Authors' objectives:

The objective of this technical query is to assess the quality of the scientific evidence on the new Recombinant Activated Protein C drug, or drotrecogin alfa (activated) (Xigris) and its efficacy and safety.

Authors' results and conclusions: - Drotrecogin alfa (activated) significantly reduces mortality after 28 days in patients with severe sepsis. - It is the first drug that shows an improvement in survival in this group of patients. - The experimental group had no major incidence of haemorrhages. - The drug has been authorised by the FDA and the EMEA for patients with APACHE II>24 plus the best treatment available. - There are deficiencies in the internal and external consistency of the data. - Modifications were made to the study protocol, the inclusion criteria were changed and patients with a major risk of death were withdrawn. - Product from two different cell cultures was supplied during the trial. - In patients with APACHE II <20, there are no differences in mortality after 28 days between the experimental group and the control group. In patients with APACHE II <25 a major incidence of haemorrhages was observed in the experimental group. - The mechanisms of action of Drotrecogin alfa (activated) are not perfectly known. - From the health point of view, the improvement in mortality after 28 days is insufficient information for taking population-based decisions. - The conduct of phase IV studies to confirm or refute the safety and efficacy of the new drug poses ethical problems and shifts the cost of the research to the patients (or to their insurers).

Authors' recommendations: Both the FDA and the EMEAj have registered this product (Xigris) although both agencies have asked the manufacturer for additional data on safety and efficacy to perform a re-assessment of the benefit/risk ratio of the drug. The FDA has restricted its use to patients with severe sepsis and a score on the APACHE II scale of >24, whereas the EMEA has authorised the marketing of the drug under exceptional circumstances since, with the current state of the art, detailed information on the safety and efficacy of the drug cannot be given by the applicant and therefore restricts it to patients with severe sepsis and multi-organ dysfunction plus the best possible treatment. It is also very important to remember that the proper use of antibiotic therapy, which reduces mortality between 4 and 8 times more than drotrecogin alfa (activated), is more fundamental and important than support treatment to patients with sepsis. Of the five publications reviewed in this study, it may be said, first of all, that in actual fact there are only two randomised clinical trials, one of which is a phase II study in a paediatric population. Secondly, the quality of the publications is variable, although it is generally low, with important methodological deficiencies. It goes without saying that if we add the things that are not said by some articles on the modifications of the study protocol and the preparation of the drug during the trial to the deficiencies detected, we must conclude that there are sufficient reasons to mistrust the results of the trial. Thirdly, the efficacy of the drug can only be guaranteed for the most severe patients (although severe enough to have a risk of imminent death according to the protocol modification) with a score on the APACHE II scale of >24. At the moment there are not enough mechanisms to guarantee that this drug will only be given to this population in a post-marketing study. Similarly, the clinical trials have demonstrated that the risk of this drug is not insignificant (underlining statistical significance versus the experimental group), and that the data on the adverse effects in the population with APACHE of >24, who are those that will benefit more from this treatment, have not been properly published. And finally, the arguments presented on the cost-effectiveness of the drug must be addressed with caution. The use of the mortality variable after 28 days is relevant to intensive care units, but it would be difficult to justify a population-based decision on the strength of these data. Against these arguments we might argue that the results (at the moment) seem to favour the drug and that all the legal requirements for its marketing and generalised use have been met, and that failure to use this technology would mean denying the best treatment available to patients. Be that as it may, the scientific evidence that supports this new drug is limited and of poor-quality, and gives an uncertain idea about its efficacy, while also presenting severe potential risks. Opting to licence the drug in a limited subgroup of patients means adopting a defendable, though ambivalent attitude, which opens the door to an inadequate administration. Therefore, we believe that it would be necessary to conduct a strict follow-up of the use of this drug and to protocolise the terms of use to further ascertain the real effectiveness of the product.

Authors' methods: Review

Project Status: Completed

URL for project: http://www.gencat.net/salut/depsan/units/aatrm/html/en/dir393/doc7921.ht ml

Year Published: 2004

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: Spain

Organisation Name: Agencia de Qualitat i Avaluacio Sanitries de Catalunya

Contact Address: Antoni Parada, CAHTA, Roc Boronat, 81-95 (2nd floor), 08005 Barcelona, Spain, Tel. +34 935 513 928, Fax: +34 935 517 510

Contact Name: direccio@aatrm.catsalut.net / aparada@aatrm.catsalut.net

Contact Email: direccio@aatrm.catsalut.net / aparada@aatrm.catsalut.net

Copyright: Catalan Agency for Health Technology Assessment and Research (CAHTA)