Vice President of Synchrogenix Regulatory Science, Certara

Steve Sibley

Most drug developers seek new drug approvals in both the US and Europe, two of the largest markets with the most evolved regulatory landscapes and highest uptakes of new medicines. Approvals by FDA and the European Medicines Agency (EMA) provide a gateway to other countries that follow FDA or EMA guidelines, further extending the benefits of a combined approach.

Historically, submission teams have viewed and managed the two document submissions separately. After all, the US and Europe are an ocean apart, with different policies and their own regulatory bodies, respectively. But is there a better way?

Before plunging headlong into submission preparation, consider your whole global submission plan and the feasibility of simultaneous document submission to optimize the process. It takes more planning and deliberation up-front but streamlines each step thereafter. This article will discuss how drug developers can minimize rework, maximize efficiencies, compile optimal data packages, and create the most direct path to dossier development for the US and Europe with the goal of avoiding many of the common pitfalls experienced.

The traditional two-lane mindset served its purpose when the US and Europe truly represented two completely different regulatory environments with little to no crossover. That changed in 2000 with the finalization and adoption of International Conference on Harmonization (ICH) guidance. ICH guidance makes it feasible to construct a new drug submission dossier that can be used for applications to the regulatory bodies of the US, EU, and Japan and make new drug registration less resource intensive.

All drug developers are familiar with ICH guidance from a regulatory perspective, and most have been pursuing simultaneous submissions for the past 15 to 20 years. However, that harmonization has been drifting apart the past several years. Despite this, dossiers for the FDA and EMA can still be initially merged and managed as one for the bulk of the work, before later being adjusted as necessary to suit the final submissions.

The US and Europe have similar documentation requirements, but we must recognize important considerations that need special attention. For instance, terminology and seemingly small grammatical distinctions can loom large if overlooked. A submission team can greatly accelerate global document submission by first creating and reviewing a checklist of differences, agreeing on the best approach to address each one, planning the summary documents based on these decisions, and collaborating closely in pursuit of a successful outcome.

It can be helpful to understand how the FDA and EMA review submissions through different lenses. FDA is very data-driven, with robust requirements for data sets and programs used to generate statistical analyses. They first look at individual listings, case report forms for patients with adverse effects, and other deep documentation, working from the bottom up to arrive at a decision. EMA reviewers, on the other hand, tend to take a more top-down approach. They prioritize key messages and information in the clinical overview to develop their interpretation of what a drug is doing for patients and modern medicine. The EMA does not require data sets or case report forms like those required by FDA. In general, the EMA is more qualitative while FDA is more quantitative.

The most notable difference is Module 1 of the ICH Common Technical Document. This consists of regional information that will need to be compiled separately. Module 1 is best set aside so it doesn’t hinder the rest of the information that can be compiled simultaneously. Additionally, there are some specific differences in requirements across other modules to which careful attention should be paid.

Aside from Module 1, submission teams should be happy to hear that Modules 2, 3, 4, and 5 are similar between FDA and EMA submissions. The US and Europe are two of the most similar regions in the world when it comes to their submission requirements, again thanks to ICH guidance on summary documents and submission format.

The main differences discussed in this article are really the exceptions, so we can reframe our approach to assume that 75% or more of the compilation can be conducted simultaneously. It is important to remember that small details can become big headaches in these large, technical documents. As such, careful planning is pivotal to gain an understanding of where the risks and opportunities lie.

It’s a lot less painful to learn from others’ mistakes than your own. Here are a few simplified examples of real-life teams running into submission roadblocks that could have been avoided:

The afterthought: A sponsor completed a full regulatory history review, accounting for all agreements and resolutions for a successful new drug Application (NDA) submission. However, they completed the NDA without considering the marketing authorization application (MAA) planned three to six months after NDA submission. This resulted in extensive rework of approved NDA versions to create MAA versions. They had also outsourced preparation of the NDA and MAA submissions to different vendors, making matter worse.

The comment carousel: With the goal of writing documents in a way that one version would work or at least require only minor revisions for all countries, the team took off running…and spinning…and sputtering. They were unable to stop commenting on standardized global introductory text, derailing a well-intended plan when version control between submissions finally caught up with them and caused delays.

The caveat: Starting with the assumption of no differences in Module 2.7 documents and identifying differences in Module 2.5, a submission team built a combined biologics license application (BLA) and MAA version up to point of first draft, including specific MAA sections highlighted. For BLA Draft 1, they removed the MAA sections. Once BLA Module 2.5 was approved, they used that approved version as the initial draft for MAA and replaced BLA-specific content with MAA-specific content. But by the time of MAA creation, data presentation agreements with EMA and team agreement to include label adverse reactions table in Module 2.7.4, required tedious EU-specific modifications to Modules 2.5 and 2.7.4 as well.

How can you avoid missteps like these? Quite simply, with planning.

The key takeaway with simultaneous submissions is that more planning and deliberation at the start of the documentation process can help alleviate issues and optimize submissions.

First, an understanding of deadlines and timing of submissions is necessary to inform planning. How soon after the first submission do you want (or need) to make the second submission? How long is the duration between submissions, and will that lead to additional study data being available or the need for a new cutoff date for safety data? What are the plans for supplements if filing for multiple indications? These are just a few of the many questions to ask early regarding timing of final submissions.

Second, there may be many possible strategies to employ when authoring dossiers, but there are four immediate considerations for authoring FDA and EMA dossiers simultaneously. These include deciding whether to use British or American English, use of “application” or “submission” as a generic identifier (rather than naming the submission, e.g., BLA vs. MAA), considerations for cross-referencing, and accounting for reviewer tendencies. Throughout the submissions, writers should be as universal as possible with language across applications and read the relevant guidelines in advance to minimize the work and uncertainty for editors later.

In the years since ICH introduction, regulatory requirements in the US and EU have slowly drifted apart. Still, the requirements are known, clearly stated, and can thus be planned for in the submission process. For example, in considering the inclusion of integrated summary of efficacy (ISE) and integrated summary of safety (ISS), it’s easier if the ISE and ISS are just the outputs. However, there are no issues with including ISS and ISE in an EMA submission after these pieces were developed for an FDA submission. Separately, for the benefit-risk sections, you can convert the content of an FDA benefit-risk framework table into subsections with the exact same text to fulfill the comparable EMA description. These are just a few glimpses of the efficiency attainable with simultaneous document submission, knowing and accounting for the regulatory requirements.

Given the similarities between FDA and EMA submissions, it’s quite feasible to pursue simultaneous drug application submissions. This is a significant undertaking by any measure but reviewing regulatory history early-on and highlighting any gaps that may present potential obstacles, should ensure timely and successful simultaneous submissions.

, vice president of Synchrogenix Regulatory Science, Certara

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