Agency is under fire for refusing to supply details of sudden deaths after first dose of multiple sclerosis drug

The European Medicines Agency has been criticised for refusing to supply the French independent drug bulletin, Prescrire, with data on cases of sudden death after the first dose of the multiple sclerosis drug fingolimod.

Fingolimod was authorised by the European Medicines Agency in March 2011 for the treatment of relapsing remitting multiple sclerosis in patients whose disease has failed to respond to a β interferon or is severe and getting worse rapidly.

On 20 December 2011 the US Food and Drug Administration reported that a patient with multiple sclerosis had died within 24 hours of taking the first dose of fingolimod, marketed by Novartis. The patient was also taking a β blocker and a calcium channel blocker.

On 22 December Prescrire contacted the European Medicines Agency to ask for a review of the serious adverse effects of fingolimod and for the initial European Periodic Safety Update Report, which must be filed with the agency within six months of marketing authorisation.

It was not until 20 January 2012 that the European Medicines Agency issued a public announcement on the subject. They said that in addition to the unexplained death in the United States there were six other unexplained deaths, including three cases of sudden death, after starting treatment with fingolimod.

On 23 January the agency told Prescrire that its request for information was rejected on the grounds that a European re-evaluation of fingolimod was underway. On 7 February Prescrire repeated its information request but has so far not had any response.

Bruno Toussaint, editor in chief of Prescrire, said: “Once again the European Agency is refusing to provide patients and healthcare professionals with important information on adverse effects after the drug has come onto the market, information that is itself the fruit of the reporting work carried out by patients and healthcare professionals.”

Prescrire criticised the agency and the European Commission’s Directorate General for Health and Consumers saying they give the benefit of the doubt to drug companies rather than to patients, and dispense information about adverse effects only sparingly. “It is high time that they get back to their primary mission: protecting patients’ health, which should take precedence over protecting the financial interests of pharmaceutical companies.”

Professor Peter Gøtzsche, from the Nordic Cochrane Centre in Copenhagen, told the BMJ: “This is completely unacceptable. Requests for access to information should never be delayed. There should be no excuses.” He continued: “The main task of the European Medicines Agency is to protect patients not protect drug companies.” He added that it is always an advantage if several groups look at the same evidence.

Professor Gøtzsche had a three year battle with the European Medicines Agency to get access to unpublished trial reports (BMJ 2011;342:d2686, doi:10.1136/bmj.d2686). He said his campaign did create tremendous change at the agency with much wider public access to documents including trial reports and protocols. “The same thing needs to happen for pharmacovigilance. The EMA [European Medicines Agency] need to be equally open about Periodic Safety Update Reports,” said Professor Gøtzsche.

The European Medicines Agency says the drug’s marketing authorisation holder, Novartis, has agreed to supply the results of its ongoing investigations into the cardiovascular effects of the drug. It says its review of the drug should be finalised by March 2012.

While the review is ongoing the agency is advising doctors to increase their level of monitoring of patients after the first dose of the medicine. This includes electrocardiogram monitoring before treatment and then continuously for the first six hours after the first dose and measurement of blood pressure and heart rate every hour. After six hours any patients with clinically important heart related effects such as bradycardia or atrioventricular block should continue to be managed and monitored until their condition has improved.

The agency says the risk of bradycardia after the first dose of fingolimod was known when it was authorised. It says the product information already includes recommendations to observe patients for signs and symptoms related to this side effect for at least six hours after the first dose.

The FDA is also investigating but says in the meantime it believes the “benefits of Gilenya continue to exceed the potential risks when the drug is used appropriately as described in the approved drug label.”

Fingolimod is the first in a new class of disease-modifying treatments called sphingosine 1-phosphate receptor (S1P-R) modulators. More than 30 000 patients have received the immunosuppressant worldwide. However, preliminary guidance from the National Institute for Health and Clinical Excellence published in August 2011 recommended that it should not be prescribed on the NHS because the drug is not cost effective and there was a lack of appropriate data. (BMJ 2011;343:d5117, doi:10.1136/bmj.d5117).