Taking On The World: Harmonization Is Not Always Simplification
By Kate Wilber
Simultaneous multimarket entry is a growing reality for the pharmaceutical industry as regulatory agencies worldwide move to further standardize the format and structure for submissions. But while advances in the standardization of formats for regulatory submissions are providing global life sciences companies with new market opportunities, there is still a long way to go to reap the full benefits.
Beyond the U.S. market, where the electronic common technical document (eCTD) has been accepted by the FDA since January 2008, the regulatory environment remains complex and inconsistent. Outside the United States, submissions requirements still vary considerably from one country to the next, especially across Europe where there are multiple procedure types — the centralized procedure, mutual recognition procedure (MRP), decentralized procedure (DCP), and national procedure. Adding to the complexity is another popular submission format, the non-eCTD electronic submission or NeeS. 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 license 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). These factors render the situation challenging, particularly in local markets that typically have small staffs — sometimes no more than just a few people — who wear multiple hats.
Consider that many large biopharma companies could have as many as 100 operating companies or affiliates all over the world, which are now being asked to shoulder a larger responsibility for regional regulatory filings. Since limiting the market opportunity is not a desirable option commercially, pharmaceutical organizations have little choice but to reduce the boundaries and introduce new efficiencies to their international regulatory submissions activities — measures that take into account country-specific differences in requirements and the potential administrative burden on local affiliates.
A Call For Collaboration
The growing importance and the changing nature of these affiliate relationships are widely accepted. In a Gens and Associates Inc. survey called 2008 eCTD Organizational Implications, 86% of respondents said the changing relationship will require closer collaboration. Changes affecting the relationship, according to respondents, included life cycle management (79%), the shift from paper to electronic documents (79%), and the evolving roles and responsibilities associated with the eCTD (79%). All of this has a strong bearing on how companies manage their relationships with affiliates and on the strategies they adopt with regard to regulatory submissions.
When it came to managing a core application for global submissions, Gens and Associates found a more centralized approach in Europe and a more decentralized approach in the United States. To delve more deeply into the issue, earlier this year ISI conducted research with a small group of its big pharma clients, and 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 such as the changing relationships between headquarters operations and affiliate or local operating companies, the goal of simultaneous (or almost simultaneous) global submissions, transparency and consistency of regulatory submissions, and the move to eCTD and life cycle management.
Asked to outline their current situations, the panelists painted a picture of various models in play: a centrally managed model where headquarters determines the technology and processes and is responsible for coordinating efforts, a collaborative model where there is an exchange of information between headquarters and the affiliate, and a “dispersed” model in which the affiliate is ultimately responsible for modifying/amending the master dossier and submitting it to the local health authority. Within these models, panelists described a host of considerations, challenges, and new opportunities.
Allowing For Affiliates
No model is without its challenges, as the panel noted. These included, significantly, how to address the particular needs of local affiliate companies. As one panelist put it, “A lot of the components are generated centrally and then pushed out to the affiliates; after that, it’s up to the affiliates to complete the dossiers. I’m a big advocate for centralization, not only from the perspective of the assembly, oversight, and provision of tools, but also with regard to regulatory tracking and archiving all the information. We are looking more toward a centralized model, but there are challenges to that.”
To overcome some of the challenges of a centrally managed model, one panelist described an effort to develop a centralized repository. “Three years ago we developed a dedicated ‘eRoom’ to which the affiliates have access as a way of preempting new versions of document management systems. Through this effort, we wanted to create more of a collaborative approach versus the perception that we were throwing content at affiliates. In this model, there’s an exchange of information. There are some network issues and file size issues, but we’ve managed to work through that. This effort has definitely improved our processes and working relationship with our affiliates.”
Another panelist suggested that within the EU a mixed model may be appropriate “where the centralized procedure, the decentralized procedure, and the mutual recognition procedure are all managed centrally, because of the way the eCTD works within those processes.” When it comes to the national marketing authorization application procedure, however, it makes more sense to decentralize the process, he suggested.
Others argued that, certainly from a software hosting perspective, adopting a centralized approach was the most practical approach. “Trying to manage this aspect from our country affiliates would be a nightmare, so having the software and tools maintained from a central point makes the most sense,” was one comment. “On one hand, much of the submission preparation and filing may also be conducted from publishing centers. On the other hand, however, the affiliates have the local knowledge, so they need to prepare their part of the submission.” The difficulty with this, the panelist elaborated, is ensuring that those affiliates — which may comprise just two or three people — know how to use the tools and technology.
The panel agreed that the more that is being handled at the center, the greater the need to control how that is managed and for this to be user-friendly. “It has to be simple so someone off-site can get access and find their way around,” as one member put it. “We develop in parallel in the United States and the EU, which applies to our regulatory filing procedures, too,” said another. “We have market regulatory people on the ground to manage registrations in a variety of places: in five European centers and then regional centers including Canada, Australia, and Singapore. This means flexibility is key: having the platform independence to enable us to conduct centralized publishing but also having a hosted platform to accommodate the regional centers.”
Regardless of model, managing the submission life cycle needs to be paramount to any strategy. “What has been the most incredible challenge — and remains a challenge — is understanding the philosophy behind the eCTD,” said one panelist. “Building the eCTD is no big deal. Maintaining it, anticipating it, getting all relevant players involved — that’s the challenge. In today’s complex development environment with various external vendors and partners, it’s challenging to align all parties to ensure the eCTD can be continuously maintained.”
About The Author
As Director of ISI’s European Regulatory Services, Kate Wilber helps global pharma and biotech companies overcome the complex EU regulatory environment. She is the former Senior Global Regulatory Operations Manager at Shire Pharmaceuticals.