Chapter 4 66 Furthermore, fitter patients are often recruited for clinical trial participation and the outcomes for more vulnerable patients are not known. Factors such as these could cause QALY values to be lower than NICE estimates suggest. Three additional issues can also lead to overestimations in incremental therapeutic benefit. First, during the time it takes to plan and conduct a trial, approve a drug, and complete a cost-effectiveness assessment, the standard of care may have shifted, and the best available comparator may no longer provide the relevant baseline for comparison. Second, a drug may have different benefits for different indications, a factor of particular relevance when off-label use is widespread or where marketing authorization is granted for a population that is broader than the tested population. Third, trials may be designed to demonstrate incremental benefit even when available treatments might demonstrate similar efficacy if tested with a different trial design. Our findings should be interpreted with caution and cannot easily be interpreted from a population health perspective, as drug-indication pairs may be reimbursed within some health systems only for specific patient populations. For example, some of these large incremental benefits mainly occur for drugs that were not considered cost-effective in earlier lines of therapy – but when all prior therapies fail, these drugs are estimated to provide substantial benefit. From the examples in Table 3, sofosbuvir-velpatasvir-voxilaprevir is estimated to generate 3.76 incremental QALYs for patients who have previously been treated with direct-acting antivirals. However, the Marketing Authorization has been granted to treat patients regardless of cirrhosis status and treatment history. These benefits must be seen in this larger context. Our study has a few limitations. First, our analysis was restricted to data presented to NICE of drugs that subsequently obtained a positive coverage decision, excluding medicine that may be accessed via private health insurance. Therefore, drugs in our review are a subset of the drugs covered in other analyses of medication approved by the FDA or EMA, a subset that is likely to be associated with higher QALY estimates than the average new drug. Not all FDA-approved drugs are subsequently approved by the EMA, and not all EMA-approved drugs are assessed by NICE. A recent assessment of oncology drugs approved via the FDA’s accelerated approval pathway demonstrated that only half (48%, 45/93) of drug-indication pairs subsequently became reimbursed within the English NHS, suggesting their therapeutic benefit was not sufficiently important or well established in relation to the associated cost to receive a positive reimbursement decision.26 Second, we could not retrieve all estimates of health benefit as some were concealed by the manufacturer, the implications of which are unclear. It seems some companies maintain a policy of not disclosing QALY figures for any indications or drugs, whereas other companies consistently
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