As regulatory requirements become increasingly harmonized across the globe, the development and marketing of pharmaceutical products worldwide are also becoming more streamlined. However, global regulations are not one-size-fits-all, and sponsors aiming to market their products in multiple regions should be aware of the current standards and processes they may encounter during the development process. In this two-part blog series, we will explore the regulatory strategy considerations sponsors should bear in mind when working with the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), with a focus on the development of drug and biologic products.
The FDA governs the drug and biologic approval process in the United States, while the EMA serves the European Union (EU) plus Iceland, Norway, and Liechtenstein. As of January 1, 2021, EU pharmaceutical regulations do not apply to the United Kingdom, which formally left the EU in January 2020. Differences in the approval process and formal meetings or scientific advice processes between the US and EU will be discussed in this post, while Part 2 covers applications for conducting clinical studies, expedited programs, pediatric considerations, and labeling.
Approval Process: FDA vs EMA Procedures
The drug approval process represents one of the most obvious differences between US and EU agencies. The FDA oversees all drug approvals in the US via New Drug Applications (NDAs), with approvals for biologic products being approved via Biologics License Applications (BLAs).
In contrast, there are four potential approval pathways for pharmaceuticals in the EU: centralized, decentralized, mutual recognition, or national. While some products have specific requirements dictating which of these pathways is appropriate, in other cases sponsors should think carefully and select the approval procedures most suitable for their products:
- Centralized Procedure: The centralized procedure for EMA approval is required for certain types of products, including treatments for HIV/AIDS, cancer, diabetes, neurodegenerative diseases, autoimmune diseases, and viral diseases, as well as advanced-therapy medicines (such as gene therapies) and orphan drugs. The EMA Committee for Medicinal Products for Human Use (CHMP) is made up of representatives from every member state and evaluates Marketing Authorization Applications (MAAs) submitted via the centralized procedure. In contrast to the FDA, the EMA does not have the authority to issue approvals. The CHMP evaluates the product’s quality, safety, and efficacy and provides an opinion to the European Commission (EC). The EC can then issue an approval decision, which is valid in all EU member states.
- Decentralized Procedure: The decentralized procedure is the most commonly used approval pathway in the EU. The decentralized procedure applies to all products without a prior marketing authorization in the EU that are not required to use the centralized procedure. An MAA is submitted to a National Competent Authority (NCA) in each member state where the sponsor seeks approval (the Concerned Member States). One member state assumes the position of the Reference Member State and leads the MAA review. An approval decision is then valid across all Concerned Member States to which the application was submitted.
- Mutual Recognition Procedure: The mutual recognition procedure can only be used for products with a prior marketing authorization in at least one member state (initially approved via the national procedure). It relies on the initial marketing authorization by the Concerned Member States’ regulatory authorities and is usually granted unless there are indications a product may pose a public health risk.
- National Procedure: Since January 1998, the national procedure is strictly limited to products not to be authorized in more than one member state, and to the first phase of the mutual recognition procedure, with an NCA in the chosen member state issuing the initial marketing authorization.
Meetings with Regulatory Agencies: US vs EU
There are two broad categories of meetings with regulatory authorities—scientific advice meetings and pre-submission meetings—with some overlap between the two. In scientific advice meetings, the goal is to confirm the adequacy of existing information to support the next steps in a development program. In addition, the sponsor seeks an agency’s agreement on its proposed plans, including clinical and nonclinical studies. Pre-submission meetings are usually associated with milestone submissions, such as applications to initiate clinical trials or marketing applications. These meetings usually focus on the administrative, regulatory, and technical aspects of a submission, while including discussion of the adequacy of the development program to support the given application.
A sponsor must submit a list of specific questions prior to a meeting with either the US or EU authorities. For EU meetings, the sponsor must also provide its position for each question, which is not required for meetings with the FDA. Another notable difference is in the authorship of the official record for each meeting: The FDA provides meeting minutes to serve as an official record, but other regulatory agencies often rely on sponsors to compose the minutes and share them with the agencies. They will then review the minutes, suggest any changes, and issue confirmation of an official record.
Meetings with the FDA
The FDA offers four types of meetings for drugs and biologics: Type A, Type B, Type B (end-of-phase (EOP)), and Type C. All four types are free of charge to the sponsor, in contrast to EU meetings (discussed below).
|Meeting Type||Meeting Purpose||Meeting Timing1
(from receipt of request)
|Meeting Package Due
(prior to scheduled date of meeting or of WRO2 response time)
|To address a stalled product development plan or an important safety issue||Within 30 calendar days||At the time of meeting request|
|To seek advice in relation to a key milestone (e.g., pre-IND, pre-NDA meetings)||Within 60 calendar days||No later than 30 calendar days prior|
|To discuss development progress at EOP2 meetings and certain EOP1 meetings||Within 70 calendar days||No later than 50 calendar days prior|
|To engage in interaction outside of a Type A or Type B meeting, often to seek advice on a specific part of a development program||Within 75 calendar days||No later than 47 calendar days prior|
1 This meeting timing represents a goal of the FDA, to which the Agency does not always strictly adhere (depending on scheduling between the FDA and sponsor).
2WRO = written response only
Meetings with the EMA/National Competent Authorities
Sponsors seeking approval in the EU through the centralized procedure should consider meeting with the NCAs in member states, as they provide experts to serve on the EMA’s scientific committees. Meeting with several NCAs prior to submitting an application allows the sponsor to build a consensus on the proposed development program to present to the EMA. The most relevant NCAs are those with experts who are likely to serve as a rapporteur or co-rapporteur for the product evaluation. Fees charged vary between NCAs.
Sponsors whose products qualify for the centralized procedure can also seek scientific advice from the EMA anytime during development. Discussion topics can include a wide array of issues across quality, nonclinical development, and clinical development. The EMA charges fees for scientific advice meetings depending on the scope of the advice. As of August 2021, these fees ranged from €44,400 to €89,000 (about $52,500 to $105,300), though fee reductions are available for orphan drugs and small businesses.
Unlike the FDA, which reviews meeting requests and schedules meetings “on-demand,” the Scientific Advice Working Party (SAWP) reviews request for scientific advice from the CHMP monthly, 11 times per year (with no meeting in August). Therefore, missing a relevant submission deadline delays the procedure by at least one month. A letter of intent, analogous to an FDA meeting request, and briefing package must be submitted by the sponsor either three weeks (when seeking scientific advice without a meeting) or approximately seven weeks (when requesting a pre-submission meeting) prior to the intended start of the scientific advice procedure. The SAWP reviews the briefing package and decides whether scientific advice can be provided without a meeting (40 days from the start of the procedure), or whether a 90-minute discussion meeting will be held (60 days from the start of procedure, with final advice being provided 10 days later).
Most pharmaceutical products in the EU are approved through the decentralized and mutual recognition procedures not overseen by the EMA. Meetings with NCAs in the Reference and Concerned Member States can be crucial to gaining agreement with the agencies on the development program and achieving marketing authorization.
As a full-service global regulatory partner, Premier Consulting can help you craft a time- and cost-efficient development strategy that enables you to attain approval in both the US and the EU. Contact us to find out how we can support your program.
Dominika Trzilova, PhD