Methodology for a multinational case–population study on liver toxicity risks with NSAIDs: the Study of Acute Liver Transplant (SALT)
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The European Committee for Human Medicinal Products (CHMP) requested a multinational study with the aim to investigate the risk of acute liver failure (ALF) leading to registration for transplantation in patients exposed to non-steroidal anti-inflammatory drugs (NSAIDs). The method of this multinational, multicentre, retrospective case–population study, named SALT (Study of Acute Liver Transplant), is documented here.
This was a multicentre, multinational retrospective case–population study performed in France, Italy, Portugal, Greece, Ireland, the Netherlands and the UK. The study period was 3 years (1 January 2005–31 December 2007). Cases were patients ≥18 years of age with ALF at the time of registration on the transplant list for liver transplantation who had been exposed to an NSAID within 30 days preceding the initial symptoms of liver disease (index date). Exposure was defined as exposure to any NSAID. Per country rates of NSAID-exposed transplantation-registered ALF were computed as the ratio of the number of cases identified in the country to total population exposure. Overall and per-drug sales for NSAIDs and for paracetamol were obtained from Intercontinental Marketing Services (IMS) Health for all participating countries. Population exposure was measured as the defined daily dose and as estimated annual number of patients exposed (primary endpoint) with 95 % confidence intervals.
The study protocol was approved by the CHMP. Of the 57 eligible liver transplant centres, 54 agreed to participate in the study. All national authorizations were received with relevant administrative burden, mainly due to bureaucracy.
The present study created a multinational research network to estimate population-based absolute rates of drug-exposed ALF leading to registration on the transplantation list. This study design was chosen to obtain a fast response to a public health issue, namely, that of an increased risk of a rare, very serious adverse reaction. This model could be used to study other drug-related issues in ALF.
KeywordsAcute liver failure Case–population Liver transplantation Non-steroidal anti-inflammatory drugs Pharmacoepidemiology
The authors wish to thank all of the physicians and staff at the transplant centres and all of the patients whose acceptance of this study made it possible, as well as the various individuals in administrative positions, data protection, ethics and R&D committees.
The study protocol was submitted to the CHMP in 2007 and approved in November 2008.
The Department of Pharmacology of Université Bordeaux Segalen (UBS, France) was the international coordinating centre and had full control of all study operations and decisions, developed study methods and documents, retrieved, managed and is due to analyze the data independently from the financer. A scientific committee composed of international experts in pharmacoepidemiology, hepatology and statistics developed the protocol and oversaw the study. In each participating country a coordinator (National Case Selection Committee Hepatologist, NCSCH) was assigned to help with country-specific aspects and with the validation of cases from their own country. All drug-exposed cases of ALF were reviewed by a case adjudication committee (CAC) composed of hepatologists and pharmacoepidemiologists with the aim to assess causality.
This study was conducted at the request of the European Committee on Human Medicinal Products (CHMP) of the European Medicines Agency, independently from the financer, Helsinn Healthcare SA, manufacturers of nimesulide. The financer had no control of protocol, data retrieval, processing or analysis. Helsinn SA contracted with University of Bordeaux for the conduct of the study. All contracts with members of the committees, with the individual local investigators and with individual transplant centres were with the University of Bordeaux. Helsinn SA was given the opportunity to read and comment this paper before submission, but the content of the paper was entirely under the control and responsibility of the authors.
The report of this study has been sent to the regulatory authorities.
Conflict of interest statements
The authors declare that they have no conflict of interest.
Nicholas Moore (NM) and Dominique Larrey (DL) had the original idea for the study several years ago and proposed it to the financer and to the CHMP. NM was the overall study supervisor, intervening when necessary for the smooth operation of the study. DL was chairman of the scientific committee and of the case adjudication committee, and was the everyday hepatology counsel for the study. George-Philippe Pageaux was the vice-chairman of the case adjudication committee. Sinem Ezgi Gulmez (SEG) and Séverine Lignot were the scientific and operational study coordinators, devising the initial document generation under the control of the scientific committee, organizing negotiations with transplant centres and study data retrieval, writing the study reports and draft article and verifying all contents. SEG also finalized this article. Patrick Blin was the study epidemiological overseer, contributing to study design, operations, analysis and understanding. Corinne de Vries, Susana Perez-Gutthann, Miriam Sturkenboom and Jacques Bénichou provided considerable methodological input to the study scientific committee. Dominique Larrey, George-Philippe Pageaux, Jacques Bernuau, Franco Bissoli, Yves Horsmans, Bruno Stricker and Douglas Thorburn were the members of the case adjudication committee, developed the case adjudication process and performed causality assessments.
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