The General Court has confirmed that EU regulators may revoke a conditional drug approval on public-health grounds without awaiting the outcome of a pending renewal application.
Drugmakers holding conditional marketing authorisations cannot rely on a pending renewal application to keep a medicine on the EU market where the regulator concludes that its risk-benefit balance is no longer favourable, the General Court has ruled. Handing down its decision in Luxembourg yesterday (23 September), the court dismissed Dublin-headquartered Advanz Pharma’s challenge to the European Commission’s 2024 decision to revoke the conditional approval for Ocaliva, a treatment for the rare liver disease primary biliary cholangitis (PBC).
The decision confirms the Commission’s ability to act swiftly where the European Medicines Agency (EMA) finds that a drug’s promised clinical benefit has not been established. It also endorses the EMA’s preference for evidence from a randomised, placebo-controlled trial over real-world data and post-hoc analyses.
The background
Ocaliva, whose active substance is obeticholic acid, was granted a conditional marketing authorisation in 2016. Such approvals allow medicines addressing an unmet medical need to reach patients before the full clinical evidence normally required for a standard authorisation is available. This was the mechanism used for the first Covid-19 vaccines in the EU, which were authorised after clinical trials had established a favourable risk-benefit balance but while further data continued to be collected.
But such authorisations are not without conditions – chiefly that the authorisation holder must complete further studies to confirm that the medicine’s benefits outweigh its risks.
Ocaliva is intended for patients with PBC, a chronic disease in which the body’s immune system attacks the bile ducts in the liver, who cannot tolerate or do not respond adequately to ursodeoxycholic acid.
Advanz, which acquired the conditional authorisation in December 2022, applied to convert it into a standard authorisation. But in October 2023, the EMA’s Committee for Medicinal Products for Human Use (CHMP) concluded that the required confirmatory study, known as 747-302, had failed to demonstrate clinical benefit.
The Commission then began a review of the conditional authorisation. Advanz submitted a renewal application in May 2024, but the CHMP concluded in June that Ocaliva’s efficacy had not been established and that its risk-benefit balance was unfavourable. The Commission therefore revoked the approval in August 2024, treating the renewal process as having become unnecessary.
Advanz disputed the decision and took its case to the General Court.
The arguments
Advanz argued that, once a valid renewal application had been submitted, the conditional approval had to remain in place until the Commission decided that application and the Commission could not use a separate review process to bypass the renewal procedure.
The company also challenged the scientific assessment, relying on biomarker improvements, real-world studies and post-hoc analyses which it said supported Ocaliva’s continued availability. It contended that the pivotal trial had been cut short after many participants stopped their assigned treatment. Some patients who had initially been allocated to the placebo group then received commercially available Ocaliva or bezafibrate through their ordinary clinical care (and therefore outside the trial), but were still counted as placebo patients in the trial’s main intention-to-treat analysis. Advanz said this weakened the comparison between the treatment and placebo groups and meant that the trial could not reliably determine whether Ocaliva delivered a clinical benefit.
The company also alleged procedural flaws in the EMA’s consultation of an ad hoc expert group, including a conflict of interest involving an expert who had advised a company developing a potentially competing PBC treatment.
Patient group CBP Portugal, which intervened in support of Advanz, argued that revocation curtailed patients’ access to a treatment on which some had come to rely.
The decision
The court rejected the challenge in full.
It held that the rules keeping a conditional authorisation valid during a renewal procedure do not prevent the Commission from commencing and completing a separate review where public-health grounds justify action. The renewal provision was intended to prevent medicines being removed from the market for administrative reasons, the court said, not to stop the regulator acting where it considers the medicine’s risks outweigh the benefits.
The court accepted the CHMP’s conclusion that the totality of the available evidence did not confirm Ocaliva’s clinical benefit. It found no manifest error in the committee’s decision to give greater weight to the randomised, double-blind, placebo-controlled trial than to real-world evidence, which could not eliminate the risk that differences between patient groups had affected the results.
It also rejected the conflict-of-interest allegations, finding that Advanz had not established a breach of the EMA’s rules or a legitimate doubt about the experts’ impartiality.
The ruling leaves the Commission’s revocation in place and offers a clear reminder that conditional approvals remain subject to continuing scientific scrutiny. Even while a renewal application is pending, regulators may withdraw a medicine where the available evidence no longer supports its clinical efficacy.
The parties
In Advanz Pharma (applicant) v European Commission (defendant), the applicant was represented by Maarten Meulenbelt, Belinda Baum, Alix Vermulst and Anne Robert of Sidley Austin (Brussels). The defendant was represented by its own Robert Lindenthal, Edwige Mathieu and Alessandro Spina.
