Orphan drugs: Treating a rarity

Before Miriam Klein received the most expensive drug in the world, she had been admitted to the hospital around 40 times for unbearable abdominal pain and pancreatitis caused by lipoprotein lipase deficency (LPDL) – an ultra-rare genetic defect that affects the breakdown of fat in the body. But since being given injections of uniqure’s gene therapy Glybera two years ago, “she lives like you and me”, according to Dr. Elisabeth Steinhagen-Thiessen, her physician at Berlin’s Charité Hospital. “My disease is still part of my life,” says the 44-year-old patient, “but it doesn’t take centre stage like before.” 

Klein is one of the just 350 people who suffer from LPDL in a European population of 510 million. Though Steinhagen­Thiessen knows patients from other countries who are still hoping to receive the therapy, it has been widely rejected by European payors due to its €1m cost per patient. Dutch Health Minister Edith Schippers branded the therapy “part of a pattern of price-gouging by drug companies”. In April, uniqure announced it will not seek renewal of its EU conditional market authorisation this autumn due to “limited patient demand”. Only patients who are approved for treatment prior to October 25 of this year will have further access to the gene therapy. 

Big Pharma’s new model

This is far from the first time that orphan drug pricing has come under fire. As long ago as the early 1990s, a US$300,000 price tag for Genzyme’s Gaucher disease therapy ceradase spawned Senate hearings, government audits and sharp criticism from payors, physicians and the media. Because target populations in mono­genetic diseases are typically extremely small (80% of the estimated 7,000 orphan diseases are genetic), prices for therapies designed to correct the underlying defect can run up to US$700,000, since the volume­-based system used to calculate prices for treatments in more common indications doesn’t apply.

Criticism towards overpricing has grown much louder recently because the number of orphan drugs (currently 500 in the US and 128 in Europe) and their market share – 41% of US market approvals in 2016 were for treatments of rare diseases – are projected to grow rapidly. The US, Japanese and EU orphan drug acts from 1983, 1993, and 2000 respectively grant market exclusivity for several years as an incentive for developing ODs (see p. 40). But watchdogs now suspect some developers of abusing their monopolies. 

Payors and policymakers are concerned that orphan drugs could strain healthcare budgets, while developers and patient groups are lobbying for better access to ODs. Market figures do clearly indicate that pharma companies have refocused pipelines to target smaller patient populations in medically underserved indications in order to overcome “unhealthy 5% annual growth rates”, according to retired pharma manager Jürgen Kleemann (Pharmind (2013) 75 , 4, 562-574)) in the overall pharma market in a post-blockbuster era.

A growing pipeline 

In May, QuintilesIMS analysts forecast that the number of approvals would rise from 66 in the last five years to as many as 90 by 2022. Evaluate’s “Orphan Drug Report 2017” predicts that OD sales will grow twice as fast globally (11.1%) as the total pharma market (US$110bn in 2016) to US$209 by 2022. “Orphan drugs are set to account for 21.4% of global prescription sales in 2022,” study author Andreas Hadjivaliliou told European Bio­technology. 

What’s more, the average cost per patient treated with an orphan drug in the US shot from US$116,216 in 2012 to US$140,443 in 2016. Median cost was also over five times higher than for non-orphan drugs last year. In the EU, where Evaluate is still analysing cost-per­-patient data, the analysts forecast ODs will account for 55% of the European pipeline’s  cumulative value in 2022. One reason, says the life science commercial intelligence provider, is that drugs targeting smaller patient populations – orphans and personalised meds – allow a price premium over non-orphans. An analysis conducted by a Belgian research team headed by Philippe Wilder (Brit J Clin Pharm, doi: 10.1111/j.1365-2125.2010.03877.x) also suggests orphan drugs are reimbursed more often than non-orphan drugs (88% of 25 ODs vs 63% of 117 non-ODs). Around two-thirds of OD approvals are currently in oncology indications.

Hadjivaliliou’s co-author Lisa Urquhart says the “image of the plucky small bio­tech striving to develop treatments for rare diseases largely ignored by Big Pharma is long gone”, and that this year Big Pharma is again dominating the sector. “Seven of the top ten companies by orphan drug sales are global industry players,” she says. Niels Riedemann agrees: “Initially, biotech companies filled the orphan-drug niche because clinical development costs are significantly lower,” says the CEO of infection specialist InflaRx. “Fewer patients are needed to provide clinical proof-of-concept than in classical, large indications. However, the US$2bn+ revenues of orphan drug pioneers like Alexion with eculizumab showed markets could be huge even in the rare disease space. So it’s not surprising Big Pharma has entered it through acquisitions and pipeline products.”

Media reports foster mistrust

Driven by budget constraints, three US Senators in February launched an investigation into six-figure annual costs for orphan drugs and potential malpractice by the pharmaceutical industry. Previous reports from US media suggested that 70 repurposed drugs initially designed for mass market use have now been given orphan drug approval, while others received multiple seven-year US market exclusivity periods in different orphan indications. Several reports in European mass media have also suggested overpricing is a common pattern in the industry. And public trust has been further eroded by reports of marketing malpractices and safety violations that led to fines totalling US$14bn from 2005-2012, according to Kleemann.

Published reports cited by the the European Confederation of Pharmaceutical Entrepreneurs (EUCOPE), however, contradict the picture of overpriced  drugs drawn by newspapers and interest groups. Model calculations from 2011, it claims, suggest OD expenditures peaked in 2016 at just 4.6% of the EU’s total pharmaceutical expenditures (Orphanet Jl of Rare Diseases, doi:10.1186/1750-1172-6-62). That’s in line with statements from the EU pharma industry federation EFPIA, which told European Biotechnology that “expenditure is expected to plateau and stabilise between 4-5% of total expenditures by 2020.” It says that incoming bio­similars – set to replace about 70 orphan medicinal products by 2019 – “are expected to help balance cost for healthcare systems.” Bertram Häussler, the head of Berlin-based market research institute IGES projects the budget impact will double from 3.1% by 2020 and then stabilise at that level. 

“We should not forget,” states EFPIA, “that governments negotiate the prices that companies are allowed to charge, either directly or indirectly. The price of a medicine is based on the value it brings to patients, healthcare systems and society. It provides the appropriate revenue for companies to invest in new therapy development.” In his view “the orphan medicine designation needs to be protected to further attract a high level of investment in R&D.” Most of the current debate on high-priced drugs for small patient populations is about the fair value they provide to patients, and how this value can be determined quickly in order to grant rapid access to life-saving treatments. But according to MEP Peter Liese (EVP), a melange of views and national interests is still hampering a European-wide health technology assessment (HTA), and what’s needed is a way to overcome the requirement for companies to go through 28 different HTA procedures in EU Member States in order to be reimbursed. EUCOPE agrees. “Better and faster access to therapies, in particular for patients that have no other alternative, is a critical issue to address,” says Dr. Oliver Sude, Legal Counsel at the European trade association for medium-sized companies in the field of pharmaceuticals and biotechnologies. “Hence, we urge closer collaboration between industry and payors towards finding suitable solutions that guarantee the possibility for patients to receive the best possible treatment without limitations like budget constraints.” 

Improving patient access

At the end of April, a non-profit alliance of 751 rare disease patient organisations from 66 countries called for better access to orphan drugs through so-called compassionate use programmes. “Compassionate use programmes can save lives by providing early access to promising new medicines for rare disease patients,” said François Houÿez, the Health Policy Advisor at EURORDIS. “Patients [with orphan diseases] are desperate, and willing to take a higher risk to use a medicine that is not authorised.” The organisation is demanding the application of the European Medicine Agency’s fast-track Adaptive Pathways or PRIME schemes to patients who need the product most urgently, hinging full approval on additional confirmatory studies. Further­more, EURORDIS proposes establishing the French Temporary Use Authorisation system in all EU Member States, and including compassionate use in the EU’s Cross-Border Healthcare Act. Those moves are in line with demands made by pharma group EFPIA: “In order to continue to keep the budget impact of orphan medicines manageable, innovative arrangements like managed entry agreements and early access schemes can be used. They provide flexibility to manage evidential and financial uncertainty when evaluating orphan medicines, while enabling timely patient access.” Critics, however, say granting companies conditional market access based on an ever-decreasing database is exactly the wrong direction to take. The head of Germany’s Institute for Quality and Efficiency in Healthcare (IQWiG) Jürgen Windeler, on the other hand, insists that highly conclusive studies are feasible even in the orphan drug field, and suggests compromises concerning significance levels might be required only when it comes to ultra-rare conditions. 

Slicing patient pools

From the EFPIA’s perspective, “the difficulty in (very) rare disease is that we cannot extend the sample size, and will have to generate generalisable evidence on a small heterogeneous patient population. The variability in the datasets cannot be offset by the volume of data gathered, as in more common diseases.” A recent review of 68 marketing authorisation application dossiers and EMA assessment reports carried out at Utrecht University shows that EMA regulatory standards are just as high for ODs as they are for non-orphan medicines. That might be true, but healthcare stakeholders have repeatedly demanded an increase in the number of randomised, placebo-controlled trials for orphan diseases. Besides assuring an adequate evidence level despite limited numbers of patients enrolled, another pharma critic concern is that heretofore broad indications could be sliced through biomarker-based molecular tumour classification. Experts at the EMA have stressed at several congresses that it is a misperception that large cancer indications could be simply sliced into orphan indications through patient selection – an issue that’s been brought up by oncologists like Wolf-Dieter Ludwig, Head of the Committee for Medicinal Products at the German Medical Association (ADKÄ). He has suggested the “orphanisation” of common diseases through precision medicine could become a problem in the future. 

A post-marketing data dilemma

Pharma critics also argue that OD developers will have little interest in possibly jeopardising their conditional market authorisation with postmarketing study data that could throw the initial positive benefit:risk ratio into question. An EMA study shows that about 50% of the drugs given conditional market approval still haven’t received full approval 10 years later (see European Biotechnology, Spring 2017). According to the EMA, however, getting data from post-marketing studies hasn’t been a problem: “Submission of specific obligations results was often done in advance of the imposed due date, and very few submissions were delayed,” a spokesman told European Biotech­nology. “Compliance in terms of study conduct can be considered generally acceptable, since new studies were only imposed rarely and based on new results, not driven by non-compliance.” 

The Next Big Thing in OD

Digitalisation of patient data and cross-border collaboration between clinicians are set to improve diagnostics and treatment of patients with rare diseases. Currently, diagnosing an orphan disease takes six years on average, and recruiting suitable patients for clinical trails is laborious. The launch of the European Reference Networks for orphan diseases at the EU Council meeting in Vilnius this March marked a milestone in overcoming current limitations by creating reference networks (ERNs) that pool the expertise of 900 medical units across 26 Member States in 24 rare disease areas. The infrastructure for data exchange created with funds from the Commission, “will lead to easier access to specialised experts in orphan diseases, collection of data and better pharmacovigilance,” an EMA spokesman told European Biotechnology. “Moreover it will boost clinical research and post-marketing studies,” he believes. 

The plan is to provide ‘virtual’ advisory boards of medical specialists across different disciplines with digitalised patient data. “A key concept of this initiative is that the information travels rather than the patient, so ERNs must have the capacity to use IT, telemedicine and e-health tools,” said EU Health Commissioner Vytenis Andriukaitis. This will provide the groundwork for genome analysis and bioIT-based pathway analytics. Next-gen sequencing market leader Illumina has already launched a programme dubbed iHope aimed at identifying the genetic causes of undiagnosed rare diseases in children, while Belgian-based Diploid has developed an IT expert system that autonomously diagnoses orphan diseases. So digitalised medicine and cross­-border research might mark the next evolutionary step not only in developing more ODs, but also in evaluating their fair value.