‘Serious Problem’: EMA Director Criticizes Unpredictable Pharma Submissions

Drug companies must come up with a better way of estimating when they expect to submit their marketing authorization applications (MAAs) for evaluation by the European Medicines Agency, as too many planned submissions are currently postponed or withdrawn at the last minute, causing a drain on the agency’s resources.

Over the years, “we have seen that applicants change their submission date up to 10 times” and seek postponements mostly “for one or two months, but sometimes it’s [for] a year,” said EMA executive director Emer Cooke. “This plays havoc with our system.”

Cooke made these comments at a multi-stakeholder workshop that explored how to improve the predictability of MAA submissions. The workshop was jointly organized by the EMA and the EU Heads of Medicines Agencies and took place on 25 September.

At the event, the agency explained that it sets aside regulatory resources (by appointing rapporteurs) as soon it receives a “letter of intent to submit” an MAA from a company. In the letter, companies signal their intention to submit an MAA to the EMA at a specific date. However, almost half of all applications are not submitted on the date first indicated on this letter and few companies explain the rationale behind these delays.

In addition to companies constantly changing their submission dates, applicants sometimes miss their submission dates completely without any prior warning to the EMA. “In 2023 alone, we had six ‘no shows’,” which means these applications “were not received when we were expecting them to arrive,” Cooke said. The sponsors of these applications had simply not bothered to inform the EMA that these MAAs would be delayed, the agency.

For three of these six MAAs, the agency was informed about the revised submission dates two to three months after the initial intended submission date had passed, while for one MAA, “we have heard nothing” about when it will be submitted, Cooke said in her opening remarks at the workshop.

“This is a really serious problem” and it is “detrimental to our system” with respect to arranging MAA evaluation resources across the EU medicines regulatory network, the EMA head said. “We want you to change the way that you look at how you predict the submission date for your dossiers,” she told drug companies.

Industry representatives at the workshop said they were committed to enhancing submission predictability and fostering better communication with the EMA and rapporteurs, but noted that “predicting our submission dates [with] 100% success is not realistic.”

Pedro Franco of the EU biotech industry group, EuropaBio, said submission predictability was a “priority on trade associations' agendas” but pointed to several factors that may affect a company’s planned MAA submissions.

These include planning for global submissions, availability of company resources and the need to prioritize other submissions, incorporating advice from health technology assessment bodies in submissions, adapting dossier content to address specific countries or regional requirements, the competitive landscape and late responses from regulators on critical topics.

The EMA said companies should inform the agency and rapporteurs as soon as it becomes evident that the intended submission date cannot be met, and not wait until the last minute and certainly not after the submission date has passed.

Stretched To The Limit

Although unreliable long-term planning for initial MAAs for centralized procedures has been a recurrent problem for many years, the issue has “become unsustainable” with resources at the EU medicines network stretched to the limit, said Enrico Tognana, senior business intelligence specialist at the EMA.

Things have become especially difficult following the UK’s departure from the EU and the “loss of staff due to burn-out during the COVID pandemic,” Tognana said. To address the issue, several initiatives are currently ongoing to improve the efficiency of the assessors in the regulatory network. These include:

• Reinforcing best practices for requests for clock-stop extensions.
• Revamping of the EMA’s two main assessment report templates.
• Offering better guidance for assessors.
• Improving pre-submission interactions with marketing authorization applicants.
• Sending automatic notifications to marketing authorization holders, requesting them to submit a list of their planned line extension and major variation submissions for the following six-month period.

Karl Broich, HMA chair and head of the German Federal Institute for Drugs and Medical Devices (BfArM), said at the workshop that predictable submission planning and resource allocation was pivotal to the efficiency and effectiveness of regulatory processes in the EU medicines network.

The EMA asks companies to specify a submission date in their letter of intent as “we need to be able to schedule our assessment capacity” accurately in the face of tight resources, explained Broich. But things do not always go as planned.

At times, foreseen MAAs do not turn up, and “then suddenly four centralized procedures are coming in for the same assessment team, which makes it impossible to do it right,” he noted. “The ripple effects of these delays are profound, affecting everything from market access to patient safety” and there is an urgent need to address the issue, Broich added.

Cooke said the practice of frequently delaying the planned MAAs or withdrawing them at the last minute was rampant across “all layers of the ecosystem,” irrespective of the type of product (eg advanced therapies or generics) or whether the submissions are being made by big or small pharmaceutical companies.

The agency is keen to understand the reasons behind such behaviour. Since 2003, it has been systematically asking companies to provide a rationale when they change their submission dates or withdraw submissions.

“If we could understand the justification, we would be able to solve it a lot better. But only half of the applicants give any justification for the delay,” Cooke noted. She urged companies to provide a detailed rationale for change in submission dates. “We want you to help us to understand why it’s happening.”

Delegates at the workshop, also raised concern over the “increasing trend” of deficient or premature submissions. 42% of companies seeking marketing authorization in 2023 requested more time to respond to questions from the EMA’s scientific committees during the assessment (ie, ‘extended clock-stops’) because their data was not mature enough when it was submitted to the agency.

While the agency has launched, or is working on, several initiatives to improve the predictability of MAA submissions and the quality of dossiers, the workshop was organized to explore further constructive solutions and to raise awareness about the detrimental impact these practices are having on the EMA’s assessment processes.

Cooke said having predictable submission dates and high quality dossiers was important for the EU medicines network as it “means we can provide the best scientific assessment” and ask “fewer questions” during the assessment process. This, in turn, could result in shorter product approval times and benefit patients with speedier access to drugs.

Case examples and other discussions at the EMA’s submission predictability workshop will be covered in subsequent Pink Sheet articles.