GxP Lifeline Feature Article
An Introduction to the eCTD
The CTD (Common Technical Document) was proposed by the ICH working committee (the International Conference on Harmonisation) back in the early 1990s and finally agreed upon in November 2000. Its purpose was to provide life sciences companies with a common structure for registering drugs for human use to the regulatory agencies. The FDA was the first agency to adopt the CTD as a common structure for receiving product registrations from companies. Although the CTD submissions were initially delivered in paper, the eCTD (electronic Common Technical Document) was implemented using the same structure but delivered to the agencies in an electronic format with a few additional specific requirements that were not included in the original CTD.
The CTD structure consists of 4 modules and 1 regional module. The following diagram clearly defines the relationship between the modules:
Module 1 is for regional administration information; every CTD submission will have module 1 containing basic information relating to the country/agency, application, type of submission and procedure, etc.
Module 2 contains summaries and overviews for the CMC non-clinical and clinical sections.
Module 3 is for detailed quality information relating to the manufacturer, control of drug substances, references to standards and materials, stability, etc.
Module 4 contains safety information and includes reports such as pharmacology, pharmacokinetics, and toxicology.
Module 5 contains efficacy information and includes study reports and data from all clinical studies
Module 1 will be the same in structure, but different in content, for each regional agency the application is submitted to. These regional differences (US, EU, Japan , Canada and Taiwan ) are defined and maintained in the DTD (Document Type Definition) in accordance with ICH specifications .
What do you need to consider before implementing an eCTD solution?
Submission Ready Documents
i. To create a validated eCTD submission it is essential that your source files be submissions ready. This includes quality control of your documents, ensuring the following:
- no embedded security,
- navigational items (bookmarks and hyperlinks),
- bookmarks and hyperlinks set to inherit zoom,
- individual file size up to 100mb (max),
- all files are the correct (most recent) version.
ii. Are your files at the correct granularity for an eCTD? This means that documents may require splitting to lower levels than previously done to meet the requirements setup by ICH guidelines. The guidelines stipulate the naming convention of all files in the eCTD (known as leaf's) as well as the XML backbone (an electronic table of contents) that holds information on each submitted document that includes title, MD5 checksum application used and version of the document.
Savings from using eCTD over Paper Filing
- As the output from an eCTD is electronic, significant savings can be achieved from no longer printing paper. This includes paper costs, cartridge costs, printer upgrades/maintenance, and delivery and storage costs.
- Agencies have begun showing preference towards eCTD filings by offering discounts to review eCTD over paper submissions (also stating that an eCTD will be given preference for reviewing).
When will eCTD become compulsory?
Although agencies will accept paper CTD registrations in Europe , several are insisting the documents are converted into PDF (Portable Document Format), compiled into the CTD structure and delivered on electronic media such as CD and DVD. For certain registrations the FDA will only accept applications in the eCTD format. The move towards an electronic format is steadily increasing in popularity with agencies, and it is expected all agencies will adopt the eCTD by 2009.
Speed of Filing
i. Agencies have stated that an eCTD will be given preference in reviewing over paper. This is an important factor if there is strong competition in the marketplace.
ii. The time taken to deliver/receive paper submissions, and also for reviewers to analyse the files, can take significantly longer in paper than with an eCTD. Take for example links to external files within a submission. With an electronic link the reference can be seen in seconds, with paper submissions this is a time-consuming process.
Managing the versions of your documents will become imperative to ensure you do not provide the agency with out-of-date information that could result in your submission not being validated. As you submit variations (or supplements and amendments in the Unite States ) to your application using the eCTD, the importance of life cycle management becomes evident.
Converting your existing legacy documents to PDF with the appropriate granularity and correct attributes is a good first step, organising your electronic documents is essential and having a process in place to manage and maintain your applications (updates or sequences as they are known in eCTD terms) should be your ultimate goal.
This article has provided a summary of some of the considerations to achieve what will become a compliant registration requirement in the future.
Further information on eCTD specifications can be found on the ICH website http://estri.ich.org/eCTD/eCTD_Specification_v3_2_2.pdf
Read more about electronic submissions, 21 CFR Part 11 and document management to improve time to market: