacy is uncertain.

Another approach is to focus on patient-reported and patient-relevant outcomes when possible. This will provide decision makers with evidence on whether the outcomes of treatment with orphan drugs are actually outcomes valued by patients.

One way to address the high cost of orphan drugs is to conduct budget impact analyses to determine the overall impact a given orphan drug will have on a healthcare budget. While orphan drugs tend to be very expensive individually, they are only used by a very small patient population and tend to have a small impact on whole healthcare budgets.

A Data-driven Look at HTA Decisions in Europe

Do HTA agencies and pharmaceutical companies seeking orphan drug reimbursement actually use these strategies? And, if so, do they work? We thought it would be interesting to see what the data shows, and used our information platform Reimbursement Risk Tracker (RRT) to examine the characteristics of successful HTA reviews for orphan drugs.

Orphan Drugs
Orphan Drugs

The Snapshot above from RRT shows that roughly one-third of EMA orphan status drugs do not receive a positive recommendation from the EU HTA agencies (NICE, SMC, HAS, and G-BA). The distribution of decisions for EMA orphan status drugs is similar to the distribution of decisions for non-orphan drugs (p=.254); 70% of orphan drugs receive a positive recommendation compared to 74% of non orphan drugs. So drugs with EMA orphan status are not more or less likely to receive a negative reimbursement decision from an EU agency.

orphan table
orphan table

One of the previously discussed strategies to get reimbursement approval for orphan drugs was to include a PRO. When we examine the use of PRO’s in orphan drug HTA submissions we see an even split between those orphan reviews that use a PRO and those that do not (49% vs. 51%). In looking at the distribution of positive and negative decisions, PROs don’t appear to significantly affect recommendation rates for orphan drugs.

pro chart
pro chart

The snapshot below shows that manufacturers do not often submit observational studies (RWE) to HTA agencies. There does not appear to be much difference between recommendation rates for submissions that include observational studies.

observational studies
observational studies


  • While orphans have hurdles to overcome to gain reimbursement we don’t see them penalized in the final outcomes of the review. Orphan drugs are not more or less likely to get a positive decisions than non-orphan drugs (within the EU and for the EU agencies)
  • Having a PRO within your orphan drug submission doesn’t appear to tip the scales toward a positive decision
  • There appears to be little difference between recommendation rates for submissions that do include observational studies. The submissions do not appear to be following the recommendation of using RWE, and even those that follow the advice do not appear to fare any better than those that not using RWE