PHARMACEUTICAL |
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eCTD: The burden and the benefits
The electronic Common Technical Document (eCTD) is here. What will be its impact on the industry, now that the world’s leading regulatory bodies are (nearly) ready to accept it?
Since 1990, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has been working to create a standardized framework for drug and biological product registrations. The ICH has been driven by representatives from three regions — Japan, the EU, and the US — and several other countries working as ‘observers’.
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The ICH defined a process by which this standardisation would occur, and in November 2000 the ICH Steering Committee met in San Diego to ratify the guidelines describing the Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD). In ICH parlance, this meant the CTD has achieved Step 4 status, signifying that consensus on a topic has been reached by the ICH member parties and that each party commits to incorporate the ICH guideline into each region’s own regulatory framework in accordance with its own legal processes. Completion of this final step is known as Step 5.
In the case of the US, the FDA publishes the guidance documents according to Good Guidance Practices (GGP) and thereby formally adopts the ICH guideline as ‘FDA guidance’. In Europe, Volume 2B of the European Notice to Applicants was revised in July 2001 to accommodate the CTD within the EU legislative system. As of July 1, 2003, it became mandatory for applicants to submit dossiers in the EU and Japan using the new CTD format. It is also the recommended format in the US.
The electronic CTD
More recently, momentum has been building on the electronic submission front. An Expert Working Group within the ICH has been developing the electronic Common Technical Document (eCTD), an electronic equivalent of the paper CTD. The eCTD is principally a specification describing an interface between industry and agency to facilitate the transfer of regulatory information. At the same time, the eCTD takes into consideration the need to help throughout the lifecycle of the electronic submission – or dossier. The chosen approach draws upon the experience of the FDA, the European Federation of Pharmaceutical Industries and Associations (EFPIA), and others in the use of Adobe® Acrobat PDF-based submission standards. Documents are submitted primarily in PDF format, with data such as SASformat statistical information, supplied in native form. Moreover, there is an increasing amount of ‘structured’ documentation being provided as exemplified by the FDA’s Study Tagging File (STF) requirement and labeling initiatives such as the FDA’s Structured Product Labeling (SPL) and Europe’s Product Information Management (PIM) standards. Where the FDA’s current guidelines call for navigation by PDF-based table of contents files, the eCTD goes further by providing a mechanism to record all interactions between industry and the regulator in a way that highlights changes between multiple submissions.
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This lifecycle-view of the submission is achieved through the use of an XML ‘backbone’ that provides information about the submission and its component parts. The purpose of the backbone is principally to manage data describing the submission and each document within the submission. This data is known as metadata, and examples at the submission level include information about the kind of submission, the submitting and receiving organisations, and the manufacturer. Examples of metadata at the document level include version information, language, descriptive information such as document names, and timestamps.
The most critical – and complex – component of the XML backbone is the mechanism by which sponsor organisations will indicate the type of lifecycle action being taken for each file. In other words, the backbone will indicate if a particular file being submitted is new, replacing a previously submitted file, appending to a previously submitted file, or removing a previously submitted file from the agency’s ‘view’. This concept will allow sponsors to effectively submit their dossiers incrementally or in a ‘rolling’ fashion. It does, though, place a great burden on these sponsors to keep track of every file ever submitted using the eCTD so that these lifecycle actions can be accurately reflected.
Current position
The CTD is now in use with a number of the regulators, with electronic submissions based around the CTD — though not using the eCTD XML approach — also being leveraged by a number of organisations. The eCTD reached ICH Step 4 in September 2002 and is now being implemented regionally, taking it to Step 5. The FDA is in a position to accept eCTD submissions and has been receiving a growing number of them. Beginning in 2009, the only acceptable electronic format for the FDA’s CDER and CBER divisions will be the eCTD.
The European agencies are in the process of determining their technical strategies that will enable them to accept eCTD submissions (and some already do), but mandatory paper CTD submissions are expected to still be provided until such time as the individual authorities have revised their legal requirements removing the paper version as the dossier of record. The current target for European acceptance of only eCTD submissions is 2009. Japan is currently accepting paper CTD submissions and has its own unique requirement for a ‘cumulative’ XML backbone. Very few eCTD submissions have been provided to the Japanese authority to date.
Challenges to the enterprise
How will industry benefit from the eCTD? What challenges will the enterprise face in implementing electronic submissions? What steps should an organisation take now, to be ready for the CTD? These are questions facing many departments in organisations across the life sciences sector. Firstly, it is important to note that changing to the CTD is not optional since, in subscribing to the principles of the ICH, the three regions have mandated its use. Furthermore, to retain competitive advantage, industry will be forced to adopt the most efficient ways to achieve marketing approval. Increasingly, this will require the use of electronic submission technology. Thus, industry effectively has no choice but to use the CTD and the eCTD. This will affect the enterprise in several key areas.
Regulatory affairs
Restructuring MAAs and NDAs to the new CTD and eCTD formats will require substantial effort. The skills needed to create an efficient submission that will achieve early approval, will need to be revised to accommodate the new structures. Some aspects of the technical content will need to be redistributed across the submission, and care will be needed to ensure the submission meets the needs of the different regulatory bodies.
In some regulatory affairs departments, this will require only careful thought and planning. In others, standards and procedures may need to be rewritten to accommodate the new structures. Furthermore, the regulatory affairs professional must be ready to advise authors throughout the business on how to write their documents in a way best suited to the new standards.
The generation of the XML backbone is not a one-time occurrence. It must be updated throughout the full lifecycle of the dossier to record and provide the navigation through all communications between the submitting company and the authority, such as amendments and supplements. The backbone structure must also be capable of being modified should the eCTD specifications change over time (as they already have). Knowledge of XML on the part of the user should not be required to do this, a factor that should be considered when looking at tools to help in submitting a dossier in eCTD format.
Other considerations include the need to support and manage the process for taking selected components from one version of a submission to the next, and the ability to reuse documents between both the CTD and eCTD structures.
Business processes
The pharmaceutical industry is continually presented with opportunities to improve processes in response to regulatory authorities. The electronic Common Technical Document (eCTD) will be the defacto standard if not a mandatory requirement for all electronic submissions in the US, Europe and Japan. When the guidance for the eCTD was introduced, it was viewed as one of the most ambitious and challenging submission formats ever. Its scope addressed not just the original submission but all subsequent updates. Many pharmaceutical companies are embracing the eCTD as more than a cost of doing business but also a way to provide the valuable submission lifecycle information to manufacturing, marketing and clinical departments.
As the new requirements for document structure extend out across the business, in small companies the challenges will be met through analysis of the new document requirements and a change in authoring style to accommodate the new structures. In larger companies, however, tasks are shared out across departments and the process of writing a report or summary may be shared among several authors. Here it may be necessary to revise the business processes to support the new requirements. Authoring guidelines will require rewriting, and review and approval workflows may need to be revised.
An electronic submission needs extensive hyperlinking and cross referencing to allow an agency reviewer to navigate around the submission. Effective hyperlinks will mean easy access to the required information, and this in turn may speed approval. To create these hyperlinks efficiently, it is important that they are built into documents such as preclinical and clinical study reports when they are written, rather than at the end of the process. In this way, the electronic submission can be prepared in parallel to the paper CTD, thus reducing assembly time. To fully enable this, the hyperlinks created must be capable of being repurposed for both paper cross references and electronic hyperlinks required by the eCTD, without changing the source document.
With the change in who creates hyperlinks, from the regulatory affairs professional to the author, the tools used must also change to provide simple and intuitive mechanisms to help authors insert hyperlinks as the documents are written. In addition, when the author is writing a document, the need for a hyperlink may be obvious, but the destination document may not be written yet, or the author may wish to keep writing rather than pause to locate the reference. A mechanism is also needed by which the author may inform readers and reviewers of the need for a cross reference, and could also include a description to help identify which document is being referenced to help the completion of the cross reference prior to submission.
The eCTD impacts more than just the processes around the authoring and hyperlinking of individual documents, though. The eCTD also requires an understanding of content currency to be maintained throughout the dossier lifecycle. As amendments, supplements and variations occur in relation to the original application, the sponsor must keep track and report how previously submitted documents are affected. This enables a kind of current active view of the evolving dossier — showing just the documents that are still relevant at any point in time. Tying this submission lifecycle information to the content management system allows obsolete documents to be ignored, allowing users to focus on what is relevant.
But this will be a challenge. Dr. Andrew Marr, director of electronic documentation in European regulatory affairs for GlaxoSmithKline says, “Currently one of the greatest obstacles to the eCTD is managing all of a product’s lifecycle documents. Most companies have fully utilised their document management and publishing tools only in support of large applications. For the eCTD to be successful, companies must capture all lifecycle documents, including responses to questions, variations/ amendments, renewals, annual reports, and so on. Bringing all those under adequate control may be a challenge.”
Next steps
According to a paper by Blair and Yetter examining how the progress with the CTD is seen in the US and EU:
“The FDA feels that there is considerable benefit to be gained by the transition to CTD formatted marketing applications. It will allow a greater harmony between the NDA and BLA as mandated by the Food and Drug Administration Modernization Act of 1997. It will aid communication within FDA and between the agency and applicants. Finally, it is hoped that the more predictable application format will facilitate more consistent review and make analyses across applications easier.” (1)
Conclusions
Clearly there is much work to be done both in industry and by the regulatory agencies. However, the benefits are obvious, with a common approach providing great economies of scale and a shortened time to market share. Widespread adoption of the CTD and eCTD will require new tools and new business processes. It is imperative that life sciences organizations build a strategy for transition to the CTD and eCTD. Early adoption of new technology and processes will help ensure that the benefits are felt as soon as the CTD and eCTD submissions become strongly recommended, or more importantly, mandatory.
And, as the amount of compliance information increases, the ability to process it and manage it decreases. Yet this information is business critical, providing inter-departmental benefits if accessible and accurate. Life Sciences companies can look to evolving submission specifications to help internally manage document obsolescence associated with the regulatory product lifecycle. In particular, the eCTD provides a model for identifying relevant documents for a particular registration, even after years of maintenance.
Pharmaceutical Executive, “E-Ticket to Global Harmonization”, December, 2002
Jim Nichols
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VP, Product Strategy & Marketing Liquent, a Thomson Business |
1. Blair JW, Yetter RA (2002) Common Technical Document: The US perspective and the European perspective. Regulatory Affairs, Focus Magazine, March
