The Common Technical Document
The Common Technical Document (CTD) is the common format in which the technical documentation of an application to register a medicine for human use is assembled. It fixes the dossier's five modules and their headings, the summaries and overviews of Module 2 and how long each runs, and the way the dossier is displayed and paginated, while the content each part has to carry comes from the guidelines behind it. Its overviews assess the evidence rather than summarise it, the clinical overview above all. The format has an electronic form, some regions still depart from it, and it replaced the separate dossiers that Europe, Japan and the United States each required before it.
The modules
The CTD was designed to give Europe, the USA and Japan a common format for the technical documentation included in an application for the registration of a human pharmaceutical product. The agreement on it within the International Conference on Harmonisation (ICH) was a major step forward in standardising and simplifying the approval process. The CTD is the basis of ICH's fourth multidisciplinary guideline, M4, and allows a global dossier to be submitted to the USA and the ICH member states.
The dossier carries information on quality, safety and efficacy in five modules, organised in three components. Module 1 holds administrative and prescribing information specific to each region, and it is not strictly part of the CTD. Modules 2 to 5 are common to all regions and form the main body of the CTD. Module 2 holds the overviews and summaries of Modules 3 to 5, which hold the quality (pharmaceutical) documentation, the nonclinical study reports and the clinical study reports. The information in Module 2 rests on the foundation material in Module 3 for quality, Module 4 for nonclinical and Module 5 for clinical information. The data produced during development are placed in allocated slots in this structure: clinical data in Module 5, nonclinical data in Module 4, and quality data, the chemistry, manufacturing and controls, in Module 3. Module 2 covers summaries of the development activities, and Module 1 the administrative information.
Module 1
Module 1 adapts the administrative information to regional, mainly national, requirements, and because its content and format are specific to each regulatory authority, it varies by region. In the European Community it should contain the table of contents of the submission, the application form, product information such as the package insert, information on the experts, specific requirements, the environmental risk assessment and, where applicable, orphan drug status. In the USA it should contain FDA form 356h, including administrative documents such as patent, environment and exclusivity information, and prescribing information such as labels and the package insert.
Module 2
Module 2 has seven sections, kept in this order: 2.1 table of contents, 2.2 introduction, 2.3 quality overall summary, 2.4 nonclinical overview, 2.5 clinical overview, 2.6 nonclinical written and tabulated summaries, and 2.7 clinical summary. The introduction is a general introduction to the product, including its pharmacological class, mode of action and proposed clinical use.
Modules 3, 4 and 5
The main headings of Modules 3, 4 and 5 must not be altered.
- Module 3, quality, presents the chemistry, manufacturing and controls reports for the product, with sections on both the drug substance and the drug product, and ICH M4Q gives full details of what it should include. Its main headings are 3.1 table of contents of Module 3; 3.2 body of data, divided into 3.2.S drug substance and 3.2.P drug product; and 3.3 literature references used in Module 3.
- Module 4, nonclinical study reports, has its structure and content specified in ICH M4S. Its main headings are 4.1 table of contents of Module 4; 4.2 study reports, divided into 4.2.1 pharmacology, 4.2.2 pharmacokinetics and 4.2.3 toxicology; and 4.3 literature references used in Module 4.
- Module 5, clinical study reports, has its structure and content specified in ICH M4E. Its main headings are 5.1 table of contents of Module 5; 5.2 tabular listing of all clinical studies; 5.3 clinical study reports, divided into 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 studies, 5.3.4 reports of human pharmacodynamic studies, 5.3.5 reports of efficacy and safety studies, 5.3.6 reports of post-marketing experience, and 5.3.7 case report forms and individual patient listings; and 5.4 literature references.
ICH M4E places clinical study reports and related information in specific sections of Module 5, to simplify preparation and review and to ensure completeness. The primary objective of a study determines where its report is placed, and each report appears in only one section. A study with multiple objectives is cross-referenced in the other sections.
Module 4 comprises all the pharmacological, pharmacokinetic and toxicological studies performed with the medicinal product, and the guidelines to follow for the format and presentation of all nonclinical studies are found in the relevant CTD guidelines. Module 5 includes all the clinical studies performed with the product. In some cases no study is required: for a generic medicinal product, for example, bioequivalence studies are not mandatory for simple oral solutions or for aqueous solutions given intravenously or intramuscularly, and cross-referral is made to the original reference product instead.
Format and content
The CTD is a general outline of the presentation and format of an application, and it gives no information on the content required to gain approval. Each module is associated with specific ICH guidelines, which must also be taken into consideration when an EU marketing authorisation dossier is prepared. The European Commission constantly revises these guidelines, so they should always be checked for updates. The CTD guideline should always be read within the framework of ICH and of the further documents the European Commission publishes.
The summaries
The quality overall summary is a summary of the chemical and pharmaceutical data in the dossier, including data for biological and biotechnological products. ICH M4Q gives guidance on its structure, which broadly follows the structure of the data in Module 3. It should not include information that is not already in Module 3 or elsewhere in the CTD. Its aim is to discuss the critical parameters of the product, but it should also address issues that arose during development and justify instances where guidelines were not followed.
The nonclinical written and tabulated summaries in Module 2.6 mainly provide a comprehensive factual summary of the nonclinical information on pharmacology, pharmacokinetics and toxicology. ICH M4S specifies their structure and content, together with the nonclinical overview's, and provides 34 templates for the tabulated summaries.
Modules 2.5 and 2.7 are usually the documents a medical writer is most likely to be asked to write, and ICH M4E specifies their structure and content. The clinical overview is a short document that provides a critical assessment of the clinical data, whereas the clinical summary is a longer document that focuses on summarising and integrating the data. Both provide the supporting information for the summary of product characteristics or the product label in Module 1, so it is important that they are consistent.
The primary purpose of the clinical summary is to provide a comprehensive factual summary of the clinical data. It draws on the clinical study reports in Module 5, information from any meta-analyses or other cross-study analyses and the reports of integrated analyses, and other information such as the literature and post-marketing data from other regions where the product is marketed. Its comparisons and analyses of results across studies should focus on factual observations and give no interpretation of the data, which is the clinical overview's task. It is divided into sections on biopharmaceutics and associated analytical methods, clinical pharmacology, efficacy and safety, and it includes the synopsis of each study report, or hyperlinks to it in an eCTD.
The length of each Module 2 document
One account gives each Module 2 document this expected length:
| Section | Expected length |
|---|---|
| 2.2 Introduction | In general not more than one page |
| 2.3 Quality overall summary | Normally not more than 40 pages of text, excluding tables and figures; for biotechnology products and products made by more complex processes, not more than 80 |
| 2.4 Nonclinical overview | Generally not more than 30 pages |
| 2.5 Clinical overview | Approximately 30 pages |
| 2.6 Nonclinical written summaries | Generally in the region of 100 to 150 pages |
| 2.7 Clinical summary | Between 50 and 400 pages, and possibly longer where more than one indication is included |
Another account recommends a length of 30 pages for each of the overviews, the short critical summaries. A third sets the nonclinical and the clinical overview at no more than 30 pages each. It puts the four documents of the clinical summary at approximately 400 pages combined, with references to the full study reports and other source documents as needed. A fourth limits the Module 2.7 summary documents to approximately 200 pages.
An account of the European dossier gives the overviews the bounds that the first account sets for the quality overall summary. Its checklist for the overviews reads:
- Have you focused on the key critical issues that pertain to the product in question?
- Do not exceed 40 pages for a "simple" product, or 80 pages for a complex one, excluding tables and figures.
- Do not include any information additional to that in the relevant modules.
What an overview is for
The summaries, and particularly the overviews, are in general more than summaries, and should include the rationale for the application and a critical appraisal of the programme and its data. Summarising large amounts of data in a short, critical document that gets key messages across is an art. The clinical and nonclinical overviews have these features in common:
- They are short documents, with a recommended length of 30 pages.
- They should be more than a summary, and should not recapitulate the data in the summaries (Modules 2.6 and 2.7) but primarily present the conclusions and implications of the data.
- They should assess the data critically.
- Issues should be identified upfront and their management discussed.
- The data should be discussed in the context of the available literature and current knowledge on related drugs.
- The nonclinical overview should emphasise how the nonclinical data support safe use in humans, and the clinical overview how the data demonstrate safe and effective use in humans.
The overviews descend from the expert report, which before the CTD was a major strategic component of the submission documentation in the European Union and eventually formed the basis for the CTD summaries. What applied to the expert report applies to the overviews as well: it should include a critical discussion of the properties of the product, the expert is expected to take and defend a clear position on the product in the light of current scientific knowledge, and a simple summary of the information in the application is not sufficient.
The expert report required the involvement of an expert, who could be internal, from the pharmaceutical company, or external, such as an academic. Three were required, pharmaceutical, nonclinical and clinical, and writing them was a challenge, because each was limited to 25 pages. Each had to make the case that the new drug should be approved by briefly summarising the data, appraising them critically, discussing issues upfront and showing that solid data supported the claims. Key messages had to be consistent between the three reports, and it was particularly important that the efficacy, safety and pharmacokinetic information in the nonclinical report was linked to the clinical efficacy, safety and pharmacokinetic data in the clinical report. In the clinical report, the clinical pharmacology studies in healthy volunteers provided the link between the nonclinical data and the studies in patients. Before adopting the CTD process, the FDA did not require an expert report, but advisory committees of independent experts were, and still are, used to discuss the issues that form the basis of one.
The main purpose of the summaries and overviews is marketing approval with a package insert that assures optimal patient benefit and financial success. The overviews show the regulatory authority that the scientific programme was of high quality and produced convincing quality, clinical and nonclinical data to support the claims and prescribing information, that all issues have been satisfactorily dealt with, and that the drug should be approved.
The clinical overview
The clinical overview should be signed by an appropriate expert. It should describe the clinical component of the dossier and show how the data are linked to the product information, and its messages should be consistent with those of the quality and nonclinical components. It is in essence a dialoguing tool that discusses critical issues upfront and indicates how they have been dealt with. It should make a convincing case that the new medicinal product should be approved because solid data on its safety and efficacy support the claims made.
In contrast to the factual presentation of the clinical summary, the clinical overview provides a critical analysis of the drug development programme and its results, including discussion and interpretation of the clinical findings and the relevance of other information, such as pertinent animal data or product quality issues that may have clinical implications. It presents the conclusions and implications of the data, and it should not repeat the information in the clinical summary or elsewhere in the CTD. It should include a critical discussion of the entire clinical study programme, negative results as well as positive, to clearly justify the benefits and risks of the product. The clinical summaries are its primary source documents, with references to individual study data as needed to support the justification for approval, and it may also include nonclinical data if they are relevant.
The clinical overview should present the strengths and limitations of the development programme and the study results, analyse the benefits and risks of the product in its intended use, and describe how the study results support critical parts of the prescribing information. It should also cover the quality of the clinical programme and the performance of the studies, including a statement on Good Clinical Practice compliance, and discuss the product's place in the clinical armamentarium if a licence is granted, with appropriate reference to the literature to put the results into context. Finally, it should provide an evaluation of the benefits and risks of the product based on the conclusions of the relevant clinical studies, interpreting how the efficacy and safety findings support the proposed dose and target indication and evaluating how prescribing information and other approaches will optimise benefits and manage risks.
The clinical overview is divided into sections on the product development rationale, biopharmaceutics, clinical pharmacology, efficacy, safety, and benefits and risks with conclusions, followed by the references. One outline gives each subheading these contents:
| Subheading of 2.5 | Contents |
|---|---|
| 2.5.1 Introduction | The pharmacological class of the new medicinal product, the target indication and the scientific background should be indicated, and the clinical development programme briefly reviewed. Any concordance or non-concordance with standard current research approaches, in the context of published literature and current regulatory guidance, should be highlighted. |
| 2.5.2 Overview of biopharmaceutics | This part should focus on the bioavailability of the new drug. It should also review the influence of food, dosage form and dose proportionality. |
| 2.5.3 Overview of clinical pharmacology | Both the pharmacokinetics (PK) and the pharmacodynamics (PD) should be reviewed critically, including discussion of healthy volunteers, the target population and any other special populations, as well as clinically relevant interactions. The PD should be reviewed, including the mechanism of action, the PD profile and clinically relevant interactions. The PK/PD and dose–effect relationship should be discussed to justify the proposed dosage regimen. The impact of age, gender, ethnicity, renal and hepatic impairment, and extrinsic factors (e.g., smoking, diet, other drugs) on PK should be critically reviewed. |
| 2.5.4 Overview of efficacy | All relevant data, positive or negative, should be reviewed critically, focusing on issues such as the studied population against the target population, subgroups, the choice of efficacy endpoints, the impact of dose, the study designs, the choice of control groups and the statistical methods. Data, or the lack of data, in children and the elderly should be reviewed. The key messages should convince the reviewer that the available data support the claims and that the product information will allow practising clinicians to use the drug safely and effectively in the appropriate patient population. |
| 2.5.5 Overview of safety | A concise and critical analysis of overall safety, including relevant animal toxicology and product quality information, the limitations of the safety database, adverse events (common nonserious and serious) and long-term safety. |
| 2.5.6 Benefits and risks and conclusions | The implications of any deviations from regulatory advice or guidelines, the expected positioning of the new medicinal product for the proposed indication, key aspects of the proposed prescribing information, and overall conclusions. |
| 2.5.7 References | Literature references and the available study reports. |
Planning and writing an overview
Writing an overview is a daunting task that requires insight, planning and good writing skills. All the data are collected and summarised in a table, from which summaries of the individual studies and publications are made, key messages supported by data are listed, and issues and problems are identified and addressed. For the clinical overview, these key messages and issues then feed its sections.
A proposed planning template for the CTD sets out these elements:
| Element | Planning entry |
|---|---|
| Guidelines | ICH M4, health authorities, company |
| Data | Galenics, nonclinical study reports, clinical study reports, literature |
| Customers | Health authorities |
| Key messages | Drug safe and effective; claims supported by solid data |
| Outcome | Successful advisory committee meeting (FDA); rapid health authority approval; no issues |
The expert should be someone with appropriate expertise relevant to the new medicinal product, such as an academic clinical expert in the specific disease area or an internal expert from the company filing the CTD. Although the overview documents are usually signed off by a single person, the expert, they are team efforts with input from many people.
In a European application, the quality expert, usually but not necessarily a pharmacist, assumes personal responsibility for the quality overview and the quality overall summary, which summarises the quality information submitted in Module 3. A medical doctor must be responsible for the clinical overview and summaries, which outline all the studies performed with the proposed product and relevant reference products in support of its therapeutic claims. A pharmacologist or toxicologist usually assumes responsibility for the nonclinical overview and summary, which summarise all the pharmacological and toxicological issues with the product, including critical issues such as impurity levels. The Module 2 summaries should be written clearly enough for the reviewer to gain an initial understanding of the entire application and to pinpoint its strengths and weaknesses. In a US application, all the functional members of the FDA review team are likely to read and refer to the summary and overview documents to gain an overall understanding of the product.
These mistakes are common in compiling a CTD:
| Mistake | Comment |
|---|---|
| Leave it to the expert | Collecting and interpreting data to compile a CTD is a team effort stretching over many years. An external expert with an impressive curriculum vitae cannot have the detailed knowledge of the product that the internal team has, and a mountain of data cannot be off-loaded on an expert in the expectation of an overview. A good overview requires a team effort that combines the team's detailed knowledge with the expert's experience and insight in the specific therapeutic area. |
| Writing a mere summary | The overviews are more than summaries and should be a critical assessment of the data. The overview should critically review the data, showing that the drug has an acceptable benefit–risk ratio, that all issues have been dealt with, and that the data support the claims made. |
| Hiding or downplaying bad news | Hiding or downplaying negative aspects of the drug is a fatal error and reflects badly on the honesty of the applicant. Negative findings should be communicated upfront, and their impact on the use of the drug in clinical practice must be communicated clearly. |
| Using superlatives | Superlatives such as "highly" effective or "very" safe should not appear in the CTD documentation. Efficacy, for example, should be expressed in terms of data, such as "MT239 lowered diastolic blood pressure by 15 mm Hg or more in 80% of patients with moderate hypertension, compared to 5% of patients who received placebo". |
It helps to write as if one were the reviewer from the regulatory agency, so as to anticipate the questions and queries the reviewer might have.
Presentation conventions
The overall structure of the CTD is detailed in ICH M4, which includes a granularity section giving guidance on document location and pagination within the dossier. That guidance is particularly useful when the dossier contains multiple indications or multiple components of the investigational medicinal product. A set of questions and answers also addresses the most common issues raised.
The display of information in the CTD should be unambiguous and transparent. ICH M4 recommends that text and tables be prepared with margins that allow the document to be printed on both A4 paper, used in the EU and Japan, and 8.5 × 11 inch paper, used in the USA. Times New Roman in 12-point font is recommended for narrative text. Acronyms and abbreviations should be defined the first time they are used in each module, and literature references should be cited at the end of each module in accordance with the Uniform Requirements for Manuscripts Submitted to Biomedical Journals.
Every document in the CTD should be numbered starting at page 1, except individual literature references, where the existing journal page numbering is considered sufficient. The ICH M4 guidelines state that page numbers need not be displayed as "1 of n", where n is the total number of pages in the document. All pages of a document should carry a unique header or footer that briefly identifies its subject matter, such as an abbreviation of the full section number and title, as in 2.7 Clinical Summary. To avoid fifth-, sixth- and lower-level subheadings such as 2.6.6.3.2.1 within a document, the M4 guidelines allow a shortened numbering string: the document number and name, such as 2.6.6 Toxicology Written Summary, appear in the page header or footer, and an abbreviated section numbering, such as 1, 1.1, 2, 3, 3.1 and 3.2, is used within the document.
The electronic CTD
Submitting an electronic CTD (eCTD) means more than delivering a dossier as electronic files. The eCTD specifications use XML to create a searchable backbone, essentially a table of contents that includes qualifying information, or metadata, about each item in it. The XML tags associated with a clinical study report, for example, might include searchable data such as the drug name, the indication and the study phase. So the eCTD format has the potential to remove the paper burden entirely, and it enables sponsors and regulatory agencies to search dossiers more thoroughly, within and between submissions, nationally and internationally.
Sponsors could still submit a CTD on paper, but the goal was eventually to have all submissions made electronically. Paper CTDs are widely accepted in regions unable to manage the technology needed to review an eCTD. Many regulatory authorities encourage electronic submission of the CTD. The eCTD facilitated the direct transfer of regulatory information from the pharmaceutical industry to regulatory agencies, and it became mandatory for Japan and Europe and highly recommended for submissions to the FDA. In the EU, the eCTD has been mandatory for the centralised procedure since 2010, and the paper CTD is destined to be replaced by it. In the United States, the FDA retired its original electronic submission guidance in 2008 and mandated that any dossier submitted electronically be delivered as an eCTD. The FDA also accepts electronic signatures, and sponsors can upload an entire dossier through the FDA's electronic gateway.
Regional departures from the format
Some regions still retain some of their original pre-CTD dossier requirements. The most common example is the FDA's requirement to submit an integrated summary of efficacy and an integrated summary of safety in a US submission, although the intent was that the clinical summary would replace them, Module 2.7.3, the summary of clinical efficacy, replacing the former and Module 2.7.4, the summary of clinical safety, the latter. The guidance is therefore to include the full integrated summaries in Module 5 and condense them into summary format for the Module 2.7 documents. The FDA requires them in Module 5.3.5.3, as reports of analyses of data from more than one study that describe and present the results from integrated safety and efficacy databases. The Module 2.7 documents and those in Module 5.3.5.3 generally follow the same outline, but the Module 2.7 summaries are limited in length and cannot go into the detail of the 5.3.5.3 documents, which can be thousands of pages long.
Japan's approach to the CTD's clinical content differs from that of other countries in that greater emphasis and focus are placed on the summarised data in Module 2 than on the clinical study reports. The CTD designates a common format for a new drug application, with the clinical study reports in Module 5, but how they should be written and what they should describe depend on the country or region. For a Japanese application, Module 2 must be prepared in Japanese, except for tables and figures, which may be prepared in English. The PMDA does not simply accept a direct translation of Module 2 documents prepared in English and submitted to the FDA or the EMA. As the PMDA seems to place emphasis on a Module 2 prepared using a Japanese language structure and logic, Module 2 is the established place in a Japanese application where claims are developed from the risks and benefits of the drug. English is acceptable for Module 5.
In Japan, Module 2.7.6 tends to be much more comprehensive than a standard ICH E3 study report synopsis, often running to 50 pages and sometimes to more than 100 pages per study. An administrative notice issued in 2011, "Format for Preparing the Common Technical Document for Submission of New Drug Applications to Reduce Total Review Time", clarified that the safety data from individual clinical studies are to be presented in Modules 2.7.4 and 2.7.6.
Japan's requirements for CTD Modules 2.7.3, 2.7.4 and 2.7.6 comply with ICH M4. China at first had only its own drug registration system, under the Provisions for Drug Registration, and did not accept the CTD format. It then applied two systems in parallel: the Provisions for Drug Registration, and a CTD format system of its own, developed largely on the basis of ICH M4, applied only provisionally while still under development, and with content that could change greatly.
Where the format came from
Before the CTD, each of the three major regulatory regions, the EU, the USA and Japan, had its own set of guidelines and its own format for a dossier seeking marketing approval for a new drug or a variation to the licensing of an existing drug. Japan required the GAIYO, which organised and presented a summary of the technical information; Europe required expert reports and tabulated summaries and recommended written summaries; and in the USA, the FDA had guidance documents on the format and content of the new drug application. Countries within the EU also had their own guidelines and formats, which made submission to multiple countries and multiple regions a time-consuming and repetitive process.
In the United States, a 1988 FDA guidance gave a comprehensive outline of the contents of the clinical and statistical sections of a new drug application, and together with associated regulations it provided the structural outline that sponsors followed to compile marketing applications for the next decade. During that decade all submissions were printed on paper, in multiple copies. Sponsors and regulatory authorities came to realise that paper submissions were costly to produce and a burden on the environment, that reviewing, storing, archiving and disseminating the critical safety information buried in them was time-consuming and inefficient, and that a sponsor submitting the same application in other world regions had to rework many documents, compile different content and go through the paper compilation again.
Development of the CTD began in 1996, when ICH industry representatives proposed assembling the information generated by the harmonised guidelines, to decrease the time and staff needed to assemble and disassemble documents for submission to the ICH regions. In 2000, representatives of the EMA, the FDA and Japan's Ministry of Health, Labour and Welfare developed, under the umbrella of ICH, a set of guidelines defining the structure and content of a dossier for the registration of a new medicine that could be used across all three regions. The aim was a common format for the technical documentation that would significantly reduce the time and resources needed to compile applications for the registration of human pharmaceuticals and would ease the preparation of electronic submissions. A standard document of common elements would also facilitate regulatory reviews and communication with the applicant, and simplify the exchange of regulatory information between regulatory authorities. The fifth ICH conference, held in San Diego in 2000, focused on assembling quality, efficacy and safety information into the CTD.
The CTD includes basically the same content that the 1988 FDA guidance recommended, but compiles it in a way that facilitates submission to other regulatory agencies. It allows all the information related to an investigational drug to be assembled into one common document.
The first ICH CTD guidelines were published in 2002, and there are four ICH guidelines on the CTD, M4, M4Q, M4S and M4E, along with four question-and-answer documents. One account puts the CTD's implementation in 2002. Another puts it in 2000. In July 2003, the CTD became the mandatory format for new drug applications in the EU and Japan, and the strongly recommended format for new drug applications submitted to the FDA. Several other countries have since adopted it, including Canada and Switzerland.
The CTD has been largely successful in providing a common format for the information included in a submission dossier, but whether it has brought the suggested reductions in the time and resources needed to compile applications is debated.