EXECUTIVE SUMMARY

  Servier believes that NICE has an important role to play in encouraging clinical excellence and effective resource utilisation within the NHS.

  As a result of our experience as a stakeholder in the ongoing NICE technology appraisals on postmenopausal osteoporosis, we have identified several areas for improvement, as presented in this submission. In particular:

Lack of transparency in economic model

  There is a lack of transparency in the economic modelling used by NICE. The economic model used to determine cost-effectiveness of technologies has not been shared with all relevant stakeholders in the consultation process.

Limited role for clinical judgement in allocation decisions

  Technology appraisals make allocation decisions based on a hierarchy of cost effectiveness ratios. These cost-effectiveness ratios overlap. We believe it would be more appropriate for a group of cost-effective treatments to be recommended where there is this level of uncertainty. Clinical judgement would then take into account factors not captured by the economic modelling in order to determine which treatment is most suitable for a particular patient.

Failing to appropriately consider important clinical data

  NICE have not adequately taken into account clinical evidence brought to the attention of the Appraisal Committee during the consultation process and especially evidence that has implications for the appropriate use of medicines.

Unfairly restricting access to treatment

  Current draft guidance unfairly restricts access to effective treatments for women under the age of 70, regardless of risk factors.

Lengthy technology appraisal process

  The review is now entering an unprecedented fifth year with guidance still in draft format. This raises questions about whether NICE would be able to cope with a further increase in workload as suggested by the OFT in its recent report into the PPRS.

  Servier Laboratories Limited is the UK subsidiary of The Servier Research Group, a leading French research-based organisation, specialising in ethical pharmaceuticals. Servier UK offers a range of products in a number of medical areas: cardiovascular disease, especially hypertension and cardiac disease, diabetes and, more recently, osteoporosis. Servier develops truly innovative drugs and we invest in therapeutic areas where there is an unmet patient need.

INTRODUCTION

  1.  Servier welcomes this inquiry into NICE. NICE has an important role to play in encouraging clinical excellence and effective resource utilisation. Indeed, as a pharmaceutical company committed to the development of innovative medicines aimed at addressing the unmet needs of patients and prescribers, Servier supports the role of NICE in driving uptake of new treatments based on clinical and cost-effectiveness leading to better use of NHS resources, and in supporting the use of innovative new treatments.

  2.  However, we have concerns about the way that NICE currently undertakes technology appraisals and we believe there are lessons to be learnt from a technology appraisal in which we are currently involved, which we have detailed below. Servier manufacture Protelos (Strontium Ranelate), one of the technologies currently being evaluated as part of the ongoing NICE appraisal on primary and secondary prevention of osteoporotic fragility fractures in postmenopausal women. [142]

BACKGROUND TO NICE TECHNOLOGY APPRAISALS ON POSTMENOPAUSAL OSTEOPOROSIS

  3.  The World Health Organisation define osteoporosis as a progressive skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue with a consequential increase in bone fragility and susceptibility to fracture. There is increased risk of fracture particularly of spine, hip, pelvis and forearm. It is pre-dominantly a disease of post-menopauasal women and risk of fracture increases with age. Fractures caused by osteoporosis affect one in two women and one in five men over the age of 50. [143]The most serious complication is hip fracture, which has a mortality rate of up to 20% at one year. [144]The combined cost of social and hospital care for patients with a hip fracture amounts to more than £1.8 billion per year in the UK and is likely to increase to £2.1 billion by 2020. [145]

  4.  NICE is currently developing guidance on osteoporosis in the form of technology appraisals on the primary and secondary prevention of fractures in osteoporosis. Primary prevention refers to the prevention of fragility fractures in post-menopausal women who have osteoporosis but who have not sustained a fracture, whereas secondary prevention refers to the prevention of fragility fractures in women who have osteoporosis and have previously sustained a clinically apparent fracture.

  5.  The NICE evaluation of osteoporosis initially started in 2001 with a review of osteoporosis and its management. NICE carried out a technology appraisal of the osteoporosis treatments to assess how they should be used and in what patient groups to reduce the number of fractures in osteoporosis. NICE then evaluated treatment of osteoporosis in the setting of secondary prevention, which resulted in published guidance in January 2005.

  6.  A further set of guidance is currently being developed with separate technology appraisals for both primary and secondary prevention in osteoporosis. Several draft appraisal consultation documents (ACDs) have been released for consultation with 26 March 2007 the closing date for the current consultation phase.

LESSONS FROM SERVIER'S EXPERIENCE OF THE NICE TECHNOLOGY APPRAISAL PROCESS IN OSTEOPOROSIS

Lack of transparency in economic model

  7.  The economic model used by NICE to determine cost-effectiveness of technologies and patient access has not been shared with all relevant stakeholders in the consultation process. This lack of transparency limits the ability of consultees to understand and comment on conclusions derived from the model, and thus on the proposed guidance. For example, prior to publication of the previous ACDs the cost of one of the principal treatments, alendronate, decreased by almost half and this input to the model was adjusted accordingly. Decreasing the cost input for alendronate in the model should improve the cost effectiveness for this treatment. However, the resultant guidance was even more restrictive as NICE also altered other input parameters to the model without explanation or justification.

Limited role for clinical judgement in allocation decisions

  8.  The current NICE appraisal process makes allocation decisions according to a hierarchy of average cost-effectiveness ratios. However, the cost-effectiveness ratios of the various treatments overlap and so it is impossible to say with certainty that one treatment is categorically more cost effective than another. Where there is this level of uncertainty we believe it would be more appropriate for a group of cost-effective treatments to be recommended. Clinical judgement would then determine which of these treatments is most suitable for a particular patient, resulting in more personalised patient care. This clinical judgement would take account of factors such as the risk of side effects and the likelihood of compliance combined with baseline risk to define which patients are appropriate for a particular treatment. The economic analysis alone cannot fully account for this inter-patient variability.

Failing to appropriately consider important clinical data

  9.  NICE has not adequately taken into account independent evidence that Servier have submitted to the Appraisal Committee during the consultation process, which we believe has important implications for the appropriate use of medicines in women with postmenopausal osteoporosis:

—  There is emerging evidence of increased risk of fracture associated with proton pump inhibitor (PPI) use, with three independent data sources that demonstrate statistically significant increases in the risk of fracture including hip. [146]Significantly, patients prescribed bisphosphonates are more likely to be prescribed a PPI to counteract the adverse effects of the bisphosphonate. Indeed, NICE have undertaken a systematic review of bisphosphonate use that demonstrates that new bisphosphonate users are up to three times more likely to require prescribed acid suppressant agents such as PPIs. [147]Such prescribing patterns may therefore be putting vulnerable patients at increased risk of fracture. However, NICE appear to have ignored these data, despite Servier's request for an urgent review of the clinical studies of bisphosphonates to determine if this evidence from clinical practice is also demonstrated in the clinical studies.

—  Strontium ranelate is the only medication with proof of efficacy in both vertebral and non-vertebral fractures in patients with post-menopausal osteoporosis who are 80 years or older. [148]In contrast, current evidence suggests that bisphosphonates do not protect against non-vertebral fracture in the very elderly. [149]This distinction is important as non-vertebral fractures may be considered to be more serious consequences of osteoporosis than vertebral fractures in terms of morbidity, mortality and cost. [150]Despite this unique evidence supporting use of strontium ranelate first line for patients aged 80 years and over, the current draft guidance recommends the bisphosphonate alendronate as the only treatment for initiation, including in the very elderly.

Unfairly restricting access to treatment

  10.  Current recommendations unfairly restrict patient access to treatment. Draft guidance on primary prevention excludes women under the age of 70 years, regardless of risk factors, from primary prevention treatment. Indeed, such an approach would effectively discriminate against younger patients even if their absolute risk of fracture were identical to or higher than that of an older patient meeting the eligibility criteria as set out in the draft guidance.

Lengthy technology appraisal process

  11.  The NICE review of osteoporosis is now entering an unprecedented fifth year with guidance still in draft format. Some Primary Care Trusts are currently restricting access to osteoporosis treatments by recommending to doctors that they do not prescribe strontium ranelate until NICE publishes its guidance. [151]In addition to escalating costs that will have to be met by the taxpayer we have got evidence that patients are being denied treatment, and therefore exposed to increased risk of fracture, while doctors wait for finalised guidance. If final guidance is produced based on the current recommendations, the result of over four years of work will simply make the recommendation that only generic alendronate (the cheapest treatment) should be used for treatment initiation in patients with postmenopausal osteoporosis. This raises questions about whether NICE would be able to cope with a further increase in workload if, as recommended by the recently published OFT report into Pharmaceutical Price Regulation Scheme (PPRS), it would have the additional responsibility of appraising all new medications as they come to market. [152]

CONCLUSION

  12.  As we have stated above, Servier supports the work of NICE in encouraging clinical excellence and effective resource allocation. However, our experience of engaging with NICE through its review of osteoporosis has highlighted some areas of concern which we believe need to be addressed, particularly if any expansion in its reach is taken forward in the future. We hope this submission will provide the Health Select Committee with some practical examples of areas of NICE's work which could be improved and lessons which can be learnt going forward. We would be happy to provide any additional information to the Committee in both written or verbal form to support this submission.

Servier Laboratories

March 2007

143   Van Staa T P, Dennison E M, Leufkens H G et al, Epidemiology of fractures in England and Wales, Bone 2001; 29(6): 517-522. Back

144   Cooper C, Atkinson E J, Jacobsen S J et al Am J Epidemiology 1993; 137: 1001-1005. Back

145   National Osteoporosis Society. A proposal to improve health outcomes for people at risk of osteoporotic fractures through the Quality and Outcomes Framework. NOS Working Party on the GMS Contract. May 2005. Back

146   Yu E W C Shinoff, T Blackwell, K Ensrud, T Hillier, D C Bauer, Use of Acid-Suppressive Medications and Risk of Bone Loss and Fracture in Postmenopausal Women; Vestergaard, P, L Rejnmark, L Mosekilde. 2006, Proton Pump Inhibitors, Histamine H2 Receptor Antagonists, and Other Antacid Medications and the Risk of Fracture Calcified Tissue International Vol 79:76-83; Yang Y-X, J D Lewis, S Epstein, D C Metz. 2006, Long-term proton pump inhibitor therapy and risk of hip fracture, JAMA, 296:2947-2953. Back

147   Myfanwy Lloyd Jones, Anna Wilkinson. 2006. Adverse Effects and Persistence with Therapy in Patients Taking Oral Alendronate, Etidronate or Risedrontate: Systematic Reviews. Back

148   Seeman E, et al. 2006. Strontium ranelate reduces the risk of vertebral and non-vertebral fractures in women 80 years of age and older. JBMR Vol 21:7:1113-1120. Back

149   Boonen S et al 2004. Safety and efficacy of risedronate in reducing fracture risk in osteoporotic women aged 80 and older: Implications for the use of anti-resorptive agents in the old and oldest old. JAGS Vol 52:1832-1839. Back

150   Center J R, Nguyen T V, Schneider D, Sambrook P N, Eiman J A 1999. Mortality after all types of osteoporotic fracture in men and women: an observational study. Lancet 353:878-882. Back

151   Primary Care Trust, 2006, Traffic Lights List 2006-07. Back

152   The Pharmaceutical Price Regulation Scheme; An OFT Market Study. February 2007. http://www.oft.gov.uk/shared_oft/reports/comp_policy/oft885.pdf. Back