Drug Makers Seek Clues to Side Effects in genes

Seven of the largest pharmaceutical companies have formed a group to develop genetic tests to determine which patients would be at risk from dangerous drug side effects.

The new group, the International Serious Adverse Events Consortium, is one of a wave of cooperative research efforts sweeping the drug industry, as companies come under pressure to cut costs and increase their success rates in developing medications. The Food and Drug Administration has encouraged the formation of such groups.

If drugs could be withheld from patients who have a genetic risk for serious side effects, it could not only protect the patients but might help manufacturers get their drugs approved or avoid having to remove them from the market.

“We have to remove drugs that are clearly offering patients benefits because a handful are getting these severe adverse reactions,” said Duncan McHale, a researcher for Pfizer and co-chairman of the consortium’s scientific management committee.

The consortium will start by trying to find genetic predictors of two side effects — serious liver toxicity and Stevens-Johnson syndrome, a rare but potentially fatal blistering of the skin. Both effects are associated with numerous drugs.

Mr. McHale said the side effects were rare enough that no single company had enough cases and enough patient DNA samples to find genetic risk factors. “The way to do the best science is for all to work together to get as many cases as possible,” he said.

Arthur Holden, the chief executive of the consortium, said the companies would contribute guidance and money. The actual research will be done by contractors and academic laboratories, including one at Columbia University.

The results will be put into the public domain, with none of the corporate sponsors having early access or being able to patent the findings, he said. Once the results are made public, any company or laboratory would be able to develop and sell genetic tests to predict side effects.

In addition to Pfizer, the companies involved are Abbott Laboratories, GlaxoSmithKline,Johnson & Johnson, Roche, Sanofi-Aventis and Wyeth. Others might possibly join later. Mr. Holden said the companies would each pay about $1 million a year.

Pharmaceuticals makers, following the lead of the semiconductor and other industries, have increasingly collaborated on research in areas that are considered outside the main realm of competition. Often, these involve basic genetic studies of drug safety.

One of the first, started in 1999 and also run by Mr. Holden, was a consortium that searched for DNA variations among people, then put the variations into the public domain so that no one could patent what the companies considered raw scientific information.

The F.D.A. has encouraged such groups, even helping to start some of them though a program called the Critical Path Initiative, which aims to speed drug development.

Janet Woodcock, deputy commissioner of the F.D.A., said developing genetic markers “requires groups to work together because there’s no entity really charged with developing them.”

Still, there are now so many collaborative efforts that there is a risk of what is being called consortium fatigue. Mr. Holden said he found financially burdened drug makers less willing to join the new organization than the one he helped start in 1999.

A meeting of the American College of Clinical Pharmacology this month in San Francisco featured a symposium with presentations on the Biomarkers Consortium, the Predictive Safety Testing Consortium, the Molecular Assays and Targeted Therapies Consortium, the Cardiac Safety Consortium and the Microarray Quality Consortium.

Mr. Holden said the new Serious Adverse Events group would rely largely on DNA samples that European academic researchers had already collected from people who suffered the severe liver toxicity or Stevens-Johnson syndrome after taking drugs.

Using DNA analysis chips, researchers will examine those patients’ DNA at one million different spots, comparing it with the DNA of control subjects, to look for variations between the groups. The DNA of about 2,000 people will be analyzed, with results available in a year or two, Mr. Holden said.

The raw results would require further studies to show if the markers really do predict who might suffer the side effects. It is possible that no such markers will be validated.

Even if relevant genes are identified, it might not be economically possible to test all patients to screen out side effects that show up in as few as one in 100,000 people. Such economic factors are one reason that pharmacogenetics, the practice of tailoring drug therapy to patients using genetic tests, has been slow to catch on.

Drug Makers Seek Clues to Side Effects in genes

Seven of the largest pharmaceutical companies have formed a group to develop genetic tests to determine which patients would be at risk from dangerous drug side effects.

The new group, the International Serious Adverse Events Consortium, is one of a wave of cooperative research efforts sweeping the drug industry, as companies come under pressure to cut costs and increase their success rates in developing medications. The Food and Drug Administration has encouraged the formation of such groups.

If drugs could be withheld from patients who have a genetic risk for serious side effects, it could not only protect the patients but might help manufacturers get their drugs approved or avoid having to remove them from the market.

“We have to remove drugs that are clearly offering patients benefits because a handful are getting these severe adverse reactions,” said Duncan McHale, a researcher for Pfizer and co-chairman of the consortium’s scientific management committee.

The consortium will start by trying to find genetic predictors of two side effects — serious liver toxicity and Stevens-Johnson syndrome, a rare but potentially fatal blistering of the skin. Both effects are associated with numerous drugs.

Mr. McHale said the side effects were rare enough that no single company had enough cases and enough patient DNA samples to find genetic risk factors. “The way to do the best science is for all to work together to get as many cases as possible,” he said.

Arthur Holden, the chief executive of the consortium, said the companies would contribute guidance and money. The actual research will be done by contractors and academic laboratories, including one at Columbia University.

The results will be put into the public domain, with none of the corporate sponsors having early access or being able to patent the findings, he said. Once the results are made public, any company or laboratory would be able to develop and sell genetic tests to predict side effects.

In addition to Pfizer, the companies involved are Abbott Laboratories, GlaxoSmithKline,Johnson & Johnson, Roche, Sanofi-Aventis and Wyeth. Others might possibly join later. Mr. Holden said the companies would each pay about $1 million a year.

Pharmaceuticals makers, following the lead of the semiconductor and other industries, have increasingly collaborated on research in areas that are considered outside the main realm of competition. Often, these involve basic genetic studies of drug safety.

One of the first, started in 1999 and also run by Mr. Holden, was a consortium that searched for DNA variations among people, then put the variations into the public domain so that no one could patent what the companies considered raw scientific information.

The F.D.A. has encouraged such groups, even helping to start some of them though a program called the Critical Path Initiative, which aims to speed drug development.

Janet Woodcock, deputy commissioner of the F.D.A., said developing genetic markers “requires groups to work together because there’s no entity really charged with developing them.”

Still, there are now so many collaborative efforts that there is a risk of what is being called consortium fatigue. Mr. Holden said he found financially burdened drug makers less willing to join the new organization than the one he helped start in 1999.

A meeting of the American College of Clinical Pharmacology this month in San Francisco featured a symposium with presentations on the Biomarkers Consortium, the Predictive Safety Testing Consortium, the Molecular Assays and Targeted Therapies Consortium, the Cardiac Safety Consortium and the Microarray Quality Consortium.

Mr. Holden said the new Serious Adverse Events group would rely largely on DNA samples that European academic researchers had already collected from people who suffered the severe liver toxicity or Stevens-Johnson syndrome after taking drugs.

Using DNA analysis chips, researchers will examine those patients’ DNA at one million different spots, comparing it with the DNA of control subjects, to look for variations between the groups. The DNA of about 2,000 people will be analyzed, with results available in a year or two, Mr. Holden said.

The raw results would require further studies to show if the markers really do predict who might suffer the side effects. It is possible that no such markers will be validated.

Even if relevant genes are identified, it might not be economically possible to test all patients to screen out side effects that show up in as few as one in 100,000 people. Such economic factors are one reason that pharmacogenetics, the practice of tailoring drug therapy to patients using genetic tests, has been slow to catch on.