Existing Facilitated Regulatory Pathways

Catherine Hoath

Overview

Many countries have developed Facilitated Regulatory Pathways (FRPs) for emergency use authorization, conditional marketing authorization, work sharing and accelerated approvals, which are included in FRPath.

Limitations in Facilitated Regulatory Pathways

While working through each pathway may be effective outside of a Public Health Emergency (PHE), there are limitations to that hinder their effectiveness, as detailed in general in Table 1 and for specific FRPs in Table 2.

Table 1: Limitations to FRPs in general

Limitation	Description
Misalignment of Submission Timeframes and Dossier Requirements	Misalignment of review timelines across different regulatory agencies can lead to delays in the approval process, as seen in the ACCESS worksharing pathway, WHO Collaborative Registration Procedure and others. Despite collaborative efforts generally also requiring identical submission dossiers across all partners, except for region-specific modules, applications must still meet specific national regulatory requirements. This can complicate the process, especially in regions with formalized parallel pathways for regulatory evaluation and health technology assessments. This can lead to extensive and cumbersome documentation, particularly concerning Chemistry, Manufacturing, and Controls (CMC) data, as well as country specific labelling requirements, etc.
Differing Risk Tolerances and Data Interpretation	Regulatory agencies often have varying risk tolerances and interpretations of data. This can lead to delays or rejections if one agency’s stringent standards influence the collective decision-making process.
Slow Speed of Marketing Authorization	While regulatory collaborations aim to expedite market authorization, this is not always achieved uniformly. Alignment across many National Regulatory Authorities can take significantly greater time for some Authorities than independent review.
Resource Constraints	Some members of collaborative initiatives often lack the resources to fully participate, leading to underutilization of these frameworks. Regional collaborative mechanisms often rely heavily on a few entities to perform the bulk of the regulatory work or on an adequately staffed secretariat to facilitate and drive the work and timelines. This can lead to inefficiencies and delays, particularly during PHEs.
Regulatory Agility	The COVID-19 pandemic highlighted the need for regulatory agility. Many regulatory authorities lacked the capacity to perform all core functions effectively, leading to reliance on better-resourced authorities. This dependence can delay decision-making and hinder timely access to medical products. Decisions about reliance or recognition are often made unilaterally without prior consultation with reference agencies. This can lead to inconsistencies and a lack of awareness among the agencies involved.

Table 2: Strengths and weaknesses of specific FRPs

FRP	Strengths	Weaknesses
ACCESS	Coverage of a wide range of therapeutic product groups Reduced duplication of effort leading to more efficient review Sharing of resources eases internal resource pressure Potential for greater alignment of regulatory decisions Greater exposure to emerging global trends and learnings Greater technical discussion of issues could make the final decision more robust Industry sponsor dealing with only a single set of questions from the group of 5 regulators (Slightly) faster regulatory approvals, although the impact on approval time varies by country and can be inconsistent Greater transparency of regulatory decisions for industry Earlier patient access to medicines in several countries	Alignment of submission timeframes can be difficult Applications must still accommodate specific national regulatory requirements and processes (such as use of advisory committees) In countries like Canada and Australia where there are formalized “parallel pathways” for regulatory evaluation and health technology agency assessment, involvement in ACCESS can complicate this process. There are differing risk tolerances and data interpretation between different ACCESS regulators. ACCESS-reviewed products may be significantly delayed at the regulatory decision-making stage because of high levels of risk-aversion within one of the ACCESS regulators. A negative view or decision by one ACCESS regulator can then build into a rejection or excessive conditions on a market authorization from all five regulators. ACCESS partners generally require that the submission dossier (except for the country -specific module) is identical across all partners. Some ACCESS partners require very extensive CMC data which can mean that the evaluation gets “bogged down” with CMC issues and that any post approval changes are extensive due to the large amount of CMC detail in the dossier. ACCESS worksharing only speeds up market authorization in certain markets. During the COVID pandemic, ACCESS members agreed that worksharing would be too slow for review of Marketing Authorization Applications for vaccines and therapeutics and instead close information sharing on submissions between ACCESS members was undertaken.
African regional collaborative pathways	Effective for generic medicines	Most regional African mechanisms have relied primarily on one or two main entities in each region to perform the bulk of the review work, with Zazibona being the most developed.
ASEAN Joint Assessment Procedure	Offers an opportunity for collaboration	The ASEAN Joint Assessment Procedure was not used during the COVID-19 pandemic due to inefficiencies; reliance or de facto recognition processes were used instead. This trend is likely to continue in future pandemics.
AVAREF	Effective for Clinical Trial Applications	Significant coordination is needed by the Secretariat, which may be infeasible if many developmental medicines, vaccines and devices are under review simultaneously. Participants have widely different review practices and timelines, which can hinder authorizations in some countries.
EMA’s Open Initiative	Allows non-EU regulators to participate in the scientific evaluation of certain medicines. Potential for significant acceleration	Limited by the independence of participating authorities and the complexity of coordinating parallel reviews.
MHRA Initiative on Recognition	Potential for significant acceleration	Can be excessively restrictive. Although the rapid timeframe of the “Recognition A” process is attractive to industry, several conditions can move a product to the slower “Recognition B” scheme or even to full MHRA evaluation. These include products with conditional approval, first-in-class new active substances, and clinical trials utilizing single-arm data and/or real-world evidence.
Orbis	Potential for significant acceleration	This pathway currently only covers oncology drugs. If it were expanded to include vaccines, it would be important to: Encourage more Orbis A and B applications versus Orbis C applications, since A and B applications are the most likely support rapid regulatory review. Expand the country membership of Orbis or permit additional regulators to have “observer status” at Project Orbis videoconferences. This would require these countries to enter into appropriate confidentiality agreements with the US FDA.

Creation of a single, global, FRP would be most efficient in a PHE.

Conclusion

While many FRPs exist in individual countries and collaborations, there are many limitations in their current form that impede effectiveness. Use of a single, global FRP for managing future PHEs is needed to align submission timelines, harmonize national regulatory requirements, and improve information sharing among regulators.