Who's Really in Charge of European Drug Registration?

Mar 01, 2013

The rather obscure case of a French orphan drug for liver disease has escalated into a debate about who really calls the shots in drug authorization decisions in the European Union—scientific experts, or Brussels bureaucrats?

The drug in question, Orphacol, is a preparation based on cholic acid for the treatment of inborn errors of primary bile acid synthesis. This is a rare condition, with less than 100 sufferers in the European Union, and is fatal within the first 10 years of life if untreated. But treatment options are limited: a liver transplant and life-long immunosuppressive therapy, or Orphacol. However, attempts to make it available across Europe have run into repeated opposition from the European Commission, despite the strong support the application has received from experts at the European Medicines Agency (EMA), and from the delegates of most of the EU's member states.

It is indeed a curious story. The product, a hospital pharmacy preparation, has been used for over 20 years in France, with a remarkable record of success—including almost complete normalization of liver function in affected children, with a return to normal quality of life, and even four normal pregnancies in two treated women that have produced babies in excellent health. No liver transplant has been necessary for any of the treated patients, and there has been no serious adverse event and no treatment discontinuation.

The product received orphan product designation in 2002, and an application for marketing authorization was made by a small French company, Cell Therapies and Research Services (CTRS), after it took the product over in 2007 to make it available across Europe. In September 2008 the EMA agreed to evaluate the medicine via the centralized procedure. And in view of the extreme rarity of the illness, and the consequent impossibility of conducting clinical studies with children, it indicated it would operate on the basis of well-established use. In 2010 the EMA's principal scientific committee, the CHMP, reached a unanimous positive opinion on the application. The EMA even described Orphacol as a medicine of significant public interest. But it is not the EMA that grants European marketing authorisations in the European Union. It is the European Commission. And the Commission immediately asked the EMA for a re-evaluation. This led in April 2011 to a second unanimous positive CHMP opinion, but in July the commission drafted a decision refusing the authorization, saying the application was incomplete.

The EU procedure then required that the case be considered by a committee of delegates of national authorities from the member states. This committee met in October 2011 and rejected the commission's draft refusal. The Commission persisted in its opposition, and the draft decision was sent to an appeal committee, which in November also rejected the draft refusal.

CTRS wrote to the European commissioner for health—who was then John Dalli—the same month, seeking immediate adoption of a decision approving market authorization, but Dalli replied in December to the effect that no authorization would be granted, as the criteria for market authorization (and specifically the need for pre-clinical tests) had not been met. CTRS then took the commission to the European Union's own court at the start of 2012, for failure to act. Over the following weeks, the Czech Republic, the United Kingdom, and France requested admission to act in support of CTRS, and these requests were accepted by the court. At the same time, a US company called Asklepion Pharmaceuticals asked to act in support of the European Commission. Its request was denied by the court.

But meanwhile, the commission had reworded its draft refusal. This it submitted to the Committee of National Representatives at a meeting in May, held on a public holiday and not fully attended. On this occasion the committee did not achieve a majority sufficient to oppose the commission draft, and two weeks later, without awaiting any ruling from the case pending before the court, the commission issued a formal refusal of the marketing authorization.

In July the court case was closed. It could not adjudicate on the merits of the case, since the basis of the CTRS appeal had been rendered obsolete by the commission's actions. However, the court did require the commission to pay the legal expenses of CTRS. The company immediately filed a new case against the commission's May decision. And there, for the moment, the legal saga rests.

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