Rare disease drug approvals were anything but rare in 2019. The surge in new products suggests regulatory efforts to encourage industry to make medicines for smaller patient populations are having a positive impact.
Such support, coupled with new approaches to patient recruitment and outreach have made rare disease R&D much more common. In addition the market’s willingness to pay for these high value, lifesaving products is further fuelling industry interest.
Rare disease regulations
Twenty one of the 48 novel drugs approved in the US were for rare or orphan diseases – those that affect fewer than 200,000 citizens. In Europe, the proportion was smaller, with just seven of the 66 products approved last year being for rare diseases.
Nevertheless, the consensus is that EMA and FDA programmes designed to encourage biopharma to develop medicines for smaller patient populations – primarily the orphan designation – are working.
The term ‘orphan drug’ was coined in the US in 1983 when the Orphan Drug Act became law. In the European Union, the Orphan Drug Regulation was adopted in 2000.
While there are differences in the specific regulations, the general idea is to offer biopharma companies longer exclusivity periods, tax credits and lower regulatory fees to encourage development.
The argument is that inducements are necessary because developing treatments for rare diseases is harder and more costly than making drugs for large populations.
Support success
According to Lavinia Meloni, spokeswoman for the European Federation of Pharmaceutical Industries and Associations, efforts to encourage development of drugs for rare diseases have had a positive impact.
“The Orphan Medicinal Product (OMP) Regulation has helped to create regulatory and market predictability, thus allowing companies to take on the higher risk of committing to do research in populations that are small and have a high burden of unmet need due to lack of scientific knowledge for many rare conditions and market challenges.
“The success is clear: before the Regulation was introduced, only eight orphan-like medicines were available for patients. Now there are over 160 orphan medicinal products approved by the EMA for more than 120 rare diseases. The Regulation and its incentives have been a crucial catalyst in generating medicines that wouldn’t have otherwise existed,” she said.
Clinical complications
Given the rarity of orphan diseases, one of the greatest challenges in developing treatments is the timely and adequate recruitment of eligible trial participants.
Simply finding participants for clinical trials, for example, is harder if patient numbers are limited. More trial centres may be required and developers may need to invest more money to publicise the research.
According to a 2019 study of uncompleted rare disease trials registered on the Clinicaltrials.gov website, 32% cited a lack of patient accrual as the main reason for non-completion.
Clinical trials in rare diseases usually enrol fewer subjects that are unlikely to be concentrated in one geographical location, thus there is often a need to enrol patients from a number of countries to obtain a large enough sample size of trial subjects to establish the clinical efficacy. Also, there are significant clinical differences between trial subjects in many rare diseases.
Thankfully, in the genomic era, biopharma has tools it can use to address some of these issues, according to Meloni, who said it was a step forward to be able to better identify patients who are likely to benefit from a treatment.
“Medical treatment for patients has historically been based on two primary elements: the expected outcome for the patient, and the ability of treatment to improve the expected outcome. The advance in genomic technologies can change this paradigm and add substantial value to current medical practice by providing an integrated approach to guide patientspecific treatment selection using the genetic makeup of the disease and the genotype of the patient.”
So-called ‘genomic signatures’ – genomic markets that can aid in patient stratification – are one example. Similarly, surrogate markers can be used to gain more information about patients’ responses to therapy.
According to Meloni, genomics are likely to play an even more important role in the future. She went on to say that such technologies – and their regulation – are key to the development of patient-specific therapies.
“It’s important to highlight that advances in personalised medicine have additional regulatory requirements, such as biomarker validation. The current biomarker qualification process lengthens already cumbersome procedures thus jeopardising access of patients to innovation.
Study design complexity
But there are other challenges beyond patient recruitment. Clinical trial design is also more difficult for treatments for uncommon diseases and this is stimulating innovation according to Meloni.
“Although trials for rare diseases might be more complex than for more common diseases, the current trend across different therapeutic areas and types of medicinal products is to introduce innovative trial designs to benefit the patient through easier access to trials.”
She cited parallel studies as an example, explaining the ability to investigate the effect of a new medicine in different subgroups of diseases or groups of patients is ideal for the development of rare disease drugs.
“The use of real-world data (RWD) can also be particularly useful in rare disease trials, for example by utilising the information in patient registries for patient stratification and sometimes replacing one study arm with information from RWD and even in some cases replacing the traditional clinical trial when the population is too low to run a randomised trial.”
Price concerns
Another argument in favour of the support given to the orphan drug industry is that rare disease drugs generate lower revenues than mass market medicines.
While this idea may have been true in the 80s and 90s, in the decades since, the prices charged for drugs for rare diseases have increased significantly,
According to a 2019 study, for example, the mean orphan drug cost per patient of the top 100 US orphan drugs was almost 4.5 times greater than the non-orphan drug cost in 2018.
The report suggests worldwide orphan drug sales will be worth $242bn by 2024, with the market growing by +12.3% which is approximately double the rate of the non-orphan drug market.
In order to be viable, the biopharmaceutical industry needs to make a profit, and recouping money spent on R&D is vital to fund the next round drug development, said Meloni.
“The opportunity to generate profit is an important incentive for biopharmaceutical investors, as there is a high risk of failure and investment loss associated with medicines’ development, particularly within rare diseases.
“In the area of orphan medicines, as the patient population is very small, the opportunities for the companies developing these new treatments to realise economies of scale are limited. As such, for biopharmaceutical investment to make sense, investors need to be confident that they will see returns from successful investments.
“The Orphan Market Exclusivity and Orphan Designation offered by the EU Regulation are crucial to provide some level of security if the product receives an MA, but they are in no way a guarantee that the product will be able to generate a profit,” she said.
Reimbursement is the key milestone, according to Meloni, who pointed out that only some EU member states provide reimbursement on approval, while others may take as long as a few years.