Medical revolutions can be so unpredictable. Consider, for instance, the potential benefits of a simple, painless procedure–perhaps nothing more than a swab of your inner cheek.
The sample is sent off to a lab for analysis. The resulting map of your genetic makeup can be used by your doctor to identify what pharmaceutical drugs are likely to work best for you, which ones probably won’t have any effect, and even those that might kill you. The trial and error of prescribing medications would be eliminated.
In a nutshell, that scenario describes pharmacogenomics, the application of genetic science and technology to pharmaceutical therapy. Pharmacogenomics is a byproduct of the successful efforts by scientists to map out the human genome, the genetic formula that holds the key to our biological blueprint. That knowledge, combined with the development of new technology allowing the rapid fire testing of a person’s DNA, promises a golden age of personalized medicine in which treatments will be tailored to work best for particular individuals. Or maybe not.
No one knows for sure whether the practical application of the science will fulfill the highest hopes of its advocates. “So many promising things haven’t panned out, such as gene therapy, that you get a little guarded in your optimism,” says Mark A. Rothstein, director of the Institute for Bioethics, Health Policy and Law at the University of Louisville in Kentucky. He is the editor of Pharmacogenomics: Social, Ethical and Clinical Dimensions, published in 2003.
But there is wide agreement that the legal system will play a key role in deciding the future of pharmacogenomics. The question is whether the law will be a help or a hindrance to the use of pharmacogenomics as an integral tool of modern medicine. Right now, experts say it could go either way–or even both ways.
Uncertainty about how pharmacogenomics will affect the financial health of the pharmaceutical industry is compounded by concerns that applying these new scientific capabilities could lead to unwelcome litigation and regulation. These worries are causing manufacturers to hold back on research, or to hoard data and diagnostic tests they’ve already produced.
“There’s a lot of pharmacogenomic research going on, but it’s never going to see the light of day,” says Howard L. McLeod, director of the Institute for Pharmacogenomics and Individualized Therapy at the University of North Carolina in Chapel Hill.
Ultimately, though, law may provide the necessary impetus for the medical industry to incorporate pharmacogenomics into its treatment arsenal. The possibility that drug companies and medical care providers would face lawsuits and regulatory sanctions if they don’t employ pharmacogenomics might spur them to overcome the caution that often stifles the widespread use of new approaches to medical treatment.
“The rate at which innovation gets translated into practice in medicine is very, very slow,” says Larry I. Palmer, a colleague of Rothstein’s at the Kentucky institute. “Doctors tend to do what they have done, and it is probable that it will be the liability system that gives them the incentive to absorb new knowledge into their practice and change their behavior.”
McLeod shares that view. “I’m the last person to encourage a bunch of lawsuits,” he says. “But when it comes to pharmacogenomics, there’s some carrot but there’s not enough stick. We’re poised to do big things, but the impetus to apply the new techniques broadly is missing.”
The Equation Changes
It has long been common medical knowledge that drugs don’t interact with all people the same way. Some medical authorities estimate that drugs typically are effective for barely more than half of the people who take them, and in the case of cancer drugs, that number drops to only about 25 percent. At times, prescribed drugs are downright dangerous for the people who take them; the Washington, D.C. based Institute of Medicine estimates that adverse drug reactions hospitalize some 2 million Americans a year and kill as many as 100,000.
Pharmacogenomics has the potential to avert much of this carnage by identifying in advance which individuals or groups of people are likely to be harmed, or at least not helped, by a particular drug. Side effects that were once seen as an inevitable risk of prescribed drugs, to be weighed against the benefits derived from the treatment, could be identified in many cases on the basis of minor differences in an individual’s genetic code. These capabilities, although not yet widely used, are more than just speculative. For instance, testing can identify a minor genetic variation that predicts a toxic response to 6-mercaptopurine, a drug used to treat a form of childhood leukemia. Patients with this genetic variation can develop a life threatening anemia from the drug.
Among other recent research initiatives, the National Cancer Institute, part of the National Institutes of Health in Bethesda, Md., recently launched a trial to examine whether genetic testing can identify the most effective treatments for women with early-stage breast cancer.
“This trial is important because it is one of the first to examine a methodology for personalizing cancer treatment,” said Dr. Elias A. Zerhouni, NIH director, when the launch was announced on May 23.
Individual genetic differences also can be used to predict whether an individual metabolizes a certain drug too quickly–meaning that larger doses are needed to be effective–or too slowly, in which case standard doses can result in toxic levels of the drug building up in the body. That information allows doctors to adjust doses, or switch to another medicine, before those problems occur.
Pharmacogenomics does offer some carrots to drug manufacturers. For instance, using genetic testing in clinical trials may help identify drugs that would be problematic for large groups of people before the process progresses very far and at great expense. “Their mantra is, ‘Fail early,’ ” says Edward Abrahams, executive director of the Personalized Medicine Coalition, a Washington, D.C. based group that advocates for policies promoting personalized medicine.
Pharmacogenomics also may allow some drugs to be salvaged from the pharmaceutical scrap heap. GlaxoSmithKline, for instance, is reaching the final stage of clinical trials for Tykerb, a new drug for treating breast cancer, notes Gary E. Marchant, a law professor at Arizona State University in Tempe who serves as director of the school’s Center for the Study of Law, Science and Technology. The company, based in Research Triangle Park, N.C., used genetic testing to screen out some participants who showed adverse reactions to the drug, he says.
“In the past they would have just had to cancel the whole project,” Marchant says, “but now they can move forward and just limit the market to a particular genotype.”
While pharmacogenomics can be a savior for drugs that are effective but cause problems for some users, it could also herald the end of the era of blockbuster drugs–lucrative one-size fits all drugs that can be widely mar keted. If genetic testing for drugs becomes standard operating procedure, drug companies may be forced to market their products more narrowly to population groups that are genetically suited to benefit from them. That means drugs are likely to become more expensive, as the costs of research and development–which already can be hundreds of millions of dollars for a single drug–are allocated for drugs that can be marketed to smaller numbers of people rather than the general population.
A lucrative pharmaceutical side business might be curtailed, as well. At least one recent study indicates that about one in five prescriptions filled in the United States is “off-label”–for a use for which it has not been approved by the U.S. Food and Drug Administration and for which extensive testing may not have been conducted. One major asthma medication, for instance, often is prescribed to treat chronic obstructive pulmonary disease, and some antidepressants are used to treat migraines and other disorders.
Off label prescriptions are legal–an FDA approved drug can be prescribed for any condition. But safety concerns about the practice would be compounded for any drugs that have been found through genetic testing to work best for specific population segments. Not only might doctors become more hesitant about issuing off label prescriptions, but a manufacturer that promotes off label uses for a drug, either explicitly or implicitly, could raise liability issues for itself. (Rothstein discusses these issues in some detail in “Liability Issues in Pharmacogenomics,” an article published in the December 2005 issue of the Louisiana Law Review.)
In light of an uncertain market outlook, pharmaceutical companies have taken a cautious approach to pharmacogenomics. The FDA, which supports the development of pharmacogenomics and other forms of personalized medicine, also is treading carefully. Under current policy, the FDA requires that companies report genetic information gathered in clinical tests under certain circumstances, but refers only to “well-established” genetic factors in its regulatory decisions.
In addition, the FDA has set up a voluntary genetics database, where companies can deposit the data gained from clinical trials with the promise that the data will not be used in regulatory decisions, according to Felix W. Frueh, associate director of genomics in the FDA’s office of clinical pharmacology and biopharmaceutics.
The FDA also has encouraged drug companies to develop genetic tests that doctors can use to screen patients before prescribing pharmacogenomic drugs. But producing such tests is not a regulatory requirement, and there is little business incentive for developing them.
Expense, Liability Concerns
Doctors may be reluctant to use genetic screening tests for drugs even when they are available. When the FDA wanted to require a genetic test before administering 6-mercaptopurine to treat childhood leukemia, for instance, physicians’ groups balked. They said genetic testing would be too expensive and that doctors could identify slow metabolizers by monitoring their blood levels and then adjust dosages accordingly. In the end, the FDA decided to include genetic testing information in drug package inserts but did not require testing.
Reluctance about pharmacogenomics could end up haunting the medical profession. It is doctors who are most likely to face possible liability when a failure to test for a genetic variation results in harm to a patient, says the University of Louisville’s Palmer. The reason, he says, is that doctors aren’t insulated from potential liability in lawsuits to the same extent as drug manufacturers.
Palmer cites a groundbreaking decision by the California Supreme Court in Brown v. Superior Court, 751 P.2d 470 (1988). The case involved the drug commonly known as DES, which caused an increased risk of cancer and reproductive disorders in the daughters of women who were given the drug during pregnancy to prevent miscarriages. The ruling applied to numerous plaintiffs who named more than 170 drug companies as defendants on grounds that the companies manufactured DES from the same formula, but failed to warn users or their doctors of the drug’s dangerous characteristics.
Affirming a state appellate court decision, the California Supreme Court ruled that the drug manufacturers could be held liable only if they had been negligent, either by failing to properly manufacture the drug, or by failing to warn doctors prescribing the drug about dangers that the companies knew or should have known at the time the drug was distributed. But in a ruling that has been widely (although not universally) followed in other jurisdictions, the court rejected strict liability for the companies on the basis of design defects.
“If drug manufacturers were subject to strict liability,” the court’s opinion states, “they might be reluctant to undertake research programs to develop some pharmaceuticals that would prove beneficial or to distribute others that are available to be marketed, because of the fear of large adverse monetary judgments. Further, the additional expense of insuring against such liability–assuming insurance would be available–and of research programs to reveal possible dangers not detectable by available scientific methods could place the cost of medication beyond the reach of those who need it most.”
“The long standing doctrine,” says Marchant, “has been that pharmaceutical drugs are ‘unavoidably unsafe products’useful products that have unavoidable side effects, but we still want to encourage their manufacture and protect them against strict liability.” Earlier this year, Marchant says, the American Law Institute amended the Restatement (Third) of Torts to extend the protection even further by stating that drug manufacturers should be immune from claims alleging that the harm caused by a product was inherent in the design of the product itself and not simply due to errors in its manufacture, as long as there is a single group of people for whom the drug is safe.
Marchant points out that drug companies still may be liable on negligence grounds if plaintiffs can show that they knew of or should have known of a risk from a drug, but failed to warn physicians of it. That is, for instance, the basis of litigation against Merck & Co. involving Vioxx, an arthritis painkiller linked to an increased risk of heart attacks. (Merck has withdrawn Vioxx from the market.)
The duty to warn applies even to existing drugs, so as new information about genetic links to adverse drug reactions emerges, manufacturers may need to issue warnings or face additional exposure to liability, says Miles J. Zaremski, a lawyer in Lincolnwood, Ill., who co chairs the Medicine and Law Committee in the ABA’s Tort Trial and Insurance Practice Section. In such cases, liability would hinge on “what is reasonable to know and when was it reasonable to know it,” he says.
But under the “learned intermediary doctrine,” the manufacturer’s duty to warn runs primarily to physicians rather than patients, according to Palmer. Court rulings in Brown and similar cases express an “implicit assumption that prescription drugs are different from most products because a physician will weigh the risks and benefits of prescribing the drug to a particular patient,” writes Palmer in an article published in Rothstein’s Pharmacogenomics.
Duty To Warn
Some courts have also held that the “learned intermediary doctrine” does not apply when the drug is a vaccine, sold over the counter or, perhaps most significant, marketed directly to consumers, including through advertising.
In 1999, for instance, the New Jersey Supreme Court ruled that when a drug manufacturer advertises directly to consumers, it has a duty to warn them directly of risks it knows about or should know about. Perez v. Wyeth Laboratories Inc., 734 A.2d 1245. Similar issues were raised in a 1999 class action suit filed in Pennsylvania against the manufacturer of a Lyme disease vaccine called Lymerix. The manufacturer, SmithKline Beecham Corp., merged with Glaxo Wellcome in 2000, becoming GlaxoSmithKline. Most of the plaintiffs had been given the vaccine without being told they carried a gene type that increased their risk of developing a form of arthritis from the drug. The lead plaintiff in the case had seen an advertisement for the vaccine and asked her physician for it.
The case was settled in 2003, with the company agreeing to withdraw the vaccine and pay the plaintiffs more than $1 million in legal fees and costs. Cassidy v. SmithKline Beecham Corp., No. 99-10423 (Pa. Ct. of Common Pleas).
Despite these exceptions, manufacturers are unlikely to be the primary target for pharmacogenomics related litigation. And, Marchant says, insurance companies that decide whether to provide coverage for innovative care like targeted drugs or genetic tests also are generally protected from liability claims by state and federal laws, such as the Employee Retirement Security Act, which bars employees from suing employer-provided health care plans.
That leaves doctors, who have the primary responsibility for evaluating the risks and benefits of drugs they prescribe, and communicating that information to patients. “When litigation comes along, it will be the doctors who are first in line,” Marchant says. “They don’t have the same types of protections, and so many have such poor understanding and training in genetics, they’re just sitting ducks.”
Standard Of Care
One key issue that needs to be sorted out in lawsuits arising out of pharmacogenomics is what standard of care will be applied to physicians.
Palmer notes that the standard of care applied by courts to determine whether liability exists tends to evolve in the wake of new medical technology. Generally, courts have been moving away from applying local standards of care since the 1950s in favor of national norms, he says. It’s not a trend likely to help doctors in cases arising out of pharmacogenomics.
Right now, the standard of care relating to pharmacogenomics is in flux, but as genetic medicine advances, the standard of care is likely to follow it, Marchant says. He foresees “a quick splitting apart in terms of quality of care as the more sophisticated research centers and hospitals are doing it while the average practitioners and local hospitals are not.”
That “average” practitioner may not have the expertise to interpret the limited genetic information available on drug labels or in the Physician’s Desk Reference, but likely will be expected to translate this information into clinical practice, adequately inform patients of the risks and benefits of treatment, and, in the event that genetic testing is obtained, counsel them about the results.
“Our ability to generate genetic information is outpacing our ability to distill it in a clinically useful manner,” says Dr. Issam Zineh, a pharmacogenomic researcher at the University of Florida’s College of Pharmacy in Gainesville.
“Some practitioners tell me they hope they retire before pharmacogenomics hits,” Marchant says.
They’re probably too late.
McLeod of the Institute for Pharmacogenomics and Individualized Therapy says there are issues in pharmacogenomics right now that may be ripe for litigation. He points to the widespread failure to conduct genetic testing before prescribing from a family of medications that includes 6-mercaptopurine for childhood leukemia and drugs used to treat autoimmune and inflammatory disease. About 6 percent of people have genotypes that can cause severe side effects from these drugs, he says.
“People have died from that,” McLeod says. “But even though there’s a test available and the FDA has included the genetic information in the insert, a lot of people are not testing before prescribing the drug. They just don’t feel that it’s a big enough issue.”
McLeod adds, “It’s a sad commentary that all we need is one high profile lawsuit where a commonly used drug and the available genetic tests were not used and something bad happened. It would be rather easy to litigate, and it would change practice faster than anything else.”
Palmer isn’t so sure that pharmacogenomics cases will be all that easy to handle, at least at first. The most likely scenario, he says, would be “some egregious case that will come to the right law firm in some city that’s used to handling a big, complex case. I think it’s going to take a highly specialized law firm that’s going to be able to take that information and leverage it.”
Yet another view is held by Michael J. Malinowski, associate director of the Program in Law, Science and Public Health at the Louisiana State University Law Center in Baton Rouge.
“It may be that litigation will drive the adoption of pharmacogenomics,” Malinowski says. “But I don’t think that’s a helpful way to do it. I believe it’s the regulatory way that will get us there.”
Malinowski says litigation may be too “clumsy” an instrument to bring about the kind of carefully constructed legal and policy changes that will be needed to help fulfill the promise of pharmacogenomics. Case law is unlikely to be able to keep up with scientific advances, he says, while most judges would be unlikely to impose decisions directing how medical practice should be conducted. And, he adds, the dearth of effective genetic tests makes it hard to bring actions against doctors who haven’t yet adapted to pharmacogenomics.
“How can you sue a doctor for not testing,” Malinowski asks, “when there’s not a test available?”
An approach that uses regulation in combination with legislation to encourage the development of pharmacogenomics also faces challenges, say experts. Regulators and policymakers would have to create a structure that imposes some guidelinessome might read those as controlsfor the development of pharmacogenomics without scaring off potential investors, researchers and manufacturers.
As a start, Malinowski says, the thicket of state laws passed in the 1990s, when the implications of genomics first became apparent, needs to be cleaned up. Much of that legislation is intended to protect patient privacy, and to assure that commercial genetic tests are valid and useful. But in effect, the laws created obstacles for companies seeking to market even the most innocuous and beneficial genetic tests. “Some well crafted federal legislation to pre empt the state laws would be very helpful,” suggests Malinowski.
Some advocates of pharmacogenomics say they would welcome regulatory incentives encouraging growth in the field. Abrahams of the Personalized Medicine Coalition, for instance, says Medicaid and Medicare reimbursement payments should be higher for drugs when companies also produce diagnostic tests to go with them.
This would encourage manufacturers to put more emphasis on tests for genetic compatibility with various drugs, Abrahams says, especially since private insurance markets tend to follow the lead of the Centers for Medicare and Medicaid Serviceswhich administers the programson the issue of reimbursements.
Regulation also may help assure that market forces alone don’t dictate who gets the lion’s share of pharmacogenomic drugs.
Suppose, Rothstein says, a drug company is deciding what to do about producing a drug that may be suitable in variations for 10 different genotype groups of people. “If I’m a savvy CEO,” says Rothstein, “the first thing I’m going to ask is, ‘Tell me what the market is for each of these 10 potential drug targets.’ ” The manufacturer’s choice might well favor groups with more common genotypes or those with other types of favorable market demographics.
To offset these tendencies, Rothstein has proposed “orphan genome” legislation, similar to the Orphan Drug Act, which Congress passed in 1983 to stimulate development of drugs to treat rare diseases. The legislation would offer subsidies and incentives for companies that develop drugs for people with less marketable genotypes.
Pharmacogenomics also is raising some difficult patent issues. In 1980, the U.S. Supreme Court ruled that a man made organisma bacterium designed to break down crude oilcould be patented. Diamond v. Chakrabarty, 447 U.S. 303. Then in 2001, the Patent and Trademark Office issued guidelines for patents on naturally occurring genes:
Researchers who discover a gene, its code, its variants or its biological action may seek to patent that information, and perhaps more important, demand a licensing fee every time the gene or information about it is used by others.
The American College of Medical Genetics in Bethesda, Md., and other groups oppose such patents. Moreover, they maintain that licensing fees, and particularly exclusive licensing agreements, could drive up costs and limit accessibility to genetic tests needed for research and clinical treatment.
But Allen C. Nunnally, a lawyer at Wilmer Cutler Pickering Hale and Dorr in Boston, says patents are an important incentive for the biotech markets that underwrite pharmacogenomic research. He suggests that a balanced policy in this area might include elements such as compulsory licensing in cases where a patentholder’s refusal to license affects the interests of specific groups of patients or the general public.
Fulfilling the promise of pharmacogenomics will require more efficient mechanisms for translating the gains of medical research into practical treatments for patients, say Malinowski and other experts. Reaching that goal is likely to take action by the federal government, they say.
“We are kind of sneaking up on this in a most unusual way,” Rothstein says. In 2004, President Bush called for establishment of a national health information database that would create an electronic medical record for every patient. That record would be widely accessible to medical care providers, Rothstein says. “If you are a physician and you make a diagnosis that a particular patient has diabetes, there will be with the electronic health record an automatic update on the latest literature and the latest thinking about what [treatment] methods are appropriate,” he says. “It will also be possible to electronically go through the individual’s medical history and identify other kinds of factors that might go into the decision.”
Electronic data records raise numerous legal issues, such as protecting personal information from employers and insurance companies. But a major benefit is that the standard of care can be brought into line much more quickly with the latest scientific advances and technologies, including pharmacogenomics, Rothstein says. Physicians also would have an authoritative source to back up their medical judgments, establishing clear standards of care and protecting them from liability.
Experts in the field say lawyers need to stay on top of new developments if they are to help their clients navigate a changing health care landscape.
“That’s an important function for lawyers to be doing right now,” Marchant says, “being proactive and helping to get their clients prepared.”
Kristin Choo is a freelance writer in New York City.
Kristin Choo is a freelance writer in New York City.