Until now, the U.K.' s National Institute of Clinical Excellence hasn't seen much that's cost-effective about Merck Serono's cancer treatment Erbitux (cetuximab). So NICE's June 1 announcement that it was, indeed, recommending reimbursement by the National Health Service for some colorectal patients came as something of a surprise.
The drug was rejected in January 2007 as a second-line treatment for colorectal cancer and more recently as a treatment for recurrent and/or metastatic squamous cell head and neck cancer. NICE preliminary guidance on the drug's use as first-line therapy for metastatic colorectal cancer, issued in September 2008, was also negative.
This time though, Merck Serono's revised economic analysis of the drug's cost-effectiveness, plus a rather generous 16% rebate, helped persuade NICE to recommend the drug.
That said, the agency has tightly defined criteria for the kinds of patients who may be treated with Erbitux. The drug is recommended in combination with the widely-used chemotherapy regimen comprising 5-fluorouracil (5-FU), folinic acid and oxaliplatin (FOLFOX), but only for metastatic colorectal cancer patients who meet three conditions - they already underwent primary surgery; their disease is confined to the liver, and they are fit enough to undergo potentially curative liver surgery to remove metastases once the drug has helped shrink the tumors. (Erbitux is also recommended, under the same conditions, for use with another chemotherapy regimen, FOLFIRI, in those patients unable to tolerate oxaliplatin.)
Alongside the rebate, Merck Serono also incorporated a 'stopping rule' whereby treatment with Erbitux is capped at 16 weeks, at which time patients are typically referred for surgery. Erbitux is indicated only for patients with EGFR-expressing, Kirsten rat sarcoma (KRAS) wild-type tumors, although these represent most patients.
In other words, Erbitux is only available to KRAS wild-type patients for whom the drug is likely to make curative liver resection - removal of part of the liver - a viable option.
The 16 percent rebate helped....
For those patients that meet the criteria, Merck Serono is offering a 16 percent rebate off the NHS price for the drug, which is already about 15 percent lower than the published list price; Erbitux costs approximately £2,850, or about $4,700 per patient per month. According to Merck Serono's Director of Health and Clinical Excellence Gillian Shepherd, the rebate will be calculated on a three-month basis and could take the form of a credit note, cash, or a stock rebate.
Merck Serono isn't the first to take such a step. Other companies including Pfizer, Celgene, and Janssen-Cilag, have made similar moves in the U.K. to refund or pay for part of the price of their drugs, believing this to be a worthwhile compromise to avoid a 'no' from NICE - which effectively kills most commercial prospects in the U.K., and, arguably, elsewhere in Europe (See 1"The Cost-Sharing Solution: The New NICE Ticket," The RPM Report, February 2009).
Still, "we've provided a flexible approach to make sure there's minimal administrative burden to the NHS," Shepherd continues. That's important, since administration has become a key issue for the U.K.' s NHS as cost- and risk-sharing schemes multiply, each with its own flavor. Celgene, for instance, has agreed to administer its U.K. cost-sharing plan for multiple myeloma drug Revlimid (lenalidomide), piggybacking on the drug's existing risk-minimization plan, which is a condition of its license (See 2"NICE Deal, Celgene," The IN VIVO Blog, Feb. 9, 2009).
...But cost-share wasn't enough
Merck Serono's 16 percent discount and its flexible approach to administering the price break weren't in themselves enough to win over NICE. According to the agency's now-public 'final appraisal determination' document, the company submitted a revised economic analysis of the drug, following the initial negative outcome, with some important adjustments beyond the cost-share.
These included revised assumptions on liver resection rates for patients on Erbitux plus chemotherapy and patients on chemotherapy alone (if a patient is deemed suitable for resection this suggests the drug has done its work shrinking the tumors). The company likewise reduced its estimates of the liver resection failure rate from almost 28 percent to 5 percent, in accordance with clinician advice.
Merck Serono's updated analysis also included the 16-week treatment duration cap. By limiting the length of time the drug can be used, the drug will appear to be more cost-effective (reducing its so-called 'cost per additional quality-of-life year gained,' or cost-per-QALY, which is the measure NICE uses). On the other hand, Merck Serono also more than quadrupled its estimate of the cost of liver surgery in the U.K. to more accurately reflect current clinical practice, according to the NICE document. This indirect cost of treatment - since Erbitux use will in theory mean more patients qualify for liver surgery than might otherwise - will have pushed the cost-per-QALY up again.
The agency's earlier concerns about the accuracy and availability of KRAS testing in the U.K. appear to have been assuaged by evidence from clinical specialists that it has become more widespread, even though testing is currently available in only two NHS centers in the UK. (In the US, some insurers are changing their coverage policies to require KRAS testing before reimbursing Erbitux (3"The Pink Sheet," April 6, 2009 p. 25).
Thus in the end, summarizes Shepherd, "there was clarification around clinical data and alignment of that data to clinical practice in the U.K. population." The overall result of these adjustments was that the drug's cost-per-QALY fell within a range "that could be considered a cost-effective use of NHS resources," according to NICE.
The lesson for other companies seeking NICE's approval is to carefully collect U.K.-relevant data on surgical and clinical practice to use in economic modeling, and to be prepared to compromise, whether through limiting treatment duration, and/or through offering some kind of simple-to-administer discount scheme.
Amgen is among those watching Erbitux's journey past NICE. Given the similarities between Erbitux and Amgen's Vectibix (panitumumab), another anti-EGFR antibody, "we'll look closely at whatever they [NICE] determine and at the nature of their approval," Amgen Chief Medical Officer Willard Dere said in a February 2009 interview. NICE has not yet provided a time-frame for Vectibix's review in metastatic colorectal cancer.
NICE's final guidance on Erbitux will be issued in July 2009. The current draft guidance is subject to appeal until June 19.
- Melanie Senior (m.senior @elsevier.com)
This article is reprinted from "The Pink Sheet" DAILY –June 2, 2009
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