Drug companies that repeatedly postpone submitting their marketing authorization applications (MAAs) as planned for evaluation via the EU’s centralized procedure, or delay MAA submissions for very long periods, could face strict new actions from the European Medicines Agency.
Key Takeaways
- The European Medicines Agency is looking to improve the sustainability of the EU medicines regulatory network in face of poor submission planning by drug companies.
- Repeated delays to planned marketing authorization applications have resulted in national competent authorities stepping down from their assigned rapporteurship.
- In such cases, the EMA has to look for new experts to take over as rapporteurs and that causes a drain on resources.
- The agency is monitoring how often it must change rapporteurships due to submission delays and is considering new measures to minimize such disruptions.
Among the measures being considered by the EMA is the “automatic release” of experts (ie, rapporteurs) from EU national competent authorities (NCAs) who have been assigned to review the MAA. Also, drug sponsors may be asked to seek prior “agreement” on its revised MAA submission date to ensure it fits with the rapporteur’s schedule.
These measures, which are still under discussion at the agency, could affect a sponsor’s filing plans. For example, the withdrawal of assigned rapporteurs could create uncertainty for a company regarding which NCA’s experts will eventually lead the scientific evaluation of the MAA when it is finally submitted. The reassignment of the MAA to new rapporteurs could mean the company having to adjust to new regulatory expectations.
The requirement for sponsors to agree beforehand on the suitability of their revised MAA submission date could create complications for them as they may have to change their submission plans to suit the rapporteur’s timetable rather than when they are ready to file.
The EMA discussed these measures at a multi-stakeholder workshop aimed at improving the predictability of MAA submissions. Almost half of all planned submissions – ie, for which companies have submitted a “letter of intent to submit an MAA”– are currently postponed or withdrawn, causing problems for the regulators.
The workshop was jointly organized by the EMA and the EU Heads of Medicines Agencies on 25 September, where senior regulators from Sweden and Austria explained that frequent delays and last-minute withdrawals of MAA submissions result in NCAs having to constantly relocate resources, which creates stress and extra workload for their assessors.
When the situation becomes overwhelming, NCAs have no option but to step down from the rapporteurship and the EMA has to find new rapporteurs to take over, explained Alberto Ganan Jimenez, head of committees and quality assurance at the EMA.
The change of rapporteurships creates more work for the EMA and wastes resources. Given its disruptive impact on the EU medicines regulatory network, the EMA has started closely monitoring this issue. Data shows that over the past four years, the postponement of planned submissions resulted in changes to rapporteurships for 5-8% of total rapporteurships for MAAs.
There is, however, no clear trend, said Jimenez. Figures show that the percentage of rapporteurship changes was nearly the same in 2021 and 2023 at around 5%, and then dropped slightly in 2023 to around 4%. However, data from this year, available until August, shows that rapporteurship changes already stand at around 8% (see table).
Table: Delay in MAA submissions triggers changes to rapporteurships
| 2021 | 2022 | 2023 | 2024 Data until Aug | |
|---|---|---|---|---|
| Total rapporteurships for MAAs per year | 210 | 193 | 190 | 171 |
| % of rapporteurship changes | 5.7% | 5.2% | 4.2% | 8.2% |
Source: EMA
Changes to rapporteurships due to MAA delays are cumbersome and the EMA has started monitoring the situation to gauge its impact. If the percentage of rapporteurship changes rises beyond 5-8% and the “situation really worsens,” the EMA may need to take action, according to Jimenez.
The agency has held internal discussions on the need for “possible additional measures that could be considered for certain applications” with recurrent postponements or very long delays, he said.
Jimenez said that while improving the efficiency of the EU medicines regulatory network was key, the EMA does not want to move to a system of “slots” where only a limited number of MAAs get accepted per month. This is because the agency wants to facilitate innovation and help bring new medicinal products to the market as soon as possible, he explained.
“But it’s true that we may consider certain [other] activities” like “automatic release of assigned rapporteurships” in case of long delays or multiple postponements for the same product, said Jimenez. Also in situations where “we may not be able to accommodate the new submission date,” the EMA is looking at the possibility of “some kind of prior agreement with the rapporteurs about the exact submission timelines with plus/minus one or two months,” he added.
Rapporteurship System Needs Advance Planning
The evaluation of an MAA via the centralized procedure is the responsibility of the EMA’s human medicines committee, the CHMP. For each application received, two CHMP members – a rapporteur and a co-rapporteur – from two different NCAs are appointed. For generic drugs, only one rapporteur is appointed.
The rapporteur and co-rapporteur conduct the scientific evaluation of the medicine independently from each other and they each form an assessment team with assessors from their respective national agencies. They may also establish multinational assessment teams (MNATs) by including experts from other NCAs as well as their own.
Jimenez explained that the rapporteurships are appointed approximately six to seven months prior to the intended submission date, and only after the sponsor has submitted a letter of intent to submit the MAA. “A letter of intent may come earlier” but the rapporteurship appointment “happens six to seven months before the [intended] submission date,” he clarified.
Delays to planned MAAs have a “big impact” on NCAs with respect to resource allocation, particularly in areas requiring high specialization (eg, advanced therapies) or specific expertise in certain therapeutic areas, Jimenez said. If an MAA is delayed, rapporteurs may find it difficult to provide the necessary expertise and re-appointment could be necessary.
For the NCAs to be able to bid for, and keep their rapporteurships, Jimenez said “predictability” and “having oversight of what is coming is crucial.” The EMA wants companies to be realistic with their planned submission dates and to communicate early in case of any delays.
The EMA has found that longer submission delays have been associated with the need to fully replace a rapporteur (from one NCA to another). Meanwhile, shorter submission delays, the agency found have been linked to changes in rapporteurship from one single EU member state to a multi-national assessment team.
