Who's Really in Charge of European Drug Registration?

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.

But the availability of the product remains restricted. It can be used in France under its named patient compassionate use program. But it cannot be used in any other member state that does not allow similar use. And that has provoked interest that goes much wider than the liver disease community. This unprecedented refusal of a marketing authorization by the commission—in the face of strong support for the product from the EMA and most member states—has revealed a hitherto unsuspected weakness in the European Union's regulatory procedures.

The commission has justified its refusal on the basis of inadequate testing and insufficient evidence of established use. Questions have been raised about the wisdom of this justification. A product for such a deadly disease in such a limited population may not be appropriate for the sort of wide-ranging clinical testing required for an anti-rheumatic or an anti-fungal, it has been suggested. And the commission has also chosen to measure established use only from the time that CTRS took the product over in 2007—ignoring its use since 1993. These are not considerations that the EMA felt were sufficient to invalidate the application.

There are systematic questions that arise from the case. Is the commission determined to over-rule scientific opinion, even though it lacks the scientific expertise that the EMA (and each national authority in the member states) possesses? The member states are—via the council —the official holders of power, and they only delegate power to the commission, which then exercises it under the supervision of the member states. In theory, member states are then able to block the commission's proposed regulations by a qualified majority vote. Can the commission restart a procedure for a second time, when it has already been defeated? Can it reinitiate a vote indefinitely in this sort of case, until it gets the result it wants? Recent changes to the EU's mechanisms, introduced by a new treaty—the Lisbon Treaty—in 2010, are still playing out. Orphacol has become a leading case in this drama.

There are other questions that have been raised. Why did a US company try to get in on the act? Asklepion Pharmaceuticals, owned by the Seventh Day Adventists Church in the United States, which tried to support the commission in the first court hearing, has submitted a marketing authorization to the EMA for what it claims is a competing product in this field. Why did the commission take such a determined—and apparently perverse—stance on Orphacol? By a strange coincidence, both the key commission officials in the Orphacol case are no longer in post. Dalli was forced to resign as health commissioner last autumn as allegations swirled around him of being too close to the tobacco industry he was supposed to be regulating. Patricia Brunko, the head of the commission's pharmaceuticals unit that handles authorizations, has retired as of the end of 2012. Their motivations for such firmness have never been elucidated.

Much now hangs on the outcome of Orphacol's second case, still before the EU court. The judgement will be awaited with more than normal interest by European pharmaceutical executives and everyone with an interest in how the EU really works.

Reflector is Pharm Exec anonymous columnist, a commentator so close to the action in Europe that his identity must be secret.