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With $6M From Pharma Partners, New Alliance Aims to Study Gene Biomarkers Linked to SAEs

Twelve drug makers, including six top-10 pharma companies, have signed up as “formation members” of the Severe Adverse Event Consortium, a far-reaching project to identify genetic biomarkers that might predict serious adverse events, according to a presentation made by the chairman of the consortium.
Abbott, Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Eli Lilly, Merck, Novartis, Pfizer, Roche, and Wyeth were listed as “formation members” of the consortium, which aims to “identify and validate” DNA variants that are “clinically useful” in predicting the risk of drug-induced serious adverse events.
The disclosure was made by Arthur Holden, chairman of the SAE Consortium and senior vice president of corporate and market development at Illumina, during a March 6 presentation at a conference sponsored by management and technology consulting firm Diamond. Holden declined to comment for this article.
As part of the project, the drug makers have put up $500,000 apiece for a total of $6 million so far, according to Paul Watkins, director of the Genetic Clinical Research Center at the University of North Carolina, Chapel Hill, and a participant in the consortium. The consortium is a public-private endeavor, and it remains unclear how much funding will come from public sources, or who those sources will be.
As Pharmacogenomics Reporter sister publication GenomeWeb Daily News reported last week, officials expect the consortium, which will look at adverse events such as hepatotoxicity, rhabdomyolysis, and QT prolongation, to be operational in the next few weeks.
Watkins told GenomeWeb Daily News that the consortium will initially try to tackle liver toxicity, and plans to develop a DNA chip for the indication by the end of the year.
The number of drug makers that have signed on to the consortium is noteworthy because the industry and the US Food and Drug Administration, which Holden also described as a formation member, have been criticized recently for marketing drugs with safety issues. Recent examples include GlaxoSmithKline’s type 2 diabetes drug Avandia, which has recently been associated with a potentially significant increase in the risk of heart attack and heart-related deaths, though Glaxo “strongly disagrees” with the findings; statins, which the FDA in 2005 said are associated with rhabdomyolysis; and Merck’s cox-2 inhibitor Vioxx, which the company withdrew from the market in 2004 after the drug was linked to an increased risk of heart attack and stroke.
Wendy Sanhai, senior scientific advisor in the FDA’s Office of the Commissioner, told GenomeWeb Daily News last week that understanding SAEs “is a huge unmet public health need” and has been a “huge priority for some time” at the FDA.
But not everyone in the industry is enthusiastic about the consortium’s prospects. One pharma official, who wished to remain anonymous because he is not a part of the group, told GenomeWeb Daily News that the consortium will be challenged by the relative rarity of severe adverse events and the number of patients needed to identify genomic biomarkers linked to them.
A Coordinated Effort
According to Holden’s presentation, the US healthcare system spent around $177 billion, or 10 percent of its total healthcare costs in 2000, on treating drug-related mortality and morbidity. He also reported that adverse drug reactions “are believed to cause” more than 200,000 deaths each year in the US, which he said places them among the top-10 causes of death.
Holden, who is also chairman of the Pharmaceutical Biomedical Research Consortium and was chairman and CEO of the SNP Consortium, said the goals of the SAE Consortium are to establish a “coordinated network for obtaining well characterized SAE cases and controls;” “define the required content for an optimal SAE genotyping panel;” develop computational methods to “effectively apply whole-genome analysis to SAE marker development;” create a publicly available “knowledge base to help predict key SAEs across all drugs;” and manage IP relating to markers useful in predicting SAEs “to ensure broad and open access.”
Academic members of the consortium include Eudragene, a European collaboration to establish a case-control DNA collection to study the genetic basis of adverse drug reactions, and Diligen, a UK Department of Health-funded program that aims to develop a test to identify patients at high risk of developing drug-induced liver disease.
The consortium’s aims dovetail with those of the FDA, which said in a recent fact sheet that it is “acting in a scientific advisory role” and is “providing guidance on the establishment” of the consortium.
According to the FDA’s “Drug Safety Initiative” fact sheet, the consortium is meant to “identify and qualify biomarkers for adverse events, including pharmacogenetic markers and identifiers; leverage/establish appropriate databases and repositories; coordinate the development of common research platforms, nomenclature, and standards; and establish effective intellectual property and data-pooling strategies.”
All information from these studies will be placed in the public domain, Sanhai said.
She added that the FDA is in discussions about the consortium with colleagues within the NIH, including the National Human Genome Research Institute, and noted that the agency hopes to attract broader participation in the effort.
“Any party willing to address this issue is welcome to join the consortium,” she said.
Risky Business
According to Nadine Cohen, head ofpharmacogenetics at Johnson & Johnson Pharmaceutical Researchand Development, the initiative is in a “very preliminary” stage. Johnson & Johnson, a consortium member, believes genetic biomarkers can play a role in identifying and mitigating adverse events, Cohen has said.
In drug discovery, we are … constantlylooking for markers of efficacy and safety as part of our duediligence research and development," Cohen was quoted as saying in a British Medical Journal article in March.
Yet not everyone agrees that the consortium will be able to answer the complex questions posed by drug-induced SAEs.
“The notion is that we will find a genomic marker that will predict” who will suffer an SAE, said one pharma official who asked to remain anonymous because he is not part of the group. “The problem is that it will take thousands and thousands of patients to screen in order to validate a particular marker.”
This official said that the SAEs the consortium would study typically occur in less than one in 1,000 patients and are “inherently unpredictable” either by pre-clinical or clinical development. “And because of the rarity of the event, the prospect of doing that is not only daunting but unlikely,” the official said. “People just haven’t done the math.”

“The problem is that it will take thousands and thousands of patients to screen in order to validate a particular marker.”

The FDA is attracted to the consortium because “they need to be more aggressive in signal detection, in getting these [SAE] reports in and figure out what’s happening” so they determine what steps to take, the official noted.
The official said the agency is becoming “more and more conservative” to the point where “if you have one, two, three cases of severe hepatotoxicity out of millions who have been treated, [then] you’re getting a Black Box warning.” The official said hepatotoxicity has been “the single-most common reason to pull a drug off the market.”
Indeed, several years ago, the FDA declared in a presentation that late identification of liver toxicity was a major problem.

In that presentation, the agency noted that Eli Lilly’s arthritis drug Oraflex; SmithKline Beecham’s hypertension drug Selacryn; Wyeth-Ayerst’s NSAID Duract; and Parke-Davis/Warner-Lambert’s type 2 diabetes drug Rezulin were withdrawn from the market because they were linked with hepatotoxicity.

“In most cases, the hepatotoxicity of these drugs was recognized late, as neither animal nor human experience before marketing yielded recognizable (or recognized) signals of hepatotoxic potential,” the agency noted in its presentation.
FDA’s Sanhai acknowledged that the consortium has an arduous task ahead.
“A lot of work has to be done to study genetic data because the population of patients who experience certain SAEs may be small,” she said. The consortium is planning studies that will be “sufficiently powered” statistically to identify patient populations at risk for suffering SAEs, she noted.
Collaborations Pave the Way
The SAE Consortium will be managed by the FDA’s Office of Critical Path Programs. There are other efforts ongoing under The Critical Path to bring together disparate entities in healthcare to improve drug safety. For instance, it is linking the Association of Clinical Research Organizations with the Clinical Data Interchange Standards Consortium to form the Clinical Data Acquisition Standards Harmonization project. This new group would be charged with “developing sample case report forms for reporting adverse events,” according to a National Institutes of Health summary of a Roadmap steering committee meeting that took place last December.
According to the summary, the Office of Critical Path Programs, which will oversee the Serious Adverse Events Consortium, directs other similar initiatives. The summary said the office is a “cross-cutting coordination and harmonization [center] of all the centers within the FDA. Areas of focus in this effort are bioinformatics and data standards, biomarkers, establishing public-private partnerships, and developing guidance and regulations.”
Rachel Behrman, director of the Office of Critical Path Programs, spoke at the steering committee meeting and said other alliances under its aegis include the ECG Warehouse, which is a partnership between the FDA and electrocardiography product maker Mortara Instruments; the Oncology Biomarker Qualification Initiative, which pairs the FDA with the National Cancer Institute and the Centers for Medicaid and Medicare Services; the Biomarker Consortium, which brings together the FDA, the NIH, the Pharmaceutical Research and Manufacturers of America; and a Memorandum of Understanding between the FDA and NCI to create the Federal Investigator Registry of Biomedical Information Research Data, or FIREBIRD, “which will enable clinical investigators, NCI, FDA, and industry entities sponsoring clinical trials of investigational drugs to manage clinical investigator information electronically in a fully secure manner.”
— Matt Jones and Turna Ray contributed to this article.

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