Letter from the Chairman
February 11, 2010
Dear Colleagues:
Welcome to the website of the International Serious Adverse Event Consortium [iSAEC]. We’re delighted you opted to spend a few minutes to understand our novel research enterprise.
We launched the iSAEC in August of 2007, as an industrial biomedical consortium, focused on identifying and validating DNA-variants useful in predicting the risk of rare, drug induced serious adverse events [SAEs]. Drug-induced SAEs present significant health issues for certain patients; while posing significant challenges to the developers of new drugs and the users of approved drugs. The rarity of drug induced SAEs and the absence of effective government surveillance/research networks, makes it extremely difficult for any one company/research entity to accrue enough SAE cases and matched controls to conduct genomic studies to look for underlying genetic risk factors. Central to the notion of the iSAEC is that industry, government and health care researchers can join forces and work together, making use of a variety of biological and data resources to study the genetic basis of drug induced SAEs. This challenge demands a highly coordinated, collaborative effort involving many parties.
Although the Consortium’s scientific scope is broad in principle, it has focused in its initial phase (2007-2009) on two core projects. We have collaborated with many partners/colleagues to identify significant genetic variants associated with both drug-induced liver-disease [DILI] and serious skin rashes [SSR]. The results and supporting data from these projects have/are being published in peer review journals. All “allowable” data from these efforts have been released to all qualified researchers at the same time. These raw data can now be requested via this web site, by qualified researchers who sign a “data use agreement”.
The iSAEC has helped to set a precedent for genetic analysis of drug-induced SAEs. Let me make a few points relative to our phase one findings:
First, we have clearly demonstrated that “common” genetic variants, with a significant impact on the risk of serious adverse events, can be detected in relatively small sample sizes (<50 cases). This bodes well for the feasibility of applying genomic methods to such medical challenges. With good collaboration, we can aggregate cohorts of this size in a reasonable period of time.
Second, most of our findings to date have been specific to a drug versus across multiple drugs.
Third, our findings clearly demonstrate an important role for the MHC genomic region in the pathology of immunologically mediated SAEs such as DILI and SSR. Our research findings also emphasize the importance of immune regulation genes, in addition to a number of well characterized ADME genes.
Lastly, a number of cross drug/ SAE genetic alleles are starting to emerge that may provide important insights into the underlying biology/mechanism of SEAs (e.g. HLA*5701 or UGT1A1*28).
These findings have helped us shape our plans for phase two of the iSAEC (2010-2012). We plan to develop novel international research consortia and new partnership with large US healthcare systems to aggregate focused case cohorts, associated with specific SAEs and causal drugs. Our goal is to deepen our understanding of the genetics of immunologic influenced SAEs, including SSR, DILI, and acute hypersensitivity syndrome (AHSS). We will continue to apply novel genomic methodologies to fulfill these aims. In addition to whole genome genotyping, we plan to pilot the application of next generation sequencing to explore the role “rare” genetic variants in SAEs. We will also conduct biological pathway analysis, using specialized assays to better understand the underlying biology.
The iSAEC conducts its work with the scientific, technical and financial support of its pharmaceutical/other members. We are deeply indebted to Abbott, Diiachi-Sankyo, GSK, J & J, Novartis, Pfizer, Roche, Sanofi-Aventis, Takeda, the Wellcome Trust, and Wyeth for their enabling support of the Consortium’s phase 1 research. We also appreciate the additional support of our phase 2 research efforts to be provided by Amgen and Merck. Lastly, we are grateful for the collaborative spirit, team work and support provided to the iSAEC by the US FDA, Japanese PMDA, and the European EMEA.
Collaboration and team work are at the heart of our efforts to conduct this research and to serve the public good. I invite all companies interested in joining our novel research consortium to contact me directly. We enthusiastically welcome researchers from around the world to collaborate with our efforts. I invite all researchers interested in contributing to our novel research efforts to contact me directly.
I can be reached at aholden@earthlink.net. Please let me hear from you. Thank you.
Sincerely,
Arthur L. Holden
Chairman and CEO
International SAE Consortium, Ltd.