Comparative Effectiveness Research to Shape Biotech Studies

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

Conservatives raised the specter of "government rationing" and "cookbook medicine." Comparative effectiveness (CE) research enthusiasts countered that more and better information about which medical products and procedures are most effective can improve care and cut unnecessary spending.

Jill Wechsler

The final legislation represents a compromise 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." However, more evaluation of clinical outcomes and treatment effectiveness opens the door to a much broader role for the federal government in selecting and shaping comparative assessments and to greater reliance on CE studies for directing medical practice.

SETTING PRIORITIES

Instead of establishing a new, independent entity to carry out CE research, as some advocated, the stimulus package divides the $1.1 billion in funds among three arms of the Department of Health and Human Services (HHS). The Agency for Healthcare Research and Quality (AHRQ) gains $300 million to expand its outcomes and effectiveness research program. The National Institutes of Health (NIH) gets $400 million to support research conducted by its various institutes. The remaining $400 million goes to the HHS secretary to support standards development, a registry, and data systems and other activities.

How these agencies dole out the money will be shaped by a June 30 report from the Institute of Medicine (IOM) recommending priorities for CE research. Dozens of interested parties presented their opinions at a public meeting in March on how CE research should be conducted and which topics should be studied. The IOM panel will consider the needs of populations served by federal programs, with an eye to including women and minorities in research.

To ensure broad input to the priority-setting process, the IOM also established an online system for anyone to submit specific proposals for CE studies. The panel is ranking these submissions according to disease burden and severity, variation in care, cost, public interest, and gaps in available information.

A positive result of CE research would be the development of standards and improved methods for conducting comparative studies. At the IOM meeting, Bryan Luce, senior vice president at United BioSource, urged "true transformational thinking" in designing CE research studies; otherwise, he said, we will "waste vast amounts of money answering the wrong questions, or the right questions too late."

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

NOTHING NEW

Although ARRA funding will spur CE-studies activity, a good deal of this 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. In the private sector, the Blue Cross and Blue Shield Association's Technology Evaluation Center has been reviewing clinical evidence since 1985 to determine the effectiveness of certain medical procedures, drugs, and medical devices. The Drug Effectiveness Review Project at the Oregon Health & Science University provides state Medicaid agencies and large insurers with comparative information on the efficacy and safety of new, high-cost medicines, and on drugs frequently used off-label.

A number of foreign CE research programs have spurred interest in the US. Most prominent is the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom, which provides Britain's National Health Service with recommendations on coverage of new drugs and diagnostics. NICE sets a clear cost-effectiveness threshold that has led to controversial no-coverage decisions on several new, but costly, biotech therapies.

INDUSTRY INVOLVED

Biopharmaceutical companies also have been underwriting more comparative studies to meet regulatory and reimbursement requirements. Payers and formulary committees weighing drug coverage options want data on superior efficacy and safety compared to available treatments. More postapproval safety studies are comparing new drugs to existing therapies. Premarket clinical trials in Europe and other nations routinely compare investigative products to comparators. Even the FDA, which generally prefers placebo-controlled studies, finds comparative clinical information useful in documenting the advantages for new drugs in crowded therapeutic classes or when serious safety issues emerge.

Johnson & Johnson's Centocor, for example, sponsored a large Phase 3 comparator trial to demonstrate that its new biologic, ustekinumab, is more effective than Amgen's TNF inhibitor Enbrel (etanercept) for treating patients with psoriasis. Eli Lilly has compared its anticlotting drug, prasugrel, to field leader Plavix (clopidogrel) to better assess efficacy and reports of internal bleeding. GlaxoSmithKline is testing its new type 2 diabetes treatment, Syncria (albiglutide), against multiple active comparators, such as metformin, insulin, and others. The multi-arm, 4,000-patient study aims to show clear benefits over existing treatments for a therapy that may require less frequent dosing.

Such large comparative studies are usually funded by the NIH, which has the resources to carry out long, multisite assessments. These can be controversial, as with the National Eye Institute's assessment of treatments for age-related macular degeneration. The aim is to determine any difference in safety or effectiveness for two similar Genentech therapies, Lucentis (ranibizumab) or Avastin (bevacizumab).

Comparator drug trials require manufacturers to address a host of logistical and quality issues to obtain appropriate comparative products. Sponsors routinely run into difficulties dealing with product availability, expiration dates, storage requirements, registration status, and costs. Comparators often have to be reformulated and retested for studies that require patient blinding. And all these issues are compounded for global multisite studies using comparators from different sources.

Manufacturers would like federal CE research initiatives to focus less on drug–drug comparisons and more on the effectiveness of various care processes. A white paper on CE research from the Biotechnology Industry Organization (BIO) urges more analysis of preventative services, diagnostic tests, and medical procedures, and how components of the healthcare system interact. Focusing on drugs and devices "misses the point," says health policy expert Gail Wilensky. "The real explosion in costs is in medical procedures."

The industry is also concerned that CE research could stymie the development of more targeted therapies that are integral to advancing personalized medicine. Comparative studies basically aim to identify drugs and establish treatment standards that are most beneficial for the largest numbers of people. Personalized medicine, conversely, involves treating small patient populations in ways that often differ from practice guidelines. CE studies frequently are not appropriate for therapies that target rare or life-threatening diseases affecting small patient subgroups. 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.

Policy makers 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. The important questions, Wilensky notes, are whether CE data has credibility, whether research practices are open and transparent, and whether studies are objective and not politically motivated.

Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, jwechsler@advanstar.com