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As part of the PhRMA Multiregional Clinical Trial Key Issue Team activities, a survey was designed, with the goal to collect actual data, experiences, practices, and examples, focusing predominantly on five key areas: the extent to which companies are expanding their reach into different regions to conduct clinical trials; the regions in which the studies are being conducted; the operational challenges experienced; management of differing, and often conflicting, regional requirements; and the sourcing models used to respond to the increasing global demands of staffing. The survey was sent to 31 PhRMA member companies on record at the time of the survey; responses were received for 15 of the 31. Nearly 80% of respondents had started trials in a new region over the last 10 years, mostly late-phase or postmarketing trials conducted across many therapeutic areas. The number one driver for this trend is the need for faster recruitment, although sponsors are also responding to the need for data to meet regional requirements. Evidence from the survey would suggest that the operational challenges of conducting trials in multiple regions are related to the mechanics of study conduct. Different methods of training are employed to drive quality of research, and such methods include formal tools such as online or instructor-led training, role certification, and the use of meetings and teleconferences. The survey also showed that differing and sometimes contradictory health authority or regional requirements present barriers to efficient clinical research, and harmonization among regulators would be beneficial to conducting global clinical trials. [ABSTRACT FROM AUTHOR]

The degree of consistency of treatment effects seen across regions within a multiregional clinical trial has important implications for all stakeholders. It can affect the ability of the trial results to be interpreted by the scientific community in an unambiguous manner and can have important ramifications for regulatory decision making. This article is part of a PhRMA team's effort to provide perspective and recommendations on this issue. A companion article from the same team focuses on relevant design considerations, while in this article the focus is on monitoring considerations specific to multiregional trials, on how the final trial results should be presented, and on thought processes that are relevant lo how signals of inconsistency should be investigated and interpreted. [ABSTRACT FROM AUTHOR]

Assessment of consistency of treatment effect across regions is often a key issue in a multiregional clinical trial (MRCT) because of differences in intrinsic and extrinsic factors. Careful consideration of consistency assessment of treatment effect across regions is necessary at the design stage. This article is part 1 of a cross-industry PhRMA team's effort to provide perspective and recommendations on the issue of regional consistency, with primary focus on design considerations. We argue that given the premise of an MRCT that there is no or limited regional variation, choices of appropriate consistency criteria for assessing regional consistency need to reflect this a priori belief and should not add an additional burden of proving regional consistency in addition to meeting the primary study objectives. The total sample size of the MRCT should be mainly driven by the primary objectives and hypotheses. Appropriate sample size partitioning and distribution across regions may be considered to achieve a target "assurance probability" based upon predefined consistency criteria such as modified PMDA (Pharmaceutical and Medical Devices Agency) methods. Prespecification and documentation of the plan for regional assessment in the protocol are important for interpreting the results. We also encourage communication with health authorities, and acknowledge negotiation may be necessary to reach an agreement, especially when there are region or country-specific interests. [ABSTRACT FROM AUTHOR]

Multiregionai clinical trials (MRCTs) present great opportunities but also challenges to the trial community. To address the challenges and fully realize the opportunities, a PhRMA MRCT Cross-Functional Key Issue Team (KIT) was formed in 2008. One of the work streams within the KIT particularly focuses on the assessment of consistency of treatment effects across regions. As the main objective of this work stream, this research explores a number of definitions for consistency assessments. We address the issues primarily for superiority trials with continuous endpoints, then extend briefly to noninferiority trials, random effect models, binary endpoints, and survival endpoints. Computations and simulations are used to study the properties of the proposed definitions, particularly the power for showing consistency. To illustrate applications of the methods, we use a trial example with a continuous endpoint. We discuss considerations for trial design as well as for data analysis. The consistency assessment relies heavily on the definition of regions and the number of regions. We recommend working with health authorities to define region in a manner that is sensible from a practical interpretation standpoint and also makes region consistency assessment a feasible undertaking. [ABSTRACT FROM AUTHOR]