Biologics Debate Heats Up Between FDA, NCCN

Is the breast cancer drug Avastin the opening salvo that brings efficacy, toxicity, and costs together? Who will blink first — health plans, providers, regulators, or patients?

About three years ago, Medicare made a key change in how it covers cancer drugs for off-label uses. It expanded the number of compendia that doctors could turn to for help when choosing how best to treat a cancer patient — a complex challenge in a specialty in which most drugs are prescribed off label. One of those newly selected compendiums is published by the National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 21 of the world’s top cancer centers.

Provided that the off-label use of the drug had been recommended in the guidelines, the Centers for Medicare & Medicaid Services (CMS) would provide coverage. And earlier this year, when an expert panel at the FDA voted unanimously that the data on Avastin — a drug that costs about $88,000 a year for metastatic breast cancer — had completely failed to demonstrate the survival benefit needed to justify risking the harsh and potentially deadly side effects it could trigger, Medicare and oncologists waited to see what the experts at NCCN would say.


Days later those specialists, including some of the most prominent cancer experts in the field, voted unanimously in Avastin’s favor, snubbing the agency’s experts with only 1 of the 25 panel members present choosing to abstain. Avastin (bevacizumab) “in combination with paclitaxel is an appropriate therapeutic option for metastatic breast cancer with the evidence designation 2A,” the specialists concurred.

That 2A ranking is the second of four grades the NCCN issues to gauge the level of consensus that exists in support of a drug’s off-label uses, preceded by a top level indicating widespread consensus and then dropping to 2B and 3 as support for its use falls. As a result, several the country’s top insurers say they will continue to pay for Avastin, bowing to an institution that has rapidly built a powerful reputation as the primary arbiter of cancer drug use in America.

Scale of 1 to 3

Just before the FDA advisory panel took its vote against Avastin for breast cancer — a position that has yet to be formally accepted or rejected by FDA Commissioner Margaret Hamburg, MD, — Reimbursement Intelligence, a consulting company that provides analysis of the reimbursement landscape, polled 55 insurers and found that 80 percent offered coverage for Avastin in breast cancer. Ninety percent of those insurers looked to the NCCN compendium for guidance, with most covering an indication ranked 2B or above.

“For oncology, our main source of information for off-label uses is the NCCN compendium,” says Jim Cross, MD, head of national medical policy for Aetna. “If it’s 2B or higher, then we recognize it as something we would clinically cover.”

For Cigna, any treatment ranked 1 and 2A gains coverage, says Doug Hadley, MD, medical officer for the insurer’s coverage policy unit. A 2B rating warrants a case-by-case review. “The further you go down in the compendium,” he says, “the weaker the evidence becomes.”

Even before the NCCN vote was taken, UnitedHealthcare — which publicly adopted the NCCN compendium as its standard guide for evidence-based approaches to cancer treatments three years ago — had already announced its plan to continue to pay for Avastin so long as the drug maintained a status of 2B or better.

“UnitedHealthcare decided to use NCCN as the source of its coverage decisions based on their solid history of performance and their acceptance by medical oncologists as a reliable source,” says Lee Newcomer, MD, who heads up the insurer’s oncology services unit.

And treatment specialists at all three insurers have had plenty of praise for the NCCN’s evaluation process.

The NCCN experts are “the best,” says Cross emphatically. “They have the representatives from the major cancer societies, and are all well recognized researchers themselves. And if you want my opinion, they are the best.”

“There are always going to be some insurers that may well deny this because it’s not approved,” says Len Lichtenfeld, MD, the deputy chief medical officer for the American Cancer Society. “But most reputable insurers, based on my conversations, are looking for a reasonable source by which they can make reasonable decisions on what their coverage should be. The NCCN puts out the most widely used, most widely recognized compendium for cancer care. And the NCCN experts have come out very strongly in favor of Avastin as a treatment for metastatic breast cancer.”


“It’s quite a statement that you have the FDA pulling this as an indication for breast cancer and you have major insurers like United still looking to NCCN to provide that guidance,” says Marc Stewart, MD, the medical director of the Seattle Cancer Care Alliance, a researcher at the Fred Hutchinson Cancer Research Center, and an NCCN board member. “It says a lot about the confidence the third-party payers have in the NCCN.”

That confidence hasn’t even been dented by several reports citing ties between the NCCN experts and drug companies that reap billions from cancer drugs. Avastin was developed by Genentech, now a subsidiary of the multinational pharma company Roche, and the NCCN Web site has highlighted ties between 10 members of the panel and the manufacturer.

For oncologists, the NCCN compendium serves as a convenient reference guide on treatments. A physician, for example, can look up breast cancer by stage of development and see how the various chemotherapy regimens stack up, check on what the clinical trial data demonstrated and see if one or a combination of drugs could be more beneficial for an individual patient, says Douglas Blayney, MD, a past president of ASCO.

Single publication

CMS’s policy on covering off-label cancer drugs was hammered out close to 20 years ago, says Blayney. Legislators looking for off-label guidance chose to rely on a recommendation in the compendia. But after two of the compendia ceased publication, CMS was reduced to a single publication — American Hospital Formulary Service Drug Information. Regulators began to review other works, formally adopting the NCCN guidelines at the beginning of 2009 along with Drugdex and Clinical Pharmacology. The NCCN compendium is the only one devoted entirely to cancer drugs.

“Oncology as a specialty has always been very quick to explore the utility of different drugs and different diseases,” says Stewart. “Oftentimes when a new drug is approved, studies show a benefit in other diseases. It’s kind of a proliferation of success that goes beyond the off-label concept. There’s a new opportunity to combine drugs new and old, or new and new. There are so many drugs that are available, many efficacious in different malignancies.”

So when CMS decided to adopt the NCCN compendium, its stock went up for all payers. But with the NCCN squaring off against the FDA, some of the experts wonder whether the compendium can maintain its position.

“It’s controversial,” says Stewart. “You have a decision made by the FDA that the oncology committee in general didn’t agree with.” It’s also rare. “When the FDA changed its opinion on erythropoietins [anemia drugs], the NCCN restructured the guidelines, agreeing that the studies consistently demonstrated diminished survival. But with Avastin, the FDA is reversing a decision even though study outcomes are mixed.”

UnitedHealthcare’s Newcomer says that “The recent difference of opinion with the FDA advisory panel is causing policymakers to ask why experts using the same data offered conflicting recommendations. As we move into the future, NCCN will need to make its decision process more transparent to continue to maintain their respected position.”

In cancer, there’s a powerful impetus to provide coverage, even if there’s no solid data in support of a drug’s efficacy.

Controlling costs

What Blayney hears from insurers is that the employer bears the risk. “Employers have an incentive to keep their employees happy and many times the employers will have influence over coverage decisions, which have been fairly liberal in the cancer area. Cancer is a hot button issue for many people, and many insurers and administrators are reluctant to interfere.”

Just because payers will defer to the NCCN on coverage policies doesn’t mean that there are no effective ways to manage costs, says Hadley. Prior authorization is useful. And Cigna’s specialty pharmacy department, along with a lineup of pharmaceutical benefit managers, is charged with making sure, by carefully monitoring of patients’ response and compliance, that none of these expensive drugs are being wasted.

“Our approach is to integrate the pharmacy and the medical benefit,” says Hadley. “We’re unique in that respect. The pharma and medical team work together to make sure an individual is getting the most appropriate drug for that person — the right drug for the right person at the right time.”

But Hadley would like to take another step in managing costs.

“We would like to develop ways to link the use of certain of these high-priced products to outcomes,” adds Hadley.

“If pharmaceutical manufacturers say a particular drug will improve outcomes by a certain percentage, are they willing to back up that claim from a financial perspective? How do we get to financing medical costs that are outcomes-based rather than unit-based?”

But despite widespread agreement on the powerful influence the NCCN has on private and public payers’ coverage practices, several of the country’s top oncologists also voiced concern that the often extraordinarily expensive cancer drugs coming into the market may eventually force payers to take a second look at their cancer drug coverage policies. And if they do, even the NCCN may not protect a patient’s supply of drugs.

New cancer drugs with big sticker prices have been approved over the past year, most notably Provenge, a prostate cancer vaccine developed by Dendreon that sells for $93,000 for a full course of treatment, and Yervoy, a melanoma drug from Bristol-Myers Squibb that costs $120,000.

“The issue has been brought to a head by the Avastin controversy,” agrees Blayney. “If the label changes on breast cancer, because it’s so expensive, it may cause insurers to rethink their reimbursement policy for Avastin.” Payers aren’t likely to spend much time reviewing the utility of a $2 drug, but “if it’s a $100,000-a-year biologic, they are likely to subject that to more scrutiny.”

Back in the ’90s, Lichtenfeld says, insurers did try to rein in the use of cancer treatments until the courts stepped in and forced them to loosen the reins. “That put a damper on insurers’ interest in intense oversight on cancer treatments.” Health plans also had bigger cost items to deal with at the time and were acutely aware of the heated arguments that would come their way if they yanked coverage of a cancer drug.

“Those things are now changing,” says the physician. “Cancer costs are increasing, and carriers are being affected.” Physicians are beginning to take costs into consideration.

Stewart says that “increasingly we need to look at costs. NCCN needs to look at that also and needs to provide physicians and patients with some realistic view of efficacy versus toxicity for several treatments. And then we need to be able to link that to the cost of the treatment.”

Right now, there’s no information on cost in the compendium, Stewart adds. But the experts at NCCN are exploring how it could fit in.

“The NCCN is developing a comparative therapeutic efficacy index,” says Stewart. “It’s an attempt to try to look at the efficacy of a regimen, toxicity, and then for each regimen to be able to compare costs. That’s a brilliant idea. There are all kinds of methodological issues, but we have to start somewhere.”

“Our approach is to integrate the pharmacy and the medical benefit,” says Doug Hadley, MD, Cigna’s medical officer in the coverage policy unit.

Fifty to 80 percent of cancer drug use is off label.

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