Which medicine to take may depend on genes

Mapping the human genome may help lead to more testing and precise targeting, and that raises a host of ethical and economic questions.

©Washington Post

© St. Petersburg Times, published June 27, 2000

WASHINGTON -- Unlike most doctors, Georgetown University physician and pharmacologist David Flockhart enjoys talking about his patients who didn't get better from the medicines he prescribed, or who got even worse because of side effects.

There was the woman who suffered excruciating pain after surgery no matter how much codeine he prescribed.

The patient whose tendons became so inflamed from taking a common antibiotic years ago that she remains debilitated to this day.

The woman who took Prozac only to find her blood pressure going through the roof.

Flockhart likes these stories because they highlight the potential of "pharmacogenomics," a new field of medicine he and others are pioneering that promises to reduce treatment failures by matching medicines to patients' genetic codes.

Among the many vaunted medical benefits promised by the Human Genome Project -- the $2-billion effort to spell out the entire human genetic blueprint, whose virtual completion was announced Monday -- none is as close to broad clinical use as pharmacogenomics.

The new science seeks to solve a simple but long-standing problem: Medicines are made and sold on a "one size fits all" basis, even though people vary substantially in how they respond to them. As a result of this variability, more than 100,000 Americans die every year from side effects of properly prescribed medicines and 2-million more are made seriously ill.

Now, with scientists identifying more and more genes that control individual responses to drugs, some leading-edge medical centers are starting to make prescribing decisions on the basis of patients' genetic makeup. Five years from now, some experts predict, it will be common for patients to take genetic tests before their doctors decide which drug, or what dose, to prescribe for them. That's far sooner than anyone expects to see similar success rates in the more widely touted but failure-plagued field of gene therapy, which aims to treat people by giving them new genes.

Drug companies, as well as patients, stand to gain from the pharmacogenomic revolution. By testing new and experimental drugs only in volunteers whose genes preordain a positive response, companies can generate data that will prove irresistible to the Food and Drug Administration, streamlining today's long and costly drug approval process. Some companies also hope to profit from sales of the genetic tests that will be used to match patients with appropriate drugs.

But like so many advances in genetics, pharmacogenomics raises difficult questions, too. As the first attempt to meld the contentious field of genetic testing with the everyday practice of medicine, it will serve as a test case of how society will deal with issues of genetic privacy and discrimination.

Many people are already nervous about their genetic profiles falling into the wrong hands.

While 61 percent of those polled want to know if their genes predispose them to illnesses, 75 percent don't want their health insurers to know and 84 percent don't want the government to know, according to a new Time/CNN poll.

But so far few people have had a reason to take genetic tests. How will people react when such a test is required just to get a proper prescription?

Of equal concern, some of the gene patterns relevant to pharmacogenomics are ethnically linked, raising issues of racial stereotyping and access to care. One fear is that profit-conscious pharmaceutical companies will use pharmacogenomics to aim their drug development efforts toward genetic subgroups of people who can best afford them, further marginalizing already underserved minorities.

"What happens when the patient comes in and says, "I hear there's a great new drug for asthma,' and the doctor says . . . "Yeah, but it's only for whites'?" asked Mark Rothstein of the University of Houston's Health Law & Policy Institute.

Pharmacogenomics alters medicine's legal landscape, too. At what point should doctors and drugmakers be liable for not taking genetic information into account? Already a group of patients has sued the maker of a Lyme disease vaccine, claiming that people with a particular genetic signature should not have been given the vaccine because they are especially prone to getting serious side effects from the shot.

All told, experts said, pharmacogenomics presents a challenge to society for precisely the same reason it offers so much promise: because it focuses on people's differences.

"We believe strongly that this is a new era and the dawning of a golden age of personalized medicine," said Elliott Sigal, a senior vice president at Bristol-Myers Squibb, one of several pharmaceutical companies that have launched pharmacogenomics programs. "It does raise important issues for society in terms of privacy, discrimination and insurance issues."

The driving force behind the emergence of pharmacogenomics is a little-known follow-up project to the widely hailed Human Genome Project. Unlike the genome project, which sought to spell out a generic "consensus" version of the human genetic sequence, the follow-up project seeks to define the subtle differences in that code from person to person.

The goal is to identify hundreds of thousands of "single nucleotide polymorphisms," or SNPs (pronounced "snips"), which are the tiny spelling variations that occur about once in every 500 to 1,000 letters within the 3-billion-letter human genetic code.

The recent shift by federally funded and privately financed gene researchers away from the genome project and over to the search for SNPs represents more than a scientific change of course. It brings with it a philosophical change of perspective that will focus not on people's similarities but on their differences.

That shift is necessary if personalized gene-based medicine is to take off. But it also brings new possibilities for genetic bias and discrimination.

Not all of the genetic variations that affect how a person will respond to various drugs track along racial or ethnic lines. But many relevant genes do correlate with race. While only 7 percent of Caucasians have the 2D6 variant that caused problems for some of Flockhart's patients, for example, more than one in four Asians carries a similar variant.

Those realities present economic and ethical quandaries.

On the economic side, pharmaceutical companies could save millions of dollars by preselecting participants in a clinical trial so that virtually everyone benefited and no one got side effects.

It would also reverse the current federal regulatory push to include more diverse groupings of people in clinical trials -- a push that arose a few years ago in response to concerns that minorities were being left out of the drug approval process. Under the new rubric of pharmacogenomics, though, expert reviewers might deem it unethical to test a new drug on people whose genes suggest they won't respond well to the drug, since those participants' sole purpose would be to demonstrate side effects.

At the same time, any drug that gained approval through such a process would have proven its mettle only in people with a narrow genetic or racial grouping, and would probably be approved by the FDA only for use in those people.

"That could be a problem," said Larry Palmer, a professor at the Cornell University Law School who is studying the legal implications of pharmacogenomics. "You know the drug companies are going to market it as best they can. And the average practitioner may use it without the deep understanding of the science needed to use it appropriately on the right individuals."

Moreover, given the chance to focus their efforts this way, would companies bother developing drugs for people with rare genes? It's too soon to say, but there is evidence that some might not.

About five years ago, for example, pharmaceutical giant Merck & Co. was supporting a small Seattle company called Ostex International to develop a test that could identify women at high risk of osteoporosis. The hope, said Gilbert S. Omenn, executive vice president for medical affairs at the University of Michigan, was to use the test as a marketing tool for Merck's new bone-building drug, Fosamax, which Merck hoped to sell widely to post-menopausal women.

But when early studies with the test indicated that only half of all postmenopausal women might actually need the drug, Omenn said, Merck pulled out of the partnership and left the little company in a state of near financial ruin, from which it is now recovering.

A Merck spokeswoman said the company's withdrawal from Ostex was not related to marketing concerns but came out of a decision to focus solely on the treatment of osteoporosis, not on methods for diagnosing it.

Others said that even if the big drug companies do end up focusing only on the most common genetic subpopulations, there are plenty of small biotechnology companies that would be happy to find niches that cover even 5 percent of the population.

Another hurdle that pharmacogenomics must clear is public wariness of genetic tests.

Proponents say gene tests that predict a person's response to a medicine should not be as controversial as other kinds of gene tests that predict, for example, a person's long-term odds of getting a fatal disease.

"It's not the same as telling someone that they're going to get Alzheimer's disease someday, which freaks people out," said Kathleen Giacomini, the University of California at San Francisco researcher. "This is a more people-friendly kind of genetic test."

-- Information from Knight Ridder Newspapers was used in this report.

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