CMS policy drives fall in ESA use

Mounting evidence suggests that a 2007 Medicare coverage decision has severely curtailed the use of ESAs for chemotherapy-induced anemia. And, despite continued support for ESA use among major professional associations such as ASCO and ASH, the CMS curbs are now hitting the patients of private payers as well.

Under the stringent new guidelines, CMS (Centers for Medicare & Medicaid Services) now covers ESAs (erythropoiesis-stimulating agents) only to prevent anemia-related blood transfusions, not to treat chemotherapy-induced quality-of-life symptoms such as fatigue.

Many viewed CMS's national coverage determination (NCD) on ESAs as a convenient maneuver to curb Medicare's burgeoning budget. CMS countered that its decision was evidence-based. CMS spoke, now what?

Apparently, CMS got what it wanted; the NCD has already cut deeply into ESA use by Medicare recipients, saving the agency millions of dollars. Shortly after the final NCD was announced, leading oncology organizations became worried that major private payers would follow Medicare's reimbursement template, further grinding ESA usage to a halt.

Echoing their trepidation, several US senators, including Arlen Specter (R-Penn), introduced a resolution stating that CMS should consult with leaders in the oncology community and revise the NCD according to their recommendations. CMS stood firm, refusing to alter the guidelines.

Usage drops

According to anecdotal data and judging from the market's response, it seems the oncology community's concern was well founded. By the third quarter of 2007, Amgen reported that use of darbepoetin (Aranesp) had dropped a staggering 36% in the United States.

In The RPM Report, Amgen's executive vice president of commercial operations, George Morrow, noted that use of ESAs in chemotherapy-induced anemia patients is down 30% to 40%, even though no private payers have adopted payment policies as restrictive as those of CMS.

Several private payers have reported a sizable drop in ESA coverage. Lee N. Newcomer, MD, chief medical officer of United HealthCare, told ONI, "We anticipated this problem before it happened and initiated a pilot preauthorization program. We don't reimburse for patients with a hematocrit level that exceeds 36. Nor do we address starting levels, dosage maximums, or specific diagnoses in our policy. And we are seeing a 35% reduction in ESA usage with this edit alone."

In issuing a national coverage determination, CMS has the luxury of broadly interpreting the phrase "reasonable and necessary" in the context of forming coverage determinations. In making a noncoverage decision, such as in the use of ESAs, the agency determined that "the evidence is not adequate to conclude that the item improves net health outcomes for the patient."

The major oncology organizations have argued that used under proper guidelines, ESAs, in fact, are "reasonable and necessary" in relieving their patients' chemotherapy-induced symptoms.

Although the FDA's labeling for use of ESAs, for now, has somewhat conformed to the ASCO/ASH guidelines, the agency contends that its policy on the use of ESAs is essentially in line with those of CMS.

Despite their rhetoric of alliance, CMS and FDA are at odds with each other, looking at the same data but interpreting it differently. The two agencies actually agree only in two ways: ESAs should be avoided in cancer patients not receiving chemotherapy, and ESAs should not be used in patients with hemoglobin levels greater than 12 g/dL.

In short, FDA's drug-safety and monitoring system has been slammed as inadequate and in need of reform by government agencies such as the Institute of Medicine and in the mainstream press. In what appears to be an effort to side-step the controversy, FDA's ESA warning label is essentially an ambiguous "swim at your own risk" sign that has baffled many oncologists around the country.

What happened to evidence-based medicine?

David H. Henry, MD, a clinical researcher at Pennsylvania Hospital who has led trials investigating ESAs, spoke to ONI about the issue.

"The current ESA issue is troubling," he said. "Despite a few explainable safety signals that came up in the 2004 ODAC [Oncology Drugs Advisory Committee] meeting, everything went well and the label was maintained. Then we came into the 'perfect storm' of the winter of 2007, and these purported safety signals pop up. It's hard to understand why there is so much retro-reaction, enough to almost eliminate the use of these drugs."

Dr. Henry stressed that ESAs, used under the proper guidelines, improve quality of life. "There are very good placebo-controlled trials that demonstrate that," he said.

Dr. Henry pointed to the work of noted quality-of-life expert, David Cella, PHD. As far back as 2003, Cella et al found a relationship between quality of life and hemoglobin levels. Using the FACT-AN scale, 25% of cancer patients with hemoglobin levels ≤ 12 g/dL reported they were unable to work, compared with only 8% of patients with levels > 12 g/dL.

Dr. Cella's work on ESAs was also noted as evidence at the pivotal May 2007 ODAC meeting. Presenter Jeffrey Crawford, MD, chief of medical oncology, Duke University, cited five Cella-led studies looking at the impact of anemia-driven fatigue on health-related quality of life that clearly "favor the use of epoetin alfa and darbepoetin."

According to Dr. Henry, CMS and FDA have caused undue friction by what the major organizations and some members of Congress see as opportunistic interpretation of the pertinent data. CMS contends their decision was made by reviewing 800 prominent articles in the literature that speak to the ESA issue.

"Why then did ASCO, ASH, NCCN, and even the European guideline writers come to a different conclusion on the use of ESAs after reviewing the same 800 papers?" Dr. Henry asked. As a clinical investigator, he referred to the CMS interpretation of the literature as nothing short of wrongheaded.

FDA labeling draws fire

As late as November 2007, testifying before a Congressional subcommittee on healthcare, the director of FDA's Office of New Drugs and of the Center for Drug Evaluation and Research, John K. Jenkins, MD, said, "At this time, FDA continues to believe that ESAs are safe and effective when used at the recommended dose and approved indication."

Many oncologists wondered how, once again, reviewing the same data as CMS did, FDA could conclude ESAs were "safe and effective" above the 10 g/dL level, which CMS had made as its cut-off point, citing lack of efficacy.

Dr. Henry explained that the two-tier coverage created by the CMS-FDA policy has left clinics and hospitals struggling. It is ethically discomforting and administratively burdensome to implement one treatment protocol for Medicare patients and another widely diverging protocol for all other patients, he said.

FDA has justified its confusing stance on ESA usage by saying, "We cannot exclude a negative survival impact when using ESAs under 12 g/dL."

What does that mean, Dr. Henry wondered, offering an analogy. "So, according to FDA logic, if you drive a car at 120 miles per hour, a bad accident is very likely, but even if you drive at a safe speed, I still can't exclude that you might be injured in a bad accident."

Imagine the ethical quandary, Dr. Henry said, "when an oncology practice falls in line with CMS and refuses to cover a privately insured patient. The patient says, 'I don't have insurance with CMS, I have it with you! So why are you withholding this drug from me?'"

Effect on community practices

For this article, more than a dozen oncologists from across the country were asked how the new ESA policy affected their practices. Not surprisingly, many declined to comment. Of those who did, most agreed that the NCD and FDA labeling had made them less inclined to prescribe ESAs for two basic reasons: extra paperwork and fear of not getting paid.

One thoughtful response came from David Mintzer, MD, a hem/onc general practitioner in Pennsylvania. His eight-doctor practice has been active in clinical trials for many years studying the optimal use of erythropoietin, under the direction of Dr. Henry.

When using ESAs, Dr. Mintzer said, the priorities are patient safety and maintaining quality of life. He stressed that a two-tiered system for ESAs is medically and ethically unappealing, and that the recommended CMS guidelines are complex, cumbersome, and confusing.

"On the other hand," he added, "I do believe that the use-and perhaps more so the cost-of these agents to the medical system as a whole needed to be reined in, even before the safety concerns were raised. Oncologists, including organizations like ASCO and ASH, need to take a more active role in controlling healthcare costs. We seem to have abdicated our role in doing so."

FDA has scheduled another ODAC meeting on the use of ESAs to convene in the first quarter of 2008. Amgen is expanding its pharmacovigilance program by initiating seven new clinical trials assessing the risks associated with ESAs. More data on ESAs will inevitably add to the mountain of existing literature. The question is, who will read the data, and how will it be interpreted?