The End-of-Phase 2 Meeting – Potential Drawbacks of Missing the Mark on this Critical Milestone

This blog, written by Eric Hardter, Director of Regulatory Affairs at Boyds, explores why the End-of-Phase 2 meeting is a critical milestone in drug development. Drawing on extensive experience supporting FDA interactions, Eric outlines the key areas where regulatory alignment is essential, including study population, endpoints, statistical approach, and dose selection, and highlights the risks to pivotal programs if these are not adequately addressed.

In practice, this alignment must be established prior to commencing a pivotal Phase 3 study for an investigational medicinal product (IMP) development program. Phase 2 study data will have provided critical insights into a proposed patient population for registration, as well as the endpoints that will allow for a determination of the IMP’s efficacy. Where relevant, it may also inform the need for further development in a pediatric population, which may potentially be deferred so as not to slow licensure in adults.

These, and other tenets, are critical for discussion at an End-of-Phase 2 (EOP2) meeting.

A failure to gain this critical feedback adds significant risk to the pivotal program. Such feedback may include but is not limited to:

• Determination of a consensus study population: Many diseases, particularly in the rare disease and CNS disease spaces, manifest heterogeneously. This may include both in clinical phenotype, as well as symptom severity. This has the potential to obfuscate the treatment effect, or determine if the treatment effect is clinically meaningful. As an example, enrolling participants with milder variants of the disease may result in regulators disagreeing that the IMP’s risk/benefit profile is appropriate.
• Establishment of efficacy endpoints: While many diseases have established, validated endpoints to determine a treatment effect, this is not always the case. However, pushing ahead with unvalidated biomarkers or participant reported outcomes runs the risk of regulators not agreeing that they’re tied to clinically meaningful benefit.
• Proposed statistical analysis: Concurrence should be sought on the Phase 3 study statistical analysis plan (SAP), but the EOP2 meeting is also an appropriate venue to begin discussion of registrational datasets. If a sponsor intended to leverage confirmatory evidence, such as data from a related indication, it should be discussed in advance of the Phase 3 study. Failure to do so may result in unnecessary data collection in the Phase 3 study, or more than one Phase 3 study being necessitated.
• Dose optimization: Activities including but not limited to dose range finding, expansion cohorts (e.g., IMPs for oncologic indications), and dedicated clinical pharmacology studies (where relevant) will inform the dosing paradigm for the pivotal trial. Regulators should be presented with the totality of evidence in hand, or they may not be able to agree to a Phase 3 clinical trial dosing regimen.

Failing to ask appropriate questions and/or include appropriate information for regulator review, or simply not holding an EOP2 meeting can significantly delay the critical path. In one scenario, sponsors could lose evaluable participants and data if regulators disagree that for one or multiple reasons, the data doesn’t support a registrational risk/benefit profile (e.g., lack of concurrence with the dosing regimen, or the explicit trial population). In a more extreme scenario, they may not view the Phase 3 clinical trial as adequate to provide pivotal data, due to concerns with the study design (e.g., endpoint selection, or choice of controlling mechanism). This could result in the need for significant amendment to the study, additional enrollment, or a completely new trial design. All of these could lead to time and cost overruns.

Obtainment of regulator feedback becomes even more critical in a global IMP development setting. While there may be some anticipated minor drift pending local regulation, it should not be assumed that guidance received in one region will be duplicated in another. Further, the approved standard of care regimen may be variable, meaning participants in one country may have different background medications or potential comparators.

Failure to meet with regulators in multiple jurisdictions may lead to an absence of these types of critical feedback. While sponsors needn’t pause their IMP development programs, consideration could be given to a more phased approach of enrolling participants in regions only after receiving regulator feedback. This has the added benefit of allowing a competent authority in one region to utilize the context of feedback received by a separate authority, so as to best harmonize across regions.

When developing a regulatory roadmap, time should be specifically allotted for review of phase 2 data and subsequent generation of briefing materials. In doing so, sponsors should further account for regional differences in scheduling meetings (e.g., continuous submission to the US FDA, versus monthly deadlines to EMA; separate meeting request and briefing package documents to the US FDA, versus a consolidated, templated package to EMA). A lack of proactive planning for this important milestone may could lead to rushed documents, missed deadlines, and delay of the pivotal program.