The life sciences industry is accustomed to waiting. The process from molecule to market can take upwards of ten years, and many factors can limit progress along the way. But with appropriate technology platforms and architectures in place and greater cohesion around guidances and standards, momentum can be gained in a number of areas, including the regulatory process.
In an effort to create greater cohesion and harmonise the submissions for approval of investigational products, an expert working group from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has developed standardised specifications for the electronic common technical document (eCTD).
The ICH is the standards-setting body for a number of initiatives aimed at improving the global regulatory process by establishing common guidelines. The ICH has developed guidelines on the structure of an eCTD submission with each submission containing many documents, including forms, reports, and data sets.
However, practical application and experience from speakers at the recent ISI eSolutions conference, an industry event that brings together industry luminaries, regulators, and company decision makers, shows transitional ‘best practices’ require sustained communication and negotiation between all the functional stakeholders within a company.
One overriding theme is that submission standards must start at the beginning of the molecule-to-market process. No longer can the regulatory function be charged with submission delivery standards as these are a direct result of the process before standardisation and data point communication is evolving and transparency across time and functional groups (for example CDISC and ICH Naming Convention). Re-purposing and re-use across time and regional borders is an area each individual functional group and company aspires to improve.
Regulatory agencies and eCTD
While the aspiration of regulatory standardisation has been touted, agencies are far from fully achieving that ambition, and that has been a source of frustration for industry. The EU has four diverse procedures in place for marketing authorisation of a medicinal product – the centralised procedure, the decentralised procedure, the national procedure, and the mutual recognition procedure – the environment looks complex.
The complexity of the European landscape, with its many member states and the fact that a move away from paper as the official means of submission may require a change in the law, means change is more gradual. While the future emphasis is emphatically on electronic submissions, industry and agencies alike are attempting to gain experience in electronic submission processing and review.
While paper is still a requirement and cannot be discounted at this stage, it can however be downgraded to the status of a delivery mechanism, akin to the decision for electronic delivery on CD, DVD or via an agency Gateway. The paper output, therefore, becomes a post-eCTD process, minimising business risk at the critical end point of the project.
The subtle shift enabled by solutions today is the change from starting the submission build point with an aim of paper to building as an eCTD whereby paper becomes the negotiable, output format – not the determinant influence on the starting point. In this way the lifecycle management is expedited and more easily manageable. This same approach lends itself to the many different interim states prior to a fully compliant eCTD and is outlined below.
Many member states are aggressively moving toward implementing the eCTD – albeit with provisions. For example, Belgium has made the eCTD the recommended type of electronic submission, but also accepts NeES (Non eCTD Electronic Submissions).
Other agencies also continue to allow other electronic formats, while the preference is clearly for the eCTD. The Netherlands’ regulatory body, the Medicines Evaluation Board Agency (MEB), has specified that companies submitting marketing applications in the Netherlands are not required to submit paper copies along with an electronic submission ‘if appropriate file formats are used and the electronic submission complies with the general and specific requirements’ that the agency stipulates in its guidance document on electronic regulatory submissions. The agency also accepts hybrids. The MEB has, in fact, been ahead of many other agencies in the electronic reviewing process. Still, it has flagged its intention to go with the model adopted by the UK’s Medicines and Healthcare products Regulatory Agency (MHRA).
MHRA, meanwhile, is demonstrating a definite preference for eCTD submissions and has stated that the import of eCTDs is much less complicated than the import of other submissions, or of paper. A possible inference is that paper-based submissions could even see a delay before review, and they will need to be converted to electronic to streamline the process. While the preference is eCTD, the MHRA model accommodates national specifications for electronic submissions not consistent with the eCTD format, and so, companies submitting electronically but not using the eCTD format still need to adhere to a certain structure and naming convention.
Preparing for change and the eCTD
The transition to eCTD requires more resources and a closer look at enterprise processes so that efficiencies can be gained from the start. For companies to achieve maximum benefit from their investments and to speed the overall submission process, they need to consider incorporating submission-ready tools into the earliest phases of drug development. Solutions, tools, and templates must also be scalable so as to grow with the enterprise.
Further, a defined set of goals and processes as well as the technology infrastructure must be in place at the outset so as to deliver on expectations. While the solutions should be designed to streamline processes and decrease time to market, implementing the solution and/or service must occur in dramatically shorter timeframes.
Best practices and approaches
There is no one-size-fits-all approach to moving to the eCTD format. Many companies find that while they do have extensive in-house IT resources and capabilities, they prefer to outsource the systems that manage the eCTDs through a software-as-a-service (SaaS) model, while others are outsourcing the eCTDs in their entirety. Some companies are taking a strategic approach, and others are directing initiatives more centrally.
According to industry presenters at the ISI eSolutions conference, the main change over the past two years is the shift from an initial focus on identifying a product for eCTD, to first enabling the business processes and selecting the right tools.
There are five best practices to follow in making the move to eCTD:
1. Confirm business needs. There are clear advantages to a centralised architecture in terms of ensuring that databases and a content management system are not replicated, but this can be an expensive exercise. Any decision must be well considered and take into account user requirements for meeting both regulatory expectations and enhancing the business process. These might include regulatory tracking, electronic document approval, easy-to-use search criteria, and tools to ensure integrity of data after revisions.
2. Determine system requirements. Establishing an organisation’s requirements – both short- and long-term – will help define the architecture that will best fit the enterprise’s needs. A company might start with a simple architecture, with the option to upgrade to a global solution at a later stage. Or, if large, multi-region submissions are imminent, it may be prudent to deploy a system capable of managing a huge volume of documents. Content management systems that are tightly integrated with publishing systems can also help ensure that documents authored in the earlier stages of the drug life cycle can be used at later points in the submission assembly process, thus creating a single, scalable system for managing all regulatory documents, for responding to changes, and for publishing submissions.
3. Involve key stakeholders. Identify as early as possible all of the organisational stakeholders – IT, regulatory, validation, and vendors – that are involved in the process change, so they all have input in the system that will be put in place, questions and concerns are ironed out before implementation, and enthusiasm for the change is built and maintained. Incorporating internal functional experts early on can be critical to success because they can answer questions pertinent to their functions and advise on how documents and data should be collated, where they should fit, and what the agencies will be looking for.
4. Consider redesigning business processes. Time also needs to be devoted to redesigning internal business processes and the work flow that supports those processes; for example, ensuring integration between technology platforms; ensuring that information on regulatory guidelines and regulations, as well as changes to the submissions process, are made known and are embraced by all groups; and also ensuring not only that the lines of communication between functions are open but also that there is a mechanism in place for this collaboration.
5. Centralise IT. Some companies have made progress by merging IT into a single
enterprise group and ensuring that all documents from every part of the company go into a central repository. One top 10 pharmaceutical company that conducts research globally has found that having a single tool set that can integrate the various submission formats – paper, hybrid, electronic common technical document, and non-electronic common technical document electronic submissions – is highly valuable. This capability comes from a desire by companies to have a single process to build submissions (all formats) in a single user interface and then make the business choice to output format.
Peter Reynolds is European Regulatory Market Specialist with Image Solutions Inc, based in Almondsbury,
Bristol, UK. For more information, visit www.imagesolutions.com