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Beyond our medicine cabinet

​A couple of months back, the story of a young baby girl called Pia resonated in the European press. The family of this nine-month-old toddler launched a social media campaign and text messaging to raise €1.9 million, the price of the medication to counteract Pia’s disease. She had been diagnosed with spinal muscular atrophy (SMA), an orphan genetic disease weakening her muscles progressively. The treatment is for the moment authorized only in the United States and not in Europe. How come there is such a difference in the authorization of medication, leaving patients in the midst of waiting to be treated?

The treatment against SMA, Zolgensma, is targeted at patients younger than two years. The firm behind the manufacturing is AveXis, which was bought by the pharma giant Novartis in 2018. Already exposed for data manipulation by the American Food and Drug Administration (FDA) after an initial approval of the medication in May, AveXis was questioned about a common issue in the medical landscape: the price at which medical treatments is set.

Searching for a cure

The particular story of SMA has been evolving continuously during the last three decades. In 1995, the disease was identified by Judith Melki’s team at Necker Hospital in Paris. The anomaly arises from a mutation in the SMN1 gene responsible for the creation of a protein for neurons called motoneurons. These are responsible for the contraction of our muscles and glands, directly or indirectly through the spinal cord. Nowadays, around 6,000 to 10,000 children are diagnosed internationally with this disease which reduces their life expectancy to two years.

The process of coming up with a treatment to correct this defective gene had taken numerous tests in France, before a patent in 2007 was delivered for the process of correcting motoneurons in the spinal cord and further research was made on mice. That is when AveXis, a biotech startup company based in Chicago, used the research by the French laboratories to test injections on patients diagnosed with Type 1 SMA, the most advanced stage of the disease. Following the promising results of these tests, AveXis signed a partnership with the French laboratory which owned the patent, valid in Europe, USA and Japan, to inject the treatment into the nervous system. AveXis was bought by Novartis in 2018 for $8.7 billion, equivalent to €7.4 billion.

Previous debate in the pharma

Pia’s parents had hoped that their daughter would become part of the treatment group during the clinical tests. Despite being treated with an already existing medication, the parents hoped for a better and more effective way to slow down Pia’s disease. Zolgensma was not the first medication to treat SMA. Another treatment, Spinraza, brought on the market by Biogen, consists of six injections of €85,000 each in the first year and three injections in the next couple of years, summing up to €750,000 in the first 12 months and to €250,000 every year thereafter. Quickly doing the math, Spinraza catches up with the price of Zolgensma after around 6 years of yearly injections. The European Medicines Agency (EMA) and individual national insurance systems have engaged in negotiations to bring down the price of each injection, with the aim of reducing the catch-up period to a little over 10 years. They will also decide how the cost of the drug will be split between the patients and their insurers.

Pia’s story spread beyond Belgium’s borders when AveXis refused to grant permission for EU compassionate use of the SMA treatment before the initiation of the crowdfunding. The compassionate use, which allows for the use of unauthorized medication, is regulated by individual Member States, with each setting their own rules and framework. This program is dedicated to “life-threatening and long lasting illnesses” which cannot be treated with currently authorized medicines. The EMA can provide an opinion with regard to allowing the treatment in a specific EU country on the condition that the manufacturer agrees with this. However, considering that Pia was already on a treatment and she was not at a life threatening stage, AveXis refused to undertake this procedure believing that it was in the EMA’s hands now to authorize the marketing of the drug on the European market after it had been granted an FDA approval five months prior. The 'ping-pong' analogy is appropriate to describe how both the pharmaceutical company and the European institutions are refuting their responsibilities, putting at stake the lives of patients in the EU states as a result. But the issue spans beyond the initial case of SMA treatment to the entire system of medicine approval in the EU, which will need to be reformed in the long run.

Is it a European problem?

In the EU, there are two ways of getting the authorisation to market a medicine; either the company, following an EMA evaluation, goes through a centralized authorization procedure via the European Commission to obtain a single permit valid for the whole of the EU, or it follows the national authorisation procedures for every EU member state individually. For some specific treatments such as biotech products or gene therapy, the approval has to be given by a dedicated EMA scientific committee composed of professionals, academics, patients and consumers.

One criticism arises from the number of therapeutic agents approved by the FDA compared to the EMA, as well as the length of the approval process. On average, in the first decade of the 21st century, the FDA regulatory reviews took 60 days fewer than in Europe and it approved 43.5% of applications for orphan drugs compared to 25% for the EMA. Current research does not demonstrate that the quality of these reviews is better than in the USA. The differences in the approval period mainly arise from the fact that novel drugs do not hold the same status in both jurisdictions. For example, some cancer drugs might be submitted for priority assessment in the US while they will not have a special status in Europe, increasing the length of the approval process in the latter region.

However, it is mostly a question of structure that differentiates the two agencies: the FDA is a mandated authority that issues binding decisions while the EMA is a decentralised agency advising the European Commission, which is the legally mandated entity making the final decision. Thereafter, in the hopes to control the costs of medicine, each EU country individually regulates prices of pharma products, which causes further delays in patients’ access to the product. For example, the UK scheme allows for the responsible entity to control company profits and demand price cuts and paybacks from companies, while in Belgium and Norway there is a more thorough economic evaluation done by insurance companies. In Denmark and Switzerland, the producer may submit supportive data of the economic benefits of the medicine to facilitate a favorable decision. These different rules contrast with the US procedure, which allows for an almost immediate access to the medication; this has, however led to a national debate on the trade-off between fair pricing and reimbursement policies, on the one hand, and speedy approval on the other.

Ethics, business and the EU

The consequences of the differences in expectations between all stakeholders and their failure to cooperate fall, sadly, on the patients, who have to rely on contributions from private individuals for the funding of research, its infrastructure and the treatments. Pia’s story highlights the conflict between the responsibilities which pharmaceutical companies are facing; that is, the usual economic profits and the societal mission they burden themselves with. It also points out the limits of the decentralized approval system, which leaves young patients and their families in the twilight zone of hospitals corridors. Remarkably, as businesses and EU institutions show their failures, the continuous support from the society to these families, dedicated researchers in our universities and startups has never been as apparent as it is today thanks to the press and social media. The stories of these young victims such as Pia spread a message of hope for humankind but also of the challenges our future scientists and policymakers in Europe will continue to face in healthcare policy.

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