EMA Hosts Subgroup Analysis Workshop; Invites Esubmission Gateway Registrations

The EMA brought together European and US expert representatives from regulatory authorities, academia, industry and a health-technology-assessment agency on Nov. 18, 2011 to discuss the use and importance of subgroup analysis in the assessment of clinical trials. The workshop, the first of its kind, aimed to present the scope and content of a proposed guideline on the topic being prepared by the Committee for Medicinal Products for Human Use (CHMP) and garner feedback on standards and methodology.

The main conclusions drawn from the meeting about the design of trials were that as clinical trial populations are frequently heterogeneous, regulators must examine the benefit–risk balance for subsets of patients that fall outside of traditional demographics (e.g., gender, age, and ethnicity). Therefore, according to the press release, “plans to explore benefits and risks in biologically defined and potentially clinically relevant subgroups should be incorporated into every development programme.” The group also agreed that early dialogue between industry and regulators about the most important subgroups to be accounted for was highly valuable and will guide assessment.

In terms of trial result analysis, “statistical methods to investigate the consistency of effects across the entire target population were discussed (tools are not limited to interaction tests), as well as methods to deal with multiplicity issues to control the probability of false positive or false negative findings. Heterogeneous results across subsets will require a further level of scrutiny in the assessment phase. A quantitative definition of internal consistency does not exist.” The group also noted that post-hoc subgroup analyses should be interpreted with caution but may convey very important information about the right target population. However, because of an inability to statistically quantify post-hoc analyses, difficult challenges are posed for the assessment. The release stated, “Whilst relevant to all subgroup investigations, biological plausibility and replication across studies (e.g., in the same therapeutic class) seem to be factors of particular importance to accept or reject post-hoc analyses.” The group agreed that this point requires refinement and should be discussed in more detail in the new guideline.

In other EMA news, registrations for the eSubmission Gateway pilot, which begins Jan. 9, 2012, are being invited. The three-month trial sees a new electronic submission channel being put into action for centralised marketing authorisations for human medicines, including new applications, supplementary information, variations and renewals. The gateway will use a secure business-to-business transfer process, which should improve the speed and efficiency of the application process. A web-based submission client is also under development to handle low-transmission volumes that may be more suitable for small- and medium-sized companies; plans will be announced in the first quarter of 2012. Following successful completion of the pilot, which is open to a limited number of applicants, the EMA will consider extending the use of the Gateway to all applicants.