NICE Rejects Javlor, But Could Products For Unmet Clinical Needs Be Rethought?

U.K. cost watchdog rejects Pierre Fabre's Javlor even though it extended the survival of patients with metastatic bladder cancer.

Although the U.K.' s cost watchdog rejected the cancer drug Javlor (vinflunine) in a draft appraisal released Nov. 23, the product's developer, French company Pierre Fabre, hopes that it can reverse this decision while at the same time stimulating a debate on how drugs that treat previously unmet clinical needs can be better assessed.

The National Institute for Health and Clinical Excellence rejected Javlor for use in advanced transitional cell carcinoma of the urothelial tract (TCCU), a condition for which there is no recognized treatment after relapse on other therapies.

In a Phase III clinical trial of vinflunine, the fact that the control arm was best supportive care meant that it included patients with late-stage disease, and short likely survival, who accepted that they might be randomized to a non-active therapy, Pierre Fabre explained.

In the study, patients receiving best supportive care survived for 4.6 months on average, while vinflunine was associated with a 2.6 month improvement over that level in median survival. Such significant activity in advanced disease suggests the medicine has potential for development in less severe disease, the company noted.

But the broad assumptions made about the resources needed for best supportive care meant that economic modeling produced incremental cost effectiveness ratios (ICERs) of an "unrealistic" £120,000 ($187,000) per quality-adjusted life year (QALY), compared with an actual treatment cost in the U.K. of £9,817, Pierre Fabre said.

NICE's appraisal committee even noted that when the acquisition cost for Javlor is reduced to £0 and the significant survival gain maintained, the cost per QALY still remains "ridiculously close" to the acceptable economic threshold, the company commented.

This is clearly an issue relating to the economic modeling process rather than the actual cost of treatment, and this problem is not limited only to Javlor, Pierre Fabre argued. It hopes that academic health technology groups will contribute to a debate aimed at resolving this problem.

10 Out OF 11 Cancer Drugs Rejected

Pierre Fabre is not alone in having its new anticancer therapies rejected by NICE. Over the past two months, NICE has turned down 10 of the 11 cancer drugs it has looked at, in draft or final appraisals. Companies had proposed patient access schemes for five of the rejected products.

The only cancer drug reviewed successfully during this time was Roche's Herceptin (trastuzumab), which was recommended for use in certain patients with metastatic gastric cancer on Nov. 24 (Also see "Roche To Appeal NICE's Rejection Of Herceptin For HER2-positive Stomach Cancer" - Pink Sheet, 6 Jul, 2010.)).

When asked, NICE said that it was just a coincidence that most anticancer products had failed to gain positive recommendations during October and November.

But the large number of rejections indicates why the present U.K. coalition government has set up a Cancer Drugs Fund (Also see "UK's New Cancer Drug Fund Might Not Alleviate Regional Access Disparities" - Pink Sheet, 1 Nov, 2010.)).

This fund will support the provision of NICE-rejected drugs to cancer patients if their doctor and a panel of local doctors think they need them. Longer term, the proposed start of value-based pricing in the U.K. in 2013/14 will mean that a positive NICE appraisal will not be needed for a drug to be reimbursed by the National Health Service.

The latest cancer therapy to be rejected by NICE is Novartis' Afinitor (everolimus). On Nov. 26 it was turned down, for the second time, for the second-line treatment of advanced renal cell carcinoma, in a new draft final appraisal determination.

The rejection came despite a proposed patient access scheme reducing the drug's acquisition cost, and with Novartis providing the first pack for free - not the first time that such schemes have failed to coerce the agency into a positive opinion. After the first rejection of Afinitor, Novartis submitted an amended access scheme, the terms of which are being kept confidential by the company, but this still failed to elicit a positive recommendation from the institute.

Still, NICE's appraisal committee agreed with Novartis that Afinitor increased progression-free and overall survival in patients with advanced renal cell carcinoma by more than three months, and in some analyses by six months. It also agreed that the drug met the criteria for being a life extending, end-of-life treatment in renal cell carcinoma, and so should be given special consideration.

Furthermore, there is no other second-line treatment recommended by NICE in patients whose disease has stopped responding to sunitinib (Pfizer's Sutent), and clinical specialists noted that advanced renal cell carcinoma is a relatively rare cancer.

Patients chipped in by saying they valued the increased life expectancy associated with Afinitor, and were prepared to cope with any adverse effects.

But all these positives left NICE and the appraisal committee unmoved. NICE said Afinitor did "not provide enough benefit to patients to justify its high cost," and the appraisal committee said the "exact magnitude of the overall survival gain was uncertain because it was based on modeled data as opposed to data directly observed in the trial (RECORD-1)."

Although Afinitor was associated with ICERs per QALY gained of around £50,000, these are not entirely out of sight for an end-of-life cancer drug. Some would argue that it's rather harsh to reject a drug just because the amount of survival benefit cannot be calculated exactly.

Novartis is expected to appeal against the draft guidance. If the company fails to change NICE's mind, Afinitor would seem to be an ideal candidate for the U.K.' s Cancer Drug Fund.

Meanwhile, Novartis was hit again last week by a rejection of Glivec (imatinib) for use at higher doses in patients with gastrointestinal stromal tumors because of insufficient evidence. The drug is, however, already recommended for use in the disease at a dose of 400mg/day.

NICE also, in a draft appraisal, rejected Roche's Tarceva (erlotinib) as maintenance therapy of non-small cell lung cancer, again because of uncertainty about the amount of clinical benefit it was associated with.

Roche estimated Tarceva extended life by around 3.3 months in these patients, and had agreed a patient access scheme that included a 14.5% reduction in acquisition cost. However, these factors failed to sway the appraisal committee.

- John Davis ([email protected] )