Getting Personal about DrugsIn September 2007, an article by Steven Reinberg, "Drug Industry Seeks Tests to Spot Side Effect Risks," appeared in HealthDay introducing a newly formed non-profit organization called the International Serious Adverse Events Consortium (SAEC). The Consortium, which includes seven of the biggest Pharma giants, will study how DNA and genetic markers may account for the serious adverse reactions some patients experience to a prescribed medication.
The age of "personalized medicine" has arrived, but chances are your doctor doesn't know it yet. Existing tests can analyze patients' genetic makeup to provide guidance on whether certain drugs--such as codeine, antidepressants, and even some cancer medications--will help them, harm them, or do nothing. And a host of even newer "pharmacogenetic" tests are now in the pipeline.
But the existing tests aren't widely ordered by doctors, a fact that bothers David Flockhart, chief of clinical pharmacology at the Indiana University School of Medicine. Flockhart, who has developed genetic tests to help guide the prescription of diabetes and high-blood-pressure drugs, says doctors are generally uneducated about the availability of such tests. But he predicts that that will change if the U.S. Food and Drug Administration recommends that doctors test two specific genes in all patients prescribed a widely used anticoagulant.
- Technology Review: In November, an advisory subcommittee you sit on recommended genetic testing for patients being prescribed warfarin, a drug used to treat blood clotting and stroke. Why did you make this recommendation?
- David Flockhart: If the FDA accepts the commendation, this will mean that it suggests everyone prescribed this valuable medication receive a genetic test at the start of warfarin treatment in order to ensure less costly and medically simpler treatment courses in which patients have fewer bad bleeding episodes and reach a stable, effective dose more quickly. It will bring pharmacogenetics for the first time to thousands of
general practitioners and family practitioners.
- TR: But the FDA has already approved a number of genetic tests to guide prescriptions. Aren't doctors using them?
- DF: No. The big, big market is going to be in doctors' offices and hospitals, but it's really only now starting there. A major problem is going to be educating physicians who are, as yet, relatively uneducated about the availability of genetic tests to guide some of their prescribing decisions.
- TR: How long will that take?
- DF: Every one of the large clinical-testing labs is jockeying for position to try to exploit the large, anticipated growth in this kind of testing. The movement of these tests into the clinic will happen gradually with fits and starts.... Demand will kick in within a year or two, as patients realize the power of these tests. That will be the biggest driver.
The Associated Press' Linda A. Johnson also covered the announcement, "Drug Makers, FDA Partner on Drug Safety." According to Arthur Holden, the consortium's chief executive, the project could bring breakthroughs that change patient care in as little as five years. Holden envisions that an individual's standardized profile of key genetic variations could be checked before he is put on a new drug that has known, gene-related risks. Holden said, "employers and insurers now spend far more on hospitalization of patients harmed by serious adverse effects than what genetic tests would cost once they are common."
Seven major pharmaceutical companies are banding together to develop genetic tests that predict which patients will have adverse side effects from drugs.
The group, a nonprofit organization dubbed the International Serious Adverse Events Consortium (SAEC), will conduct two studies, one to look at drug-related liver toxicity and the other aimed at a rare drug-related skin condition called Stevens-Johnson syndrome.
"SAEC's focus is to identify and to validate DNA variance or genetic markers that are useful in predicting a drug-induced serious adverse event," Arthur Holden, the chairman of the group, said during a midmorning teleconference Thursday.
The findings of the consortium could have an impact on improving the ability of patients to safely use existing drugs, Holden added. "We hope it will improve the productivity and
effectiveness not only for those who develop drugs but for those who regulate drug development," he said.
"The immediate goal would be to develop a test that could identify who will have a problem with a drug before they get it," said Dr. Paul Watkins, director of the General Clinical Research Center at the University of North Carolina in Chapel Hill.
"The ultimate goal is to look at the genes that are causing the susceptibility and work back to figure out how we can design drugs differently so that no one would have that problem," he added.
"The two drug reactions that are being studied, Stevens-Johnson and liver toxicity, are very common reasons for problems with drugs either being restricted, not being developed, not being approved or being pulled off the market," said Dr. Janet Woodcock, Deputy Commissioner and Chief Medical Officer at the U.S. Food and Drug Administration.
"This effort is part of personalized medicine -- personalized safety -- that will make treatments safer by understanding individual benefits and risks," she added. "This will help in
the development of drugs both in avoiding these side effects in the future and maybe developing tests to help identify people at high risk," she said.
Findings from these studies could lead to the FDA requiring genetic tests to determine risk before the drug is prescribed, Woodcock added.
A recent survey found that most Americans are more concerned with drug safety than with speeding more medications to the
Members of the consortium include Abbott, GlaxoSmithKline, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Pfizer, Roche, Sanofi-Aventis and Wyeth. In addition, the FDA will consult on the design and conduct of SAEC studies.
The actual research will be done at academic centers in Europe and the United States.
The results of the studies will be made public domain, and none of the companies will have early access or be allowed to patent the findings. When the results are made public, any company can develop and sell the genetic tests that predict side effects.
SAEC is one of several consortiums formed by the pharmaceutical industry to conduct basic research. One of the first was started in 1999 and was headed by Holden. That consortium looked for DNA variations among people. Their data were also put into the public domain.
The SAEC is also discussed on Pharmalot, "Pharma and Academia Form Consortium to Study Side Effects and Genetics," and the Wall Street Journal Health Blog, "Drug Makers Gang Up on Side Effects."
Drug Makers, FDA Start Global Partnership to Make Drugs Safer
A rare collaboration of top pharmaceutical companies, regulators and university researchers has begun attacking one of the toughest problems in medicine: why severe drug side effects strike a small percentage of patients.
Pharmaceutical companies have a lot at stake. Serious adverse reactions during testing generally doom experimental drugs, and ones that surface after a drug is on sale often lead to it being pulled from the market or having its use restricted.
"If you can prevent these types of reactions, it's going to have a significant impact on health care," because adverse drug effects cause considerable illness and death, said Raju Kucherlapati, scientific director of the Harvard Medical School-Partners Healthcare Center for Genetics and Genomics, who is not
involved in the project.
Holden envisions people getting standardized profiles of key genetic variations, which then could be checked before they are put on a new drug that has known, gene-related risks. He said employers and insurers now spend far more on hospitalization of patients harmed by serious adverse effects than what genetic tests would cost once they are common.
Dr. Franklyn Prendergast, director of the Mayo Clinic's Center for Individualized Medicine, said that given the clear evidence that genetic variations put some patients at high risk of bad drug effects, he is sure the project will have a big impact. He added that making its findings available to scientists worldwide will help "profoundly" in related research.
Holden said the participating drug companies together have put up millions of dollars to fund the work. Other partners include Columbia University, which will coordinate and analyze data, plus the European Agency for the Evaluation of Medicinal Products and two academic consortia in Europe, called Diligen and Eudragene.
Fortunately, big pharma is not the only source of research for genetic testing to benefit patients' health and lives. In October, the Howard Hughes Medical Institute (HHMI) announced the addition of 15 physician-scientists to their team of investigators nationwide. (See "Improving Patient Care through Science: The Howard Hughes Medical Institute adds 15 Patient-Oriented Researchers")
“These 15 physician-scientists are changing the way we think about and treat a variety of diseases,” said HHMI President Thomas R. Cech. “The impact of their research is already being felt by people suffering from malaria in Africa, by those with post-traumatic stress disorder in the United States, and by people worldwide with leukemia or lung cancer. As a group, they have demonstrated extraordinary creativity and innovation.”
One of the newly appointed HHMI investigators is Vivian Cheung, M.D., Associate Professor of Pediatrics and Genetics at the University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia. Ultimately, Cheung would like to see genetic tests become an essential component of medical care.
“My dream is that eventually everyone will have a genetic test done, so we'll know how best to treat that person.”
So what does this mean for patients, insurers, and employers?
Dr. Cheung...is often frustrated about how little knowledge in basic research has been translated into patient care. She is especially interested in a disorder called ataxia telangiectasia, a genetic disease that first appears in young children. It presents particular challenges to doctors because children with the disease—characterized by neurological problems, immunodeficiency, and cancer—can react very differently to treatment. “Many patients suffer side effects from the therapy we give them,” she says. “How do we make sure we do more good than harm?”
Cheung wants to create a genetic tool that will give physicians
the information they need to make better decisions. Such a test, built from genetic data from her own studies, would predict a patient's response to the most commonly prescribed therapeutics to “guide physicians and patients in selecting therapeutic options and designing preventive care,” she says.
“When you walk into a doctor's office, you want the doctor to look at all your relevant risk factors, not just whether you
smoke and other matters of lifestyle, but also risk factors that differ by gender, by family medical history, even by ethnic group,” says Cheung. “We're starting to see genetics play a role
in that process, but it's not a major focus of most medical practice.”
Cheung wants to change that. Genetics should be a “foundation of predictive and preventive medicine,” she says, not just a “medical subspecialty.”
Cheung studies the effects of genotype—the sequence of DNA letters on a person's chromosomes—on phenotype—a person's observable traits. But the phenotypes she studies are unusual. She uses DNA microarray technology to measure the expression levels of genes in a cell. “Gene expression is a very convenient phenotype, because we can take a large number of measurements quickly using microarrays,” she says. “And
understanding gene expression has a direct impact on disease, since disease is almost always associated with an aberration of gene expression.”
Cheung and her colleague Richard Spielman at the University of Pennsylvania have done a large study linking differences in DNA sequences to differences in gene expression. Using extensive genetic data collected from families and from the International HapMap Project, which has catalogued genetic differences among people from Asia, Africa, and Europe, they identified thousands of places in the genome that affect gene expression. Many of these regulatory regions are quite distant from the genes they help control.
Now Cheung's group is working to apply this knowledge directly to medical practice. They are studying how gene expression changes in response to various therapeutic agents, such as drugs and radiation, in cells from different individuals. They then connect the differences in responses that they observe to sequence variations in the regulatory regions.
The result will be a map of regulatory regions that can be used to predict how a person will react to a given drug or treatment.
Cheung wants to use information from this kind of basic science research to guide diagnosis and treatment of diseases so that a doctor will no longer have to start a patient on one drug and wait for a reaction to decide whether to continue the drug or try something else.
Ultimately, Cheung would like to see genetic tests become an essential component of medical care. “My dream is that eventually everyone will have a genetic test done, so we'll know how best to treat that person.”
Once everybody has had their standard genetic tests done, which will certainly be included in our universally-accessible electronic medical records as part of improved health IT, how will those results be used?
Will insurers find a way to charge higher premiums based on your genetic make-up? Will the elimination of severe adverse drug reactions create a system of severe adverse selection problems in acquiring insurance?
Will employers discriminate, ...I mean manage risk..., based on the potential cost of your future healthcare needs?
Will patients make choices based on the implications of their genetic code?
Will "individualized medicine" negate the efforts of agencies in establishing standard protocols and strict requirements for "evidence-based" care? Will managed care dictate availability of care or treatment based on DNA?
More importantly....Will medicine become safer for the patient?
Inquiring minds want to know...