Latest Drugwonks' Blog
Here's how it begins:
"AMERICANS HAVE, at best, a love-hate relationship with the life-sciences industry—the term for the sector of the economy that produces pharmaceuticals, biologics (like vaccines), and medical devices. These days, the mere mention of a pharmaceutical manufacturer seems to elicit gut-level hostility. Journalists, operating from a bias against industry that goes as far back as the work of Upton Sinclair in the early years of the 20th century, treat companies from AstraZeneca to Wyeth as rapacious factories billowing forth nothing but profit. At the same time, Americans are adamant about the need for access to the newest cures and therapies and expect new cures and therapies to emerge for their every ailment—all of which result from work done primarily by these very same companies whose profits make possible the research that allows for such breakthroughs."
During the course of his article, Troy discusses the issues that threaten to derail medical progress (litigation, an overly cautious FDA and, of course, legislation to put Uncle Sam in charge of our healthcare). Troy concludes:
"Just as there is potential danger from the way in which Americans take the power of the antibiotic for granted, so, too, one of the greatest threats to our health and continued welfare is that Americans in the present day, and particularly their leaders, are taking for granted the power, potency, and progress flowing from life-saving medical innovations. And in so doing, they may unknowingly prevent the kind of advance that could contribute as vitally to the welfare of the 21st century as the discovery of the antibiotic altered the course of human history for the better in the century just concluded."
Tevi's complete article can be found here.
All the rest is, well, commentary.
We talked about it here:
“The Vast Reich Wing Conspiracy”
And here:
“Pink Cadillac”
And now we welcome the Wall Street Journal to the debate. Here’s what they had to say on this today:
Taxing Health Care
Obama and Democrats owe John McCain an apology.
Democrats have spent years arguing that proposals to equalize the tax treatment of health insurance are an outrage against the American people. Workers pay no income or payroll taxes on the value of job-based plans, but the same hand isn't extended to individuals who must buy coverage on their own. Last year liberals mauled John McCain for daring to touch the employer-based exclusion to finance more coverage for the individually uninsured. He was proposing "a multitrillion-dollar tax hike -- the largest middle-class tax hike in history," said Barack Obama, whose TV ads were brutal.
But now Democrats need the money to finance $1.2 trillion or more for their new health insurance entitlement. Last week Senate Finance Chairman Max Baucus released his revenue "policy options" and high on the list is . . . taxing health benefits. Or listen to White House budget director Peter Orszag, who recently told CNN's John King that the exclusion "was not in the President's campaign plan, it wasn't in our budget. Clearly, some Members of Congress are putting it on the table and we are going to have to let this play out."
Mr. King tried again. "Let this play out. But would the President sign a bill that includes a pretty significant tax increase? That would be a tax increase." Mr. Orszag: "We're not going to be -- I think it's premature to be commenting on individual items . . . There are lots of ideas that are being put on the table." Translation: You betcha he'd sign it.
The tax exclusion is such a big revenue prize because Mr. Baucus is scrubbing every other tax nook and cranny and only coming up with rounding errors. A sampler:
- Impose an excise tax on hard alcohol, beer and some kinds of wine. That would be in addition to a sin tax on beverages sweetened with sugar or high-fructose corn syrup, such as soda. Mr. Baucus doesn't offer revenue estimates, though the Congressional Budget Office says a $16 per proof gallon alcohol tax might raise $60 billion over 10 years, and another $50.4 billion at three cents per 12 ounces of sugary drink.
- End or limit the tax-exempt status of charitable hospitals, which only costs currently a mere $6 billion a year.
- Make college students in work-study programs subject to the payroll tax. Also targeted are medical residents, perhaps on the principle that they'll one day be "rich" doctors. CBO has no score on these.
- Reducing Medicare reimbursement rates for supposedly "over valued physician services," such as diagnostic imaging. CBO says that requiring doctors to get prior clearance could save $1 billion in 10 years.
- For individuals with high-deductible insurance plans, contributions to health savings accounts would no longer be tax deductible. That would penalize patients who choose plans that encourage them to be informed consumers. CBO says that banning HSA payments entirely would yield all of $10 billion.
By contrast, the employer-based exclusion offers a huge money pot -- an estimated $226 billion in 2008. Yet as liberal MIT economist Jonathan Gruber recently told Mr. Baucus's committee, "no health expert today would ever set up a health system with such an enormous tax subsidy to a particular form of insurance" (his emphasis). It creates a coverage gap between workers who receive it from their employers and those who pay -- or can't afford to pay -- with after-tax money.
The tax exclusion is also one reason health costs continue to rise. It encourages workers to take an extra dollar of compensation in fringe benefits instead of cash while also routing low-deductible health spending through third parties. Some 84 cents of every medical dollar is spent by someone other than the patient. The insured have no incentives to make cost-conscious decisions about care.
So reforming the exclusion would inject a dose of discipline into American medicine. But for most Democrats the goal isn't to create a more rational health-insurance market. They simply want the revenue for another government program. Mr. Baucus won't target gold-plated employer insurance plans in general, because union-negotiated benefits are usually gold-plated. Rather, he may cap or phase out the exclusion by income, starting with workers earning more than $200,000. Insurance options that don't conform to government diktats (health savings accounts) would also lose any tax advantage. This would do nothing for market efficiency, but it would be one more stealth tax increase.
Democrats owe an apology to Mr. McCain, and it'll be fascinating to see if they will now suffer a political backlash of their own making. Having told the country that this tax reform is really a tax increase, Democrats are opening themselves to the same attacks they leveled against Republicans.
They could avoid that fate if they used the tax exclusion money to finance, say, a tax credit for the uninsured. That would be a genuinely bipartisan reform. But liberals won't accept that because they want to take one giant step toward government-run health care. And the only way they can pay for it is by taxing everything in sight, including your current health insurance.
Sir Michael noted that comparative effectiveness cannot be conducted by relying on randomized clinical trials and should instead use tools that allow doctors to determine who responds best to what treatments over time. Predictive and interventional approaches are obviously the most valuable. Such tools can provide every one a clearer idea of the value of care.
Over the course of the four hours we spent together that the way forward requires an approach described artfully by Ralph Snyderman, Chairman Emeritus of Duke University Medical Center:
- Start with high power predictive tools for big time clinical decions with short term impact on major diseases
- Create model clinical settings where clinical data and genetic information can be collected and combined
- Use clinical setting to establish predictive reliability of clinical decision tools and measure clinical outcomes
- Measure value of such tools to employers, individuals and health plans
Ultimately the reimbursement for health care will have to be inverted to pay for prospective care and reward targeted therapies.
But our critical path group is committed to doing the hard work. We don't need any more conferences about comparative effectiveness. We need to take the first steps forward.
Specifically:
To ensure that executive departments and agencies include statements of preemption in regulations only when such statements have a sufficient legal basis:
1. Heads of departments and agencies should not include in regulatory preambles statements that the department or agency intends to preempt State law through the regulation except where preemption provisions are also included in the codified regulation.
2. Heads of departments and agencies should not include preemption provisions in codified regulations except where such provisions would be justified under legal principles governing preemption, including the principles outlined in Executive Order 13132.
And here's a direct slap at the FDA's New Labeling Rule preamble:
3. Heads of departments and agencies should review regulations issued within the past 10 years that contain statements in regulatory preambles or codified provisions intended by the department or agency to preempt State law, in order to decide whether such statements or provisions are justified under applicable legal principles governing preemption. Where the head of a department or agency determines that a regulatory statement of preemption or codified regulatory provision cannot be so justified, the head of that department or agency should initiate appropriate action, which may include amendment of the relevant regulation.
The complete memo can be found here.
This should put to bed any lingering doubts as to the Administration's views on the topic. Happy Hour for the trial bar begins immediately.
Pretty subjective proposition.
The draft guidance (which can be found here) also introduces a new term, "net impression." DDMAC will now consider the “net impression” of consumer ads and physician detailing materials to determine if a piece conveys accurate information about a particular product.
In other words, rather than creating brighter lines so that industry can be in compliance, the agency is opting for even greater regulatory ambiguity.
Not good.
On May 4-5 the Harvard Business School Health Alumni Association along with the Young Presidents Organization/World Presidents' Organization (YPO/WPO) sponsored a conference in Washington, DC, "Health Reform at the Intersection of Government and Markets.” After two days of robust debate and discussion over a wide range of issues, the event ended with a troubling episode.
So troubling, in fact, that one physician in attendance along with another independent businessman felt obligated to write to Randy Cohen, who pens “The Ethicist” column at the New York Times, with the following query:
“We were attending a conference on health reform which had included an impromptu presentation on the swine flu pandemic. As the conference was closing, a physician was introduced and he said that as a “treat” for all his fellow attendees he would write prescriptions for TAMIFLU and that if he ran out of scripts, he would send one to anyone who emailed him a request. A large line immediately formed of people eager to avoid the risk of shortages or rationing. When confronted with our question as to the ethics and legality of his offer, he explained that he was a physician and had worked with the CDC and was confident he was acting in a morally and professionally correct manner – was he? For that matter, were the conference organizers in ethically troubling territory?”
To which Cohen replied:
“As you know, it is a violation of medical ethics to prescribe to a non-patient, i.e. to someone you've not examined (albeit a violation committed by, one study suggests, 100% of physicians). It is also a more general ethical transgression for a healthy person to stockpile a medication that might end up in short supply. In a more just world, this guy would have his license suspended. But I wouldn't count on that happening.”
Over lunch the other day, my doctor friend shared the rest of the story:
“From every angle, this was reprehensible and should not have been permitted. From a medical professional code of conduct point of view, it is an abuse of prescriptive authority to offer Rx of any drug to people who are not patients of a prescribing physician. It is medically irresponsible to give access to drugs which are not without risk as any adverse event could not be accountable (or appropriately handled) to this particular physician prescribing Tamiflu.
This is an act that can be considered illegal in several states, ethically wrong, medically reckless and dangerous, and inexcusable, especially in the manner it was presented to the conference attendees. From a "conflict-of-interest" point of view, this physician was offering Rx as a "treat" (code word: perk/kickback) to conference attendees who had paid to come to the conference. So, while there is no direct exchange of money for the Rx which will benefit this physician, it could easily be interpreted that he was an agent of the conference (since the conference organizers condoned the offer by allowing him the podium to present his offer and did not rebuke or stop him from doing so) and therefore Rx access was exchanged for money. From a supply chain, he was encouraging stockpiling of Rx, which is to give people access to a Rx for storage in their medicine cabinets (which will likely not be used) and taking it out of the supply for the nation.
Given how much we were talking about economic forces of supply/demand affecting behavior, it is highly ironic that this was permitted. From a public health perspective, this physician took advantage of a perceived panic (pandemic only means "widespread" and does not indicate severity) and called his actions "giving access" to a "needed therapeutic" during a "pandemic." It seems interesting that if he truly felt that way, then why did he not go out onto the streets or to the inner city and offer his scripts to others (who wouldn't necessarily have access). Funny how he should only offer this to people who most easily can gain access to their physician should they want and need the Rx (members of HBS Health Alumni Association). This could also be interpreted as an odious way to win friends and influence people.
And finally, from a medical practice point of view, Tamiflu is not without risk. When challenged, this physician merely mentioned that he was asking everyone if they had kidney problems (a contraindication for prescribing the Rx), but he did not warn anyone that there have been quite a number of cases internationally of behavioral changes that are reported with the use of Tamiflu. Without discussing risk and only touting benefit could be defined as medical malpractice.
As organizers of this event, this behavior should not have been encouraged nor condoned. Silence is the wrong action because it is not recognizing that everything this did in the final two minutes, in effect, undermined the intention and perception of the conference.”
Indeed.
Dr. Brock – what can you do about this?
Somehow, I don't think Adam Smith had this in mind.....
I bought my daughter Botox jabs for her 18th birthday...says mother who has spent £45,000 on plastic surgery
By Tamara Cohen
May 26th 2009
Most mothers would aspire to pass on something of themselves to a teenage daughter.
But for Margaret King, that didn't mean offering young Jodie advice on the opposite sex or even guiding her on her wardrobe choices.
For her 18th birthday, she bought her Botox injections to get rid of the 'wrinkles' on the teenager's forehead.
Jodie King and mother Margaret, who bought her daughter Botox injections for her 18th birthday
Mrs King, who has spent £45,000 on cosmetic surgery procedures for herself, said: 'Jodie's forehead is like mine - she gets pronounced lines when she makes a facial expression. I knew Botox would solve the problem.'
Many surgeons do not recommend using Botox under the age of 30 because the skin has not sufficiently wrinkled and it could lead to an unnecessary loss of facial expression.
But Jodie, who had been worried about her complexion, is now addicted to the jabs and has spent £1,000 on them. "
"According to the Congressional Budget Office, taxing all employee health benefits would yield a whopping $246 billion every year. Even limiting the tax to higher-income employees would go a long way to funding universal health care. Employer-provided health insurance is the biggest tax break in the whole federal income tax system.
Tax-free employer-provided health care is also, in effect, the government-backed health insurance system we now have. It now covers three-fifths of the American population under 65. Seventy percent of the 253 million Americans with health insurance receive at least some of it through their employers."
Lately we've been hearing about all those "wealthy executives" who get "Cadillac health plans." Reich joins in as follow:
"Top executives and their families get gold-plated plans guaranteeing top-notch medical attention for just about every risk imaginable, along with extra coverage in retirement."
(For more on "Cadillac" health plans, click here)
And here comes who gets it in the neck -- "The good news is that a program providing universal health care doesn’t need the full $246 billion a year generated if every employee now receiving tax-free health benefits had to start paying taxes on them. Obama’s health care reserve fund needs around $650 billion over ten years. So a sensible and politically feasible alternative is to limit tax-free employer-provided health benefits to workers whose incomes are under, say, $100,000 a year, and subject those with higher incomes to progressively higher taxes on them."
That's right -- higher taxes for Americans with employer-provided healthcare who earn over $100,00 a year.
Do you feel like a "wealthy executive" yet?
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."
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.
