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Pharmacogenomics Reporter
A health care research and education organization interested in advancing personalized medicine is planning to lead an effort to develop an "opportunities list" and road map for how clinical evidence should be reviewed for regulatory approval and reimbursement of pharmacogenomics-guided medicine.
The Center for Medicine in the Public Interest told Pharmacogenomics Reporter this week that it plans to put together a formal proposal outlining areas where the US Food and Drug Administration and the Centers for Medicare & Medicaid Services can harmonize the way they evaluate outcomes and guide treatment selection for genetically-defined subpopulations.
CMPI's efforts follow CMS' proposal earlier this month that the government would only pay for genetic testing to dose warfarin for Medicare beneficiaries when it is part of a prospectively designed, randomized-controlled trial.
CMS considers RCT's the gold standard for evaluating evidence when determining coverage for medical interventions. In its 2006 guidelines outlining data collection criteria for getting coverage under clinical trials, CMS notes that sponsors "may include a broader range of studies than randomized clinical trials to include observational research." However, positive coverage decisions from CMS based on observational studies are uncommon.
With regard to PGx-based warfarin dosing, CMS-proposed criteria for reimbursement appear to be at odds with the FDA's evidence requirements to update the label for the drug.
FDA updated warfarin's label with genetic risk information two years ago based on meta-analysis of nine studies and an observational study [see PGx Reporter 09-05-2007].
When the FDA updated warfarin's label two years ago, it did not recommend genetic testing to doctors, saying the agency was awaiting completion of additional clinical trials before including stronger language in the label. At the time, the agency did not specify the design of the studies required (ie. RCT, observational, etc.) for adding a genetic testing recommendation to the label.
Lawrence Lesko, director of FDA's Office of Clinical Pharmacology, previously indicated at a conference that RCTs may not be universally necessary when a sponsor wishes to update a label for a drug that has been out on the market for several years, such as warfarin, with genetic testing data [see PGx Reporter 02-28-2007].
According to CMPI Vice President Robert Goldberg, a requirement that researchers and test developers conduct an RCT for coverage would keep reimbursement policies "years behind research."
The RCT requirement in CMS' coverage-with-evidence-development proposal for warfarin genetic testing not only ignores data from observational studies that show genetic testing improves outcomes, but "the proposal was clearly put forth without weighing FDA's input," Goldberg said.
Healthcare stakeholders had been eagerly awaiting CMS' decision on PGx-guided warfarin dosing, often upheld as a positive example of healthcare's moving away from a one-size-fits-all paradigm to more personalized medicine. Now that CMS has decided not to broadly cover warfarin testing for all Medicare beneficiaries, personalized medicine advocates are viewing it as a major step back for the field.
Meanwhile, despite FDA's update to the warfarin label, most national payors do not yet provide coverage for genetic testing in this setting. In finding insufficient evidence demonstrating that pharmacogenomics-guided warfarin dosing improves health outcomes for Medicare beneficiaries, CMS' decision gives additional cause for private payors to not provide coverage as well.
In support of their decision to not cover warfarin genetic testing, payors often cite a highly publicized study, published in the Nov. 7, 2007 issue of Circulation, which randomized more than 200 patients initiated on warfarin to either PGx-guided or standard dosing, but failed to reach its primary endpoint of a reduction in bleeding outcomes, as measured by out-of-range international normalized ratio. However, supporters of personalized medicine tend to focus on the fact that the study did show that "an algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation" [see PGx Reporter 12-07-2007].
Ultimately, CMS' coverage decision on warfarin genetic testing illustrates how differently CMS and FDA view evidentiary standards for pharmacogenomic products and has enflamed a longstanding debate on how to get two agencies with very different mandates to work together on a common goal: advancing personalized medicine.
CMS is accepting public comments on its proposal for warfarin genetic testing until June 3.
Alignment Problem
In crafting its proposal to align CMS and FDA's evidentiary standards for PGx tests, CMPI plans to enlist the help of an expert group, such as the Critical Path Institute, the Reagan-Udall Foundation, or the Federal Coordinating Council for Comparative Effectiveness.
The Critical Path Institute does not support a particular agency's evidence criteria as more appropriate for pharmacogenetic tests, but chief scientific officer Jeffrey Cossman suggested there should be more discussion on the matter between CMS and FDA.
"It seems like it would be beneficial … if there was a strong line of communication between agencies in HHS, particularly the FDA and CMS, so that each could benefit from how the other sees this," Cossman told Pharmacogenomics Reporter last week.
"FDA could learn from CMS how they evaluate the clinical utility of a diagnostic" such as a test for warfarin dosing. Vice versa, "CMS could see how FDA evaluates the performance and credibility of the analytic value of the test."
The two agencies should communicate with each other to come up with "an informed, scientific, medical, and economic" method for evaluating tests, Cossman suggested.
Diagnostics developers have often cited CMS and FDA's differing criteria for genetic testing as a barrier to personalized medicine. Healthcare leaders, most notably former HHS Secretary Michael Leavitt, have recognized that the field can benefit from “closer alignment” between FDA and CMS particularly when it comes to standards of evidence [see PGx Reporter 11-14-2008].
“The different missions and capabilities of FDA and CMS will both be needed to usher in … products and services that reduce costs in the future by identifying disease earlier," Leavitt said at a conference last year. "I believe a new kind of collaboration between them could be important for progress."
However, aligning the work of the two agencies is challenging due to their divergent mandates, Issam Zineh, associate director of genomics at FDA's Office of Clinical Pharmacology, pointed out to Pharmacogenomics Reporter in December.
Since FDA must approve products for marketing based on the clinical validity of products, while insurers must decide whether to pay for products based on their clinical utility, "it’s really tough to come to consensus about what CMS or a third-party payor might need in terms of them paying for a test and what we would need to consider the test useful," Zineh said.
He added that although synthesizing the methodologies of the two agencies will be difficult, the FDA has enlisted the help of the Agency for Healthcare Research and Quality in identifying areas for alignment [see PGx Reporter 12-31-2008].
Major Setback?
Although personalized medicine advocates have long discussed the need to bring together FDA and CMS' evidentiary standards, CMS' decision to limit coverage of PGx-guided warfarin dosing motivated CMPI to get proactive in this area.
CMS' RCT proposal for warfarin genetic testing is viewed by many supporters of personalized medicine as a major setback to the burgeoning field.
Diagnostic test developers have accused CMS of succumbing to lobbying pressure from more established healthcare players that stand to benefit from discouraging adoption of pharmacogenetic testing, which requires a move away from the blockbuster drug mentality and greater focus on subpopulations. Some researchers, meantime, specifically take issue with CMS' randomized-controlled trial proposal as unethical and not based in science.
"This illogical decision perhaps has been influenced by the lobbying of big pharma," according to Ramanath Vairavan, senior VP of sales and marketing for AutoGenomics, one of several companies marketing a genetic test for warfarin sensitivity. The Carlsbad, Calif.-based AutoGenomics' Infiniti Warfarin XP dose-response assay for identifying patients with CYP450 2C9 and VKORC1 genetic variants received 510(k) clearance from the FDA last January [see PGx Reporter 05-06-2009].
Similarly, Genomas President Gualberto Ruano also took issue with CMS' decision, questioning whether conducting RCTs "would be ethical given the risk of exposure to unsafe warfarin dosing that can be prevented with genotyping."
Genomas is currently conducting a clinical trial with Hartford Hospital on PGx-guided warfarin dosing. "The cumulative evidence is already overwhelmingly positive on the predictive value of warfarin genotyping," Ruano noted.
According to FDA's Lesko, RCTs, while necessary in certain cases, are not required for a drug such as warfarin, which has been on the market for more than 50 years. In the case of warfarin, "we have significant 'prior knowledge,'" he told Pharmacogenomics Reporter last week. Lesko emphasized that he was not speaking on behalf of the FDA but as a clinical pharmacologist.
"We need different study designs for different problems," he said. "One size does not fit all."
Lesko's overriding concern with CMS' decision is that coverage for testing under RCTs will not help meet the public health need, given the large number of people experiencing adverse reactions from warfarin and the growing number of genetic tests rapidly entering the market.
Approximately 2 million people are initiated on warfarin therapy each year to prevent blood clots, heart attacks, and stroke. According to FDA's adverse events reporting database, complications from warfarin are the second-most common reason for emergency room visits, behind adverse reactions from insulin.
"The time, the money and the need have to be considered seriously by the scientific community for the good of our patients," he said. "Rational decisions must be made as to the best use of resources. When RCTs are not possible, inappropriate, inadequate or unnecessary, let us use well-constructed, well-analyzed observational trials that can provide the answers we seek.
"RCTs will always fulfill a valuable role, and both types of studies can happily co-exist," he added. Lesko pointed out that while both CMS and FDA "have a duty" to interpret scientific data, their statutory requirements differ. "So, two views will co-exist and may, in some cases, be different," he said.
Rapidly Evolving Science
For personalized medicine supporters, RCTs, since they take many years to complete, are particularly incongruous with the rapidly evolving genetics field, in which new genetic disease risk associations are uncovered nearly every day. Many industry observers have pointed out that in the case of warfarin, by the time some of these randomized-controlled trials are completed, new SNPs will be discovered and new, improved anticoagulants will have replaced warfarin in the market.
Sanofi-Aventis markets the anticoagulant Lovenox, also called enoxaparin, which the FDA approved last May for prophylaxis and treatment of deep-vein thrombosis, prophylaxis of post-op DVT, and unstable angina or non-Q-wave myocardial infarction.
Bayer is seeing FDA approval for the anticoagulant rivaroxaban for the treatment for stroke prevention in atrial fibrillation and for long-term secondary prevention of venous thromboembolism. The company is also studying the drug’s effectiveness in the management of acute coronary syndrome.
Researchers are hoping rivaroxaban and enoxaparin can eventually replace warfarin since there have not been any reports of significant bleeding events in clinical trials. Comparative studies have shown that bleeding rates with rivaroxaban and enoxaparin are similar.
Case for Observational Studies
Of the researchers and clinical pharmacologists who have spoken out in reaction to CMS' coverage-with-evidence-development proposal, most agree that in the case of warfarin, CMS should provide coverage for genetic testing conducted as part of observational studies.
"I feel strongly that an RCT is not necessary to show that PGx-guided warfarin dosing is beneficial," Susan Horn, senior scientist for the Institute for Clinical Outcomes Research, told Pharmacogenomics Reporter last week. "A large observational study with detailed patient information, including PGx information and other medications being taken simultaneously, would be able to show the association of PGx with outcomes."
In Lesko's view, RCTs are not needed to define the best dose for the typical patient since standard doses in package inserts are already provided. However, for the subgroup of patients genetically predisposed to experience adverse reactions to warfarin, the very design of an RCT would not allow researchers to determine the right dose.
"Doses that are in package inserts for patients with hepatic impairment or renal impairment, for pediatric or geriatric patients, or for patients taking concomitant drugs are best answered by prospective, observational trials, not RCTs," Lesko said. "That is what is done in drug development today. Genotype, like kidney function, defines a patient subgroup that needs a different dose than the usual dose for the patients studied in RCTs before approval."
Furthermore, monitoring international normalized ratio is well established in medical practice as a surrogate marker for assessing the safety and efficacy of a warfarin dose. "For every increase in INR above 3-4, the risk of bleeding goes up 30 percent," Lesko noted. "If one accepts INR as a clinical outcome, RCTs looking at bleeding events are unnecessary."
Lastly, Lesko emphasized that genetic testing is not meant to replace INR monitoring, but complement it. "There is no documented harm of genetic testing, so being 100 percent sure of the intended benefit is less critical than a decision about whether a drug is effective or not," he said. "So, even if the genetic test was measured incorrectly, the risk is small to the patient because INRs are measured. That is, in fact, what is done now. Thus, RCTs are not needed."
Whenever using observational trials, researchers must critically evaluate the results, Lesko noted. He suggested using the Bradford-Hill criteria to evaluate the strength of evidence establishing the dose-response relationship and the temporal relationship between disease and its causes.
Meanwhile, researchers from the pharmacy benefits manager Medco and the Mayo Clinic are conducting an observational study on how PGx-guided warfarin dosing impacts patient outcomes within its own system [see PGx Reporter 12-06-2006].
In comments to CMS, Medco previously held that PGx-guided warfarin dosing “is reasonable and necessary” under the Medicare program, based on pharmacological mechanisms, clinical data, and physician, patient, and payor demand for PGx testing for warfarin within its own system.
Preliminary results from the Medco/Mayo study show that half of all patients contacted agreed to participate in the trial and 75 percent of doctors ordered the test. When the PBM offered the test commercially to its customers, nearly 99 percent of patients took the test and 50 percent of the physicians contacted ordered the test, according to the firm [see PGx Reporter 10-29-2008].
Final results from this study are expected to be released in the coming weeks. Medco did not respond to questions for this article prior to deadline.
Payors' Mandate
The field of personalized medicine poses a challenge to the structure of the current insurance system. Insurance based on population-wide risk pooling doesn't fit squarely with pharmacogenetics-based medicine, which offers more insight on individual disease risks. Additionally, healthcare providers fear they will invite more lawsuits by using new genetic technologies, for which there is scant clinical evidence [see PGx Reporter 09-26-2007].
Most large insurers, unconvinced by current clinical evidence, are awaiting data from several ongoing RCTs before deciding to cover warfarin genetic testing. Most likely, for many private insurers, CMS' decision to provide coverage with evidence development for warfarin genetic testing will not alter their current stance on the matter.
The AHRQ and the National Heart, Lung, and Blood Institute are funding randomized controlled trials that will enroll more than 1,500 patients starting on warfarin. In addition, the University of Washington in Seattle, the University of Utah, the US Food and Drug Administration, the principal investigators of the Harvard Creating an Optimal Warfarin Nomogram Trial, and the Warfarin Pharmacogenomics Consortium are enrolling 5,000 patients in a study to develop a PGx-based dosing algorithm for warfarin.
However, "RCT is not a panacea," Lesko said, pointing out that RCTs introduce new problems from a design and public health perspective.
"The current NHLBI study will look at INR, not bleeding outcomes, as the primary endpoint," Lesko said. "This reflects the problem with RCTs for drug safety where the event is relatively rare and may take years to measure.
"Many RCTs have low generalizability. The current NHLBI study will use a clinical algorithm that is not validated, and the study will be conducted in centers that are not representative of those patients in primary care settings."
Furthermore, Lesko pointed out that observational trials have been accepted in the past without evidence from RCTs in the case of combination chemotherapy, insulin for diabetes, and certain anti-infectives for serious diseases.
In the view of one former FDA official, whether observational or RCT, CMS's coverage-with-evidence-development strategy is ultimately the right decision for the Medicare population.
"It was a difficult decision for CMS, but I think [the CED process] does fit the existing evidence that is out there, particularly for the geriatric population," Steven Gutman told Pharmacogenomics Reporter. "I just don't think there is very much information on the geriatric population to figure out how to use the markers." Gutman was head of the Office of In Vitro Diagnostic Device Safety and Evaluation since 2002, but left the agency last year to join the University of Central Florida in January, where he is a professor of pathology.
"I am not sure" whether a RCT would be the most appropriate way to get that data, Gutman said. "But what I am sure about is that right now, there is not enough information to make an intelligent decision."
The issue at hand is taxing employer-provided health benefits – another third rail in the battle for healthcare reform.
60% of the American public gets their health benefits through their jobs -- and they’re not “free.” According to the Kaiser Family Foundation, the average American worker with “employer-provided” healthcare pays about 41% of the cost.
Two of the “players” in Congress, Senators Baucus and Wyden, want to tax employer-provided health benefits (according to an article by Robert Pear) “above a certain value.”
Question: is that “certain value” before or after the 41% cost-share?
For those of you with selective memory issues, during the most recent presidential election, candidate Obama called candidate McCain’s proposal to tax employer-provided health benefits “the largest middle-class tax increase in history.”
Here’s what Josh Karden, Mr. Wyden’s chief-of-staff has to say on the matter – “Cadillac health plans should be treated as income, regardless of who is receiving them.” Mr. Karden specifically mentions “wealthy chief executives.”
Welcome “Cadillac health plans” to the rhetoric of healthcare reform. It’s not the last time you’ll be hearing it.
How do you define a “Cadillac” health plan? Didn’t candidate Obama say that he wants every American to have “the same healthcare as members of Congress?” (Hint – yes, he did). Are the “employer-provided” health benefits that federal employees have “Cadillac?” (Hint – yes, they are – if you define “Cadillac” as comprehensive in formulary and patient choice.)
Does this mean Uncle Sam will tax the healthcare benefits of members of Congress, federal government employees, teachers, fire fighters, police officers, as well as “wealthy chief executives?”
Consider a new website set up by American Federation of State, County and Municipal Employees and the AFL-CIO -- www.stopwydenshealthtax.com.
Is that a coalition I hear breaking apart?
Also, does this mean the touted “public plan” that’s getting so much attention won’t be of the “Cadillac” variety?
Perhaps it will be more like a Yugo or a Zhiguli.
This is healthcare reform?
That is a discussion we all expect to occur next month – and we’re looking forward to it.
Senators Max Baucus, D-MT, and Tom Harkin, D-IA, are drafting legislation to use tax incentives as an incentive for businesses to develop a healthier workforce through employer-sponsored wellness programs.
“Prevention and wellness should be a centerpiece of healthcare reform,” said Harkin, who regularly climbs the stairs to his seventh-floor office on Capitol Hill.
Certainly seems like a common sense approach, as employees with elevated cholesterol and blood pressure, poor blood glucose control and excess weight are more likely to get sick, develop chronic disease, experience absence and disability and over utilize their fair share of expensive healthcare resources, making U.S. firms less competitive and makes the tax incentive concept seem like a no-brainer.
Maybe. But there’s a more efficient and practical alternative without enacting yet another undue burden on business: Personal tax incentives to adults and their dependents for achieving and maintaining healthy body weight. See here to see how.
To facilitate public participation, a grass-roots social marketing campaign should be undertaken. One of President Obama’s eight principles for health legislation is that it must “invest in prevention and wellness. Yes we can.
Check Out CMPI's New Book:
Few relationships are more personal, private and important than the one between doctor and patient. Yet, today, one both sides of the Atlantic, physicians are increasingly having there decisions second-guessed by distant third parties. “Physician Disempowerment: A Transatlantic Malaise,” a new book from the Center for Medicine in the Public Interest (CMPI) chronicles the recent -- and pronounced -- intrusion by government and other disinterested third parties into the private medical relationships patients have with their doctors.
While this insidious “adverse event” has been an issue in Europe and Canada for many years, it is just now emerging as the hidden third rail of American healthcare reform. The book also includes essays by physicians and policy makers who work in the oft-vaunted socialized healthcare systems of our neighbor to the North and
Dr. François Sarkozy, a pediatrician (and also the brother of the French President) shared his impressions of the state of the French medical profession. "There’s a relative loss of status in being a physician. There’s a malaise with the French physicians," he says. "We’ve seen that independent private practice has become less attractive in France than it was before.
The book is based on a conference recently held by CMPI in Washington,
An electronic copy of Physician Disempowerment: A Transatlantic Malaise can be downloaded at by clicking here. Hard copies can be obtained by contacting CMPI at (212) 417-9169.
All in favor, say "yea."
Here is the entire decision from CMS on CTC for colorectal
Click Here to View the Decision
And note the key word that runs throughout... AVERAGE as in one size fits all. The key to disallowing advances is to insure that the benefit has to be shown to fit everyone in a large scale randomized trial... Or as CMS says (and you better get used to this phraseology... the evidence is not sufficient to conclude that screening CT colonography improves health benefits for asymptomatic, average risk Medicare beneficiaries. While it is a promising technology, many questions on the use of CT colonography need to be answered with well designed clinical studies that focus on health outcomes for the Medicare population.”
Why not try getting evidence of cold fusion?
May 19, 2008
CMS initiates this national coverage analysis for the use of screening CTC for colorectal cancer. The public has 30 days to submit comments on this topic. CMS considers all public comments, and is particularly interested in clinical studies and other scientific information related to the technology under review. We are especially interested as to the types of studies needed if the evidence is determined to be premature for coverage or if the appropriate frequency interval is uncertain.
November 19, 2008
CMS convened the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) to review the available evidence on the use of CTC as a screening test for colorectal cancer for average risk individuals, including test characteristics, screening frequency, cost effectiveness, safety and training requirements.
February 11, 2009
CMS posts a proposed decision memorandum and the 30 day public comment period begins.
March 3, 2009
CMS met with representatives of the American Cancer Society, the American College of Radiology, and the American Gastroenterological Association and listened to their concerns regarding the proposed decision memorandum and asked them to reflect those concerns in the written comments they submit during the public comment period.
March 10, 2009
CMS met with representatives of the Medical Imaging and Technology Alliance and listened to their concerns regarding the proposed decision memorandum and asked them to reflect those concerns in the written comments they submit during the public comment period.
Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.
