Is the quality of clinical evidence for reimbursement of cancer medicines declining?

Pharma News: The Adelaide Health Technology Assessment (AHTA), who is contributing to the current HTA Review, has shed light on recent trends in the quality of clinical evidence submitted for government subsidy decisions on cancer medicines in Australia over the past 15 years.

According to the latest statistics, over 1 million people in Australia are diagnosed with cancer each year, leading to a substantial disease burden that places significant strain on healthcare resources. A remarkable 32% of the Australian Government’s expenditure on medicines is directed towards antineoplastic and immunomodulating agents, underscoring the urgent need for effective, safe, and affordable treatment options.

A first-of-its-kind study from the AHTA found that a significant proportion of regulatory approvals for cancer medicines do not include randomised controlled trials (RCTs). Approximately half of the direct evidence has a high risk of bias, casting doubt on the reliability of the evidence supporting their use.

“In addition, there is an increase in the utilisation of surrogate outcomes in oncology research while the association between surrogates and true clinical benefits has been questioned. A lack of direct comparative evidence and the utilisation of surrogate outcome measures results in increased uncertainty about the clinical benefits and risks associated with medicines,” the authors Gao et al noted.

In Australia, concerns about the quality of clinical evidence have been voiced before. Two prior studies expressed reservations about the rigor of clinical evidence presented in submissions for listing on the Pharmaceutical Benefits Scheme (PBS). Hill et al highlighted problems in estimating comparative clinical efficacy, often stemming from poor-quality trials and misinterpretation of trial results. Wonder et al found that a significant portion of clinical evidence failed to support reimbursement claims, especially in terms of medicines’ comparative performance.

Only a small proportion of cancer drug submissions had overall survival (OS) data that had reached maturity (30%).

“Data immaturity in oncology trials has become common, and this poses a challenge for decision making for both market authorisation and reimbursement. In addition, to achieve an early submission to regulatory and HTA bodies, pharmaceutical companies may pursue clinical endpoints that take less time to follow up, such as progression-free survival (PFS). However, evidence has shown that such surrogate outcomes frequently fail to translate into real clinical benefit,” Gao et al said.

The study’s findings also unveiled an increase of 30% in the reporting of risk of bias in head-to-head trials.

“Many factors could have contributed to this decline in quality, such as increases in cross-over/treatment switching between trial arms, the use of open-label trials in conjunction with subjective outcomes, composite primary outcomes, and incomplete outcomes due to censoring or loss of follow-up,” the authors noted.

Over the past decade, Australia has witnessed significant changes in HTA and PBAC evaluation processes. The emergence of companion tests, which target cancer treatments based on genetic biomarkers, has led to a parallel assessment of these tests and treatments. This “co-dependent submissions” approach aims to provide a more comprehensive evaluation by considering diagnostic evidence alongside clinical trial data. Moreover, the adoption of a parallel processing system for regulatory and reimbursement submissions has expedited the evaluation process. However, concerns have been raised that this accelerated approach could lead to insufficient evidence being available at the time of market approval.

The study highlighted a nearly 50% increase in the submission of personalised medicines to PBAC, emphasising the growing influence of pharmacogenetics in oncology. In addition, the study revealed a rise in submissions of second-to-market drugs, indicating a trend toward drugs with marginal incremental benefits over existing treatments.

This was the first study to evaluate the evolution in the quality of clinical evidence for oncology medicines, as determined by the PBAC, when considering submissions for reimbursement in Australia.

“We found that funding decisions for cancer drugs in Australia are made in the context of significant uncertainty as the quality of clinical evidence provided is frequently poor and has deteriorated over the last decade. As the evidence dossiers submitted in Australia are reflective of dossiers submitted to other HTA bodies internationally, this poor-quality evidence contributes to a high degree of uncertainty in decision making, with opportunity costs to society and potentially consequent risks to patients,” the authors from the AHTA concluded.

The insights from this study hold significant relevance, particularly as the HTA Review Reference Committee actively engages with AHTA and the Centre for Health Economics Research and Evaluation (CHERE) to navigate ongoing reforms in the evolving landscape of novel health technologies.

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