GlaxoSmithKline, 15 th July 2010

Response to Appraisal Consultation Document for Ofatumumab (Arzerra ) for the treatment of chronic lymphocytic leukaemia in patients who are refractory to fludarabine and alemtuzumab GlaxoSmithKline, 15 th July 2010 GSK is disappointed by the decision of the Appraisal Committee ( the Committee ) to not recommend ofatumumab for the treatment of chronic lymphocytic leukaemia refractory to fludarabine and alemtuzumab ( DR CLL ). We believe that this decision is unfortunate considering the history of ofatumumab, which provides context to the whole appraisal, and mitigates some of the criticisms contained within the ACD. Ofatumumab was not expected to gain marketing authorisation until the middle part of this decade. However, a promising set of interim results from a phase II trial (Hx CD20 406) persuaded the regulatory authorities in both the EU and the US otherwise: that despite the relative paucity of data, ofatumumab had something positive to offer to a small group of patients for whom there was otherwise no credible treatment. Correspondingly, ofatumumab has been designated an orphan medicinal product and granted marketing authorisation by the European Medicines Agency ( EMEA ), as well as an accelerated approval by the US Food and Drug Administration ( FDA ). GSK has offered a significant discount to help ensure that ofatumumab provides value to the NHS without the complexity of implementing a patient access scheme, and to ensure that it reaches this small group of patients who present a significant unmet clinical need. We urge the Committee to be mindful of the small number of potential patients and corresponding low budget impact whilst reviewing the evidence, and to recommend the use of ofatumumab in this indication. Has all of the relevant evidence been taken into account? Data from a health state preference study commissioned by the manufacturer were not available at the time of the appraisal. section 3.11 the ERG noted that the utility values were taken from one published health state preference study and reflected a health state after second line treatment, rather than after third line treatment" section 3.15 The cumulative impact of these three changes resulted in an alternative estimated ICER for ofatumumab compared with best supportive care of more than 81,500 per QALY gained section 3.16 As previously stated to NICE and discussed at the Committee meeting on 5 th May 2010, a utility study was undertaken by GSK for ofatumumab in the target population, but the final study report was not available at the time of our original submission. In response to the Committee s request the final study report was sent to NICE for the Committee s attention on 18 th May 2010, but GSK was subsequently informed that the report would be considered only at ACD stage. Therefore we have included it as part of this response. 1

We would like to point out that contrary to the statement made in the ACD, preliminary data from this study were provided in our response to the ERG s clarification questions (4 th March 2010). Those data were subsequently used by the ERG in an exploratory analysis (sections 5.2.3.6 and 5.4.1.5 of the ERG report) and mentioned in section 4.15 of the ACD. The utility results in the final report are identical to the preliminary data supplied to the ERG as part of this appraisal. The ERG s exploratory analysis resulted in their proposed alternative ICER decreasing from more than 81,500/QALY to more than 60,500/QALY. The ERG......expressed concern that the manufacturer chose to exclude from the formal analyses the Tam study that was identified by the literature search section 3.14 GSK explored this issue at an expert advisory board prior to submission; our reasons for this exclusion were: An absence of data regarding progression free survival (PFS) in the Tam publication 1 as would have been necessary for this data to inform the GSK economic model. A work around, involving correlation of PFS and overall survival (which was reported in the paper) would have been possible, but would only have introduced further uncertainties into the model s output. A concern that the treatment received by the Tam cohort would not be representative of current treatment in the NHS. Firstly, some of the data from the DR CLL cohort is relatively old, being collected between April 1998 and September 2006. Secondly, the patients were treated in a recognised international centre of excellence, the MD Anderson Cancer Centre (US), whose treatments and results often vary from those seen elsewhere; as such, the cohort s treatment and outcomes are unlikely to represent current UK practice. The clinical specialists stated that studies of alemtuzumab may contain data from ofatumumab naive controls and patients with double refractory disease which could be used for comparisons with the effectiveness of ofatumumab. The Committee concluded that there was a paucity of submitted evidence on the clinical effectiveness of ofatumumab, and that more could have been done to identify and include other appropriate sources of evidence. section 4.5 GSK appreciates that the approach suggested by the clinical specialists is interesting. However, following discussions with experts, and a review of evidence in the public domain, we believe that the available data are insufficient to be incorporated into our economic model: in general, the results of the group failing alemtuzumab are not reported separately, and detailed progression free survival (PFS) data are not reported at all. While there are possible approaches to the first aspect, the approach required to estimate PFS would inevitably introduce further uncertainties into the outputs from the model, and both approaches would be reasonably open to criticism. GSK also acknowledges the paucity of evidence in this area; this is a consequence of ofatumumab s status as an orphan medication, the difficulties of conducting an RCT in an indication with no established best treatment, and its subsequent early marketing authorisation based on interim phase II data. We would greatly welcome a positive dialogue with NICE regarding directions and strategies for further evidence generation, possibly aimed toward clearer determination of the outcomes of best supportive care. 2

The Committee also noted that the manufacturer had chosen not to provide more recent data from the Hx CD20 406 study (the interim analysis was from May 2008, with no further data expected before 2011). The Committee therefore concluded that there was insufficient data on overall survival to provide valid estimates of the effectiveness of ofatumumab. section 4.6 GSK disagrees with the implication and conclusion of this statement. Two points should be noted: 1. The timing of the analysis was determined only by the logistics of the trial design; it was not expected that the interim analysis would lead to regulatory filings or health technology appraisals. Unfortunately, the data from the final analysis is not yet available. 2. The interim analysis presented was pre planned, within the study protocol. To conduct a second and unplanned interim analysis in order to gain more information for this appraisal would be highly irregular. This approach, to quote ICH E9: may flaw the results of a trial and possibly weaken confidence in the conclusions drawn. Therefore, such analyses should be avoided. 2 GSK would like to assure the Committee that all available data from the Hx CD20 406 study has been submitted for consideration, and that doubts regarding the completeness of our submission are misplaced. We therefore ask that the committee reconsider any conclusions regarding the effectiveness of ofatumumab which might have been misinformed, on this basis. We would also ask for that aspect of the FAD to be reworded, to ensure that there is no impression that GSK has not provided all available evidence from study Hx CD20 406. Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence? The Committee concluded that a controlled trial could have been conducted to investigate the clinical effectiveness of ofatumumab for chronic lymphocytic leukaemia refractory to fludarabine and alemtuzumab. section 4.4 GSK maintains its position that a two armed, randomised controlled trial ( RCT ) design for the Hx CD20 406 trial, in which ofatumumab would have been compared with best supportive care, would have been both unethical and difficult to recruit. However, now that ofatumumab is known to be efficacious as shown by the results of Hx CD20 406, and its licence an RCT of this design would be impossible: it is highly unlikely that any patients would volunteer for a trial with only a 50% chance of receiving the only known efficacious treatment for their disease, and given the known efficacy of ofatumumab in DR CLL, the outcome would not reasonably be in doubt, meaning clinical equipoise is not exhibited. We are therefore frustrated in our desire to generate evidence to further support ofatumumab, and allow its use in patients with DR CLL: its efficacy is such that to conduct an RCT is no longer possible, yet an RCT appears necessary to provide sufficiently robust evidence of efficacy. GSK believes that for an orphan drug, the absence of a controlled trial should not, in itself, be a barrier to recommendation. GSK asks that the committee consider whether an acceptable dataset for this orphan product might reasonably be allowed to vary from what would otherwise be expected for a non orphan product. 3

The Committee concluded that, based on expert evidence, it was plausible that ofatumumab may offer clinical benefits to patients, but that that it was not possible to determine this from the evidence presented. The Committee also stated that there was insufficient robust evidence available for it to conclude that this technology was innovative and would make a significant and substantial impact on health related benefits. section 4.9 This statement appears to be at odds with the expert evidence reported in section 4.3 of the ACD: The Committee then heard from the clinical specialists and patient experts that ofatumumab appeared to be effective in early phase trials. The clinical specialists acknowledged that ofatumumab, like rituximab, targets CD20, but considered that it may offer a novel mechanism of action because it targets a different epitope. Ofatumumab is a very different molecule to rituximab: it is a fully human monoclonal antibody 3, rather than a chimeric mouse/human monoclonal antibody 4 and should therefore suffer fewer issues arising from the formation of human antibodies against the treatment. No such antibodies have yet been found in trial subjects 5. Ofatumumab also targets a different epitope on the CD20 protein 6 to that targeted by rituximab; this may explain findings from pre clinical studies which suggest that ofatumumab offers more potent cytotoxicity, with substantial differences in CDC and ADCC killing profiles. 7,8 Finally, as demonstrated in Hx CD20 406, where there was no difference in overall response rate between patients who had received prior rituximab and/or had been refractory to rituximab containing treatment regimens versus those who hadn t, there appears to be a real world clinical difference between the agents 5. This efficacy is likely due to the unique molecular biology of the product, as described. It is therefore difficult to see why ofatumumab would not be considered an innovative and valuable product. The Committee concluded that ofatumumab for the treatment of refractory chronic lymphocytic leukaemia meets the criteria of a short life expectancy and small patient population but because the evidence for the extension to life was not sufficiently robust, the criteria for consideration as a life extending, end of life treatment were not fulfilled section 4.19 GSK disagrees with the conclusion that the evidence for the extension to life is not sufficiently robust. While the available efficacy evidence, being from an incomplete phase II study, is likely less extensive than for most appraisals considered by NICE, this is a reflection of the orphan status of ofatumumab, and the difficulties of conducting trials in this disease area. The evidence thus far from the Hx CD20 406 trial shows that treatment of DR CLL with ofatumumab resulted in a median progression free survival time of 5.7 months and a median overall survival time of 13.7 months 5, with the upper 95% confidence interval not yet reached at the time the analysis took place. Patients with DR CLL are known to have a very poor prognosis, as reported by Tam, whose cohort had a median survival of 8 months when using a range of treatments including biologics in an international centre of excellence 1. Treatment with ofatumumab therefore offers a gain in median survival of over 5 months, a figure which correlates closely with the survival gain predicted by the GSK economic model 9. 4

In addition, regulatory authorities in the EU and the US have acknowledged the efficacy of ofatumumab: Efficacy in terms of response rate was demonstrated in a pivotal and a supportive open label, single arm trials conducted in fludarabine and alemtuzumab double [r]efractory patients. Overall, a response rate of 58% was observed. Treatment with ofatumumab was associated with adverse events indistinguishable from the underlying disease which don t give rise to particular concern. Therefore, the risk benefit balance of the medicinal product, as defined in Article 1(28a) of Directive 2001/83/EC, is positive. 10 [T]he U.S. Food and Drug Administration granted accelerated approval to ofatumumab......for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. The approval was based on a clinically meaningful and durable overall response rate observed in a single arm trial (Hx CD20 406). 11 GSK believes that the efficacy of ofatumumab has been established, and all available evidence clearly points to a median prolongation of survival greater than the three month criterion contained within the NICE supplementary guidelines for assessing life extending, end of life treatments. In addition, we firmly believe that ofatumumab is an innovative product. We would venture that DR CLL as a disease area, and ofatumumab as a treatment, reflect both the letter of the end of life guidelines and also the spirit behind their creation, and as such would ask the Committee to reconsider their decision. Are the provisional recommendations sound and a suitable basis for guidance to the NHS? GSK would like to touch on two broad areas. Firstly, we hope that this response has answered many of the concerns raised about our submission in the ACD, and has put into context some of the issues which are unfortunate and unavoidable consequences of bringing an orphan medication to market in this indication. As discussed, further randomised clinical studies in DR CLL would now be difficult and unethical to perform. However, we believe that the existing data supporting the benefits of ofatumumab in DR CLL are clear, and as robust as possible in the circumstances, and therefore we would ask that the committee consider the evidence in this light, especially considering the small budget impact to the NHS. In addition, we firmly believe that ofatumumab meets the criteria laid down by NICE for the consideration of life extending, end of life treatments, and future discussions and conclusions should be considered under the auspices of these guidelines. Secondly, whilst GSK acknowledges the remit of NICE to appraise the cost effectiveness of medicines in order to best direct limited NHS resources, we believe that the current process may not be appropriate when dealing with drugs such as ofatumumab. Both EMEA and FDA have successfully introduced regulations to allow the early approval of orphan treatments for rare diseases which are very serious or life threatening. There is an explicit recognition that the available evidence will, understandably, be more limited than otherwise. It follows that the absence of guidance on the appraisal of orphan medications by NICE, which would allow appraisal committees to take a pragmatic approach when evidence is more limited especially considering the lower budget impact of these medications is of concern. To expect the manufacturers of orphan products to provide evidence of the same level as non orphan medications renders these regulatory processes and the spirit behind them redundant. We hope that GSK can work with NICE to find an innovative solution to the challenges that have arisen within this appraisal. 5

1 Tam CS, et al. The natural history of fludarabine refractory chronic lymphocytic leukemia patients who fail alemtuzumab or have bulky lymphadenopathy. Leuk Lymphoma 48:1931 1939, 2007 2 ICH Harmonised Tripartite Guideline E9 Statistical principles for clinical trials. http://www.ich.org/cache/compo/276 254 1.html retrieved 24 th June 2010 3 Ofatumumab SmPC. http://www.medicines.org.uk/emc/medicine/23022 retrieved 24 th June 2010 4 Rituximab SmPC. http://www.medicines.org.uk/emc/medicine/2570 retrieved 24 th June 2010 5 Wierda W, et al. Ofatumumab as single agent CD20 immunotherapy in fludarabine refractory chronic lymphocytic leukemia. Journal of Clinical Oncology, 28(10):1749 1755, 2010 6 Teeling JL, Mackus WJ, Wiegman LJ, et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol 177:362 371, 2006 7 Beum PV, et al. Complement activation on B lymphocytes opsonized with rituximab or ofatumumab produces substantial changes in membrane structure preceding cell lysis. J Immunol 181:822 832, 2008 8 Pawluczkowycz A, et al. Binding of submaximal C1q promotes complement dependent cytotoxicity (CDC) of B cells opsonized with anti CD20 mabs ofatumumab (OFA) or rituximab (RTX): Considerably higher levels of CDC are induced by OFA than by RTX. J Immunol 183: 749 758, 2009 9 GSK STA submission Ofatumumab for the treatment of chronic lymphocytic leukaemia in patients who are refractory to fludarabine and alemtuzumab 10 CHMP assessment report for Arzerra, London, 20 January 2010. Doc.Ref.: EMA/CHMP/195135/2010 11 http://www.fda.gov/aboutfda/centersoffices/cder/ucm188221.htm retrieved 24th June 2010 6