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Healthcare Stakeholders Pushing for Pharmacogenomics to Guide Comparative Effectiveness Reviews

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With the US government allocating $1.1 billion for comparative effectiveness studies to determine which medicines should be paid for by insurance, some industry stakeholders, researchers, and patient advocates are urging for the use of pharmacogenomics tools to focus on improving patient outcomes and not solely on reducing healthcare costs.

As part of the America Recovery and Reinvestment Act the US Congress granted $400 million to the National Institutes of Health, $300 million to the Agency for Healthcare Research and Quality, and $400 million to the Office of the HHS Secretary, to develop the Federal Coordinating Council for Comparative Effectiveness Research.

However, many in industry fear that this council will in effect become the US equivalent of UK's National Institute for Clinical Excellence, an agency that advises the National Health Service on which treatments it should reimburse based on a cost-benefit calculation. NICE utilizes Quality Adjusted Life Years, or QALYs, to calculate whether the cost of a treatment delivers benefits in terms of quality and quantity of life.

At a recent White House conference on health care policy, Pfizer CEO Jeffrey Kindler expressed concern that comparative effectiveness studies will be used by the government to make coverage decisions.

Detractors of comparative effectiveness maintain that if health insurance is expanded to more people in the US, then comparative effectiveness will only be a vehicle for the insurers to cover the cheapest drugs.

One way to avoid that would be to use pharmacogenomics to place the focus on giving patients the most value and on long-term healthcare savings by maximizing effectiveness and minimizing adverse reactions from drugs, according to Edward Abrahams, executive director of the Personalized Medicine Coalition.

"The PMC is not opposed to comparative effectiveness," Abrahams told Pharmacogenomics Reporter this week. "We just hope that it's done right.

While the PMC is encouraged to see language in the "Comparative Effectiveness Research Act of 2008" discussing subpopulations, it is not currently clear how that will be interpreted by the government.

The "Comparative Effectiveness Research Act of 2008," which was introduced in the Senate last July, states that "research shall be designed … to take into account the potential for differences in the effectiveness of health care treatments, services, and items as used with various subpopulations, such as racial and ethnic minorities, women, different age groups, and individuals with different comorbidities; and seek to include members of such subpopulations as subjects in the research as feasible and appropriate."

Since the stimulus resolution makes no specific mention of personalized medicine or the use of pharmacogenomics, however, the PMC is concerned. "If we allow the only engine to drive comparative effectiveness the need to cut cost, then we can overlook what the new science is telling us about individual variation," Abrahams said. "There may be patient resistance built up [to the program] if they feel they are not getting the medicine that would work for them.

The law charges the Institute of Medicine with setting the research priorities for the Federal Coordinating Council for Comparative Effectiveness Research and issuing a report by June 30. AHRQ will also have a significant role developing the research agenda for comparative effectiveness, but it is not clear to what degree pharmacogenomics will factor into these studies.

Meanwhile, to ensure that pharmacogenomics does guide comparative effectiveness research, the Center for Medicine in the Public Interest is working to develop protocols and measures for a so-called "Critical Path for Comparative Effectiveness." The CMPI is a non-profit, non-partisan organization that provides the public and policymakers analysis on various issues, including personalized medicine, drug safety, health care reform, and comparative effectiveness.

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When it comes to comparative effectiveness, CMPI Director Peter Pitts has been urging stakeholders to move away from the traditional large randomized studies designed to look at population averages and focus on running PGx-driven studies to gauge the safety and effectiveness of drugs in subpopulations.

"At the end of the day you can't do comparative effectiveness without pharmacogenomics," Pitts told Pharmacogenomics Reporter this week. "Comparative effectiveness minus pharmacogenomics is guessing, and guessing when it comes to public health is not healthcare reform."

Value, Not Just Cost

At a luncheon hosted by the PMC in Washington, DC, last week, Mayo Clinic President Denis Cortese urged government, academia and industry to work together to reform the US healthcare system to measure the value of the care given instead of focusing exclusively on its cost.

"If we believe in individualized medicine, unless you think you're all the same, the blockbusters are going to go away," Cortese said at the luncheon. "We have got to think of the 10 percent to 15 percent where [treatments] would work, identify [the subpopulations] quickly, and get paid for that."

Through the new comparative effectiveness institute, "you can have an accelerated process in finding out where [treatments] do work," he added. "I don't know how much this will play out, but there's a commitment to make this happen, and I've encouraged people to get involved rather than hope it doesn't happen."

The PMC luncheon was funded by Johnson & Johnson, a company that has invested in personalized medicine and pharmacogenomics.

At the luncheon, Paul Stoffels, J&J's group chairman of global pharmaceutical research and development, said the company uses diagnostic tests to target treatment for its HIV drugs and is using an internal database of 10,000 DNA samples to identify response markers and adverse events for two unnamed central nervous system drugs.

"The pharmacogenetic approach is used for almost every compound we develop now," Stoffels said at the conference.

One fear within industry is that the comparative effectiveness approach will advance cheaper drugs in an effort to garner immediate cost-savings and fail to recognize the value of personalized medicine in terms of saving healthcare dollars in the long term. This will certainly negatively impact pharma companies' earnings, which in turn could impact their R&D budgets for pharmacogenomics-driven personalized medicine.

"Today, our society doesn't recognize the value of good information," Stoffels said. "And we absolutely need to work on that before [personalized medicine] will ever take off."

However, the dearth of available data on the cost-effectiveness of pharmacogenetic tests has done little to encourage payor support behind personalized medicine.

For instance, in the case of the highly variable anticoagulant warfarin, a recent meta-analysis from the University of Cincinnati concluded that while it many not be cost-effective to perform genetic tests to guide initial warfarin dosing in "typical" patients with atrial fibrillation, though it may be cost-effective to test individuals at high risk for hemorrhage [see PGx Reporter 01-21-2001].

Although most large payors don't yet cover genetic testing to dose warfarin, this type of clinical data may eventually lead insurers to cover the technology for the high-risk subpopulation that would derive benefit.

A New Critical Path?

Based on the principles of the US Food and Drug Administration's Critical Path Initiative for drug development, which aims to use "21st Century tools" to develop targeted treatments, the CMPI is working on a "Critical Path for Comparative Effectiveness."

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"Current comparative effectiveness studies … when it comes to pharmaceuticals, are large-scale randomized clinical trial results that were used for licensing," Pitts said. "For example, when you are comparing the clinical trial of one statin with the clinical trial of another statin, you are comparing apples to oranges because they are not alike molecules.

"What you want to do is use pharmacogenomics tools, or diagnostics, to understand which medicine is right for which patient in the right dose and in the right circumstance," he said, adding "that is 21st Century comparative effectiveness."

In Pitts' view "it is inevitable" that at the end of the day comparative effectiveness program will "morph into a US version of NICE." However, he hopes that by incorporating pharmacogenomics tools the center will focus on getting the best health outcomes for the dollar and not just the cheapest healthcare.

Pitts noted that the UK government is looking to overhaul the way NICE conducts cost-effectiveness reviews, and cautioned the US government against repeating the mistakes of NICE.

In the UK, NICE's preliminary finding that the National Health Service should not reimburse for certain targeted cancer drugs put the agency's cost-effectiveness analysis under fire from patient groups and the media.

CMPI, in collaboration with other partners, is developing the protocols and tools for using pharmacogenomics to determine comparative effectiveness of treatments. Pitts did not provide a timeline for when these protocols will be released, but noted that the CMPI will be getting input from UK's NICE.

The fear that comparative effectiveness will turn into a US version of NICE is especially palpable "if you consider that those decisions have been made without individual variation in mind," PMC's Abrahams noted. Those working on developing the new comparative effectiveness program "are talking about using a lot of retrospective data that may or may not be sophisticated enough to appreciate variation and response to therapy," he said.

While the AHRQ has been conducting comparative effectiveness reviews for several years under its Effective Health Care program, and the stimulus bill has provided funds to expand this program, the agency has not been using pharmacogenomic strategies specifically.

"AHRQ is gearing up to make the most of this additional funding," the agency said in a statement. "We are undertaking a process to determine what will be funded, as guided by the Federal Coordinating Council, the Institute of Medicine and other external sources. We will work closely with NIH and the Office of the Secretary to ensure that we use these funds in the most effective manner and that we are coordinating our plans to maximize effectiveness of this important investment."

AHRQ was not able to respond to requests for an interview prior to deadline.

"If it's done right, [comparative effectiveness] could propel us into better healthcare and lower cost. But if it's done wrong, it's going to trap us into the old system of static ineffective care, of one-size-fits-all, and trial and error," Abrahams added. "We want to get away from that. We want to move into an era of targeted therapeutics where especially patients benefit but where the government can also benefit."

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