Special Report II
When I was a resident in the late 1970s and early 80s, I met my clinic patients every Friday afternoon. As inpatients, all of them had been under my care, and after their discharges I followed some of them in the clinic throughout my entire residency. Many had hypertension. In those days, the first line therapy was thiazide diuretics. We were taught to select and try a generic thiazide more-or-less randomly from the several on the formulary. If the blood pressure did not respond adequately, we’d go up on the does. If at maximal doses the desire result was not being achieved, or if side effects at that dose or some lower one were unacceptable, we were to begin a second agent, typically a beta blocker, repeating the process. If that didn’t work, we’d try something else. Eventually, we would hit upon a regimen that kept both pressures and side effects within acceptable limits.
Sometimes, this outcome could be achieved with gratifying promptness. Often, however, it took months. During those months the patient’s pressure was inadequately controlled, so he was at risk for all the associated morbidity, including strokes and heart attacks. Since most of the patients had a variety of comorbidities, that risk was substantial. Non-response was hardly surprising. A 2001 study showed that patient response to medications of different therapeutic classes ranged from ~80% (analgesics) to ~25% (oncology).
Worse than non-response were adverse reactions. As I was taught on the very first day of my very first course in pharmacology: 1. No drug has a single action; 2. every drug has side effects. In the 36 years since, I have yet to find a single exception. When I wrote for thiazides, I also wrote for potassium supplementation required by the potassium-wasting so characteristic of that class of drugs. Though not insignificant, the hypokalemia was relatively mild and usually not life-threatening. The same cannot be said of the adverse effects of many other medications. An estimated 2.2 million adverse drug reactions occur each year in the United States, including more than 100,000 deaths.
So, in my clinic I did the best I could, attempting to steer a safe course between inadequate treatment and unacceptable side effects. When I was in training and indeed until quite recently, no one knew any model better than trial-and-error. Now we do. Unfortunately, we have apparently decided, at least for now, not to pay for it.
Personalized Medicine Defined
Personalized medicine, also called precision medicine, means providing the right drug to the right patient at the right dose at the right time. More formally, the National Academy of Sciences defines precision medicine as “the use of genomic, epigenomic, exposure and other data to define individual patterns of disease, potentially leading to better individual treatment.”
Pharmacogenomics (PGx), one variety of precision medicine, is “the study of variations of DNA and RNA characteristics as related to drug response.” PGx studies the role of genetic variation in drug response phenotypes. Pharmacogenomics uses genomic technology to understand the effects of all relevant genes on the behavior of a drug or conversely the effect of a drug on gene expression.
An individual’s drug response can range from serious, potentially life-threatening adverse drug reactions at one end of the spectrum to therapeutic ineffectiveness at the other. While many factors play a role in the safety and efficacy of a given drug in a given patient, his genetic endowment is critical. Hence, clinical implementation of PGx could avoid adverse drug reactions, maximize drug efficacy, and allow selection of medications to optimize effect for specific indications.
It should come as no surprise that one’s genetic makeup can have a significant impact upon the efficacy and toxicity of medications:
Examples of how these [gene-related variations in drug effects] manifest include:
● Reduced or no response because of
- the failure to convert a pro-drug to its active form
- increased metabolism of an active drug to an inactive metabolite
● Increased toxicity because of
- more rapid conversion to the active form or to a metabolite which is more active than the parent drug
- failure to metabolize an active drug to inactive metabolite(s).
- the genetic variations, such as genes coding for receptors or drug transporters also can influence overall response, e.g., the mu-opioid receptor or P-glycoprotein transporter and the response to opioids. Induction or inhibition of CYP450 activity also can result from a drug-drug or drug-food interaction causing similar manifestations to those resulting from genetic variation.”
The Promise of Precision Medicine
Precision medicine promises significant advances in the management of many of the most serious medical problems we face. It allows tumors with specific genetic characteristics, for example, to be identified by a companion diagnostic test so that the physician knows in advance that he is prescribing a medicine likely to work against the patient’s specific neoplasm.
As another example, consider warfarin, the most commonly used anticoagulant. Warfarin is prescribed for long-term treatment and prevention of thromboembolic events, with more than 21 million prescriptions annually in the United States alone. In use for six decades now, warfarin interferes with the function of Vitamin K, needed for the proper function of clotting factors II, VII, IX, and X, and of certain anticoagulant proteins. Its indications include prophylaxis and treatment of venous thrombosis and pulmonary embolism; prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement; and reduction in the risk of death, recurrent myocardial infarction (“MI”), and thromboembolic events such as stroke or systemic embolization after MI. These are of course extremely serious problems, highly prevalent in the U.S. and in many other nations. Warfarin, then, is a critically important drug. It is readily available and comparatively cheap. Unfortunately, it is also a very dangerous drug, associated with increased risk of hemorrhage, potentially fatal or neurologically devastating. Nor is it easy to use: its therapeutic index is narrow. The warfarin dose needed to achieve target anticoagulation has been shown to vary by as much as 20-fold between patients. Patients on warfarin are monitored by their prothrombin times (PTs) and their international normalized ratios (INRs). When a patient’s INR falls below 2.0, thrombosis risk increases, and when it rises above 4.0 serious bleeding risk increases. Hence, the prescribing doctor can easily err by over-treating, perhaps causing serious bleeds, or by under-treating, putting the patient at risk for ischemia, including vital organ ischemia, as a result of thrombotic obstruction of blood flow.
In pharmacogenomics, the doctor has a solution. According to the FDA label for warfarin, identifying genetic variants in two genes -- CYP2C9 and VKORC1-- can help determine the right warfarin dose. The VKORC1 gene is involved in the clotting process, and the blood of patients with mutations in this gene does not clot properly. Warfarin inhibits the enzyme vitamin K epoxide reductase, encoded in VKORC1, and decreases the amount of vitamin K available for synthesis of coagulation factors. Warfarin is metabolized by CYP450 enzymes, mainly CYP2C9. Patients with variations in this gene--particularly CYP2C9*2 or *3 alleles--cannot metabolize warfarin well. Both CYP2C9*2 and *3 cause a reduction in warfarin clearance, with 10-fold variation observed from the genotype linked with the highest (CYP2C9*1/*1) to lowest (CYP2C9*3/*3) activity. A combination of the effects of the VKORC1 genotype or haplotype together with those of the CYP2C9 genotype and factors such as age and body size are estimated to account for 35% to 60% of the variability in warfarin dosing requirements.
Because of their genetic makeup, some patients are highly sensitive to warfarin, and for them a lower dose is therefore appropriate. A large study just published demonstrates that in the first several months of warfarin therapy, patients who are sensitive or highly sensitive responders are at higher risk of bleeding. In those patients, who can be identified with pharmacogenomic testing, treating with edoxaban, a newer anticoagulant, was much safer than treating with warfarin. In the first 90 days of starting on warfarin, the risk of overt bleeding was 1.3 times greater among sensitive responders and 2.7 times more among highly sensitive patients who received edoxaban had fewer bleeding complications compared to those who received warfarin; for normal responders either treatment seemed to have comparable safety. As the authors stated in their abstract, “CYP2C9 and VKORC1 genotypes identify patients who are more likely to experience early bleeding with warfarin and who derive a greater early safety benefit from edoxaban compared with warfarin.” In light of the value of pharmacogenomics testing to warfarin prescribing, FDA has updated the warfarin product label to include a dosing table with recommended close ranges according to VKORC1, CYP2C9*2 and *3 genotypes.
Consider another example. Clopidogrel (Plavix) impairs the activation and aggregation of platelets, a key component of the coagulation mechanism. According to its label, clopidogrel is indicated for acute coronary syndrome [“ACS”] (unstable angina, STEMI [ST-segment elevation myocardial infarction], and non-STEMI), recent MI, recent stroke, and established peripheral artery disease. These are serious disorders, with high mortality and morbidity, and all too prevalent in the U.S. population, especially among seniors. Small wonder that clopidogrel is one of the most commonly prescribed medications in the entire therapeutic armamentarium. Since March 2010, however, the drug’s label has also featured a black box warning: “Diminished effectiveness in poor metabolizers.” The warning is needed because clopidogrel’s activity arises mainly from activation to a metabolite by CYP2C19, and those unable to achieve adequate levels of the metabolite “exhibit higher cardiovascular event rates following ACS or percutaneous coronary intervention than patients with normal CYP2C19 function.” “Cardiovascular events” refers to such life-threatening and major organ-threatening disorders as heart attack and stroke. Approximately 2% of whites, 4% of blacks and 14% of Chinese are poor CYP2C19 metabolizers. The label points out that genetic test can identify the patient’s 2C19 genotype, and prescribers are admonished to try a different approach in patients identified as poor metabolizers. For patients afflicted with any of the indications for clopidogrel, distinguishing between those who need that medicine and those who need another can quite literally be a matter of life or death.
Over the past decade, numerous other PGx variants have also been identified, and FDA has required the information to be incorporated into drug labels.
The U.S. Government Recognizes the Value of Pharmacogenomics
Recognition of the promise of precision medicine reaches the highest office in the land. In his 2015 State of the Union address, President Obama spoke eloquently of the benefits now possible with this technology: “I want the country that eliminated polio and mapped the human genome to lead a new era of medicine--one that delivers the right treatment at the right time.” Nor was this the first time Mr. Obama had advocated for pharmacogenomics. During his tenure in the Senate, he co-sponsored a bill to promote personalized medicine. S. 3822, 2006, “A bill to improve access to and appropriate utilization of valid, reliable and accurate molecular genetic tests by all populations thus helping to secure the promise of personalized medicine for all Americans.”
Over the past decade, we have unlocked many of the mysteries about DNA and RNA… Moreover, scientists have translated this genetic knowledge into several treatments and therapies prompting a bridge between the laboratory bench and the patient’s bedside.
HHS has also recognized the value of personalized medicine:
If we are to achieve higher quality care for all Americans at a sustainable cost, we must look to those changes that improve the productivity of healthcare...Personalized medicine seeks to use advances in knowledge about genetic factors and biological mechanisms of disease coupled with unique considerations of an individual’s patient care needs to make healthcare more safe and effective. As a result of these contributions to improvement in the quality of care, personalized medicine represents a key strategy of healthcare reform. The potential application of this new knowledge, especially when supported through the use of health information technology in the patient care setting, presents the opportunity for transformational change. Today, it is common for a medical product to be fully effective for only about 60 percent of those who use it. As the medical community is now learning, this in part reflects biological variation among individuals that affects the clinical response to medical interventions. In the past, they have not had the tools or knowledge to understand those differences. In the future, when doctors can truly prescribe the right treatment, to the right person, at the right time, we will have a new level of precision and effectiveness that will provide the knowledge-driven power that is necessary to achieve our highest goals in healthcare reform — including more effective disease prevention and early disease detection.
These pronouncements are not without a measure of fiscal support. The President’s 2016 budget, for example, includes his Precision Medicine Initiative, “a bold new research effort to revolutionize how we improve health and treat disease.” The Initiative proposes:
● $130 million to NIH for development of a voluntary national research cohort of a million or more volunteers to propel our understanding of health and disease and set the foundation for a new way of doing research through engaged participants and open, responsible data sharing.
- $70 million to the National Cancer Institute (NCI), part of NIH, to scale up efforts to identify genomic drivers in cancer and apply that knowledge in the development of more effective approaches to cancer treatment.
- $10 million to FDA to acquire additional expertise and advance the development of high quality, curated databases to support the regulatory structure needed to advance innovation in precision medicine and protect public health.
- $5 million to ONC to support the development of interoperability standards and requirements that address privacy and enable secure exchange of data across systems.
Testifying before a U.S. House subcommittee on March 3 in support of the Initiative, NIH Director Francis Collins, M.D., said that scientific advances are accelerating progress toward a new era of precision medicine.
Historically, doctors have been forced to base their recommendations for treatment on the expected response of the average patient. But recent advances, including the plummeting costs of DNA sequencing, now make possible a more precise approach to disease management and prevention that takes into account individual differences in genes, environments, and lifestyles.
Congressional action suggests interest, as well. The recently released draft 21st Century Cures Act includes a “placeholder” for the Precision Medicine Initiative. Beginning in 2017, the Protecting Access to Medicare Act of 2014 (PAMA) will provide special payment terms under Medicare for certain advanced diagnostic tests.
Unfortunately, despite support at the highest levels of government, in most parts of the country the genetic testing required to permit personalized prescribing is not covered under Medicare. By a Local Coverage Determination (“LCD”) issued last year, a Medicare Administrative Contractor (“MAC”) has decided that the evidence for the value of such testing is insufficient to justify coverage. And since commercial carriers often follow Medicare’s lead, reimbursement is a problem.
Consider clopidogrel, discussed above. Under the LCD, genetic testing of the CYP2C19 gene is considered medically necessary, and thus covered, for patients with ACS undergoing percutaneous coronary interventions that are initiating or reinitiating clopidogrel treatment. Only for those Medicare beneficiaries fitting that description, however, is coverage available. That the label makes clear that the drug is indicated in many other situations, and that poor metabolizers ought to be treated with other therapies, seems to make no difference.
Coverage for genetic testing for patients under consideration for warfarin therapy is even stingier. Testing for the CYP2C9 gene to predict warfarin responsiveness is covered under NCD 90.1 only (coverage with evidence development). That is, Medicare will cover CYP2C9 testing only in the context of a clinical study. All other CYP2C9 testing for warfarin is deemed investigational, and is therefore not covered.
Certain members of the California Clinical Laboratory Association and a Medicare beneficiary who was denied coverage for pharmacogenetic testing are suing HHS, alleging that the use of private contractors by the Centers for Medicare & Medicaid Services to establish local coverage decisions for lab tests is illegal and unconstitutional. That case is pending and its outcome is difficult to predict. In the meantime, however, Medicare coverage is not available.
As a result of the MAC’s decision, fewer Medicare beneficiaries will be tested. Fewer doctors will be able to design therapy with the guidance of pharmacogenetic data. More adverse events will occur. Some will be serious; some will be fatal. The problem will be compounded if commercial carriers follow Medicare’s lead, as they often do.
All the rhetoric from the President, members of his cabinet, and other national leaders rings rather hollow when we realize that a refusal to cover the services that permit identification of genetic information to guide therapy means that the potential benefits of this technology will not be realized. During residency, I could not have provided to my patients the benefits of pharmacogenomics because the science simply had not been developed yet. In 2015, I would still be unable to offer them the benefits of the technology because while the science is well-developed, we have not decided to pay for it.
Joseph P. McMenamin, MD, JD
Chief Legal Officer, W Medical Strategy Group
Joseph P. McMenamin, MD, JD is an Executive Vice President of W Medical Strategy Group, specialized in regulatory and litigation of pharmaceutical, medical device, and biotechnologies. Joe has more than 25 years of experience in defending organizations such as these against a variety of allegations in state and federal court. He also has advised them on Internet and marketing communications, informed consent, risk management, regulatory, and contract issues. Joe has counseled hospitals, nursing homes, physicians, and other healthcare providers with respect to a wide array of legal issues as well, including their interactions with regulated industry. For much of his career, Joe practiced as a partner at McGuireWoods LLP. Previously, he practiced emergency medicine for seven years at hospitals in Pennsylvania and Georgia.
Joe earned a B.S. in chemistry from Washington & Lee University in 1974, an M.D. from the University of Pennsylvania in 1978, and a J.D. from the same university in 1985. Between 1978 and 1981, he served a residency in internal medicine at Emory University Hospital and Grady Memorial Hospital in Atlanta.