Abstract PS7-21: Timelines to initiate an adjuvant phase III trial across the globe: A sub-analysis of the APHINITY trial

Abstract

Abstract Background:Previous analysis of an adjuvant breast cancer trial (NCT00490139) suggested that geographical location and income affected the time required to set up a clinical trial, being significantly longer in South American and upper-middle income economies, potentially affecting access of innovative therapies in these locations. Understanding that this can be a dynamic process, we performed a similar analysis for the recent global phase III APHINITY trial (NCT01358877), which investigated the addition of pertuzumab to chemotherapy and trastuzumab as adjuvant therapy for patients with HER2-positive primary breast cancer. Methods:Time to regulatory authority (RA) submission to approval, time to ethics committee/institutional review board (EC/IRB) approval, time from study approval by EC/IRB to first randomized patient, and time from first to last randomized patient were collected prospectively. Analyses were conducted by grouping countries either by geographical region or economic income classification as per 2019 World Bank criteria. Descriptive statistics of medians and ranges were calculated for the different timelines evaluated. Differences between geographical regions and economic income classification groups were calculated using one-way analysis of variance (ANOVA) following data normalization on square roots of the time to local RA. Geographical regions represented by only one participating country were not included in the ANOVA calculations. Results:APHINITY randomized 4805 patients between November 2011 and August 2013. Of the 42 participating countries, 41 had data available regarding all relevant timelines. Of those, 21 (51.2%) were located in Europe, 9 (21.9%) in the East Asia-Pacific region, 8 (19.5%) in Latin America and Caribbean, 2 (4.8%) in North America, and 1 (2.4%) in Sub-Saharan Africa. Twenty-seven (65.8%) of the participating countries had high, 11 (26.8%) upper-middle, and 3 (7.3%) had lower-middle income economies. Except for time from first patient to last patient randomized, there was wide variation in timelines within geographical region and across economic income classification. For example, the median time from EC/IRB approval to first recruited patient across all geographical regions was 118 days, but the range was wide (13– 463 days). There was, however, no statistical difference between the time to RA according to geographical region (p=0.47) although there was a trend to longer time to RA in upper-middle income economies compared to the others (p=0.07). Conclusion Our results did not demonstrate a significantly longer time for trial activation in Latin American & Caribbean countries and upper-middle income economies compared to other groups in the APHINITY trial. When compared to a previous report, this may reflect collective work from collaborative research groups, pharmaceutical industry sponsors and regulatory authorities across the globe and is to be welcomed. Variability in timelines within geographical regions and income classifications may exist and should be further investigated. Table 1: Timelines in the activation process of APHINITY across geographical region and economic income classification.Time to RA (days)*Time to EC/IRB (days)Time from EC/IRB approval to first patient (days)Time from first patient to last patient randomized (months)Europe and Central Asia56 (4-135)67 (22-164)109 (13-257)17.6 (13.2-21.7)North America31 (30-32)73 (19-126)126 (86-165)17.6 (13.8-21.5)East Asia and Pacific53 (15-372)67 (31-421)108 (56-147)18 (8.7-19.9)Latin America and Caribbean51 (15-276)43 (19-273)232 (98-463)14.6 (6.5-17.5)Middle East and North Africa-141 (141-141)92 (92-92)13.9 (13.9-13.9)Sub-Saharan Africa103 (103-103)14 (14-14)185 (185-185)18.2 (18.2-18.2)Overall53 (4-372)56 (14-421)118 (13-463)17 (6.5-21.7)High income45 (4-276)60 (19-273)98 (13-257)18.2 (11.9-21.7)Upper middle income92 (15-372)54 (14-421)185 (73-463)14.2 (6.5-18.2)Lower middle income55 (32-111)33 (32-78)201 (147-209)15.1 (13.5-17.4)Overall53 (4-372)56 (14-421)118 (13-463)17 (6.5-21.7)Data are medians (range)*The protocol was not submitted to a country regulatory authority for Israel. The corresponding timelines for Israel cannot be calculated.EC/IRB = ethics committee/institutional review board; RA = regulatory approval Citation Format: Maria Alice Franzoi, Marion Procter, Orianne Emond, Damien Parlier, Noam Pondé, Daniel Eiger, Sebastien Guillaume, Linda Reaby, Christopher Twelves, Emma Clark, Evandro de Azambuja, Jose Bines. Timelines to initiate an adjuvant phase III trial across the globe: A sub-analysis of the APHINITY trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-21.