Points of View Analysis of decision-making factors in HTA institutions

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Mariko Hirozane, Researcher, Pharmaceutical Policy Studies, Graduate School of Pharmaceutical Sciences, The University of Tokyo
The Office of Pharmaceutical Industry Research Yosuke Nakano, Senior Researcher
Visiting Associate Professor, Department of Pharmaceutical Policy Studies, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Associate Professor, Health and Social Medicine Unit, Yokohama City University School of Medicine
NAKA IGARASHI

1. Introduction

Policy applications of cost-effectiveness assessment, or HTA (Health Technology Assessment) in the so-called narrow sense, have been implemented in countries around the world for the purpose of prioritizing the appropriate allocation of limited budgets to various health services. Many countries (e.g., the United Kingdom, the Nordic countries, Australia, Sweden, South Korea, and Thailand) use HTA to determine the availability of medical technology benefits, and the decisions of HTA agencies have a significant impact on a country's healthcare program options. As long as HTA is used to determine whether a technology is eligible for benefits, it is inevitable that there will be cases where a drug application is approved, but the HTA agency's decision will result in the drug not being covered by the program. On the other hand, "not providing benefits at the discretion of the HTA agency" is not necessarily synonymous with "not providing benefits because of poor cost-effectiveness. It would be helpful to examine what criteria were used to make the decision to "not provide" a drug in order to examine the value of the drug more broadly. In this paper, we focus on Australia's PBAC as an organization that discloses relatively detailed information on the reasons for non-endorsement in countries where HTA is used to determine whether or not a drug is endorsed, conduct an analysis of whether or not a drug is endorsed by HTA organizations, and summarize the findings.

2. HTA agency PBAC in Australia

Australia's public health care system is tax-based.

Prescription drugs are first approved by the Therapeutics Goods Administration (TGA) within the Department of Health, and then registered with the Australian Register of Therapeutic Goods before they can be used. Then, they apply for inclusion in the Pharmaceutical Benefits Scheme (PBS), a public health care system.

The Pharmaceutical Benefits Advisory Committee (PBAC), an HTA body within the Department of Health and Ageing, reviews data submitted by companies on prescription drugs three times a year and determines whether a drug is eligible for inclusion in the PBS. Since 1993, cost-effectiveness data have been required for PBS coverage. If the PBAC review determines that a drug is not reimbursable, the reason for the determination is provided and the company may submit new data to the PBAC for a second review. The company can then submit new data to the PBAC for a second review.

3. Non-grant decisions at PBAC and the reasons for such decisions

The results of the public summary document for each drug are available on the PBS ^website1). Based on this public summary document, we analyzed the results of PBAC evaluations and their content, which covered 1,485 evaluations from the period 2008-2019. As with NICE in the UK, when the same drug has multiple indications, data are submitted for each indication and a decision is made as to whether or not the drug can be listed. Therefore, there have been many cases in which a drug was ruled not to be covered under one review but was approved for other indications, or a drug was ruled not to be covered but was eventually approved after a reapplication was made for other indications.

Figure 1 shows the results of the review at PBAC. The results show that there are three types of reviews: benefit, non-benefit, and pending. The percentage of benefit reviews varies from year to year, but for the most recent five-year period, the percentage of non-benefit reviews was about 62%. In addition, we examined what factors led to the decision to deny benefits, focusing on the reviews that were denied benefits. The reasons for not providing a benefit were categorized as "efficacy," "comparator," "safety," "price," "uncertainty of cost-effectiveness (large variability)," "poor cost-effectiveness," and "cost-effectiveness (incremental cost-effectiveness ratio, ICER value). （The issues were categorized as "poor cost-effectiveness" (high incremental cost-effectiveness ratio ICER value), and factor analysis was conducted. In some applications, multiple items were pointed out, and in many cases, the application was judged to be ineligible for benefits. The "price" was pointed out as being too high compared to existing drugs, and there were criticisms regarding the inclusion or exclusion of additional costs necessary for treatment, etc. The analysis focused on the price alone. In this analysis, the review of 1,485 applications was reviewed, of which 474 applications were further analyzed for non-payment.

The results are shown in Figure 2. The most common reasons for denial were the issue of relative "effectiveness" and "uncertainty in cost-effectiveness evaluation. In other words, factors other than "poor cost-effectiveness" were found to contribute significantly to the decision not to provide benefits under PBAC.

Many of the comments on "efficacy" pointed to a lack of clinical data on existing drugs as a problem. In many cases, insufficient data were pointed out because single-arm clinical trials are conducted for serious diseases.

On the other hand, the main issues pointed out regarding uncertainty in cost-effectiveness (i.e., the large range of variability) were the uncertainty of data showing clinical usefulness in the target patient population (issues of outcome data and data source selection criteria) and uncertainty regarding analysis methods (e.g., which analytical model to use).

The latter issue of uncertainty has consistently accounted for over 40% of the data over the past five years and has surpassed "poor cost-effectiveness" in recent years (Figure 3).

These results clearly indicate that drugs determined to be non-awarded at HTA agencies are affected not only by poor cost-effectiveness, but also by other reasons such as those listed above.

4. relative effectiveness, responses to uncertainty and implications

In recent years, as the target indications for pharmaceuticals have become more refined, and the number of drugs for cancer and rare diseases selected based on biomarkers and other factors has increased, it is expected that the relative efficacy and uncertainty will be pointed out more frequently in HTAs in the future. Clinical trials of these drugs are often single-arm or placebo-controlled with no active comparator due to the small number of patients. Even when regulatory approval is granted in terms of absolute usefulness, i.e., efficacy and safety compared to no treatment or placebo, issues of efficacy and associated uncertainty are pointed out due to lack of data on relative (additional) usefulness and other factors in cost-effectiveness evaluations that lead to whether benefits can be granted.

The following is an overview of the discussions on the above issues. First, the existence of a gap in judgment and evaluation axes between clinical trial evaluation organizations and HTA organizations (equivalent to TGA and PBAC in the case of Australia) has been pointed out in several countries, and collaboration between the two organizations has been cited as an issue ^.2), 3 In addition, the design of clinical trials to reduce uncertainty in HTA from an early stage is being discussed with relevant stakeholders. In addition, it is necessary to consider the design of clinical trials and analytical methods that reduce the uncertainty of HTA from an early stage through dialogues with relevant stakeholders. In addition, reanalysis using real-world evidence and value-based contracting for post-launch medicines through managed entry agreements at the time of reimbursement, and temporary budgetary provision while additional data are obtained, such as the Cancer Drugs Funds in the U.K., should be considered in the future. Such special measures have been taken in an increasing number of cases in recent years. In a world that is shifting toward personalized medicine, reimbursement responses are also diversifying, and international views argue that it is difficult to take a single ^method4)-6.

In Japan, discussions on how to determine the value of each treatment are inevitably taking place amidst the problem of rising medical costs. Although cost-effectiveness evaluations have been conducted for some pharmaceuticals for the purpose of price adjustment, we should be aware that the issue of how to evaluate the value of treatments, including uncertainty, will become even more important in the future as the number of treatments continues to diversify. Furthermore, issues related to comparator drugs and analysis methods are also expected when evaluating the multifaceted value of pharmaceuticals, and should be considered according to the type of drug.

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