Initial data generated by the Serious Adverse Events Consortium with regard to DNA variants associated with drug-related serious skin rash will be available at the end of 2008 or in January 2009, SAEC executive director Arthur Holden predicts.

Similar information for drug-induced liver injury should be released by the end of 2009, he said in an interview with "The Pink Sheet."

SAEC was formed in September 2007 to identify and validate genetic markers that may help predict patients at risk for serious adverse drug reactions. It is among many industry, government and academic efforts aimed at developing techniques to reduce the cost and increase the speed of drug development through better predictive modeling of patient reactions to products.

Serious reactions are defined as life-threatening or requiring immediate cessation of the drug, Holden said. Participants in the consortium include pharmaceutical companies and research groups, with FDA providing scientific and strategic input.

Initially, the consortium is focused on identifying the genetic mutations that are associated with serious adverse events. Data from these efforts will be the basis for subsequent research to validate the role of genetic variants in drug-related serious adverse events.

Serious skin rash - Stevens-Johnson Syndrome and Toxic Epidermal Necrosis - and drug-induced liver injury were selected for the group's first two projects because of the availability of case-control DNA sample collections for the two adverse events.

The existence of the samples allowed the consortium to move quickly to test its analytical systems, create a genotyping infrastructure and establish a data analysis and coordinating center (DACC) at Columbia University, Holden said.

GlaxoSmithKline provided the bulk of the SSR cases, which were collected through the company's pharmacovigilance effort to correlate patient genotype with drug reactions. The cohort consists of adjudicated SSR cases from clinical trials with a variety of drugs.

The consortium has access to about 180 drug-induced liver injury cases through collaboration with DILIGEN and EUDRAGENE, two U.K.-based drug safety research networks. The two groups, as well as the University of Malaga and the University of Dundee continue to recruit, enroll and conduct whole genome genotyping of liver injury patients.

Analysis of the first 200 cases has produced results that are "highly significant," Holden reports. "We've found identifying genetic markers that may be associated with drug-induced liver injury."

A lot more analysis needs to be done to obtain definitive answers about whether genetic factors move across types or classes of drugs and whether there is some common underlying genetic pathway, Holden said.

More cases are being added to the liver injury cohort because the number needed to get a "significant result" is unknown. "It depends on the strength of the signal. It depends how related [the signal] is to an individual drug or to multiple drugs."

But at this point, Holden noted, "We are identifying genetic variants that are significant enough to likely be connective."

Researchers Will Have Access To Data

Data generated through the consortium will be made available on an open-source Web site being built at the DACC for analysis by researchers.

Users must agree not to file patents for conclusions drawn directly from the database. However, the consortium says intellectual property protection may be appropriate for downstream inventions, such as assays, drug targets, therapeutics and diagnostics. To ensure the data stay in the public domain, the consortium may file provisional or utility patent applications and abandon them following publication, or convert to a statutory invention registration.

Other severe adverse drug reactions on the consortium's agenda include rhabdomyolysis, QT prolongation, anemia and neutropenias.

With its progress thus far, SAEC has shown that "We can generate results far faster and with far greater significance if we work together in these sort of open approaches," Holden said. The big challenge ahead is to build "larger and more effective cohorts for research in this area."

Such an endeavor requires resources, novel use of information technology, standardized case terminology, different approaches to using electronic medical records and the ability to enroll across broad geographical areas, he suggested. SAEC will be working on these issues as it moves forward.

Current SAEC members, which provide funding, data and consultation, are Abbott, Daiichi Sankyo, GlaxoSmithKline, Johnson & Johnson, Novartis, Pfizer, Roche, Sanofi-Aventis, Takeda, Wyeth and Wellcome Trust.

All the firms, except Daiichi Sankyo, Takeda and the Wellcome Trust, also are participating in the Predictive Safety Testing Consortium, which recently obtained FDA and EMEA validation of biomarkers for early identification of nephrotoxicity (¹ Also see "Nephrotoxicity Biomarker Prepares For Clinic After FDA Blesses Animal Test" - Pink Sheet, 2 June, 2008., p. 8).

Collaborating in the SAEC effort are Cerner, Inc., Columbia University, Dundee University, Diligen, Eudragene, Expression Analysis, Malaga University, Illumina, Inc. and the U.S. Veterans Administration Center for Drug Safety.

FDA is involved in several collaborative efforts to study biomarkers as part of its Critical Path Initiative, which was launched in 2004 to enhance the drug development process (² Also see "“Critical Path” Is On The Road Forward; FDA Reports Industry Activity Is High" - Pink Sheet, 22 January, 2007., p. 29). A public/private consortium with the pharmaceutical industry is looking for biomarkers of treatment response in major depressive disorder.

An International Cancer Genome Consortium was launched in April to identify the key genetic mutations involved in as many as 50 types of cancer. Participants include the U.K. Cancer Genome Project at the Wellcome Trust, Genome Canada, Ontario Institute for Cancer Research, Chinese Cancer Genome Consortium, and Institut National du Cancer in France.

Knowledge about the genetic changes that occur with each cancer could direct research to identify new therapies, diagnostics and preventive strategies, according to organizers.

"Virtual Man" To Speed Drug Development

Research on biomarkers could help create the "virtual man" predicted in a June PricewaterhouseCoopers report on how the pharmaceutical industry can cut drug development time and costs.

A mathematical model of the molecular and cellular components of the human body, the virtual man could be used to simulate the physiological effects of a drug's interaction with specific targets, the accounting firm's Pharmaceutical and Life Sciences Group says in "Pharma 2020: Virtual R&D."

Virtual patients will enable researchers to screen drug candidates in a digital representation "which can be adjusted to reflect common genetic variations and disease traits, such as a weakened cardiovascular system," the report states.

Such technology could cut the time to bring a drug to market by two-thirds, and potentially halve R&D costs, PWC forecasts.

Already, PWC notes, the American Diabetes Association and the biopharmaceutical firm Entelos have developed a diabetic virtual mouse to study cures for Type 1 diabetes and the company has deals with Lilly to do computer simulation research in diabetes and with Pfizer to use computer models to identify drug targets for diabetes and obesity.

FDA has been working with Entelos for more than a year to design software to enable people to anticipate if a drug is likely to cause hepatotoxicity.

Robert Powell, associate director in the Office of Translational Sciences, says it is one of several FDA projects using modeling and simulation to predict safety problems. Powell notes that with system biology - the study of complex interactions in biological systems - researchers are able to "construct mechanistical normal body function and layer disease function on top of it."

PWC predicts that such advances will render the current model of drug development, with four distinct phases of clinical testing, obsolete. Instead, a study will be conducted in a single, continuous phase, the firm says.

PWC suggests that the licensing process will be revamped, with FDA issuing "live licenses" to market a drug on a restricted basis. The firm likens this approach to FDA's conditional approval of orphan drugs in small patient populations.

The future also will see approval decisions based on risk/benefit analyses rather than data on average outcomes, and reimbursement of new therapies contingent on performance, the firm says. That approach has been taken with Johnson & Johnson's Velcade (bortezomib) in the U.K. (³ Also see "U.K. May Turn To “Value-Based” Drug Pricing In Place Of Price Limits" - Pink Sheet, 31 March, 2008., p. 22).

The plus side of the new regulatory era for drug makers will be the ability to get to market sooner and recoup costs more quickly, PWC concludes.

- Cathy Dombrowski (c.dombrowski@elsevier.com) & Brenda Sandburg (b.sandburg@elsevier.com)

Serious Adverse Events Consortium Expects Data On Genetic Variants Shortly

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