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The International Serious Adverse Events Consortium (SAEC) officially announced its formation this morning. The new global, non-profit partnership between leading pharmaceutical companies, the U.S. Food and Drug Administration (FDA), and academic institutions plans to identify and validate genetic markers that may help predict which individuals are at risk for serious adverse drug events. The goal of the consortium is to publish a set of predictive SNPs for all drug-related serious adverse events (SAEs), reducing significant patient and economic costs as well as improving the flow of safe and effective medical advances by addressing safety issues of new drugs before they reach the market.

Dr. Janet Woodcock, deputy commissioner for operations at the FDA, which has been under pressure to ensure drug safety, especially following Merck’s withdrawal of Vioxx from the market three years ago, said today [1]:

This is what personalized medicine is really about, finding out for the individual, not just the general population … what their risks are. Up until now we’ve been kind of helpless [in dealing with adverse effects].

Indeed, a recent study found that the incidence of serious adverse drug events reported to the FDA doubled between 1998 and 2005; painkillers and immune-system boosters were responsible for the majority of occurrences [2].

Pharmacogenetics and SNPs

Not all people respond similarly to the same medication. Pharmacogenetics is the study of genetic variation that gives rise to diverse response to medication with a particular emphasis on improving drug efficacy and safety. One type of difference in DNA between people are single nucleotide polymorphisms (SNPs). I’ve written about SNPs previously. SNPs (pronounced “snips”) are DNA sequence variations that occur when a single nucleotide – A, T, C or G – in the genome is changed, producing different alleles (meaning sequences that code for the same gene). Common SNPs only have two alleles. For example, ATCGATCG and ATCAATCG represent two alleles: G and A. These small variations in DNA sequence make up approximately 90% of all human genetic variation and occur every 100 to 300 bases along the 3-billion-base human genome [3]. SNPs occurring in genes that code for drug-metabolizing enzymes (meaning enzymes that break down drugs in the body for elimination) may affect the amount of drug in an individual’s body at a given time and thus elicit variable responses to the drug [4].

Serious adverse drug events

Identifying and validating SNPs that affect drug metabolism is a crucial first step toward constructing a set of predictive SNPs for all SAEs. According to the FDA, a serious adverse drug event is a negative event that results in death, a birth defect, disability, hospitalization, was life-threatening or required intervention to prevent harm. PricewaterhouseCoopers, which provides industry-focused assurance and advisory services, reports that blockbuster drugs are typically efficacious in only 40% to 60% of the patient population [5]. Serious adverse drug events in patient subpopulations result in that drug being removed from the market (think Vioxx) at a huge financial and public relations cost to the manufacturer. The identification of genetic variations linked with SAEs is believed to be essential for the development of safer drugs while also identifying patients for whom a medicine will have the greatest probability of providing medical benefits with the fewest risks.

Initial studies

The SAEC is conducting two studies that will address drug-related liver toxicity, the leading cause of acute liver failure [6], and Stevens-Johnson Syndrome (SJS), a severe and life-threatening adverse reaction to medication that afflicts many children as well as adults and is associated with over 200 different medicines. Researchers will use data from The SNP Consortium and Hap Map Project, which mapped SNPs in conjunction with the Human Genome Project, to identify genetic variations linked with SAEs.

Three SAEC partners are conducting clinical studies and analyzing data: Newcastle University, currently conducting the Diligen study, which is investigating the genetics of drug-induced liver injury relating to the antimicrobial agents flucloxacillin (Flopen/Floxapen), a narrow spectrum bata-lactam antibiotic of the penicillin class, co-amoxiclav (Augmentin), a combination antibiotic containing amoxicillin and clavulanic acid, and the standard anti-TB drugs; EUDRAGENE, a European academic consortium to establish a case-control DNA collection for studying the genetic basis of adverse drug reactions, currently studying liver injury caused by non-steroidal anti-inflammatory drugs; and Illumina, a leading developer, manufacturer and marketer of next-generation life-science tools and integrated systems for the analysis of genetic variation and biological function. Columbia University is hosting the Consortium’s data analysis and coordinating center. The pharmaceutical companies Abbott, GlaxoSmithKline, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Pfizer, Roche, sanofi-aventis and Wyeth have been closely involved with the consortium launch and development of its scientific model, and are contributing data and underwriting costs.

SAEC chairman and CEO Arthur Holden said [7] in the announcement:

The traditional research model only provides one piece of the puzzle in understanding the genetic variations that could lead to an increased risk of an adverse event. Because of the number of patients needed to tie a genetic variant to an SAE, and the resulting cost of doing these studies, no one company, research center, or agency can efficiently conduct this research on its own. The most efficient way to study drug-related SAEs is to create a global, publicly available ‘knowledge base’ that will help identify the genetic variations that may predict SAEs.

SAEC research study results will be made available to the research community within 12 months of completion of the group’s genotyping for validation and further investigation. If initial studies are successful, the SAEC plans to examine every major drug-related serious adverse drug event to determine it’s underlying genetic cause.

References

1. Drug Makers, FDA Partner on Drug Safety. Associated Press. 2007 Sep 27.
2. Moore et al. Serious adverse drug events reported to the food and drug administration, 1998-2005. Arch Intern Med. 2007 Sep 10;167(16):1752-9.
   View abstract
3. SNP Fact Sheet. Human Genome Project Information.
4. Roden et al. Pharmacogenomics: challenges and opportunities. Ann Intern Med. 2006 Nov 21;145(10):749-57.
   View abstract
5. Personalized Medicine – The Emerging Pharmacogenomics Revolution. PricewaterhouseCoopers Global Technology Centre, Health Research Institute. 2005 Feb.
6. Drug-Induced Liver Toxicity. U.S. Food and Drug Administration. Created August 3rd, 2005. Updated March 9th, 2007.
7. FDA, Leading Pharma Companies Launch Global Collaboration to Research Genetic Markers Linked to Drug Safety. PharmaLive. 2007 Sep 27.