The Pharmacogenomics Horizon

Abstract

A new report, Realizing the Potential of Pharmacogenomics: Opportunities and Challenges, is one of the first comprehensive descriptions of the current state of this emerging science and the challenges that lie ahead—and has helped bring needed attention and publicity to the field, according to translational researchers interviewed here. The report, created by the Secretary of the Department of Health and Human Services’ (HHS) Advisory Committee on Genetics, Health, and Society (SACGHS), marks one of the first full-fledged attempts by U.S. government health agencies to lay out the promise of pharmacogenomics and provide direction on how to address the challenges of bringing this science into the healthcare marketplace. At the same time, some researchers believe the report does not go far enough in highlighting the difficulties that lie ahead—and the specific solutions that will be needed. “The report shows the huge potential of pharmacogenomics, the great need for more research, but also points out that we are on the edge of clinical applications for this science,” says David Flockhart, MD, PhD, chief of the division of clinical pharmacology at the Indiana University School of Medicine in Indianapolis. Dr. Flockhart has been involved in the development of new pharamcogenomic tests, and one focus of his research is how to best communicate the value of pharmacogenetic tests to physicians and pharmacists in clinical practice. At the same time, the report did not go far enough in addressing one of the biggest problems facing pharmacogenomics researchers: pharmaceutical companies are unwilling to fund the development of new tests because of few financial incentives, says MarkRatain, MD, Leon O. Jacobson professor of medicine at the University of Chicago Medical Center in Chicago, Illinois. He helped develop a test for a genetic variation that causes cancer patients to have low white blood-cell counts after taking irinotecan, even at standard doses. “The biggest barrier to widespread public use of pharmacogenomics tests is that they are not very profitable because it's difficult to protect the intellectual property of the tests,” he says. The report notes that pharmacogenomics has the potential to enhance understanding of how individuals metabolize and respond to drugs; improve the efficiency of clinical drug trials; increase the safety and efficacy of new, existing, and failed drugs; and enable more drugs to reach the market by targeting them to genetically defined population subgroups. Pharmacogenomics could also decrease the time it takes to identify the most beneficial drug and dosage for a patient, minimize exposure to ineffective treatments, and reduce adverse drug reactions. Quickly identifying slow and fast metabolizers and nonresponders to drug treatments could improve efficiency, and thus lower the costs of clinical trials. In fact, this could reduce the time needed to develop a drug from 10 to 12 years to as few as 3 to 5 years, according to the SACGHS. The committee acknowledged, however, that the uses of pharmacogenomics in clinical practice are still few and far between. While there is a lot of promising ongoing research, and information on early scientific discoveries about genetic variations in drug response is available, the clinical utility of these discoveries is still not widely understood. And that's a problem, leadingto lack of coverage by insurers and lack of knowledge on the part of healthcare providers, who could bring the tests into clinical practice. In fact, establishing an evidence base for pharmacogenomics tests was one of the goals mentioned in the report as crucial to widespread use and acceptance. To that end, the report recommended collaboration among basic, translational, clinical, and outcomes researchers, the dissemination of research findings through information clearinghouses, and the creation of genomic data standards, among other measures. “We’d like to get people involved from both basic and clinical research in moving products from the lab bench, through clinical trials and to the marketplace,” says Kevin FitzGerald, PhD, research associate professor in the department of oncology and David Lauler Chair in Catholic healthcare ethics at Georgetown University in Washington, D.C. Dr. FitzGerald helped coordinate the SACGHS report. “Establishing clinical utility of pharamcogenomic tests is crucial to that effort.” Dr. Fitz Gerald notes that the FDA has traditionally evaluated products based on their safety and efficacy, and it will be a challenging for the agency to use clinical utility as a standard for pharmacogenomic tests. “We need a whole new level of information to do these kinds of evaluations—and right now there's a paucity of that kind of information out there,” he says. However, Dr. FitzGerald notes a number of recent advances that will help disseminate and evaluate pharmacogenomic tests and discoveries in the future. Among them: The Center for Disease Control and Prevention (CDC) Evaluation of Genomic Application in Practice and Prevention: A pilot project initiated by the CDC National Office of Public Health Genomics to establish and evaluate an evidence-based process for assessing genetic tests. The National Institutes of Health (NIH) Pharmacogenetics Research Network: An organization of 12 independently funded research groups that conduct studies addressing questions in pharmacogenomics, and maintain a Web-based knowledge base on the field. The CDC's Human Genome Epidemiology Network (HuGENet): A collaboration of organizations aimed at exchanging information about the human genome and health, providing training for genomic researchers, developing an accessible knowledge base on the Web, and promoting this knowledge base among healthcare providers, researchers, industry and government. The question of how to provide incentives to industry to pursue pharmacogenomics is a difficult one. “Existing business models don't provide incentive for industry to develop pharmacogenomic tests,” says Dr. FitzGerald. “So the challenge is to come up with new business models. We need to have a discussion about what elements need to be present in such models, and how we can be creative in developing incentives for industry.” He continues, “We do need to be honest that it's possible that the promise of pharmacogenomics won't come to fruition because of such challenges. The effort to bring these products to clinical practice is not cheap, and it takes creative thinking. At the same time, we need to realize that the benefits are worth the trouble. Personalized medicine brings a real advantage to the public, and that is the right treatment for the right person at the right time.” Currently there is no simple way to determine whether people will respond well, badly, or not at all to a medication. If pharmacogenomics could provide a solution, it would be a giant step forward for healthcare—leading to a scenario in which genetic screenings in a doctor's office could routinely determine a patients response to a drug prior to prescription. “We really need to have a national dialogue about this problem, and this report is a good first step,” says Howard McLeod, PharmD, Fred Eshelman Distinguished Professor in the division of pharmacotherapy and experimental therapeutics at the University of North Carolina School of Pharmacy in Chapel Hill. “One of the problems currently is that we’re not very good in avoiding toxicities when we prescribe drugs. And unfortunately we’ve become comfortable with being lousy at prescribing drugs.” One of those steps involves increasing funding for peer-reviewed independent studies that will validate pharmacogenetic tests. “There's a real need for clinical trials that take a pharmacogenomic approach, but until now there hasn't been a lot of funding available for these sorts of trials,” says Dr. Flockhart. There also needs to be research into genetic response to existing drugs, he adds. Dr. Flockhart says he was pleased to find that the federal report recommended increased allocation of funding for pharmacogenomics research, as well as increased Food and Drug Administration (FDA) and NIH efforts to work with industry to identify patients who might benefit from pharmacogenomics. “Support for pharmacogenomics research is critical— and that's a highlight of the report's recommendations,” agreed Kathleeen Giacomini, PhD, professor of biopharmaceutical sciences at the University of California, San Francisco. Dr. Giacomini's research concerns the role that genetic variation in membrane transporters plays in clinical drug response. “The report also touched on other things that were important, including regulatory barriers and lack of coverage from healthcare providers,” she says. The SACGHS report notes that regulatory and payment requirements will need to be adapted to pharmacogenomic tests, a process that involves validating tests with clinical trials as well as clear guidance from the CDC, FDA, and NIH among others. However, Dr. Ratain notes that he would have liked the SACGHS to provide more specific solutions to the problem of how to fund pharmacogenomics research, making the development of tests profitable. The result would be easier entry of such products into the healthcare marketplace and clinical practice. “For each pharmacogenomic test, the current patent is a ‘use’ patent, and these are impossible to protect,” says Dr. Ratain. The test he helped develop— which looks for mutations in the gene UGT1A1 as a marker of serious reactions to irinotecan—has made $1 million so far, “not a lot of moneyin the pharamaceutical marketplace. The cost of the test, for instance, is about 10% of the cost of a single dose of the drug,” he says. The federal report delved into another potentially troubling area for pharmacogenomics—the problem of how to protect privacy and genetic information once pharmacogenomic testingbecomes more commonplace. Stronger data security measures will be needed as more pharmacogenomics researchers access patient data. The report called on HHS to develop guidelines on how to balance the protection of privacy and confidentiality of personal data with the need of researchers to access pharmacogenomocis data. “One of the big issues is confidentiality and informed consent. As pharamacogenomics develops, there will likely be huge databases of personal genetic information that healthcare and scientific professionals can access. And we need to provide individual protection to make sure confidentiality isn't breached,” Dr. FitzGerald says. The solution to this problem is not likely to be simple, and the measures needed to protect security of genetic information are likely to be multi-factorial, including legislative efforts, he adds. “We need to start addressing this in a very public way, and promote ethical public policies that will not only safeguard genetic information, but provide ways to protect people from losing insurance or experiencing stigmatization based on pharmacogenomic data,” he says. The report shows the huge potential of pharmacogenomics, the great need for more research, but also points out that we are on the edge of clinical applications for this Science.—David Flockhart, MD, PhD