Are We in a Brave New World of “Personalized” Medicine?
BiDil, a new drug labeled for treatment of blacks with severe heart failure, has begun to arrive in pharmacies. Approved by FDA in June, it has stimulated speculation that we're entering a brave new world of "personalized" medicine in which genetic tests or other "biomarkers" will be used to predict positive—or sometimes negative—responses to various therapies.But diagnostic tests and therapeutic interventions targeted to certain ethnic, racial, or other groups are nothing new. In order to screen for a number of genetic diseases that occur predominantly in Jews of Ashkenazi, or Eastern European, extraction, there is a group of genetic tests called the Ashkenazi Jewish Genetic Panel (AJGP). Sickle-cell anemia occurs exclusively in blacks, and a hereditary enzyme deficiency that causes sensitivity to fava beans and certain drugs is found primarily in Africans and persons of "Mediterranean" descent; after exposure to quinine-like drugs as many as 10 percent of black men develop a serious condition in which red blood cells lyse, resulting in severe anemia. There are also genetically determined differences in sensitivity to the commonly used anticoagulant warfarin (Coumadin) that are due to variations in the molecular structure of the receptor for the drug. More generally, drug efficacy is known to be affected by variants of genes coding for the enzymes that metabolize chemical compounds; one genetic locus, for example, is responsible for the enzymes that degrade as many as 20 percent of commonly prescribed drugs; in the population, there exist a large number of variants of this gene, some of which only poorly metabolize the enzymes' substrates.In addition to the genetics of patients, genetic anomalies in malignant tumors can sometimes be used to predict the effectiveness of therapies. For example, the amplification of a gene called HER2 that is seen in approximately 25 percent of breast cancers leads to overexpression of HER2 protein, which results in increased cell division and more rapid cell growth -- and a worse prognosis. However, it also correlates with responsiveness to a drug called Herceptin, which has been dubbed the first "pharmacogenetically developed drug."There is another group for whom a kind of personalized medicine is badly needed. Although not due to genetic differences, some of the most important variation seen in response to drugs is due to aging; for several reasons, older patients are far more likely to experience adverse drug reactions. For one thing, clearance by the kidneys and liver—the two most important routes for the elimination of drugs—is reduced; as people age, these organs get less blood flow, and there is diminished activity of the hepatic enzymes that metabolize drugs.Another interesting age-related anomaly concerns the decrease in total body water and the relative increase in body fat seen in older people. These changes cause water-soluble drugs to become more concentrated in the blood, and fat-soluble drugs to have longer half-lives. Moreover, serum protein levels decrease in the elderly (especially if they're sick), which reduces the protein binding capacity of the blood, and leaves more free—that is, active—drug circulating. (And yet, surprisingly few physicians routinely reduce drug dosages in older patients.)Whether or not BiDil is a harbinger of additional personalized therapies, there remains the unsettled question of how widely useful the drug will be. Its approval by the U.S. FDA was based largely on the results of a single clinical trial that involved 1,050 self-identified black patients with severe heart failure who had already been treated with (but had not responded to) the best available therapy. That study was conducted because in two previous trials of BiDil in a general population of severe heart failure patients, which did not demonstrate efficacy, there was a suggestion of benefit to black patients.Another question that has been raised is whether drug companies lack significant incentive to search for biomarkers that better predict drugs' efficacy, given that this targeted approach could ultimately narrow the population eligible for a given product. Although it is desirable in theory to test drugs of potential value widely and to ascertain the potential breadth and limitations of their use, the resources available for clinical trials are not infinite, and it is not unreasonable for companies to expend resources preferentially on testing in populations in which there is a high expectation of success.Commentators have expressed a wide spectrum of views about the appropriateness of a therapy designated for one group, some even calling it discriminatory. Francis Collins, director of the U.S. National Human Genome Research Institute admonishes that "we should move without delay from blurry and potentially misleading surrogates for drug response, such as race, to the more specific causes." He is correct, of course, but to paraphrase Secretary of Defense Donald Rumsfeld, you go to war against disease with the data you have, not the data you wish to have. Drug testing, approvals and labeling must go wherever the data lead.<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />