1 Guidance

1 Guidance

This technology appraisal considers the clinical and cost effectiveness of fludarabine monotherapy only. No recommendations have been made with respect to fludarabine plus cyclophosphamide combination therapy because the current marketing authorisation does not specifically provide a recommendation that fludarabine should be used concurrently with other drugs for the treatment of chronic lymphocytic leukaemia.

Clarification was sought with the MHRA on the issue of the inclusion of the combination of fludarabine and cyclophosphamide in the marketing authorisation of fludarabine. In all correspondence received from the MHRA, including that shared with NICE by Schering Health Care Limited, it has been made clear that 'the MHRA does not consider that the current marketing authorisations for oral and intravenous (i/v) Fludara (PL/0053/0239 and /0290) specifically provide a recommendation that fludarabine should be used concurrently with other drugs for the treatment of chronic lymphocytic leukaemia'.

The MHRA has further clarified that, in general, it would expect a manufacturer or sponsor to request a variation in the marketing authorisation when: 1. The summary of product characteristics (SPC) in general, and specifically the 'therapeutic indications' section, does not contain references to the combination therapy and the company wishes to promote the use of combination therapy, and 2. The use of the combination has implications for the dosage specifications in the 'posology and method of administration' section of the SPC.

In the case of fludarabine, the SPCs do not contain references to the combination therapy. With reference to the second point, the dosage of fludarabine (i/v 25 mg/m2 for 3 days and oral 24 mg/m2 for 5 days) in the evidence base for the combination therapy that was submitted by the manufacturer (the CLL4 trial) is different from the fludarabine dosage specified in its SPCs (i/v 25 mg/m2 for 5 days and oral 40 mg/m2 for 5 days).

1.1 Fludarabine monotherapy, within its licensed indication, is not recommended for the first-line treatment of chronic lymphocytic leukaemia.