Over the past couple of blogs – Be Prepared and Understand the eCTD challenge – I have talked about the challenges pharmaceutical companies with limited marketed product experience face, particularly when seeking to bring products to the larger markets. An important consideration is to understand the expectations and preference of the authorities.

Regulators want to ensure all processes are managed properly. To that end they tend to look at the work in four domains: capacity, instruction, evaluation and mitigation. Can the person or technology involved carry out the task properly? Are the instructions correct? Can the task be reviewed and evaluated so as to detect failure in a timely manner? If they fail, is there something in place to prevent that failure from causing harm?

These questions apply at the frontline production, laboratory systems and distribution stages, but regulators are equally concerned about document management and whether the systems in place to manage the documentation meet regulatory requirements. If drug developers decide to implement computer systems to support any of these areas, they need to be conscious of the specific requirements surrounding e-signatures. These are very specific and it is a fair rule of thumb that if your IT suppliers do not volunteer how they comply, they likely don’t comply.

Whether implementing systems in house or outsourcing to a service provider, manually or as computerised systems, the regulated entity (that is, the company bringing the product to market) has to be happy that they can answer the question “Why did you trust this service provider/computer system to discharge YOUR regulatory responsibility?” This requires that you have documentary evidence showing that the provider/system has been verified as having the capacity to discharge the responsibility, has been clearly instructed to discharge it and that the regulated entity has processes in place to evaluate the performance and mitigate any risks arising from failure. This is the essence of “Validation” regardless of the prefix qualifier that may be applied (for example, computer system validation, process validation and so on).

Bringing a product to market will, of necessity, involve deploying strong document management systems and regulatory submission management systems. It will probably involve these being computerised, either as a dedicated system or using the services of a partner. Whichever way it is addressed, it is vital that the route chosen is robust and demonstrably fit for purpose – in other words, validated. Failure to address these requirements early in the development process, well ahead of the need to deploy, can be the cause of either significant delay or significant additional cost when it comes to submitting a marketing application.

From having a document management backbone, to understanding and preparing for eCTD, to addressing issues around validation, it’s in your interest to ensure your organisation has these matters in hand. If you don’t, do “future you” a favour and start looking now.

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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.

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The push to conduct clinical trials and bring products to market in the EU often catches companies with limited marketed product experience off-guard.

As they progress through the clinical development phases, they develop a large library of completed and approved documents which comprise their dossier. There is an assumption that this emerging monument to effort will be immutable and that from here on in it is a case of  simply adding further to it.

However, it’s never that simple, especially in the largest pharmaceutical markets, including the EU, the United States, and other global markets with similar regulatory requirements, such as Japan, Canada and Australia.

In the early stages of development, documents are for the most part linear, that is to say they are developed through their natural life cycles, approved and then held as final versions. However, as development progresses, more and more summary documents are created, and, as a result, the approved version is revisited and periodically updated. Documents such as the investigational medicinal product dossier (IMPD), the investigator’s brochure and even protocols evolve post initial approval so understanding who has what version of each document starts to become an issue.

As the product moves into approval, further documents are generated as updates are circulated to multiple third parties in a form that allows comparison to the last version received. Moreover, as the product moves into manufacture the manufacturing scale up process also gives rise to further changes to existing documents.

The Reality is that to successfully submit a product to regulatory authorities in the EU or US, companies need a solid document management backbone. This is crucial to ensuring every stakeholder – across clinical, regulatory, safety, CMC and commercial – can access and work on relevant elements of the document. Whether this is achieved with “manual controls” or through deployment of a fully-fledged DMS (or some compromise in between) is essentially irrelevant; however it is worth remembering that  in both the US and the EU, as well as several other major markets, all regulatory submissions must be made electronically through the electronic common technical document (eCTD), which pre-supposes the existence of well-defined IT and document management capabilities.

In the next two blogs, I will share my thoughts on what it means to Understand the eCTD challenge, and what the regulators expect in terms of submission processes. As you prepare to bring your products to market and gain approval from the European Medicines Agency, the Food and Drug Administration and other regulatory authorities, paying heed to standards, dossier structures and submission expectations will help you achieve the outcomes you are hoping for – product approval in the largest global markets.

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