Module 1 of the CTD: Key Components of a Marketing Authorisation Application

Highlights

• What is the Common Technical Document?
• Key components of Module 1 of the MAA dossier
• Module 1.2: The application form
• Module 1.3.1: Product Information
• How Module 1 of the MAA integrates with Modules 2-5
• Paediatric requirements for Module 1 of the MAA
• Orphan designation requirements for Module 1 of the MAA

Introduction

What is the Common Technical Document?

The common technical document (CTD) is the structured format for submitting new medicine applications to regulatory authorities, including the European Medicines Agency (EMA) and the Food and Drug Administration (FDA). It is comprised of five modules which correspond to different aspects of a medicinal product's development, including quality, non-clinical and clinical aspects.

What are the five modules of the CTD?

Module two of the CTD includes overview and summary documentation related to quality, non-clinical and clinical development of a medicinal product. Modules three to five include the detailed quality, non-clinical and clinical documents and evidence about a medicine's development, respectively.

Module 1 is not part of the formal CTD and contains region-specific information. It is the module that comprises a substantial number of documents, with administrative and product-specific information. It’s worth noting that Module 1 is part of an initial MAA under the centralised procedure. In the European Union (EU), the Module 1 key components are (the list is not exhaustive):

CTD Module 1 key components¹

CTD Module 1.2 application form

The application form alone is 30 pages long and requires a significant time investment because it pulls together a lot of key details from the submission. There are also a series of annexes, and some of them can have significant lead times, particularly concerning manufacturing. This will require you to include a manufacturing flow chart including information on all of the sites involved in a drug’s manufacture.

You must provide manufacturing authorisations, GMP certificates and a batch release certificate from the qualified person. Additionally, you must provide TSE certificates if your medicine uses any bovine materials. You must also include any scientific advice you received throughout development, as well as a copy of the orphan drug designation if such a designation has been granted for your product. 

Module 1.2 Application form (~30 pages) – annexes¹

NOTE: This list is not exhaustive.

• Proof of establishment of the applicant
• Manufacturing flow chart; manufacturing authorizations and good manufacturing process certificates; batch release certification from the Qualified Person
• Transmissible spongiform encephalopathy certificates
• New active substance justification
• Scientific advice
• Orphan designation decision

Common technical document Module 1.3.1

Module 1.3.1 is a key component of the MAA because it includes the Summary of Product Characteristics (SmPC), package leaflet and labelling. The SmPC and package leaflet will be one of the last documents you need to finalize in Module 1 so that it aligns closely with Module 2.

The user consultation for the package leaflet is also something to think about as it takes approximately 3 months to complete. You can complete this ready for the initial MAA submission or agree with the EMA to defer this until the submission of the responses to the Day120 list of questions (LoQ). If you choose to complete the user consultation on the package leaflet when you submit the initial MAA, you may need to conduct additional focus test on the changes that were introduced to the package leaflet in response to the Day 120 LoQ.  

How Module 1 integrates with Modules 2-5

Module 1 relies heavily on the rest of the dossier, especially the clinical data in Module 2 and the clinical study reports in Module 5. Module 1 must include a coherent presentation of information from these modules, as it’s also reflected in the Risk Management Plan (RMP), SmPC and the package leaflet.

Essentially, pulling a CTD together such that Module 1 is fit for purpose in the EU is a vast undertaking that requires significant planning and cooperation from multiple teams.

Paediatric requirements for Module 1 of the CTD

The Paediatric Regulation (EC) No 1901/2006³  stipulates that all applications for new medicines are required to have an agreed paediatric investigation plan (PIP) before you submit your MAA, unless the medicine is exempt because of a deferral or waiver.

Before filing the Marketing Authorisation Application

Paediatric Investigation Plan (PIP): Before submitting an MAA, applicants must agree on a PIP with the EMA’s Paediatric Committee (PDCO). The PIP outlines the proposed studies and measures to ensure that the data necessary to support the paediatric use of the product is obtained.³

Deferrals and Waivers: In some cases, a deferral and/or waiver may be granted. A deferral allows for the paediatric studies to be conducted after the initial marketing authorization, while a waiver may be granted for the whole or subsets of the paediatric population if: ³

• the disease or condition does not affect children among other reasons,
• the specific medicinal product or class of medicinal products is likely to be ineffective or unsafe in part or all of the paediatric population, or
• the specific medicinal product does not represent a significant therapeutic benefit over existing treatments for paediatric patients.

At the time of the Marketing Authorisation Application

Compliance Check: The EMA will check for compliance with the agreed PIP. A product cannot be authorized for marketing in the EU unless the studies outlined in the PIP have been conducted unless a deferral or waiver has been granted.

Inclusion in Module 1: Documentation demonstrating compliance with the PIP or evidence of granted waivers or deferrals must be included in Module 1.³

Orphan designation requirements for Module 1 of the CTD

Orphan Designation (OD) Application and Opinion:⁴

• The COMP (Committee for Orphan Medicinal Products) opinion document
• The European Commission’s official decision to grant the orphan designation.

Justification for orphan status and orphan maintenance:⁴

If your product has an orphan designation, you must submit a report on maintenance of the orphan designation at the time of MAA submission. To maintain the orphan designation, the maintenance report should include current and updated data at the time of the MAA submission compared with what was submitted in the original orphan designation application.

 The following topics should also be justified based on data available at the time of the submission: ⁴

• Any changes in the orphan designation status should be documented, with appropriate justifications.
• If there are existing orphan medicines authorised for the same condition, a similarity report must be included.

Summary

Module 1 of the MAA dossier is a large-scale undertaking, not just because it is region-specific, but because it involves seamlessly incorporating and amalgamating information from Modules 2-5. It is time-consuming; detail-driven and involves careful planning and cooperation from several different teams involved in the MAA itself.

How Somerville Development Partners can help

We can support every aspect of the filing, including the following:

• Developing a Common Technical Document (CTD) table of contents for the submission and conducting a gap analysis to ensure that all submission components have been identified and planned.
• Preparing key messaging and the company core data sheet.
• Preparing regional labelling such as the Summary of Product Characteristics and US Prescribing Information.
• Planning the data presentation, analysis and discussion in the dossier.
• Conducting detailed reviews of the data (tables, figures and listings) shells to ensure the required analysis and outputs are planned.
• Writing Modules 1–5 of the electronic CTD.
• Publishing and submitting the completed submission.
• Responding to questions from the agency during the evaluation.
• We frequently, work as part of the global filing team for parallel submission to the US, EU and additional authorities. If possible, it is worthwhile writing a submission with common US and EU Module 2–5 components, especially the Module 2 summaries, so that multiple consistent submissions can be made to streamline regulatory agency interactions.
• We can also provide peer review of existing projects, to stress-test the work that has been done and recommend solutions to address any gaps. Peer review may be especially useful to prepare for the MAA submission, where an additional perspective may help to highlight any potential risks.

Read the video transcript

Turning now to Module one. Although Modules two to five of the CTD are intended to be the same or similar between regions, Module one is not part of the CTD and it differs significantly. In the EU, module one is a pretty significant undertaking.

The application form alone is thirty pages long and requires a significant investment in time, as it draws in a lot of the key details from the submission. There are also a series of annexes, some of which can have quite significant lead times. In particular, there’s a lot of information on manufacturing. So, it’s necessary to include a manufacturing flow chart, which includes all the sites involved in manufacture; you need to provide manufacturing authorisations, GMP certificates and a batch release certificate from the Qualified Person.

You also have to provide TSE certificates if there’s any bovine material used; a justification for the new active substance, and you’re expected to include any scientific advice and any orphan designation as an annex as well.

And, lastly, you need to indicate if you intend to use an invented name for the product.

Aside from the application form, this slide lists some of the significant components of module one. Without spending too much time on each one individually, I want to flag 1.3.1, which is the product information. This is a really critical part of module one because it includes the SmPC and the package leaflet.

And then I also want to highlight module 1.8. This includes the summary of the pharmacovigilance system master file or PSMF, and also details of the qualified person responsible for pharmacovigilance or QPPV.

And 1.8.2 is the risk management plan which Bill will cover in more depth, shortly.

Needless to say, module 1 relies heavily on the rest of the dossier. So, especially the clinical data in the module five reports. These have to be presented and discussed in an integrative fashion in modules 2.7.3 and 2.7.4, so the summary of clinical efficacy and safety and coherent conclusions are presented in 2.5 which is the clinical overview.

The output of this needs to be a coherent presentation of information in module one as reflected in the risk management plan, the summary of product characteristics, and the package leaflet as well.

Pulling a CTD together such that module one is fit for purpose in the EU is a really significant undertaking and needs to be planned well in advance of the submission.

Watch the webinar

Watch the full webinar recording here: Unlock the Secrets of the EU Marketing Authorization Application.