Observations on Three Endpoint Properties and Their Relationship to Regulatory Outcomes of European Oncology Marketing Applications

Abstract

Background. Guidance and exploratory evidence indicate that the type of endpoints and the magnitude of their outcome can define a therapy's clinical activity; however, little empirical evidence relates specific endpoint properties with regulatory outcomes. Materials and Methods. We explored the relationship of 3 endpoint properties to regulatory outcomes by assessing 50 oncology marketing authorization applications (MAAs; reviewed from 2009 to 2013). Results. Overall, 16 (32%) had a negative outcome. The most commonly used hard endpoints were overall survival (OS) and the duration of response or stable disease. OS was a component of 91% approved and 63% failed MAAs. The most commonly used surrogate endpoints were progression-free survival (PFS), response rate, and health-related quality of life assessments.There was no difference (p 5 .3801) between the

Selection of Endpoints in Clinical Trials: Trends in European Marketing Authorization Practice in Oncological Indications

“…2,6,7 Available articles constitute a systematic review of oncological medicines with marketing authorization granted by the European Medicines Agency (EMA) in the years 2009 to 2013; they, however, do not answer the questions about the results and trends observed for particular oncological indications. 8,9 The aforementioned issues seem to be crucial because of the heterogeneity of oncological indications, especially hematological and other oncological indications (solid tumors). The objective of this analysis was to determine the types of endpoints that constitute the basis for drawing conclusions on the efficacy of medicines used in specific oncological indications, including hematological ones.…”

Use of depth of response to predict progression‐free survival in relapsed or refractory multiple myeloma: Evaluation of results from 102 clinical trials

“…Beyond MRD, international myeloma working group (IMWG) response rates such as overall response rate (ORR), very good partial response (VGPR) or better rate, and complete response (CR) rate can be used to evaluate efficacy in a much shorter time period than PFS . Response rates can be used as surrogate endpoints in hematological oncology for accelerated drug approval by regulatory agencies, with several recent examples of accelerated approvals by the US Food and Drug Administration in multiple myeloma such as daratumumab and pomalidomide . In fact, in approximately 40% to 50% of the oncology indications recently approved by the United States Food and Drug Administration, response rates have been used as the primary endpoint .…”

Relationship between response rates and median progression‐free survival in non‐Hodgkin's lymphoma: A meta‐analysis of published clinical trials

“…Overall survival (OS) is widely regarded as the “gold standard” among the primary endpoints for the approval of oncology drugs . Because of the long follow‐up time with improving survival rates and impact of subsequent therapies on OS, progression‐free survival (PFS) is now more commonly used as a primary endpoint . However, even the evaluation of PFS requires increasingly longer patient follow‐up times within a clinical trial due to continued improvement in treatments, limiting the use of PFS to make timely decisions in developing a particular new therapy.…”

“…[1][2][3] Because of the long follow-up time with improving survival rates and impact of subsequent therapies on OS, progression-free survival (PFS) is now more commonly used as a primary endpoint. [3][4][5][6][7] However, even the evaluation of PFS requires increasingly longer patient follow-up times within a clinical trial due to continued improvement in treatments, limiting the use of PFS to make timely decisions in developing a particular new therapy. In hematological malignancies, this is particularly true in the more indolent lymphomas, such as follicular lymphoma (FL), where efforts are currently under way to validate the surrogate endpoint of complete response (CR) at the landmark time point of 30 months of therapy.…”

“…4 Besides CR, other response endpoints often being used in place of PFS include partial remission (PR) and overall response rate (ORR), which can similarly be measured in a much shorter period of time than PFS. Response rates can be used as surrogate endpoints in hematological oncology for accelerated drug approval by regulatory agencies, 1,5,6,8,9 with an increasing use of these surrogate endpoints for the approval of oncology drugs in general. 10 In approximately 40% to 50% of the oncology indications approved by the United States Food and Drug Administration (FDA), response rates have been used as the primary endpoint.…”