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Facing the Challenges of Global Product Registration Robin Robinson One could say keeping track of global product registrations and staying compliant with regional and international regulations is more difficult than herding cats — if that common phrase used to describe a situation where numerous and competing elements that constantly change and need to be coordinated toward an uncertain outcome resonates with you. “One of the keys to success in global product registration involves establishing a filing and registration master plan,” says Henrietta Ukwu, M.D., senior VP and head of global regulatory affairs, PPD. “A forward-thinking master plan enables proactive engagement with all stakeholders, determination, and incorporation of unique agency requirements in the development plan to achieve target product profile (TPP), and a data readiness for filing and successful registration. However, customizing the registration materials to meet the requirements of each constituent can be resource intensive.” Dr. Ukwu notes that another important aspect of global product registration is the specific country/regional regulatory intelligence required to enable compliance with regulatory requirements and processes. “Critical to achieving this goal as well as local country/national regulatory agency engagement is the establishment of a trust-based relationship with the regulatory agencies,” she explains. “Therefore, having a local footprint and presence representing the global reach of the business is necessary. When a company doesn’t have that capability available directly, there are outsourcing opportunities with CROs that have both a global footprint, as well as a local presence in countries of business interest. This local presence provides up-to-date regulatory intelligence to ensure the evolving and dynamic regulatory environment is considered aptly and proactively in the product development and filing/registration plans.” Health economics assessment of the product value is an additional essential success factor. Dr. Ukwu points out that the importance of the link between the registration and the ability to access the market means expertise in health technology assessment should be available throughout development — not just at the time of licensure. This entails a health economics value proposition and a differentiation for the product profile that will satisfy reimbursement and payer criteria. This has become very important, especially as regulatory authorities and governments work together to find new ways to manage healthcare costs. Another important issue relates to the compliance of product labels to current regulatory requirements in the countries in which they are registered. “Companies with many products registered in many countries need to assure compliance to and consistency of product information and labels to current regulatory expectations,” Dr. Ukwu explains. “This requires periodic gap analysis with regulatory intelligence and gap remediation with the necessary variation filings across many regulatory agencies. Related to compliance matters are the automated systems used for tracking and maintaining data on registration status of the product across the regulatory agencies and their requirements.” Of the myriad challenges involved, our experts have identified three others that they consider to be the weakest links in an incredibly complex system — miscommunication, silos, and the disparity caused by electronic and paper systems. Good Communications Lead to Clearer Guidance The submission process is only as strong as its weakest link, so it is important that management communicates corporate goals and priorities frequently and without ambiguity so employees receive clear guidance as to where to focus their efforts. For larger companies with a broad portfolio of products, that direction may not be as easy to define; in small to midsized companies, this can be less of an issue because company priorities are usually self-evident. Additional considerations include increasing need for technical specialization in evolving/established areas such as biosimilars, adaptive trial design, personalized medicine, orphan drugs, pediatrics, use of companion diagnostics, and specialized products such as genetically modified organisms, Dr. Ukwu says. “As companies move into these product/ portfolio areas, the new regulations have to be understood a priori, and effective engagement with regulatory agencies is necessary to clearly define pathways imperative to product development and registration success,” she says. Silos Lock in Information According to Wim Cypers, VP of regulatory affairs at ArisGlobal, major challenges include the multiple and disparate silos of regulatory information created by the conventional approach to product registration management. The lack of transparency due to a disconnect between central regulatory affairs departments and local affiliates; R&D, manufacturing, clinical, safety-pharmacovigilance, and regulatory affairs teams within an organization increases the chance of errors and costly resubmissions. “The organizations that are able to address this challenge using a truly end-to-end, integrated regulatory information management and tracking system will be the leaders in the ISO-IDMP future of medicinal product regulatory affairs,” Mr. Cypers says, referring to the European Commission’s recent regulation mandating electronic submissions to medicinal products dictionaries for all medicinal products. Paper Records Make Tracking Difficult Despite the recent push in certain countries to move submissions to an electronic base, many countries have yet to accept electronic common technical documents (eCTD), and still require paper submissions. “Without the proper electronic data to track and manage submissions, it makes it incredibly difficult for companies to have an overall picture of their true global product portfolio,” says Jennifer Wemstrom, head of software solutions group strategy, CSC Life Sciences. Many pharmaceutical companies view data that are moved through local offices to be a significant risk, due to a lack of security on centralized systems and the difficulty in providing the proper oversight. “But our perspective is that the regional resources can be a benefit by providing real-time, accurate information with a proper electronic system and empowerment,” Ms. Wemstrom adds. The eCTD system promises to streamline the worldwide submission and product approval process and in regions where it is used — North America, European Union, Asia-Pacific — it has been very successful, Ms. Wemstrom says. However, when the number of countries where eCTD is not used is combined with the fact that the majority of submissions from large pharma companies are maintenance submissions on established products for product changes, the result is legacy formats that have not been converted to eCTD. Therefore, managing changes to existing registrations on a global level becomes a real challenge. For instance, Ms. Wemstrom says if a company using a paper-based system switches out just an inactive ingredient within an existing product, this single change will create complexity that grows exponentially because of the various different ways that change in information has to be submitted. “Such an ingredient change can be managed electronically in North America, but will have to be done via paper in Greece and Turkey,” Ms. Wemstrom says. “A company in this situation cannot electronically track and manage the full scope of even this small change.” Not many companies have a true picture of their global registrations and rely on local offices and affiliates to ensure compliance. This discrepancy is not likely to be resolved anytime soon, especially since most companies today have a hybrid of several custom systems and databases and manual processes. “Flexible, configurable systems that can be easily changed without significant impact to the business are a must,” Ms. Wemstrom says. “In addition, the systems must be easy enough to use so that local offices can access and utilize the centralized system with minimal training.” Implementing such a system would certainly solve a large portion of the problem, but for the foreseeable future, the paper aspect will continue to be managed manually. Other Challenges There is no lack of challenges in the global product registration process. The word myriad hardly covers the scope of them all, but here are a couple more our thought leaders have highlighted as some of biggest hurdles for the industry. They include the ever-changing regulatory environment as well as the ever-changing process environment. According to ArisGlobal’s Mr. Cypers, within the past two years, the regulatory environment across the globe has been going through a generational change. The more regulations that a company needs to deal with, the less visibility the company has into local affiliate regulatory planning and activities. This is a major challenge for organizations that file often in separate jurisdictions. One of the key challenges that the product registration management process is facing stems from the European Commission’s recent regulation mandating electronic submissions to medicinal products dictionaries for all medicinal products. This global convergence is creating a massive shift in regulatory and is referred to as the European Medicines Agency’s Extended EudraVigilance Medicinal Product Dictionary or simply, XEVMPD ISO-IDMP. This represents the first step toward global adoption of ISO IDMP (Identification of Medicinal Products) standards in support of ICH M5 by 2015–2016. Changes in regulations require changes in procedures, but the regulations change faster than the procedures can keep up with them. Due to system rollout expense and system validation requirements, pharmaceutical companies in general are slower to upgrade their systems in comparison with other industries. While these changes from the various health authorities and expert working groups are in general based on lessons learned with the intention to improve the process, the rate at which pharmaceutical companies can implement these procedures from both a process and technical perspective means at times these procedures won’t be implemented for very long before a new one comes out, Ms. Wemstrom says. “Pharma companies and software vendors alike are in a constant state of chasing the guidance, meaning that by the time a procedure has been implemented, a new one will emerge or an existing one will change,” she says. Early futility assessment and applying rigorous competitive evaluation of an asset to make rigorous and appropriate decisions on product progress or exit can be challenging, Dr. Ukwu says. “A significant number of products fail in Phase III,” she says. “Of those that progress to regulatory review, there are equally significant regulatory review failures and/or delays. To effectively address comprehensive and robust product development and regulatory strategy, companies may benefit from an independent regulatory and product development strategic review of their product performance at earlier stages involving competitive benchmarking to alternative and similar therapies approved and in development. The outsourcing of this effort to CROs provides objective consideration of the go/no-go decision points.” Solutions to Meet the Challenges Savvier companies are treating these challenges as opportunities to improve processes and prepare themselves for the future. “Companies that treat the regulatory challenges as an opportunity and make informed and bold decisions will be stronger,” Mr. Cypers says. ArisGlobal has observed many companies following common steps in the areas of business, regulatory, and IT systems to ensure better outcomes during product registration. Dr. Ukwu suggests maintaining a master Gantt chart of activities, milestones, timelines, and a calendar of planned submissions with regularly scheduled updates to maintain a unity of direction. “This document serves to inform all stakeholders of what is in the pipeline for submissions and when those submissions will occur so that resources can be planned accordingly,” she says. Outsourcing is another way to meet the challenges of the submission requirements when internal resources can no longer sustain the workload demands and the complex activities necessary to keep all submissions on track. Many companies are using a blended model in which new submissions, such as new drug applications, marketing authorization applications and Japanese new drug applications, are handled in house, Dr. Ukwu says, compared with postapproval/postmarketing submissions, such as pharmacovigilance, clinical trial applications to support new indications, or product line extensions, Phase IV studies, and registries that are being outsourced. Dr. Ukwu also stresses that in today’s environment, specific technical regulatory affairs expertise is highly valuable, so companies have to determine whether to develop existing staff in these areas or to buy these services. “There is an increasing need for technical specialization in evolving/established areas such as biosimilars, adaptive trial design, personalized medicine, orphan drugs, pediatrics, use of companion diagnostics, and specialized products like genetically modified organisms,” she says. “As companies move into these areas, the new regulations have to be understood a priori, and effective engagement with regulatory agencies is necessary to clearly define pathways imperative to product development and registration success.” “A filing and registration master plan is key to success in global product registration. ” Dr. Henrietta Ukwu / PPD “Companies that treat regulatory challenges as opportunities and make informed and bold decisions will be stronger. ” Wim Cypers / ArisGlobal “Pharma companies and software vendors alike are in a constant state of chasing the guidance. ” Jennifer Wemstrom / CSC Life Sciences Experts Wim Cypers. VP, Regulatory Affairs, ArisGlobal, a provider of integrated software solutions for pharmacovigilance and safety, regulatory affairs, research, and medical. For more information, visit arisglobal.com. Henrietta Ukwu, M.D. Senior VP, Global Regulatory Affairs, PPD, a contract research organization providing drug discovery, development, and lifecycle management services. For more information, visit ppdi.com. Jennifer Wemstrom. Head of Software Solutions Group Strategy, CSC Life Sciences, a provider of regulatory software and services for the life-sciences industry. For more information, visit csc.com or email email@example.com.