How Can We Move Clinical Genomics Beyond the Hype?

How Can We Move Clinical Genomics Beyond the Hype? Timely Analysis of Immediate Health Policy Issues October 2011 Michael L. Millenson “All of the fruits of the tremendous explosion in innovation that’s been occurring in biomedical research – which make the molecular metamorphosis possible – fulfill their purpose only when they are translated into interventions and solutions that are applied to patients.” —Dr. Andrew von Eschenbach, U.S. Food and Drug Administration Commissioner, 2006 Introduction or no value to be marketed to challenges beyond the direct doctor- providers and patients. The result of patient interaction. Health More than a decade after the this policy vacuum is a disturbing information technology systems successful mapping of the human paradox. Genomics as a field is typically possess neither the ability to genome, clinical genomics1 is beginning to demonstrate its present genomic information in a starting to permeate important parts profound potential to improve health structured way clinicians can use nor of patient care and propel ripples and health care. At the same time, the the large data storage capabilities throughout the entire U.S. health care evidence suggests that the current use such information demands. system. of clinical genomics tests and Comparative effectiveness research therapies often contributes to needs to focus on identifiable Although the field has fallen far short wasteful spending and even patient subpopulations where clinical of the transformational therapeutic harm. genomics interventions can have the impact once widely predicted, most powerful impact, but the particularly in regard to common A 2008 article in Health Affairs concept of “identifiable” can raise diseases, specific interventions have warned that the low threshold for awkward questions about race and crossed the divide between rarity and allowing “unsubstantiated [genomic] ethnicity. regular use. Genetic testing routinely technologies to enter into practice guides therapy in several common [has] the potential to overwhelm the Finally, the science involved is cancers and in HIV disease, and use health system.”3 Since then, private- complicated and often confusing to of costly molecularly targeted anti- sector efforts to encourage use of patients, payers, providers and cancer drugs is rising sharply. Six in clinical genomics have intensified, policymakers alike, making informed 10 primary care physicians have while efforts to ensure appropriate decisions that much more difficult. ordered a genetic test.2 use have lagged. Evidence-based guidelines for clinicians remain Controversies over appropriate Pharmacogenomics, the science of scarce, despite growing efforts to genetic testing related to the risk of how genetic differences can affect address the problem, and those that breast cancer have already drawn in individual drug responses, has do exist can be contradictory. A all three branches of the federal become an established part of drug federal advisory committee that government and numerous private discovery and of the guidance given pushed for greater regulation and players. As issues related to clinical to physicians on the labels of drugs more reliable data had little impact genomics become a regular part of approved by the Food and Drug and was disbanded last year. access, cost and quality discussions, Administration (FDA). Meanwhile, government funding for it is time for a policy community long fluent in the argot of DRGs and Yet while increased adoption is assessment of the evidence on genomic interventions has plunged. billing codes to acquire similar partly due to growing acceptance of proficiency in the language of DNA useful interventions, it is also due to Integrating clinical genomics into and genetic codes. This paper aims to a porous regulatory structure that routine care poses multiple system assist that process by examining what allows diagnostic tests of unproven is hype, what is hopeful and what is The result has been a surge in and opioid agents.9 starting to make a genuine difference scientific discovery unparalleled in in clinical genomics. It also makes Western medicine.5 Consider: Genes, chromosomal abnormalities, proteins in the blood and similar specific recommendations about the type of information that would help • More than 3,000 genes have been indicators are called biomarkers, and linked to Mendelian (single- they are the key to clinical genomics. policymakers, payers, providers and 6 the public make better decisions gene) disorders. For example, certain proteins are about the use of clinical genomics. associated with more aggressive • Genome-wide association cancers, while other biomarkers can The Beginning of the studies, searching beyond single- predict the response to a medication. gene disorders, have found Bench-to-Bedside Journey significant correlations between In 2003, the FDA began asking companies to voluntarily submit When a draft map of the human more than 1,200 common genetic some types of biomarker data related genome was announced in 2000, variations and 210 traits. These to clinical usage in order to enhance followed by a complete map in 2003, ranged from the clinically drug safety and effectiveness. In breathless predictions of imminent important (abdominal aortic cases where having biomarker breakthroughs blossomed aneurysm) to the curious (the information is critical to safe and everywhere from opaque scientific ability to smell asparagus in 7 effective use, the FDA would not journals to the set of Oprah. If the one’s urine). allow voluntary submission. The expected clinical cornucopia has not • Different genes code for different FDA also now requires drug yet materialized, other metrics show enzymes. One family of companies to ensure that a substantial results. The $3.8 billion enzymes, cytochrome P450 companion diagnostic test is the U.S. government invested in the (CYP450), has been identified as approved with the drug approval. Human Genome Project from 1988 involved in the metabolism of 90 through 2003 helped spark $796 percent of all drugs.8 Just one As of June 30, 2011, the agency had billion in economic impact and $244 member of this family, CYP2D6, approved genomic biomarker 10 billion in total personal income. In is involved in the metabolism of information for 76 unique drugs, 2010 alone, genomics research and 100 different drugs, including including the following: industry activity directly and analgesics, anti-arrhythmics, 4 • Twenty-six different genetic indirectly supported 310,000 jobs. antidepressants, beta-blockers biomarkers affecting 18 different Precision Labeling for “Precision Medicine” therapeutic areas ranging from anti-infectives to psychiatry. Language shapes perceptions, but not always accurately. Proponents of “personalized” and “predictive” medicine tend to use those terms within a • Common medications used to framework of DNA determinism that pays little more than lip service to individual treat heart disease, depression characteristics unrelated to genetic biomarkers. Yet 40 percent of the factors and pain. contributing to premature death among Americans are linked to behavior, 30 percent to genetics, 15 percent to social factors, 10 percent to medical care and 5 • A preponderance of oncology percent to environment.1 A personal genotype remains a much less powerful drugs, with more to come: the predictor of future health than a good family history. oncology drug pipeline contains an estimated 300 Phase II or As genomic medicine enters the health care mainstream, those in the field should higher candidates with the consider a description of their role that recognizes the importance of other potential for testing against a approaches. Terms such as “genetically personalized medicine” or “personalized 11 genetic medicine” would make policy discussions about “precision medicine” a genetic biomarker. great deal more precise. _____________ 1McGinnis JM, Williams-Russo P and Knickman JR. “The Case For More Active Policy Attention To Health Promotion.” Health Affairs, 21(2): 78–93, 2002. Timely Analysis of Immediate Health Policy Issues 2 Genomic Science: Harder Than It First Looks Almost every cell in the human body contains two copies of the genome, with one each from the father and mother. (Egg and sperm cells contain only one genome copy, while red blood cells have none.) The genome itself is a kind of “book of life” composed of 23 chapters (chromosomes), each containing a thousand or more stories (individual genes), and each of those stories is made up of base-pair DNA “words”—a total of nearly three billion of them.1 Rather than being static, though, the genome is dynamic. Genetic code translates into a functional biological effect when the gene is “expressed” as a protein. When this happens, the underlying “genotype” (the total information in the genome) is actualized as a “phenotype” (the manifestation of an individual’s genome, including characteristics ranging from eye color to a disease state). A cause-and-effect relationship between a specific disease and a specific protein was first established by Linus Pauling and colleagues in a seminal 1949 paper on sickle cell anemia. Pauling confidently predicted “significant progress in the field of medicine as it is transformed from its present empirical form into the science of molecular medicine.”2 Six decades later, testing for sickle cell disease has improved, but there have been few advances in treating it. Despite the mapping of the human genome, there are three major reasons

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