The discussion about cancer treatment in the United States has changed from the hope and promise of new innovations to considerations of whether a treatment is worth the personal and societal cost. This philosophical shift coincides with the aggressive application of comparative effectiveness evaluations of cancer care under the American Recovery and Reinvestment Act (ARRA, 2009) and the Affordable Care Act (ACA, 2010), which are the cornerstones of U.S. health-care reform. To meet cost-containment criteria, the Affordable Care Act included $500 billion of cuts to Medicare over 10 years.

In 2012, the Affordable Care Act will create the Independent Payment Advisory Board to "recommend payment policy revisions to contain Medicare cost growth" while the Medicare population swells with the baby boomer generation. As described by a Centers for Medicare & Medicaid Services (CMS) document entitled, "Affordable Care Act Update: Implementing Medicare Cost Savings," almost $24 billion in Medicare cost savings is projected by 2019. These cost savings are assured, as the "Independent Payment Advisory Board's proposals on how to improve care and control program expenditures are binding when Medicare cost projections exceed certain targets, unless Congress acts to reduce expenditures in other ways." The law also stipulates that the Independent Payment Advisory Board will publically report system-wide health-care costs, patient access to care, utilization, and quality of care.

Recently, various Federal agencies have scrutinized treatment with biologic agents for metastatic disease resulting from three of the most common malignancies in the United States-colorectal, breast, and prostate cancers.
In January 2010, the Agency for Healthcare Research and Quality (AHRQ) initiated evaluation of the "real world" benefits and harms of the FDA-approved regimen of cetuximab (Erbitux) and bevacizumab (Avastin) for the treatment of metastatic colorectal cancer.

In July 2010, the FDA Oncologic Drugs Advisory Committee (ODAC) recommended against full FDA approval for bevacizumab as a first-line treatment of metastatic HER2-negative breast cancer.

In November 2010, the CMS Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) evaluated the use of autologous cellular immunotherapy with sipuleucel-T (Provenge) for metastatic hormone-refractory prostate cancer.

Cetuximab and Bevacizumab in Colorectal Cancer

Acknowledging on its website that "clinical trials support the efficacy of the biologic therapies cetuximab and bevacizumab for the treatment of metastatic colorectal cancer," the AHRQ began an evaluation of the "real-world effectiveness in diverse populations" in January 2010. This study, using cancer registries, the Medicare program, National Comprehensive Cancer Network (NCCN) data sources, NCI's Cancer Care Outcomes Research and Surveillance Consortium, and a phase IV industry-sponsored registry, is measuring the size of the "implementation gap."

As defined by the Agency for Healthcare Research and Quality, the implementation gap is the difference between efficacy and effectiveness in clinical trials and in the nonexperimental setting. The AHRQ further defines these terms as follows: "Efficacy trials [explanatory trials] determine whether an intervention produces the expected result under ideal circumstances," whereas "effectiveness trials [pragmatic trials] measure the degree of beneficial effect under 'real world' clinical settings."

The implementation gap will be evaluated by this registry-based data analysis for patients with attributes similar to clinical trial participants, and among populations that were either excluded or underrepresented in the clinical trials. The degree of beneficial effect is broader than overall survival, and, in terms of comparative effectiveness research, relates also to functional and symptomatic outcomes, including the burden of therapy.

Bevacizumab in Breast Cancer

The importance of quality-of-life measures and outcomes featured prominently in the ODAC recommendation against full FDA approval for bevacizumab as a first-line treatment of metastatic HER2-negative breast cancer. Although the FDA does not generally use quality-of-life measures in the approval process, the importance of quality-of-life outcomes was noted in public testimony and in ODAC member decision-making.

In public testimony, members of a breast cancer advocate group-SHARE Leaders-made the following three arguments: First, "trials subsequent to accelerated approval failed to demonstrate a clinically meaningful benefit that is either an improvement in overall survival, or a sufficient magnitude of progression-free survival together with improved quality of life." Next, the advocates challenged the merit of progression-free survival as a credible endpoint, noting, "Overall survival, without compromising quality of life, must remain as a primary goal of research." Third, the advocates argued, "a meaningful, progression-free survival time frame combined with few toxic side effects and a better quality of life could be an acceptable endpoint, particularly in metastatic disease."

During the voting regarding bevacizumab in metastatic breast cancer, many ODAC members subsequently cited the lack of quality-of-life measures and outcomes data. Comments included:

"Even with the 2.9 months of progression-free survival, there's still no overall survival benefit to the patient, there's very significant risk to the patient, and there's no demonstrated positive patient outcome in terms of quality-of-life measures."

"What we are here to judge is whether or not there is a clinically meaningful-from a patient's point of view-quality-of-life benefit."

The burden of therapy was addressed by one ODAC member who commented: "We keep talking about quality of life. But we haven't addressed the quality of life [and] what's required when you're on an agent like this [bevacizumab]."
Beneficial effect, defined by quality-of-life outcomes, again took the forefront in the assessment of biologic agents for metastatic disease.

Sipuleucel-T in Prostate Cancer

In November 2010, the Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) considered on-label and off-label use of sipuleucel-T for asymptomatic or minimally symptomatic metastatic, hormone-refractory prostate cancer. Although not explicitly discussed by the Committee, media coverage of the Medicare Committee meeting highlighted the $93,000 cost of the course of sipuleucel-T therapy relative to the 4‑month increase in overall survival.

The Committee was asked to evaluate the evidence that sipuleucel-T "significantly improves" overall survival and control of disease-related symptoms, and avoids or minimizes "the burdens associated with anticancer therapy while maintaining overall survival and control of disease-related symptoms." The panel gave the agent an intermediate confidence score in overall survival. Despite the FDA's requirement to perform a postmarketing study of sipuleucel-T to evaluate the risk of stroke, the Committee also turned in an intermediate confidence vote that treatment-related symptoms were avoided. However, there was low confidence in the ability of sipuleucel-T to control disease-related symptoms. No confidence was related in the off-label use of sipuleucel-T in metastatic prostate cancer for moderate to severe symptoms, in hormone-responsive metastatic prostate cancer, and when prostate cancer has not metastasized.

Like the experience with bevacizumab in metastatic breast cancer, the sipuleucel-T clinical trials offered little quality-of-life data.

Conclusions

Following the mandates of the American Recovery and Reinvestment Act, the Institute of Medicine detailed comparative effectiveness research priorities in 2009. These three evaluations of biologic agents for metastatic disease in 2010 fulfill the Institute's priorities. Each of these evaluations involves a biologic agent for incurable metastatic cancer, a lack of quality-of-life measures and outcomes data, and the implicit issue of cost.  Clinical benefit is no longer defined by an increase in overall or progression-free survival. Now clinical benefit is defined by the AHRQ as efficacy and effectiveness, and, especially for metastatic disease, improved quality-of-life outcomes. Comparative effectiveness assessments that include quality-adjusted life-year (QALY) calculations will increasingly influence practice guidelines and reimbursement.

These three evaluations were performed by the three most powerful agencies in the Department of Health and Human Services: AHRQ (which spearheads the Federal comparative effectiveness efforts), the FDA, and CMS. Despite originating in different agencies within the Department of Health and Human Services, each one of the evaluations has consistent language regarding clinical benefit and effectiveness. These three high-profile examples respond to increasing economic pressures and set expectations for the evidence required from ongoing and future clinical trials to merit FDA approval and Medicare reimbursement of novel agents. Those expectations include validated quality-of-life measures and outcomes data that meet QALY criteria.

In response to these clear messages, clinical trials should determine symptom burden from cancer and its treatment early on in clinical trials. Quality-adjusted life-year calculations performed early in the course of a clinical trial will provide insight into clinical benefit beyond survival, help determine the clinical trial course, and avoid restrictions in the use and reimbursement of the agent following FDA approval. ■

Dr. Janjan is Senior Fellow in Healthcare Policy and Dr. Goodman is President and CEO, National Center for Policy Analysis, Dallas. The National Center for Policy Analysis is a nonprofit conservative think tank established in 1983 and headquartered in Dallas, Texas.
Disclosure: Dr. Janjan served as a consultant to Dendreon prior to the Medicare Evidence Development & Coverage Advisory Committee meeting on sipuleucel-T (Provenge).