Comparative Research to Shape Clinical Trials

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 set off a firestorm about using comparative study results to limit coverage of more expensive medicines.

Jill Wechsler

Conservatives raised the specter of "government rationing" and "cookbook medicine."

Comparative effectiveness (CE) enthusiasts, including Obama administration officials, countered that more and better information about which medical products and procedures are most effective can improve care and cut unnecessary spending. But a White Paper last year from the Congressional Budget Office looked to CE research to "provide a basis for applying costly new technologies only when they are likely to confer added benefits."

The final ARRA legislation compromised 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, however, that once CE research results are available to the public, health plans and payers can use the data as they see fit.

Expanding studies

In any case, the government-funded CE research program opens the door for the federal government to play a larger role in selecting and shaping comparative assessments. Instead of establishing a new, independent entity to carry out CE research, as some advocated, the stimulus package divides $1.1 billion among three arms of the 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 fund CE research conducted by its various Institutes. The remaining $400 million goes to the HHS secretary to support standards development, establish 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. The importance of the committee's deliberations was seen in the dozens of interested parties that presented their opinions at a March public meeting on 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, the disabled, and subpopulations, including women and minorities.

To ensure broad input, the IOM also established an online system for anyone to submit specific proposals for CE studies. The questionnaire requests a brief summary of the research question, study design, study population, and likely comparators. The panel is ranking these proposals according to disease burden, disease severity, variation in care, cost, public interest, and gaps in current information.

A new Federal Coordinating Council for CE Research will monitor how well HHS meets the IOM priorities in awarding CE research grants. The 15-member council includes top officials from HHS, NIH, AHRQ, OMB, the FDA, and others.

In the spirit of transparency, HHS will publish information on grants and contracts awarded under this program, will disseminate the research findings that result, and will report annually to Congress on the program. Grants may go to government agencies and to private organizations with demonstrated experience in this area.

One benefit of a broader CE research program would be to improve methods for conducting comparative studies. Research experts see a need, and an opportunity, to use some of the federal funding to develop innovative trial designs for real-world assessment of medical treatments.

At the IOM meeting, Bryan Luce, senior vice president of UBC, urged "true transformational thinking" in designing CE studies; otherwise, he said, we will "waste vast amounts of money answering the wrong questions, or the right questions too late."

Nothing new

The federal CE research initiative builds on years of activity in this area. 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, 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 or 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 that are frequently used off-label.

A number of foreign CE research programs have spurred interest in the United States. 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 the coverage of new drugs and diagnostics and on clinical best practices. NICE sets a clear cost-effectiveness threshold that has led to controversial no-coverage decisions on a number of new, but costly, therapies.

Pharmaceutical companies also are underwriting more comparative studies to meet regulatory and reimbursement requests. Payers and formulary committees want data on superior efficacy and safety of new drugs compared to available treatment.

More postapproval safety studies are comparing new drugs to existing therapies. Premarket clinical trials in Europe and other nations routinely test investigational products against active comparators. Even FDA, which generally requests placebo-controlled studies, finds comparative clinical information useful in documenting advantages for new drugs in crowded therapeutic classes or where serious safety issues arise.

Johnson & Johnson's Centocor, for example, sponsored a large Phase III comparator trial to demonstrate that its new psoriasis drug, ustekinumab, is more effective than Amgen's TNF inhibitor Enbrel (etanercept). Eli Lilly has compared its anticlotting drug prasugrel to field leader Plavix (clopidogrel) to better assess efficacy as well as reports of internal bleeding.

GlaxoSmithKline is testing its new long-acting type-2 diabetes treatment Syncria (albiglutide) against multiple active comparators such as metformin, insulin, and other drugs, in a multi-arm, 4000-patient study seeking to show clear benefits over existing treatments.

Such large comparative studies are usually funded by NIH, which has the resources and research networks to carry out long-term, multisite assessments. Several of these high-profile trials, though, have concluded that newer, more costly drugs may not perform any better than older, cheaper medicines, much to the dismay of pharma companies.

Future directions

Instead of such drug-drug comparisons, pharma companies want CE research to weigh medicines against surgery or other invasive treatments and to compare care processes, such as disease management, care coordination, and various benefit designs. But the clamor on all sides for more information on the value and quality of drugs and medical products means that pharmaceuticals will be a visible focus of the new CE initiative.

Drugs are ready targets, moreover, because there is much more information on FDA-regulated products from clinical trials, outcomes studies, and adverse event reports. NIH's lengthy list of possible ARRA-funded research projects includes dozens of drug CE research topics, such as comparisons of new treatments for fibromyalgia, for depression in children, and for treating autoimmune rheumatic and skin diseases.

To offset any rush to link CE research to coverage limitations, sponsors and patient advocates raise the prospect that broad comparative research could stymie development of more targeted therapies integral to advancing personalized medicine. Comparative studies basically aim to identify drugs and to establish treatment standards that are most beneficial for the largest numbers of people. Personalized medicine, conversely, involves treatment of small patient populations in ways that often differ from practice guidelines.

The challenge for policy makers, sponsors, and investigators is to develop research methods and systems that can support more informed standards of care, along with flexibility to address individual patient needs. Policy makers insist that CE research will not lead to coverage denials, but will steer providers to treatments that offer greater benefits for particular patients.

The important questions, comments health policy expert Gail Wilensky, 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 the Washington editor of Applied Clinical Trials, (301) 656-4634 jwechsler@advanstar.com