The Comparative-Effectiveness Controversy

The economic stimulus package approved by Congress in February 2009 provides more than $1 billion to support research on competing medical products and services. Although it is a fairly minor piece of the larger $789 billion American Recovery and Reinvestment Act of 2009 (ARRA), the provision generated considerable controversy.

Jill Wechsler

Comparative effectiveness (CE) research enthusiasts insist that more and better information about which medical products and procedures are most effective for treating certain conditions can improve care and cut unnecessary costs. A white paper last year from the Congressional Budget Office (CBO) looked to CE research to "provide a basis for applying costly new technologies only when they are likely to confer added benefits." And the Obama administration has stated frequently that reducing healthcare spending is critical to economic recovery and to maintaining a viable Medicare program.

However, the initial CE research legislation set off a firestorm by stating that by "knowing what works best and presenting this information more broadly to patients and health professionals," procedures and interventions "found to be less effective and, in some cases, more expensive, will no longer be prescribed." Conservative columnists raised the specter of government rationing and "cookbook medicine" that offers the same treatment for everyone. Pharmaceutical companies predicted that comparative cost assessments would lead to price controls if payers refused to reimburse companies for drugs that fall below a cost-effectiveness threshold.

The final ARRA legislative report defused the outcry by stating that Congress does not intend for CE research to be used to "mandate coverage, reimbursement, or other policies for any public or private payer." Observers noted, though, that once CE research results are available to the public, health-plan managers and payers will be free to use the data as they see fit, which could include imposing limits on coverage and reimbursement.

More new research

In any case, the new government-funded CE research program opens the door to a much broader role for the federal government in selecting treatments and topics to be analyzed and in shaping methods for conducting comparative studies. Even though ARRA does not establish a new, multibillion-dollar independent entity to carry out CE research, as envisioned by leading health authority Gail Wilensky, senior fellow at Project HOPE, in her seminal November 2006 article in Health Affairs, it promises to expand the scope of CE research considerably. Whether or not an independent CE agency is established is not the critical issue, Wilensky says. The important questions are whether CE data have credibility, whether research practices are open and transparent, and whether studies are objective and not politically motivated.

As an initial step, the legislation divides the $1.1 billion in funds among three arms of the US Department of Health and Human Services (HHS). The Agency for Healthcare Research and Quality (AHRQ) gains $300 million to bolster its relatively small outcomes and effectiveness research program. The National Institutes of Health (NIH) gets $400 million to support CE research conducted by its various Institutes, in addition to the $10 billion in ARRA to fund general research and medical-facility improvements. The remaining $400 million goes to the HHS secretary for activities such as standards development and support for registries and electronic data systems to generate outcomes data.

How these agencies dole out the money will be shaped by a report from the Institute of Medicine (IOM) recommending priorities for CE research. The legislation provides $1.5 million for an IOM panel chaired by Harold Cox, editor of the Annals of Internal Medicine, to issue a priorities assessment by June 30, 2009. The importance of the committee's deliberations was seen in the dozens of interested parties who presented their opinions at a March 2009 public meeting about how CE research should be conducted and which topics should be studied. In recommending study areas, the IOM panel will consider the needs of populations served by federal programs, such as the elderly, children, and the disabled, and will look for research that includes women and minorities.

In Washington This Month

To ensure broad input on this important issue, IOM also established an online system for people to submit specific proposals for CE studies. The panel is ranking these submissions according to disease burden, disease severity, variation in care, cost, public interest, and current gaps in information. The questionnaire requests a brief summary of the research question, study design, study population, and which alternatives should be compared.

A new Federal Coordinating Council for CE Research will monitor how well HHS meets the IOM priorities in awarding CE research grants and will coordinate government-funded CE research initiatives. The 15-member council includes top officials from HHS, NIH, AHRQ, the US Food and Drug Administration, and other federal agencies. In the spirit of transparency, HHS will publish information about grants and contracts awarded under this program, will disseminate the research findings that result, and will report annually to Congress on the program.

One effect of government investment in CE research would be to develop standards and to improve methods for conducting comparative studies and to develop innovative trial designs for real-world assessment of medical treatments. At the IOM public meeting, Bryan Luce, senior vice-president of United BioSource, urged "true transformational thinking" in designing CE research studies. Without it, he said, we will "waste vast amounts of money answering the wrong questions, or the right questions too late."

Existing models

Although ARRA funding will spur activity in this area, a good deal of CE research has been going on for some time. The Medicare Modernization Act of 2003 provided limited funding to AHRQ for research to determine the clinical effectiveness and appropriateness of various health services, including prescription drugs. AHRQ now has a $50-million Effective Health Care program, which synthesizes existing clinical information.

Comparative-cost issues are examined more explicitly by private-sector comparative-research programs supported by health-insurance companies and payers. The Blue Cross and Blue Shield Association's Technology Evaluation Center has been reviewing clinical evidence since 1985 to assess the effectiveness of certain medical procedures, drugs, and medical devices. The Drug Effectiveness Review Project (DERP) at the Oregon Health and Science University provides state Medicaid agencies and large insurers with comparative information on the efficacy and safety of new, high-cost medicines; on widely used drugs; and on therapies that are frequently used for off-label indications. Consumer Reports's Best Buy Drugs program uses the DERP analyses to develop information comparing the effectiveness and costs of widely used medicines.

Several foreign CE research programs have established models for CE advocates in the US. The National Institute for Health and Clinical Excellence (NICE) in the United Kingdom provides Britain's National Health Service with recommendations about the coverage of new drugs and diagnostics and about clinical best practices. NICE sets a clear cost-effectiveness threshold that has led to controversial no-coverage decisions on several new, but costly, therapies.

Australia's Pharmaceuticals Benefits Advisory Committee reviews clinical evidence and makes coverage recommendations to the nation's health minister. Germany's Institute for Quality and Efficiency evaluates drugs and health services to help a Federal Joint Committee determine reimbursement and benefits. These programs generally assess commonly used drugs and established medical procedures and rely on literature searchers and epidemiological surveys to support recommendations.

Industry involvement

Pharmaceutical manufacturers consequently have been sponsoring more comparative studies on their own to meet regulatory and reimbursement requirements. Payers and formulary committees increasingly want to see data indicating superior efficacy or safety of new drugs compared to available treatments. FDA is demanding more postapproval safety studies comparing new drugs to existing therapies. Premarket safety and efficacy studies in Europe and other regions routinely test new products with comparators instead of placebos. And although FDA generally requests placebo-controlled studies, comparative clinical information can be critical for gaining agency approval and market access, particularly in crowded therapeutic classes or for new products that raise safety issues.

GlaxoSmithKline (London) is testing its long-acting type-2 diabetes treatment Syncria (albiglutide) against several active comparators such as metformin, insulin, sulphonylurea, and other drugs. The multiarm, 4000-patient study aims to show clear benefits over existing treatments for a therapy that may only require weekly or less frequent dosing.

Most large, multiyear comparative studies are funded by NIH and frequently yield results that dismay manufacturers. Probably the most controversial comparative study in the works is the National Eye Institute's assessment of treatment for age-related macular degeneration (AMD). The aim of the study is to determine any difference in safety or effectiveness for patients receiving Lucentis (ranibizumab), which is approved to treat AMD, or Avastin (bevacizumab), a colon-cancer therapy that has been widely used off-label for AMD. Both drugs are produced by Genentech (South San Francisco, CA) and derived from the same monoclonal antibody, but using Avastin to treat AMD costs less than one-tenth the price of Lucentis.

Comparative drug trials raise a host of logistical and regulatory issues for obtaining high-quality, uniform, and appropriate comparator drug products. Sponsors often run into difficulties with comparator availability, cost, expiration dates, storage requirements, and registration status. All these issues are compounded for global multisite studies that may require comparators from different sources. And for blinded studies of solid oral dosage forms, comparators often must be reformulated and retested to ensure uniform stability, dissolution, and bioequivalence. Study sponsors must document that comparators meet good manufacturing practice guidelines, have appropriate expiration dates, and are registered for use in all study sites.

While the most reliable source for a high-quality comparator usually is the original manufacturer, sponsors often must look elsewhere because of cost, strategic, and competitive reasons. Many manufacturers agree to supply comparator products for research at a price, knowing that they will want similar access in the future. Several wholesalers and specialized comparator suppliers facilitate such arrangements and ensure access to appropriate comparators to meet study needs.

Future directions

Demand for comparator products may increase along with growing interest in independent drug–drug studies. Although pharmaceutical companies want CE research to weigh medicines against surgery or other treatments, pharmaceuticals are ready targets because much more information about drugs is available from clinical trials, outcomes studies, and adverse-event reports. NIH's lengthy list of possible ARRA-funded research projects includes dozens of CE drug-research topics such as comparisons of new treatments for fibromyalgia, depression in children, and for autoimmune rheumatic and skin diseases.

But focusing on drugs and devices "misses the point," says Wilensky. "The real explosion in costs is in medical procedures." A Duke University study published in the New England Journal of Medicine in February 2009, for example, found that in certain situations, clot-busting drugs alone provided as much benefit for many heart-attack patients as did drug-coated stents—at much less cost. The Pharmaceutical Research and Manufacturers of America asked the IOM priorities committee to support studies that compare care processes, disease-management services, and benefit design. In a white paper on CE research, the Biotechnology Industry Organization backs CE research on preventive services, diagnostic tests, and medical procedures, as well as the interactions among components of the healthcare system.

A related industry concern is that a greater emphasis on broad patient responses to drugs and medical treatments will stymie advances in personalized medicine and development of targeted therapies. CE research basically seeks to identify therapies and to establish practice guidelines and treatment standards that are most beneficial for the largest numbers of people. Personalized medicine, conversely, involves selecting treatment choices for small patient populations and making patient-centered choices that may not conform to common practice guidelines. And therapies targeting rare or life-threatening diseases may not fit CE study designs because of the small size and heterogeneity of these populations.

Drug and device makers have formed the Partnership to Improve Patient Care and enlisted support from patient and medical groups to press for CE research on clinical value and outcomes, as opposed to cost effectiveness. The group recently signed up former Congressman Tony Coelho of California to headline its campaign to ensure that CE studies are well-designed, promote continued medical innovation, and protect patient access to "advanced treatment options."

The challenge for policymakers and scientists is to develop research methods and systems that support informed standards of care, along with the flexibility to address special needs. CE research advocates believe that the nation's bloated healthcare system contains so much excess spending that even modest curbs on unnecessary use of costly products and services will be beneficial. The CBO white paper notes that though some expensive new technologies and medical services provide enormous clinical benefits, "some medical services could be used more selectively without a substantial loss in clinical value." Policymakers insist that CE research will not lead to coverage denials, but will steer doctors and providers to treatments that offer greater benefits for particular patients and lower costs for everyone.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com