Unleashing the Power of Reliance for Post-Approval Changes with 48 NRAs
Francesca Mangia
Melly Lin
Susanne Ausborn

F.Hoffmann-La Roche, Basel
John Armando
F.Hoffmann-La Roche – Genentech
Srinivasan Kellathur Nadathur
F.Hoffmann-La Roche, Singapore

ost-approval changes (PACs) are an essential part of product lifecycle management to ensure continuous supply of life-saving medicines in case of increased demand, to support continuous improvement and optimization of the manufacturing process, to remain state-of-the-art with analytical techniques, and to ensure continuity to comply with the updated regulatory requirements. However, bringing chemistry, manufacturing, and controls (CMC) changes through global health authority (regulatory) systems can be a complex, lengthy process that can take several years. At the same time, PACs represent a large proportion of regulatory submissions and their timely approval is critical to maintaining and ensuring continuous supply of quality medicinal products.

To facilitate timely access to safe, effective, quality-assured medical products and make the best use of available resources and expertise, the World Health Organization (WHO) strongly promotes reliance amongst National Regulatory Authorities (NRAs). NRAs are encouraged to rely on the assessment performed by a reference regulatory authority. While some promising developments have been made with reliance pathways for initial marketing authorizations, they are still less commonly used for PACs. More needs to be done to bring reliance into action on PACs around the globe.

Supported by the European Medicines Agency (EMA) and WHO, a multinational biotech company is currently running a reliance pilot encouraging NRAs to use an abridged regulatory pathway based on reference country approval. A supply-critical variation for a monoclonal antibody, which constitutes a major change to the approved drug substance manufacturing process, was simultaneously submitted in January 2024 within a week’s time to 48 NRAs who have agreed to participate in this global pilot and is currently under review. Participating NRAs are invited to leverage the outcome of the EMA assessment and approve the change within a predefined timeline. Sameness of the product is ensured since the same variation package, as submitted and approved in the EU, was submitted to all participating NRAs. The EMA Assessment Report, approval letter, and Q&As were provided to all participating NRAs as part of the submission package. To enable full transparency, any questions received during the review, together with answers provided by the sponsor, will be shared among all participating NRAs. In addition, a third-party cloud-based Q&A platform was adopted to enable sharing of Q&As in real time. Nevertheless, NRAs can choose whether to use the cloud-based platform or their standard Q&A process.

The overarching objective of the pilot is to increase predictability for implementation of changes and reduce complexity of global life-cycle management through reliance. The company aims to reduce the global approval time from approximately 2.5 years to 6.5 months, build trust with key stakeholders, and promote regulatory convergence by waiving country-specific requirements.

The implementation of this PAC reliance pilot involves three phases, (1) Planning, (2) Engagement, and (3) Execution.

  1. During the 9-month Planning phase, different products were screened. A suitable PAC project was identified upon discussions between regulatory policy leads and different product teams. After that, the regulatory and supply strategy was defined for each country based on supply-critical factors.
  2. During the 6-month Engagement phase, the criteria for pilot participation were established and presented to EMA and WHO to seek recommendations and agreement from EMA to be a reference regulatory authority. Engagement and support from the company’s affiliates worldwide was a crucial step to connect with the 84 NRAs impacted by the variation, to encourage pilot participation, and to discuss the defined pilot criteria, including: 1) adhering to the proposed approval timeline (6.5 months maximum); 2) accepting EMA as a reference agency; 3) avoiding requesting country-specific documents unless scientifically justified; and 4) waiving sample testing. Of the 84 NRAs covering all geographic areas that were approached for the pilot, 48 (57.1%) agreed to participate, 31 declined, and the five (5) that did not respond were clustered in Latin America.
  3. With the approval of the variation by EMA in hand, the company embarked on the pilot Execution phase and arranged the PAC reliance pilot virtual kickoff meeting with EMA, WHO, and all 48 participating NRAs to present the pilot outline and clarify questions about the procedure. In January 2024, 48 affiliates and agents submitted the dossier package simultaneously to the 48 NRAs within 7 working days using the local national submission procedures.
  4. The company’s expectation is that the pilot will be reviewed and approved within the next 6.5 months (maximum) after submission, which includes a 75-day review period, followed by 45 days of responding to questions by the company, another 45 days of reviewing the answers by NRAs, and then 30 days of granting the approval or sharing rationale for refusal. The latest expected approval by the 48 participating NRAs is the end of July 2024.

Key considerations for the successful launch and broad participation in the pilot include:

  • Transparency and dialogue are crucial in establishing trust between industry and regulators, and in turn fostering regulatory reliance. To enable this, sharing the same variation package approved by EMA as well as the unredacted assessment report and EMA Q&As was a key element in this pilot.
  • Support provided by EMA and WHO, both strong advocates for reliance around the globe, was equally important. EMA’s and WHO’s joint participation in the pilot kickoff meeting, and EMA’s offer of clarification on the contents of the assessment report, were influencing factors for NRA participation as mentioned or implied by several NRAs during this pilot.
  • Choice of the product and a supply-critical variation was another key factor in the regulators’ agreement to join the pilot: This medicine is used for treating life-threatening diseases and involves a major supply-critical variation with high public health and business impact.
  • Overall product strategy, especially the impact of the pilot on change implementation, should be continuously and carefully assessed. Considerations include change implementation, grace period policies in the impacted countries, acceptance of parallel submissions of changes, and impact of accelerated approval on supply planning.
  • Regulatory affiliates of each participating company, which operate in the countries impacted by this variation, play a crucial role as the primary contact with their respective NRAs. Close collaboration and continuous dialogue between affiliates and the pilot team ensure consistent messaging about the importance of reliance and the pilot’s objective to NRAs, eventually securing the NRAs’ participation. Longstanding relationships and trust between affiliates and the local NRAs, which can only be built over time, were instrumental in making this happen. Finally, affiliates’ contributions are essential in ensuring a timely and simultaneous submission aligned with the target review timeline.

This PAC reliance pilot is the largest ever conducted, which demonstrates the strong interest and willingness of many NRAs across the globe to bring reliance into action for PACs. Transparency in building trust with regulators, achieved through industry openness in sharing the reference agency’s dossier package and unredacted assessment report, is key. Applying reliance throughout the lifecycle of the product, including PACs, represents a contribution towards global convergence and harmonization and supports the goal of ensuring continuous supply of medicines for patients through global regulatory convergence, harmonization, and reliance.

Look for a future report in Global Forum on the outcome of this pilot.

Read our conversation with Accumulus Synergy CEO Francisco Nogueira for insights on the broader implications of this pilot project.