The National Institute for Health and Clinical Excellence (NICE) has issued draft guidance asking Roche to provide more information on the use of its skin cancer drug Zelboraf (vemurafenib).

The request specifically concerns Zelboraf's use in the treatment of unresectable locally-advanced or metatastic BRAF V600 mutation-positive melanoma, for which NICE said, in draft guidance issued in June, that it would not be making a positive recommendation.

Zelboraf "is an expensive drug and its long-term benefits are difficult to quantify," commented Professor Carole Longson, director of NICE's health technology evaluation centre, speaking as the new draft guidance went out for consultation. 

During consultation on the first draft recommendations, Roche had submitted additional analyses on the effectiveness of the drug in relation to its cost, she noted. When asked to consider this new information, NICE's independent advisory committee had concluded that they required further clarification to be able to make the decision to recommend or not recommend it for routine use in the NHS, and the panel has therefore asked Roche to provide further analyses and clarification, Prof Longson explained.

"We hope that Roche will be able to provide this additional information so that the Committee can consider it at its next meeting on the topic," she added.

Patients with advanced or metastatic malignant melanoma are usually treated with carboplatin-based chemotherapy or dacarbazine, or given best supportive care. The data for this use of Zelboraf which Roche submitted to NICE came primarily from the BRIM3 study, which compared the drug with dacarbazine and indicated that it offers an extension to life of at least three additional months, compared with current NHS treatment. 

However, NICE's advisory committee felt that the evidence from the BRIM3 study was uncertain, as many of the patients receiving dacarbazine transferred to Zelboraf and patients whose disease progressed after treatment with dacarbazine were able to receive a range of other therapies, including Bristol-Myers Squibb's Yervoy (ipilimumab) and investigational treatments.

Specifically, the panel is asking Roche to supply further clarification in the following areas:
- a full explanation of the assumptions made and parameter values used for the rank preserving structural failure time (RPSFT) method to adjust survival estimates to account for patients who switched from dacarbazine to Zelboraf on disease progression. A discussion of the plausibility of using alternative approaches that adjust for switching in the BRIM3 study population, or the use of data from other trials to represent the clinical effectiveness of dacarbazine should also be provided; and

- an additional scenario analysis for Zelboraf compared with dacarbazine, estimated by separately fitting exponential hazards to each arm of the BRIM3 study, using February 2012 data cut-off, from 14 months. For this analysis: - information that would allow sufficient critique of the model and its parameters should be provided, including details of how censoring was incorporated into the progression-free survival, post-progression survival and overall survival analyses; - probabilistic sensitivity analyses should be provided; - incremental costs and Quality-Adjusted Life Years (QALYs) gained should be reported; and - a revised, fully-executable economic model should be provided that is amenable to verification of the above revisions.

NICE's advisory committee had agreed that the most plausible Incremental Cost-Effectiveness Ratio (ICER) for Zelboraf was highly uncertain, given the assumptions made on estimating overall survival and the drug's long-term benefit, and that it could be significantly higher than £50,000 per QALY gained.

Zelboraf costs £1,750 for a week's supply - one pack of 56 x 240mg tablets - and treatment for an average duration of 30 weeks would cost £52,000. Roche has agreed a patient access scheme (PAS) with the Department of Health, with a discount on the drug's list price which is commercial-in-confidence.

NICE's advisory panel heard from Roche and clinical specialists that the total number of people who would be eligible for treatment with Zelboraf would be less than 1,000 each year in England and Wales.

The Scottish Medicines Consortium (SMC) is due to publish guidance on Zelboraf’s use in this indication in September.