BioWorld International Correspondent

Spanish firm Zeltia SA is considering its options following the failure last week of its drug development subsidiary PharmaMar SA to obtain European Union marketing approval for Yondelis (trabectedin) as a third-line treatment for soft tissue sarcoma.

The Madrid-based company had undertaken a high-profile lobbying campaign in support of its application, enlisting the support of professional sarcoma bodies and individual specialists. However, the Committee for Proprietary Medicinal Products (CPMP) of the London-based European Medicines Evaluation Agency (EMEA) rejected Zeltia's registration dossier on six grounds.

The company has 15 days from the date of the decision in which to notify the EMEA of its intent to lodge an appeal. "Zeltia is considering all possible alternatives in the light of the CPMP opinion. The decision will be taken by its board," a company spokesperson told BioWorld International.

The appeals process has been invoked only about half a dozen times in the EMEA's eight-year history, as most applicants tend to withdraw a drug dossier before receiving a negative opinion. About half of the appeals submitted have been successful, EMEA spokesman Harvey Allchurch told BioWorld International.

The CPMP decision, which was determined by majority vote rather than consensus, was based on a range of factors. First, it did not consider claims for the drug's efficacy to be sufficiently outstanding to justify approval without data from randomized clinical trials. Second, it said the subpopulation for evaluating efficacy and the historical control group was identified retrospectively, a factor that could introduce bias in assessing the drug's risk-benefit balance. Third, it concluded that partial contradictions in comparisons between time to progression and progression-free survival (PFS) data indicated bias in comparisons between Yondelis and historical ifosfamide data.

Fourth, it questioned "the possibility to estimate with reasonable certainty the antitumor activity of trabectedin for patients in clinical practice" because of wide confidence intervals around the point estimates for objective tumor response rate and PFS at six months, trends toward lower antitumor activity seen in a French compassionate-use program, and the possible non-representativeness of the patient subgroup used in the retrospective evaluation of efficacy.

It also stated that efficacy could not be established based on what it called "a modest and currently rather ill-defined tumor activity" in a disease in which the predictive value of the endpoints used are open to question. Finally, it stated that the toxicity profile of the compound remained a concern in the absence of unequivocal efficacy data.

Not surprisingly, Zeltia took an opposing view. "The CPMP negative opinion is disastrous for the European patients suffering from this rare and difficult-to-treat cancer indication," Zeltia Chairman José Mar a Fern ndez Sousa-Faro said in a company statement.

Robert Maki, co-director of the sarcoma program at Memorial Sloan-Kettering Cancer Center in New York, is one of the oncology specialists who expressed support for Yondelis. "I have seen people respond well to the drug, and on that basis alone would like to see ET743 [Yondelis] available for patients with sarcoma," he told BioWorld International.

"PharmaMar's approach was certainly the quickest way to try to get approval for the drug," Maki said. "That being said, it will now be important for PharmaMar to continue their studies to do their best to unequivocally show there is usefulness for this drug in sarcoma patients. It is an active drug, and like the problems in getting [the colon cancer drug] oxaliplatin registered in the U.S., it will be necessary to do more studies to properly demonstrate this activity." Maki is not a shareholder in or consultant to Zeltia or its U.S. partner, Johnson & Johnson, but has received some research funding from the former company to evaluate the drug and may receive funding from the latter firm as part of a forthcoming Phase II trial.

The current impasse has come at a time when sweeping proposals to reform the EMEA - which was set up in 1995 in order to provide a rapid and centralized route for approving novel biotechnology drugs - are under consideration. The EMEA's Allchurch told BioWorld International that under current legislation, the agency is not permitted to offer conditional approval, which would allow a company to generate more clinical data while also providing initial marketing authorization for up to a year. "I'm not saying there's a direct link between that and what might or might not happen with Yondelis. It's an interesting footnote," he said.

Other proposals on the table include extending EMEA's remit to cover all drugs in development for AIDS, cancer, diabetes and neurodegenerative disease and introducing a fast-track procedure for drugs with the potential to have a major impact on public health. The agency is looking to have its revised mandate in place before the EU expands to include 10 new Eastern European states on May 1, 2004. "We are hoping it will come into force before May of next year," Allchurch said.