As I discussed in my last blog, solid document management is paramount for successful regulatory submissions in the larger markets. In the majority of major markets submissions must be done electronically through the electronic common technical document (eCTD).
In principle, the eCTD is a simple structure to allow the dossier of all those documents created during the product development cycle to be sent to the regulators in a way that is seamless to navigate. It implements the CTD definition, which in turn provides a defined list of documents required and a description of each document’s content and purpose. What could be simpler?
It is made up of five modules
- Module 1 – this is market-specific and must include involvement from any local commercialisation partners. Strictly speaking, Module 1 is not common since it must adjust to local market needs.
- Module 2 — this is a summary of the documents in modules 3-5 and a reviewer will expect to be able to hyperlink between the module 2 summary and the detailed documents in Modules 3, 4, and 5, as well as within documents.
- Module 3 – this contains the CMC information for the product
- Module 4 – this section contains all the pre-clinical information
- Module 5 – this section contains the clinical information. The level of detail required varies among regulatory authorities; for example, the US FDA wants a PDF of every CRF from every trial, while most other regulators are happy with more summarised information
The first version of a dossier that is sent to the regulator is “sequence 0” in that application. Every time there is a change there is a new sequence – be it a one-page letter or a multi-document submission to add a new indication. Each of these sequences can add, replace/update or remove one or more documents from your overall dossier (replacements/removals need to reference the sequence in which the document was originally provided).
An important consideration is that any change to any document will result in/be part of a variation, and each variation carries an additional fee. Some variations reflect changes in the product, it’s packaging or manufacturing processes that have to be requested before they are made and can only be implemented after approval. Some require that the regulator is advised of the change in advance, with the potential for rejection within a time window. And some only require providing the regulatory authorities with periodic advice (allowing multiple small changes to be “rolled up” and thereby saving on fees). Unfortunately for these rolled up changes, regulators do not work to a single global reporting calendar, so it does not take many changes before keeping track of who you told what and when becomes a very significant task. Furthermore, continuous improvement is key to survival in any manufacturing industry, and this continuous improvement carries continuous change and continuous regulatory communication. This means that three-figure sequence numbers are not uncommon.
Those “what and when” questions really come into their own when making changes. Every variation must specify which documents are new, which are to be deleted and which are to be amended or replaced with the new version. Consider, for example, that to reference any previously submitted document the precise sequence in which it was last referenced must be cited.
In addition to changes you initiate, the regulatory review process is also likely to result in some required amendments as each health authority asks for clarification – and that means further variations. Each change may be small and easily comprehended; however, the number of changes and their interaction gives rise to huge complexity. It is not uncommon to see three-digit sequence numbers on eCTD submissions – in other words, hundreds of changes to a single product in a single market…
Given the complexity involved across the life cycle, IT tools to support the process become almost unavoidable. For many companies this means investing in one of the dedicated software tools available on the market. For others, especially smaller companies, cost and complexity often mean that contracting to a service provider that offers regulatory operations services can make more sense.
As you begin your eCTD journey, deciding how best to manage these different complexities will help you meet and manage your regulatory obligations.