Dr Panos Kanavos is an Associate Professor, Programme Director of Executive MSc in Healthcare Decision-Making at the Department of Health Policy, LSE.
Research into 1500 medicine-indication pairs across 7 countries (England, Scotland, France, Germany, Sweden, Canada and Australia) and covering the period between 2011 and 2020 has brought new light into how health technology assessment (HTA) processes are used to shape access to medicines, the resulting constraints on their use and the type of evidence that makes a difference to arrive at positive coverage decisions.
The majority of medicines assessed by HTA agencies received a positive outcome, i.e. they were covered as applied for or covered with restrictions (87%), while the remainder 13% were rejected; nearly half of all rejections were related to oncology drugs, and the lack of an active comparator accounted for 63% of all rejections.
Sixty-five percent of positive but restricted HTA outcomes (71% of the sample) were subject to one or more clinical restrictions, notably, population restrictions (restricting indications to population sub-groups showing the highest benefit), prescribing restrictions or both. This practically means that the outcome of the HTA process results in the narrowing of the respective label indications.
Risk sharing agreements accounted for 44% of all positive but restricted HTA outcomes, while a further 5% were linked to special funding agreements, notably earmarked funds, or funding under data collection conditions. Over time the proportion of RSAs has increased from 15% of all HTA cases in 2011 to a high of 40% in 2017.
Twenty four percent of all HTA submissions had at least one prior rejection, implying failure to satisfy HTA agencies on certain criteria, including the quality of evidence and clinical benefit. Of the drug-indication pairs that received a final rejection, 31% had at least one previous rejection. Resubmissions increased steadily over time (11% in 2011 and 29% in 2020).
Most submissions (86%) presented at least one Phase III RCT as main evidence supporting clinical benefit claims. Progressively, the number of HTA submissions informed by earlier phase evidence (e.g. Phase II) increased. More than half of the sample drugs were either compared to “placebo”, including best supportive care (47%), or had no comparator, relying on single arm trials (8%). Most drugs (82%) relied on surrogate endpoints as their primary outcome and 77% of rejections had a surrogate as the primary endpoint. High quality evidence was identified in only 20% of all submissions whereas 47% and 33% had average or poor quality, respectively; over time these percentages have not changed significantly.
Numerous clinical and economic uncertainties were identified with the vast majority of drugs appraised. Key among them were uncertainties relating to clinical benefit size (48% of the sample), followed by generalizability concerns (34%), and adverse event concerns (27%). Among countries using clinical and cost-effectiveness, modelling concerns were the most frequently raised economic uncertainties (33% of the sample), followed by model input concerns relating to costs and utility values informing economic models (28%).
Finally, several social value judgements were also identified which seem to have acted as decision modifiers in a number of cases across countries. Recognition of unmet need by HTA agencies was present in 43% of the sample, followed by severity (26%), administration advantage (22%) and innovativeness (14%). No significant changes were detected over time, suggesting a consistent approach towards SVJ consideration by HTA agencies.
The analysis highlights that, now more than ever, it is critical to understand assessment and appraisal processes by HTAs and that important differences may arise as part of those processes across countries, which also need to be understood. Equally, the complexity of HTA processes and the requirements for robust evidence (clinical, economic and on broader societal benefits) require a unique mix of skills for submissions to be successful.
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