European Medicines Agency Perspective on Oncology Study Design for Marketing Authorization and Beyond

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By legislation, approval of medicinal products within the European Union only relies on the demonstration of a favorable benefit‐risk (efficacy/safety). As a corollary, marketing authorization of a new medicinal product for the treatment of cancer is valid in all 28 member states, Norway, and Iceland.1
Drug approval is only a first step to meaningful uptake in the clinic as, in most member states, reimbursement is necessary in order to achieve this and may not be warranted for costly drugs when economic resources are limited. As an illustration, in 2014, the per capita expenditures on cancer drugs in the European Union varied from €7 in the Baltic States to €60 in Austria. In major West European member states, per capita expenditures also varied: Spain (€36), United Kingdom (€37), Italy (€40), France (€50), and Germany (€59), (i.e., varied roughly in parallel with per capita expenditure on cancer care and total health care).2
It may be noticed that expenditure on cancer care has remained stable at about 6% of total health care expenditures since 1995 in all member states. The proportion related to cost for anticancer drugs, however, has increased rapidly in Western Europe and it is foreseen that it will be tough to compensate for this increase in the future as it is hard to further reduce costs by switch to ambulatory care or through other means.2 An increase in the overall cost of cancer care as a percentage of health care expenditures is, thus, foreseeable based on current trends, but can certainly be justified if improved patient benefit is demonstrated in parallel.
From a regulatory perspective, it is sometimes possible to conclude on a favorable benefit‐risk based on single arm trials and convincing data on response rate and duration of response. Such data are unsuitable for a conventional health economic appraisal. In other cases, a modest survival benefit has been demonstrated and benefit‐risk has been found favorable, but a health economic appraisal shows poor cost‐effectiveness. In both cases, reimbursement may be refused (Table1).3
High antitumor activity may lead to marketing authorization, which is subject to the conduct of a conventional confirmatory trial as an obligation. This may lead into what has been named an adaptive pathway in which risk‐benefit and cost‐benefit are iteratively reassessed during the development of the drug.3
The adaptive pathway concept can accommodate innovative designs of postapproval efficacy/safety and effectiveness studies. Based on the objectives of the trial, planning could involve a number of stakeholders, including patients, health professionals, health technology assessment bodies, payers, and regulators. According to the objectives, large and simple or nested trials, randomized or not, conducted or not within existing registries, involving one or more newly licensed drug, are only examples of possible designs.
At the other end of the spectrum, we as regulators too rarely meet well‐planned, well‐powered, and well‐executed exploratory studies. Especially, if possible, to conduct in treatment‐naïve patients, conventional measures, such as data on exposure/adverse events/tumor response, may be complemented with, for example, use of functional imaging and tumor and liquid biopsies with the aim to enable stratified drug development, and an early confirmatory approach with respect to predictors of patient benefit.5 The implementation of these more advanced exploratory objectives has been slow and it is acknowledged that it is hard to identify persuasive role models due to lack of such data in success stories, as well as in phase III failures.7
Another aspect related to exploration and confirmation is to define factors of importance for primary and secondary resistance. Such data are clearly warranted and, when available or not, information thereof should normally be put forward in the European Union summary of product characteristics.
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