Thoughts on: The routine use of Infliximab for Rheumatoid Arthritis. Prof Marc Blockman MAG August 2009 RECAP: Why should Pharmaceutical expenditure be controlled in South Africa? Second highest consumer of healthcare budget. Healthcare resources limited High disease burden Price of pharmaceuticals increasing significantly (especially biologicals) Selection Criteria Equally effective drugs to be compared best cost advantage best researched best pharmacokinetic properties best patient adherence if possible INFLUENCING FACTORS: Ethical, Transparent, Appropriate Decision for Resource Allocation Economics Ethics Evidence-based medicine WHY? If a new drug is not as effective as current therapy, why should it be paid for? If a new drug is no better than existing therapy, why pay more? If a new drug provides added benefit over existing therapy, does the cost of this extra benefit represent value for money? Cost-effective thresholds?? WHO: Highly cost-effective (less than GDP per capita); Cost-effective (between one and three times GDP per capita) ie about R100-120 000 per quality adjusted life year gained (QALY) UK: £20 000 to £30 000 per quality adjusted life year (QALY) gained USA: $50 000 per quality adjusted life year (QALY) gained Guiding principles in selection Hard Outcome focused Best available evidence Method used to synthesize=Robust Multidisciplinary team Flexible and adaptable to local conditions Resource constraints Validity and usefulness evaluated Revised regularly Level I Good quality patient-orientated evidence Systematic review of RCTs with consistent findings High quality individual RCT Level II Limited quality patient orientated evidence Systematic review of lower quality studies or studies with inconsistent findings Low quality clinical trial Cohort studies Case-control studies Level III Other evidence Consensus guidelines, extrapolations from bench research, usual practice, opinion, diseaseoriented evidence (intermediate or physiologic outcomes only), or case series Important to remember: •MCC registration = superiority over placebo •Therapeutic decisions = comparison against current standard of care and what is “cost-effective” Infliximab The infliximab dose is variable. The usual dose is 3mg/ kg (Doses of up to 10mg/ kg have been studied) Doses are given at 0, 2, and 6 weeks and then every 8 weeks (4 weeks have been used in trials) Infliximab usually added to methotrexate Evidence of Efficacy Infliximab and methotrexate vs methotrexate and placebo Steroids allowed if at stable doses Minimum trial duration: 6 months Results of Cochrane Review 3 studies included- all by the same authors One study (Lipsky 2000) was a continuation of one of the studies to 54 weeks 6 month data was available for 529 patients All patients were refractory to methotrexate treatment Definition of Outcomes An ACR 20, 50, 70 response were the primary outcome measures E.g An ACR 50 response is: a 50% improvement in tender and swollen joint count plus a 50% improvement in 3 of 5 core measures (patient and physical global assessments, pain, functional status and acute phase reactant.) - - Results at 6 months Cost to achieve ACR 50 in one patient For 3mg/ kg 8 weekly . NNT = 4.76 4.76 x 5 doses x 2 vials (+-R12 000) = R 285 000 (not taking into account initial 3 doses) Cost to achieve an ACR 70 NNT = 12.5 Cost = R 750 000 (not taking into account initial 3 doses) Harder End Points? End point for studies of infliximab for RA: ACR criteria and symptom scores Employability Radiological progression To prevent major radiological progression at 1 year NNT= 4.35 Maini 2004- sustained protection from radiological progression Radiological Progression The scale is 0 - 440 In this table we must look at the median change because the SDs are different and therefore variances are different CANNOT compare means- they have reported BOTH- IQRs overlap This data tells us that if we use 3mg/ kg for 14 doses over 2yrs we will prevent radiological progression (median) by 4.25- 0.43 = 3.82 points What is the clinical significance vs statistical significance? Treatment naïve patients were randomised to MTX or MTX/Infliximab Actual employment figures did not change over 46 weeks However, more people felt they were able to work in the infliximab arm if employment were offered Some published cost-effective data “$30,500 per discounted QALY” “If society were willing to pay as much as $50,000 per QALY, the probability that infliximab would be cost-effective is less than 1 percent.” “They reported a cost-effectiveness ratio of $38 200 per discounted quality-adjusted life year (QALY). However, this (similar to the present study) was predicated on the use of infliximab for no more than 2 yr!” “Results: The primary analysis suggested that infliximab plus MTX had an ICER of € 33 618 per QALY gained.” Wong JB et al. AMJMed: ( 113)2002, Pages 400-408 Rothchild BM et al. Rheumatology 2003; 42: 1572-1573 Wailoo A J et al. NHS Economic Evaluation Database (NHS EED)2008 Accessed May 2nd 2009 at http://pharmacoeconomics.adisonline.com/pt/re/phe/fulltext.00019053-200523060-00007.htm Goldman L. NEJM. 353(14): 1523-1515 Maetzel A.Arthritis Rheum 2005;53:3-4. Safety with a focus on TB Data from the Spanish Society database 86% treated with infliximab Incidence compared with national incidence figures after stratification by sex and age. Risk ration for development of TB in the infliximab compared to the population incidence was 53 (CI 34.5-89.0) in 2001. Gomez- Reino J et al:Arthritis and Rheumatism 2003;48: 2822-7 WHO report. Global tuberculosis control 2007; 137- 40 TB risk cont… The confounder was that these patients were better followed, therefore the data used was from a cohort in 1999, before the introduction of biologicals in Spain. Increased risk of 19.9 (CI 16.2-24.8) Of note the B/G rate in Spain was 21 per 100 000 vs. SA 600 per 100 000.WHO Gomez- Reino J et al:Arthritis and Rheumatism 2003;48: 2822-7 WHO report. Global tuberculosis control 2007; 137- 40 British Guidelines for the use of biologicals in RA Patients must have failed therapy of DMARDs or not tolerated therapy One of these therapies must have been MTX Criteria for discontinuation due to poor efficacy after 3 months. Inflix must be used with MTX Conclusion Infliximab may not be “cost-effective” in the SA environment. Limited long-term data for sustained benefit. No “hard-outcomes” High acquisition cost. Seemingly high cost per QALY Limited safety data in a high TB prevalence setting. Way-forward Demonstration in randomized trials of reduction in clinically significant endpoints, e.g. hospitalizations, joint replacements. Evidence of sustained, clinically relevant improvement upon cessation of infliximab Account of the significant safety concerns of this agent in the SA population. A reduction in acquisition costs.
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