| dc.description.abstract | Abstract
Background: Overall Survival (OS) has been traditionally the gold standard for the approval of anticancer treatments in advanced cancer. However, in light of the significant advances in treatments, clinical trials with OS as the primary endpoint are challenging because long follow-up is required and the drug effect on survival is confounded by post-progression treatments. Progression-Free Survival (PFS) is an earlier endpoint which has been increasingly used as a primary endpoint in advanced cancer and a number of anticancer drugs have been approved based on PFS benefits. Nevertheless, this is not unanimously agreed upon within the scientific community, and there is doubt about whether PFS measures clinical benefit. Some experts contend that the approval of anticancer drugs should not be based solely on PFS benefits, considering also several cases that a PFS increase has not translated into an OS increase.
Aim: To identify and characterize the attitudes and the arguments in favor or against PFS as the primary endpoint in advanced cancer as expressed by the stakeholders. Also to assess how these may vary among the stakeholder groups and the different tumor types and classes of drugs.
Methods: A systematic literature review was conducted and records were retrieved from Pubmed, Embase and via citation searching. An artificial intelligence tool (AS Review) was used to screen and select the relevant publications from the initial set of retrieved records. Two different types of data were extracted according to the type of the publication and for this reason, the publications were divided into two sets. In the first set (reviews, opinion articles, editorials, commentaries, correspondences, research and analysis articles, and taskforce and congress results) the attitudes and the arguments in favor/against PFS were identified. The second set comprised the preferences studies that reported either the preference of patients, patient advocates and healthcare professionals for PFS compared to other efficacy measures or their perception of the term irrespective of other efficacy measures.
Results: From the initial set of 97.134 records, by screening approximately 1.500, 243 relevant publications were identified and included in the review. The analysis of the first set of 203 publications led to the identification of 207 attitudes and a number of arguments in favor or against PFS, expressed either by the author(s) themselves or by other stakeholders and reported by the authors. The results point to a recognition by all stakeholders of the potential of PFS to reduce the duration and the size of the trial and to provide a clear effect of the treatment. In addition, the susceptibility of PFS to measurement error and to certain types of bias was of concern for all stakeholders. Nevertheless, a discordance was found about whether PFS measures clinical benefit. On the one hand, regulators and pharmaceutical industry seem to accept PFS as a clinically relevant endpoint per se and as a potentially appropriate primary endpoint. Regulators further noted that this depends on the case at hand. On the other hand, academic hospitals and HTA agencies/payers appear more reluctant to accept PFS as a measure of clinical benefit. They requested confirmation of the PFS benefit with OS benefit or validation of its surrogacy if PFS is to be used as a primary endpoint.
Conclusion: The results provide a comprehensive overview of the attitudes about PFS as a primary endpoint as expressed in literature. Considering the underrepresentation of regulators, HTA/payers and pharmaceutical industry, in the future, interviews or surveys to the respective stakeholders could further shed light on this topic and confirm the observed trends. | |
