Planning Phase

The pilot planning phase started with defining pilot selection criteria. After successful product selection a cross-functional PAC Reliance Pilot team (referred to as ‘the team’) was formed with representatives from the CMC International Operations department and CMC Regulatory Policy to develop a detailed pilot roadmap and define internal and external engagement plans (Fig. 2).

The team firstly made the decision to use EMA as the reference country considering EMA’s strong commitment and support to international collaboration and reliance and availability of the final CHMP assessment report. WHO was considered as a key stakeholder to engage considering its crucial role in driving and supporting the implementation of regulatory reliance globally.

Besides external engagement activities, a detailed global filing plan was established to assess the impact on internal resources and drug supply with the consideration of submission and approval timeline of related PACs, possibility of parallel submission, global implementation timeline, grace period, etc.

Engagement PhaseFirst Engagement Meeting with EMA & WHO

The company held the first engagement meeting with EMA and WHO in March 2023 to present objectives, plans and timelines on the PAC Reliance Pilot. Both stakeholders were very positive and supportive of Roche efforts to initiate the pilot using reliance to get timely approval of an important variation, as it is also in line with EMA’s commitment to prioritize high quality, robust and rapid assessment of medicines in oncology.

Engagement with NRAs

From June 2023 to October 2023, Roche affiliates, with the support from the team, contacted NRAs in 84 countries to present the pilot by email, tele/video conference or Face-to-Face meeting. An introduction package was submitted to all NRAs, including a slide deck on PAC reliance pilot introduction, a Q&A document outlining the background and addressing critical aspects of the pilot, the rationale for the change classification and an invitation letter from EMA to NRAs to practice reliance leveraging their assessment and participate in the pilot.

NRAs Participation

Among the group of 84 NRAs targeted for the pilot program, 48 (57,1%) agreed to participate, while 31 declined and 5 did not provide a definitive response. Figure 3 provides a visual representation of the global distribution of the participating NRAs in the pilot program.

One of the primary objectives of the pilot was to uncover any potential obstacles, such as regulatory or legislative challenges, that may hinder the successful implementation of reliance. The pie chart (Fig. 4) provides analysis of reasons for refusal to participate. Some countries, including Mongolia and Myanmar, declined the pilot because their standard approval timelines for such a change are shorter than the proposed pilot timeframe. Malaysia was not able to join the pilot due to the NRA portal limitations for parallel submission. In some countries, including Palestine, Lebanon, Libya, Syria and Venezuela, the current socio-political situation made their participation in the pilot not possible. South Korea preferred not to participate in the pilot as their current efforts are focused on collaborative review. Certain countries either did not respond within the specified timeframe (Aruba, Brazil, Mauritius) or encountered resource constraints within their respective NRAs (Albania, Bolivia, North Macedonia, Iraq and South Africa). These insights provided valuable information about the barriers that need to be addressed in order to facilitate the implementation of reliance principles in the future.

Fig. 3

World map showing pilot participation status. In green are shown countries participating in the pilot, while in cyan are shown countries that did not participate. Created using mapchart.net

Fig. 4

The pie chart on the left displays the percentage of NRAs participating in the pilot and those that declined. The pie chart on the right shows the reasons provided by the declining NRAs for not participating in the pilot. Created using Inkscape

Execution PhaseKick off Meeting with all Stakeholders and NRAs

Following EMA’s approval, a pilot kick off meeting was scheduled with EMA, WHO and all participating NRAs. The purpose of the meeting was to emphasize the benefits of reliance and introduce the pilot framework and guardrails including the objectives, timeline and Q&A handling. The participating NRAs engaged actively in the discussion with questions around assessment reports, review timeline, provision of country specific requirements, reliance pathway, etc.

Submission Achieved within One week

In order to allow the same review times for all participating NRAs, 48 Roche affiliates and agents submitted the dossier package simultaneously (within one week time frame) to their respective NRAs using the national submission procedures. This achievement is especially remarkable considering the submission restrictions in some markets, e.g. limitations in portal capability, payment procedure, appointment for submission, etc.

Convergence of PAC Requirements

According to the sponsor’s internal database, 38 NRAs have country specific requirements for the change (Table 1) in scope. At the time of submission, all NRAs accepted the same package as EMA without requesting any country specific documents, which demonstrates the willingness for NRAs to align regulatory requirements. In 5 countries this major process change may be considered as a new registration, however with early communication and further engagement meetings, all 5 NRAs agreed to align their reporting category with the reference country, EMA. For this specific pilot only one country, Egypt, requires local retesting for the first shipped batch after the variation is approved, and we requested a waiver of sample testing as part of the PAC Reliance pilots.

Table 1 Country-specific requirements for the variation application

During the pilot program, some participating NRAs made specific requests to the company in order to be part of the initiative. A crucial requirement for the pilot to proceed was to harmonise the filing requirements to the fullest extent by adopting a uniform approach. Hence, the company carefully evaluated the individual requests from each NRA to determine if minor modifications could be considered acceptable. Table 2 provides an overview of these requests and the company’s stance on each of them. As Argentina and Colombia requested the variation dossier in Spanish for their participation in the pilot, the company agreed to provide a translated Spanish dossier to all other countries requiring it, to accommodate their request and ensure fairness.

Table 2 Analysis of participating NRAs’ specific local requests and company’s positionParallel Submission and Grace Period

Navigating the complexities of the global regulatory environment can be quite challenging, especially when handling multiple changes affecting the same product and facing variable and often unpredictable approval timelines.

The product in scope of the pilot was undergoing another major variation affecting the control strategy with hard implementation at the end of 2024. This control system change required parallel review with the manufacturing process change in several countries because of long approval timelines or the lack of grace period. Eight out of 48 NRAs that participate in the pilot do not allow the submission of a new PAC when the review of another PAC affecting the same CTD section is ongoing or no parallel filings are allowed at all. In line with the pilot objectives to harmonise the filing requirements, NRAs were asked to allow parallel submission.

6 NRAs granted parallel review in order to be able to participate in the PAC reliance pilot. Two NRAs didn’t accept parallel review but took other measures to accelerate the review of the ongoing PAC application so that it could be approved prior to the start of the pilot.

Another particular challenge arose from the fact that countries have different grace period policies for the implementation of the variation, that some countries do not even allow any grace period (i.e. after approval only post-change material can be supplied). Therefore customised regulatory and especially supply planning, was critical to ensure continuous supply to patients. Within the 48 NRAs, 5 NRAs usually do not permit any grace period. However, upon engagement with the health authorities, a minimum of 6 months grace period was granted to handle the complex supply situation.