3. Format of the Submission – the Common Technical Document (CTD)

1. Format of the Submission – the Common Technical Document (CTD)

(This section is organised in the form of a book, please follow the blue arrows to navigate through the book or by following the navigation panel on the right side of the page.)

The Common Technical Document (CTD) is the internationally agreed format for the preparation of Marketing Authorisation Applications (MAAs) for a medicine to be submitted to regulatory authorities agreed by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

In July 2003, the CTD became

• the legally mandatory format for new medicine applications in the EU and Japan
• the “strongly recommended” format in the US for NDAs submitted to the Food and Drug Administration (FDA)
• the official standard for the dossier format accepted in ICH Observer countries (Canada, Switzerland) and in more and more countries and regions around the world.

The CTD:

• determines the appropriate format to assemble all the Quality, Safety and Efficacy information required
• describes the organisation of modules, sections and documents to be used in a regulatory dossier
• is applicable for MA applications irrespective of the procedure (CP, MRP, DCP or NP) and of type of application (stand alone, generics etc.; see below 7. Types of Marketing authorisation applications)
• is organised in five modules (modules 2 to 5 constitute the actual CTD; module 1 is different according to region
• gives no information about the specific content of the different parts of a dossier (besides the overall scope given in the headers) and does not indicate which studies and data are required for a successful approval.

The CTD Triangle – a graphic representation of the CTD structure, decreasing detail towards the top

Fogure 1: The CTD Triangle. Adapted from https://www.ich.org/page/ctd

2. Module 1 region specific

Module 1 contains region-specific administrative and product information. The EU has developed its own version of Module 1. The EU eCTD Module 1 Specification has been updated to reflect clarifications and the updated version 3.0.4 is approved and should be used from April 2021.
The module contains the following elements:

1.0 Cover letter.

1.1 Comprehensive table of contents.

1.2 Application form.

1.3 Product information documents.

1.4 Information about the experts.

1.5 Specific requirements for different types of applications (if required).

1.6 An Environmental risk assessment.

1.7 Information relating to orphan market exclusivity (if required).

1.8 Information relating to pharmacovigilance.

1.9 Information relating to clinical trials (if required).

1.10 Information relating to paediatrics.

Regulatory Affairs (RA) professionals are responsible for advising on, collating and reviewing the elements before submission.

In addition, other items such as answers to regulatory questions, rationale for variations and renewal documentation could also be included in Module 1.

1.1 Comprehensive table of contents

(In eCTD the XML backbone acts as a table of contents)

1.2 Application form

The application form (1.2), contains administrative data, information about the type of application and submission procedure, extensive basic information about the medicine or medical device, a summary of the pharmacovigilance system, and all companies involved in manufacturing or in clinical trials (contract companies, CROs).

In addition, it is stated whether scientific advice was sought prior to the submission. The advice will be included to facilitate the work of the assessors. Seeking scientific advice is helpful for the applicant when planning various steps of the development process. The success rate is much higher for submissions when scientific advice has been sought and adhered to. From 2008 to 2012, approximately 85% of such applications were approved. For those not adhering to the advice, the success rate was only of approximately 40%.

Of note: As from 01/01/2016, use of electronic application forms for all procedures is mandatory. The Application form presently applicable is “Medicinal Products for Human Use, VOLUME 2B, Module 1.2: Administrative information Application form September 2021 (Rev. 15)” (see also below 4.2. Electronic Application Forms (eAF))

1.3 Product information

Product information (1.3) refers to the summary of product characteristics (SmPC), a detailed document for healthcare professionals, the labelling (outer and immediate packaging) and the package leaflet (PL), formerly called patient information leaflet (PIL). based on the mandatory format and lay-out (see “QRD template” on the EMA Website). The SmPC and PL must be written to be easily understood by a lay person. The applicant must demonstrate the required consultation with target patient groups, often referred to as ‘user testing’ and predominantly using a so-called ‘readability test’. Likewise, information that will appear in Braille on the printed outer packaging material should be mentioned. (See also the “Guideline on the Readability of the Labelling and Package Leaflet of Medicinal Products for Human Use”)

1.4 Information about the experts

Experts in each field should write the summaries and overviews in Module 2 and provide detailed reports of the documents and particulars which constitute Modules 3, 4 and 5. Each of the experts should provide a curriculum vitae (CV) in section 1.4. Furthermore, they must sign a declaration that they have followed the rules of the applicable directive when creating the summaries.

1.5 Specific requirements for different types of applications

 Section 1.5 should indicate the “legal basis” of the application – the corresponding Article of Directive 2001/83/EC such as applications of type: “full”, “generic”, “hybrid”, “similar biologic”, well established use”, “fixed combination”, “conditional”, “under exceptional circumstances”, etc.

1.6 An Environmental risk assessment

All active substances in medicines may potentially be of risk to the environment, as they or their metabolites will ultimately end up in the environment. Therefore, the pharmaceutical company needs to address these problems in the application in section 1.6 and ask what could be the problems for the environment in the use, storage, and disposal of the medicine.

1.7 Orphan market exclusivity

If the medicine is for treatment of an orphan or rare disease, specific information is needed in section 1.7. The new medicine may have received orphan designation. Another medicine on the market may already have market exclusivity for the same indication. In this case a new medicine may only be approved under special conditions, i.e. during the market exclusivity period similar medicines will not be granted a marketing authorisation for the same therapeutic indication. An exemption exists if the MAH  for the orphan product approved first gives consent, is unable to supply sufficient quantity of the medicine, or the second applicant demonstrates that although ‘similar’, the medicine is ‘clinically superior’ to the already authorised orphan medicine.

1.8 Pharmacovigilance

In section 1.8 the applicant should describe the pharmacovigilance and risk management systems. These elements are important. The applicant needs to demonstrate that surveillance of adverse reactions and potential risks are in place.

1.9 Clinical trials

Clinical trials performed in the EU need to follow a specific set of regulatory and ethical requirements. In many cases, some of the clinical trials are performed outside the EU. In such cases, the applicant should include in section 1.9 a statement that those trials also respect EU requirements.

1.10 Information relating to paediatrics

All new medicines need to be considered for the paediatric population in the EU (Regulation (EC) No 1901/2006 (‘paediatric regulation’). In general, they should be tested in children. However, a waiver for this requirement may be granted if the disease is seen only in elderly people or other adults, or the new medicine is likely to be ineffective or unsafe in part or all of the paediatric population. If a waiver is not possible, the pharmaceutical company must produce a plan for testing in children, a Paediatric Investigation Plan (PIP). If the activities (usually clinical trials) under the PIP cannot be completed in an adequate time a deferral can be granted in which case the PIP can be delayed. In section 1.10 a copy of the waiver or of the decision on the PIP should be included.

3. Module 2

The respective experts will also produce the various summaries in Module 2. Summaries should make it easier for assessors at the regulatory agencies to get an overview of the application. Again, the regulatory affairs professionals are involved.

Module 2 contains seven sections:
2.1 Table of contents
2.2 Introduction
2.3 Quality Overall Summary
2.4 Non-clinical Overview
2.5 Clinical Overview
2.6 Non-clinical Written and Tabulated Summaries
2.7 Clinical Summary.

Section 2.3 The Quality Overall Summary (QOS):

• a summary that follows the scope and the outline of the body of data in Module 3.
• should not include information, data or justification that was not already included in Module 3 or in other parts of the CTD.
• should include sufficient information from each section to provide the Quality reviewer with an overview of Module 3.
• should emphasize critical key parameters of the product and provide, for instance, justification in cases where guidelines were not followed.
• should include a discussion of key issues that integrates information from sections in the Quality Module and supporting information from other Modules (e.g., qualification of impurities via toxicological studies discussed under the CTD-S module).

Section 2.4 Non-clinical Overview:

• should present an integrated and critical assessment of the pharmacologic, pharmacokinetic, and toxicologic evaluation of the pharmaceutical.
• where relevant guidelines on the conduct of studies exist, any deviation from these guidelines should be discussed and justified.
• the nonclinical testing strategy should be discussed and justified.
• should contain a comment on the GLP status of the studies submitted.
• any association between nonclinical findings and the quality characteristics of the human pharmaceutical, the results of clinical trials, or effects seen with related products should be indicated, as appropriate.
• should include assessment of the impurities and degradants present in the active substance and product along with what is known of their potential pharmacologic and toxicologic effects.
• the implications of any differences in the chirality, chemical form, and impurity profile between the compound used in the nonclinical studies and the product to be marketed should be discussed.

Section 2.5 Clinical Overview should:

• provide a critical analysis of the clinical data in the CTD
• provide a succinct discussion and interpretation of the clinical information in the CTD together with any other relevant information (e.g., pertinent animal data or product quality issues that may have clinical implications).
• present the strengths and limitations of the development program and study results, analyse the benefits and risks of the medicine in its intended use, and describe how the study results support critical parts of the prescribing information.
• describe and explain the overall approach to the clinical development of a medicine, including critical study design decisions;
• assess the quality of the design and performance of the studies, and include a statement regarding GCP compliance;
• provide a brief overview of the clinical findings, including important limitations
• provide an interpretation of how the efficacy and safety findings support the proposed dose and target indication and an evaluation of how prescribing information and other approaches will optimise benefits and manage risks;
• address particular efficacy or safety issues encountered in development, and how they have been evaluated and resolved;
• explore unresolved issues, explain why they should not be considered as barriers to approval, and describe plans to resolve them;

Section 2.6 Non-clinical Written and Tabulated Summaries:

• guidance, not intended to indicate what studies are required. It merely indicates an appropriate format for the non-clinical data that have been acquired.
• brief information concerning the medicine’s structure (preferably, a structure diagram should be provided) and pharmacologic properties;
• information on the medicine’s proposed clinical indication, dose, and duration of use.
• whenever appropriate, age- and gender-related effects should be discussed.
• relevant findings with stereoisomers and/or metabolites, as appropriate.
• in the Discussion and Conclusion sections, information across studies and across species; exposure in the test animals should be related to exposure in humans given the maximum intended doses.

Section 2.7 Clinical Summary:

• intended to provide a detailed, factual summary of all of clinical information in the CTD.
• includes information provided in ICH E3 clinical study reports; information obtained from any meta-analyses or other cross-study analyses for which full reports have been included in Module 5; and post-marketing data for products that have been marketed in other regions.
  • the comparisons and analyses of results across studies should focus on factual observations.

The bulk elements of the documentation for quality, safety and efficacy are in Modules 3 – 5. This documentation is produced by various functions in the company, each expert in their field. The Regulatory Affairs (RA) professionals ensure that the documentation is in line with all relevant regulations, directives and guidelines.

4. Module 3 Quality

Module 3:

• presents the chemistry, manufacturing, and controls reports for the product.
• full details of what should be included in Module 3 are provided in the ICH M4Q guideline.
• sections on both active substance and medicinal product are included.
• main headings:
  • 3.1 Table of contents of Module 3
  • 3.2 Body of data
  • 3.2S Active Substance
  • 3.2P+ Medicinal Product
  • 3.3 Literature references used in Module 3

5. Module 4 Non-clinical study reports

Although it is recognised that the non-clinical data help to address the safety of the product, there are non-clinical studies (primary, secondary pharmacology stating the effects of the active substance on the different organs showing or not showing the intended efficacy. Therefore, the key issue here is to know that this module contains the result of the investigations performed in vitro and in animals (non-clinical data).

Module 4

• presents the non-clinical reports (pharmacology/toxicology) - non-clinical study reports).
• structure and content are specified in the ICH M4S guidelines.
• main headings:
  • 4.1 Table of contents of Module 4
    • 4.2 Study reports

- 4.2.1 Pharmacology

- 4.2.2 Pharmacokinetics

- 4.2.3 Toxicology

• • 4.2 Literature references used in Module 4.

6. Module 5 Clinical study reports

Module 5: This module includes the clinical data for the analysis of the benefit-risk balance (efficacy and safety) of the product and should include the results of the studies performed in humans.

Module 5:

• presents the clinical study reports (CSRs).
• structure and content are specified in the ICH M4E guidelines, which provide a specific placement of clinical study reports and related information to simplify preparation and review and to ensure completeness.
• main headings:
  • 5.1 Table of contents of Module 5
  • 5.2 Tabular listing of all clinical studies
  • 5.3 Clinical study reports
    • 5.3.1 Reports of biopharmaceutic studies
    • 5.3.2 Reports of studies pertinent to pharmacokinetics using human biomaterials
    • 5.3.3 Reports of human pharmacokinetic (PK) studies
    • 5.3.4 Reports of human pharmacodynamic (PD) studies
    • 5.3.5 Reports of efficacy and safety studies
    • 5.3.6 Reports of post-marketing experience
    • 5.3.7 Case report forms and individual patient listings
• 5.4 Literature references