What Sponsors Need to Know About EU and US Clinical Trial Submissions

Executive Summary.

Clinical trial submissions in the EU and US follow broadly aligned scientific principles, but are governed by distinct regulatory frameworks that shape how data is compiled, structured, and assessed. In the EU, Clinical Trial Applications (CTAs) require an Investigational Medicinal Product Dossier (IMPD), while in the US, sponsors submit an Investigational New Drug (IND) application to the FDA.

Although both pathways rely on core technical data — including CMC, non-clinical, and clinical information — the format, submission processes, and supporting documentation differ significantly. EU submissions are centralized through the Clinical Trials Information System (CTIS), whereas IND applications are submitted directly to the FDA and may support multiple studies under a single application.

Crucially, documentation cannot be transferred between regions through simple reformatting. Each dossier must be adapted to meet region-specific regulatory expectations, terminology, and data requirements.

As a result, sponsors planning global clinical development must adopt a strategic, region-aware approach to submission preparation, ensuring compliance while minimizing delays and regulatory queries.

Introduction.

Clinical trials are an essential step in medicine and drug product development, enabling the compilation of important information on safety and efficacy of new treatments being developed and, thus, improving public health and the lives of patients worldwide.

As of 2023, the region with the highest number of clinical trials was Western Europe, followed closely by North America. However, overall, there has been a decline in the number of trials conducted across Europe (Western, Central and Eastern) and an increase in North America, China and Asia-Pacific.

When establishing the studies needed for a specific product or submission, it is fundamental to think of the clinical trials as a global activity, and not just a national one – global clinical trials are considered very important to enable the assessment of new treatments and/or solutions in different populations. This will strengthen the data gathered and ensure that the product will be safe and effective for a much wider range of patients.

To obtain authorization to conduct clinical trials in any specific country, a sponsor must compile all the available information on the investigational medicinal product (IMP), as required by the regulation in force, and submit a clinical trial application (CTA) to the concerned National Competent Authority (NCA) for assessment. In the US, an Investigational New Drug (IND) application must be submitted to the Food and Drug Administration (FDA) to request authorization before an investigational drug or biological product can be administered to humans.

In practice, this requires submitting several documents as part of the IND or clinical trial application. These can be divided into those that are administrative and those that contain the technical details on the product and proposed study. This includes the protocol, investigator’s brochure, informed consent forms, investigator information, and the technical data for the investigational medicinal product, including the chemistry, manufacturing and controls, and non-clinical and clinical study data, if available, which is compiled in the format of the investigational medicinal product dossier (IMPD).

There are specific guidelines issued by each Competent Authority outlining the requirements to be included when preparing the specific documentation.

For the purposes of this article, focus is given to the CTA process in the EU and the IND application to the US FDA, and some of the main considerations to take into account when preparing applications in these two regions.

Background and Legal Framework.

To be able to perform a clinical trial, the clinical trial application must be reviewed and approved by two separate entities – the health authorities (national competent authorities (NCAs)), responsible for assessing and regulating the use of the investigational medicinal products in the concerned country; and the ethics committees (e.g., Investigational Review Boards (IRBs) in the US, and Ethics Committees (ECs) in the EU), responsible for ensuring the protection of human subjects who participate in the studies testing investigational drugs.

Good Clinical Practice (GCP) is a set of detailed, harmonized guidelines from the International Conference on Harmonization (ICH) – ICH E6(R2) –, which provide an overall description of the responsibilities and expectations of all teams involved in the conduct of clinical trials.

In parallel, specific requirements are defined by each individual Health Authority, to guide the sponsors on all steps of drug product development, whether that would be on the manufacturing process, non-clinical studies, clinical trials, safety monitoring, among others.

In the US, the regulations relating to the Good Clinical Practice and Clinical Trials are linked to the Code of Federal Regulations, Title 21 (21 CFR), with special focus given to 21 CFR Part 312 – Investigational New Drug Application. IND content and format are displayed in 21 CFR 312.23, with the CMC requirements also being found in FDA’s webpage on IND applications for clinical investigations – CMC information (21 CFR 312.23(a)(7)).

In 2022, a new Clinical Trial Regulation (EU) No. 536/2014 was implemented in the EU by the EMA, resulting in the revocation of the previous Clinical Trial Directive (EC) No. 2001/20/EC and the national legislation in the individual EU Member States. In consequence, any clinical trial application to an EU Member State must now be submitted through one unique portal (and not individually to each NCA).

Furthermore, the EMA has issued individual scientific guidelines to address the documentation and information required to support the investigational medicinal product dossier – namely, in what concerns the CMC data needed for submission of chemical (EMA/CHMP/QWP/545525/2017 Rev. 2) and biological/biotechnology derived drug substances (EMA/CHMP/BWP/534898/2008 Rev. 2).

Although, generally, the basis of information is the same when preparing the IMPD-Quality for any clinical trial application, it is important to ensure that the data compiled in the documentation package (and the way that it is presented) is aligned to each NCA’s requirements.

How to Properly Prepare Clinical Trials Applications?

To properly prepare a clinical trial application, and guarantee that all information and documentation is aligned with the expectations of each authority, the sponsor of the clinical trial must carefully assess and review the concerned guidelines and regulation, focusing on the type of application, drug substance/pharmaceutical form, target therapeutical indication, population and national requirements.

Focusing on the region with the second highest number of CT submissions, the US, the IND applications are submitted to FDA either electronically (recommended) or by mail (hard copy), with FDA assessing and deciding on whether the application is safe to approve, from a scientific and ethical point of view.

Before detailing the submission options, it is important to mention that there are two main IND categories: commercial INDs, usually submitted by pharmaceutical companies and intended for drug products that will eventually have a Marketing Application/distribution; and noncommercial INDs, submitted by academia/investigators (research), and for products to which there is no intention of future Marketing Application/distribution.

The submission through electronic format has been implemented for certain investigational new drug applications (INDs), submitted to the Center for Drug Evaluation and Research (CDER) and to the Center for Biologics Evaluation and Research (CBER) – namely, the commercial INDs must be submitted through the FDA Electronic Submissions Gateway NextGen (ESG NextGen).

These applications must be submitted in alignment with the eCTD version supported by FDA at the time of submission. The FDA may accept exceptions to a submission of a commercial IND not under eCTD requirements; this waiver must be requested, prior to filling, to CDER (esub@fda.hhs.gov) or CBER (esubprep@fda.hhs.gov), as applicable.

Noncommercial INDs are exempted from the eCTD requirement, thus, not requiring to submit a waiver request. Thus, their submission is possible through the CDER NextGen Portal, which does not require an eCTD documentation package.

In the option of hard copy submission, three sets of documentation packages must be sent to the appropriate address (original plus two photocopies). It is advised that the sponsor keeps one third of the photocopied package.

Once the IND is submitted, the FDA team reviews the IND submission within a 30-day timeline. Two results can come up from the review: authorization of the IND application or clinical hold to delay/stop the investigation.

In the EU, CTAs are submitted through the Clinical Trials Information System (CTIS), a new system that allows the exchange of communication and information between the sponsors, the NCAs from each Member State, EEA countries and the European Commission. The Clinical Trials Information System permits a single submission of a clinical trial application to all NCAs and ECs of the chosen Member States.

In the EU, the IMPD is not required to follow eCTD requirements; however, the dossier sections should be prepared using the CTD template.

According to the new Clinical Trials Regulations (CTR) in force, it is expected that the assessment of a CTA will be carried out within 60 days, which can be impacted in the case of questions raised by a Member State Concerned (additional 15 days in validation phase; additional 31 days in assessment phases).

As previously referred to, the sponsor must provide enough data in the clinical trial application to demonstrate how the drug product is manufactured and how its control is performed to guarantee quality, efficacy and safety to the subjects that will take it, what were the results of the tests performed so far and what is the proposed plan for exposing first humans to the product.

Whether discussing a submission to an NCA in the EU or to the FDA, some information will always have to be considered for inclusion in the application, independently of the format in which it is done so, such as: CMC information, non-clinical information, pharmacology, protocols, investigator’s brochure or informed consent forms.

Part of this required information will be compiled and presented in the form of an investigational medicinal product dossier (IMPD) in the EU and an investigational new drug (IND) application in the US.

CTA versus IND – Documentation.

As explained, the initiation of a clinical trial by a sponsor is dependent on the authorization of a CTA or IND application. Although some of the information required is similar, the submission of a clinical trial application must follow the guidelines and requirements set by the individual authority.

The submission of an IND to the FDA includes documents specific to this agency, for example, several forms that follow the FDA’s requirements and templates – such as, Form FDA-1571 (IND application cover); Form FDA-1572 (Investigator’s statement); Form FDA-3674 (Certification requirement and mandatory registration and reporting of results for applicable clinical trials through ClinicalTrials.gov.). In parallel, technical documentation is required by the FDA, as listed above in this article – non-clinical data, detailed CMC information, study protocol and investigator’s brochure.

Most of this information is submitted as part of the initial IND, with any new information or documents submitted as amendments to the IND – this can include new protocols, allowing for the conduct of multiple clinical studies under the same IND (as long as the IMP and indication are the same).

The equivalent to this process in the EU is the CTA. The preparation of the submission of a CTA is grounded on four base documents – the protocol, informed consent forms, investigator’s brochure and the investigational medicinal product dossier (quality; safety/efficacy). However, the submission also requires the preparation of certain specific declarations for each submission/site, with templates also provided by the authorities – for example, the compensation for trials participants; investigator curriculum vitae template; declaration of interest template; site suitability form; compliance with applicable rules for biological samples.

The compiled documentation package is provided to the authorities in the initial submission and updated documentation related to that specific study may also be submitted as amendments to the application (or submitted in the initial application, if requested during a request for further information (RFI)). However, unlike in the US, in EU a new CTA must be submitted for each interventional clinical study; thus, any new document related to a new protocol is submitted with each new CTA.

Focusing on IMPD-Q vs IND.

The investigational medicinal product dossier is one of the main documents of a clinical trial application, with this document including a summary of the CMC details of the investigational medicinal product, data from non-clinical studies and data from its clinical use – it is acceptable to present a cross reference to the investigator’s brochure for the non-clinical and clinical topics.

Regardless of whether the objective is to prepare the CMC/quality section of an IMPD (IMPD-Q) for a European submission using an existing IND, or conversely to draft an IND based on an EU IMPD, the documentation cannot be transferred through simple copying or reformatting, as each dossier is developed in line with region-specific regulatory expectations.

In what concerns the writing and structuring of this document, whether intended for an EU or US submission, orientations must be taken from the relevant ICH guidelines, keeping in mind that a CTD format is required for both. However, the specific requirements must be assessed, to understand how the data needs to be complemented, if additional studies must be performed or what documents/information must be added to the dossier.

Table 1. Summary of example adaptations between EU and US:

In a scenario where the information is not clear or no guidance is available, as some types of products are also still new for the assessors, the sponsor should seek advice from the authorities, so a proper discussion can occur, and both parties can be aligned on the best approach to take.

Conclusions.

The main goal of developing an investigational medicinal product, besides the obvious need to address a medical issue or bring new and more affordable options to the market, is to guarantee the product will present a profile of high quality, safety and efficacy to the patients.

That is why robust data must be generated by the sponsors, following specific requirements and guidelines from each NCA, to allow a proper assessment of the product prior to any administration in humans – starting with clinical trials and culminating on a subsequent marketing authorization application.

Whether the purpose is to submit subsequent applications or to perform parallel ones, the individual requirements of each NCA must be addressed and the documents must be appropriately revised to guarantee alignment and avoid future questions during the assessment of the clinical trial submission.

Thus, and using the examples discussed, it is important to understand that the documents prepared for one specific country (e.g., US submission) cannot simply be replicated for another country and Authority (e.g., EU submission), and a proper review and update must be performed.