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One promise of a common standard for electronic submissions has clearly been new market opportunities in the form of simultaneous or multi-region submissions. But while advances in the standardization of formats for regulatory submissions are providing global life sciences companies with new opportunity, there are also associated challenges as they struggle to empower their local operating companies or affiliates to make local regulatory filings by reusing content from headquarter-created Master Dossiers and incorporating local requirements.
Follow the bouncing ball
Consider that a typical big pharma company may have as many as 100 operating companies all over the world managing registrations in various formats—the electronic Common Technical Document (eCTD), paper, and Non-eCTD electronic submissions (NeeS). The eCTD is the preferred format for submissions by U.S. FDA as of January 2008. Meanwhile, when the International Conference on Harmonisation—an organization representing the U.S., Europe, and Japan—sought to standardize pharmaceutical product registrations in the eCTD format several years ago, NeeS was introduced in Europe as a temporary, hybrid format, to ease the transition to full eCTD-standard electronic submissions. The approach has become so popular among European national agencies and local operating companies that the format is now expected to remain valid for several years to come. This is contrary to the initial expectation that NeeS-based licence applications would be phased out by the end of 2009, in preparation for full eCTD adoption. In fact of all submissions made to EU agencies in 2008, 43% were electronic (3% eCTD and 40% NeeS).
This tenuous balancing act also includes various procedure types being accepted in Europe—the Centralised Procedure, Mutual Recognition Procedure (MRP), Decentralised Procedure (DCP), and National Procedures. Complicating matters, the European Medicines Agency (EMEA) has plans to accept electronic submissions only in eCTD format beginning January 2010 for the Centralised Procedure, but the numerous countries that make up the EU are at varying points in their move to electronic submissions, making NeeS a more viable route for some non-Centralised products.
Each EU procedure type is intended for a different outcome:
• Centralised Procedure: An approval for a medicinal product intended for use in all EU countries may be obtained by applying to the EMEA. Centralised procedure is mandatory for certain types of products, such as products that address an urgent health issue, most biologics, vaccines, etc. Other types of products may be filed through the Centralised Procedure with prior approval from EMEA.
• Mutual recognition may be used to leverage an existing license in one EU country (called the reference member state or RMS) to expand to other EU countries. The full application will be provided firstly to the RMS and following approval, to the remainder of the desired EU countries. The RMS approval should in principle be mutually recognised by the other markets, however each market has the ability to raise their own questions.
• The Decentralised Procedure is used for products that have not yet received authorisation in any EU country. The concept of DCP is very similar to MRP, however the evaluation of the application by the reference and concerned member states occurs in parallel.
• National Procedure is a product registration that is only valid in a single EU country.
And beyond the EU, companies are preparing for emerging and expanding markets where acceptance of the CTD common dossier content is becoming more prevalent, electronic submissions are the next step forward and where they can tap into large patient populations.
Various models in working with local affiliates
Nearly every pharmaceutical company has a different model, strategy, and approach to local market submissions. Most fall into one of three categories: the centrally managed model where headquarters determines the technology and processes and is responsible for coordinating efforts; the collaborative model where there is an exchange of information between headquarters and the affiliate; and the dispersed model in which the affiliate is ultimately responsible for modifying/amending the Master Dossier and submitting to the local Health Authority. Within these models there are a host of options on how much the affiliate contributes.
Decision points for companies must include infrastructure, the technology platform to build eCTDs (shared system or local deployments), those who support those systems, and those who support the business process. Other sticking points that might arise include acceptance or preference for eCTD at the local level, language barriers, locating regulatory experts in some countries, and increased complications surrounding the lifecycle management of the eCTD, especially since companies need to track all of the sequences of a submission. Local offices typically have small staffs with sometimes no more than just a few people who wear multiple hats. There could also be third party contractors that are doing some of this work on the company’s behalf. There are some larger affiliates in more established markets like Spain, Germany, or the UK, that may have enough staff to fill the gaps. With this in mind, companies may pursue a different strategy across EU affiliates as well as emerging markets.
The growing importance and the changing nature of these affiliate relationships are widely accepted. In the Gens and Associates Inc. survey, 2008 eCTD Organizational Implications, 86% of respondents said the changing relationship will require closer collaboration. Changes affecting the relationship, according to respondents, included lifecycle management (79%), the shift from paper to electronic submission (79%), and the evolving roles and responsibilities associated with the eCTD (79%).
But relationship and culture are just one aspect of a highly complex business process. As stated, companies must also consider the various procedure types in Europe. In fact, company-working models are being driven by type of procedure. For the Centralised Procedure, for example, affiliates are typically involved with local language translations, but that affiliate would not be involved in the marketing authorization process for a centrally registered product. In the other procedures, companies may provide a master dossier to the affiliates who would then in turn add in their documents and pass along to the Health Authority. Finally, some companies require their affiliates to post their content to a central document management repository where a dedicated headquarters’ group does the final compilation. Regardless of model, the affiliates are increasingly actively engaged from a content perspective.
On the national level, there is more autonomy when it comes to affiliates. Sometimes, submissions are managed solely by the affiliate where there is no oversight or contribution by the headquarters’ operation, and sometimes there is a master dossier from which the local team makes significant changes.
All of this has a strong bearing on how companies manage their relationships with affiliates and on the model they adopt with regard to regulatory submissions—whether centrally managed, collaborative, dispersed, or a mix. In September 2009, ISI hosted its annual conference, eSolutions, in Barcelona, Spain, where it convened a panel of industry experts who discussed a range of topics: 1) relationships between headquarters operations and affiliate or local operating companies—relationships that are rapidly changing due to globalization; 2) the goal of making simultaneous (or almost simultaneous) global submissions; 3) transparency and consistency of regulatory submissions; and, 4) the move to eCTD and lifecycle management.
Key fundamentals in multi-market submissions
While presenting organizations Roche, Sanofi-Aventis, and Johnson & Johnson all had varying views on how to best manage the submission process globally, all agreed on some essential considerations:
• Map your business process through a collaborative process with your affiliates; there are very specific process issues to be considered.
• Undertake a cost analysis: determine the most cost-effective process given the company’s pipeline growth, goals for new markets, and cost constraints and then estimate the best path forward—whether a totally outsourced approach or an internally built capability.
• Whatever the model, don’t jump, explore doing a pilot first to test both the process and the tools you’ll be using. Evaluate the various technology options (e.g., a hosted systems, locally deployed software, etc).
• Figure out how you will manage life cycle management at the corporate level right from the start. • Conduct a thorough resource planning exercise to estimate whether you will need additional resources, particularly if your company plans to centrally manage the process.
Kate Wilber, Director of Regulatory Services, ISI Europe.