The U.K.'s National Institute for Health and Clinical Excellence has just rejected the use of three anticancer products in the National Health Service, a move suggesting it is not backing down from a tough approach to cost-effectiveness when it comes to cancer drugs.

The three products covered in the March 10-11 final appraisal determinations are: Roche Holdings' Tarceva (erlotinib), for use as maintenance therapy for non-small cell lung cancer; Pierre Fabre SA's Javlor (vinflunine) for the second-line treatment of bladder cancer; and PharmaMar's Yondelis (trabectedin) for use in combination with peglyated liposomal doxorubicin for patients with relapsed ovarian cancer.

The manufacturers have until March 24-25 to appeal the recommendations before final guidance is issued by NICE. Roche has already said that it will appeal to have NICE's FAD on Tarceva overturned.

The likelihood of a successful appeal by any of the three companies looks slim, however, as they had previously responded to NICE's rejection at the initial draft stage. Two of the products, Tarceva and Yondelis, already have patient access schemes attached to them, and unless these can be adapted to make the products markedly cheaper, the schemes are unlikely to affect the outcome of NICE's deliberations.

There has been widespread concern that oncologics rejected by NICE, such as these three, might still be clinically useful in some patients. This has led to establishment of a £600 million ($963 million) Cancer Drugs Fund with government monies to cover individual use deemed necessary by local clinicians.

A public consultation on the fund's procedures was completed at the beginning of this year, and it is expected to begin operations shortly. There has been some concern that physicians in different locations will use differing criteria for providing drugs and that a "postcode lottery" to access will arise Also see "Regional Disparities Threaten Effectiveness Of U.K. Cancer Drugs Fund" - Pink Sheet, 19 January, 2011.).

NICE previously recommended two of the products for different indications. Erlotinib was recommended in November 2008 as an alternative to docetaxel (Sanofi-Aventis SA's Taxotere) for the treatment of non-small cell lung cancer. In February 2010, NICE recommended the use of trabectedin for the treatment of advanced soft tissue sarcoma.

Uncertain Benefits

In the latest FADs, NICE's appraisal committee concluded that the benefits are uncertain for erlotinib's use as maintenance therapy. Roche's SATURN trial, which evaluated use of maintenance erlotinib, involved only a small number of patients in the post-hoc analyses which gave rise to survival estimates in patients with squamous and non-squamous disease.

Roche presented analyses showing that erlotinib was associated with a survival benefit of 4.2 months in stable squamous disease patients and 4.5 months in stable non-squamous disease patients, compared with the 3.3 months of survival benefit associated with best supportive care.

The incremental cost-effectiveness ratio (ICER) was more than £50,000 per quality-adjusted life year (QALY) gained, even though Roche had agreed a patient access scheme that meant erlotinib would be supplied to the NHS at a discount of 14.5% on the list price, that is, £1,394.96 for a pack of 30 tablets 150mg. The total population of patients which erlotinib was licensed for was also not small enough to allow the end-of-life criteria to be applied, the appraisal committee added.

For trabectedin, NICE concluded that the cost associated with its use in combination with pegylated liposomal doxorubicin was too high for the NHS, considering its uncertain clinical benefits.

The appraisal committee calculated that the ICERs could be higher than £95,000 per QALY gained in some ovarian cancer patients. The actual cost of therapy for six cycles of therapy was £23,917.

In some patients, and taking into account a patient access scheme where PharmaMar would pay the cost of trabectedin after the fifth cycle of treatment, the best ICER estimate was still £68,000 per QALY gained, too high to gain a NICE recommendation.

Regarding Pierre Fabre's Javlor, NICE CEO Sir Andrew Dillon said the company was unable to provide conclusive evidence of the effectiveness of vinflunine as a second-line treatment for advanced transitional cell carcinoma of the urothelial tract (TCCU).

NICE therefore confirmed its negative review of Javlor made at the draft appraisal stage in November 2010 Also see "NICE Rejects Javlor, But Could Products For Unmet Clinical Needs Be Rethought?" - Pink Sheet, 29 November, 2010.).

NICE's appraisal committee estimated that the overall survival benefit associated with vinflunine, based on the results of Pierre Fabre's clinical trial No 302, was 2.3 months in the intention to treat (ITT) population and 2.6 months in the eligible ITT population. The eligible ITT group comprised the ITT population minus 13 patients who were excluded because a retrospective analysis found they did not have progressive disease when they entered the study. In contrast, Pierre Fabre's modelling suggested that vinflunine was associated with an overall survival benefit of 3.2 months.

The committee concluded that the most plausible ICER was more than £120,000 per QALY gained, and the uncertainties around the costs of adverse events, such as grade 4 constipation requiring hospitalization and the modelling of survival data, increased this cost further.

Because an extension to life of more than three months had not been proven, NICE's "end of life" provisions, which would allow a more flexible interpretation of its usual upper QALY limit of £30,000, could not come into play.

- John Davis (j.davis@elsevier.com)

NICE Continues Tough Approach On Cancer Drugs, Rejects Tarceva, Javlor and Yondelis

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