Global Regulatory Authorities Put Emphasis on Patients and Improved Processes


Applied Clinical Trials

Regulatory authorities around the world have worked over the past year to further streamline processes, with major markets making harmonisation and patient safety their priorities. Despite moves to bring countries closer on submission standards, regional differences remain.



The European Medicines Agency’s announcement in July 2011 that the EudraVigilance Medicinal Product Dictionary (EVMPD) would become mandatory underscored the importance that the European Parliament and the regulatory authorities were placing on patient safety. The introduction of the EVMPD did create some concerns for industry, from awaiting information in the lead-up to the July 2, 2012, deadline to some early discontent from companies regarding problems with the portal going down or timing out. With those issues mostly resolved, companies’ biggest concerns now lie in keeping the data up-to-date both internally and externally. The EVMPD guidelines state that any changes to data must be submitted within 15 working days, and companies are asking for clarification on what that means more broadly for the updating of information.

While there were some concerns that the European Medicines Agency would start asking for structured substance information, most companies say they believe the agency is unlikely to act on that until the Identification of Medicinal Products (IDMP) standards are issued. Currently, companies in Europe submit drug information through the EVMPD, while in the United States, such submissions are made through Structured Product Labeling Drug Listings and Establishment Registration. The purpose of both of these is to ensure accurate representation for each drug product and help quickly identify the responsible parties . An International Conference on Harmonisation (ICH) working group has been developing IDMP standards aimed at standardising the exchange of product information and the terminology related to products across ICH members. The IDMP standard recently was approved by the  International Organization for Standardization (ISO) but is not expected to be implemented until late 2014 or early 2015 at best.

The goal in part is to improve insight into where products are sold and used, in case adverse events or product recalls occur, and prevent counterfeit product from being distributed. That improved insight will be achieved through an ID number based on the approval number of a product in each ICH country.

Safety First Across the Globe

The emphasis on patient safety is also a top priority in Japan. The Ministry of Health, Labour and Welfare has formulated guidance around the development of a risk management plan, including efforts to reduce the risk of drugs, as an extension of the Pharmacovigilance Planning notification of 2005.

As of April 2013, companies filing approval applications for new drugs and follow-on biologics will be required to develop a risk management plan.

South Korea’s national regulatory authority, the Korea Food and Drug Administration (KFDA) is also looking to update the way it monitors drug safety. The plan is to adopt a Periodic Safety Update Report-based system in the next few years. As part of its realignment, the KFDA changed its adverse-event-reporting site in October 2012. (See

Meanwhile, in China, the State Food and Drug Administration (SFDA) seeks to monitor drug safety via modernised pharmacovigilance systems during the clinical period as well as for postmarketing surveillance. It is likely that with increasing awareness about drug safety, those systems will be in place within the next few years.

Patient Leaflets

The quality of patient information about pharmaceuticals has become a growing priority. To ensure that the language in patient leaflets is friendly, the European health authorities have developed strict guidelines to control the wording on packaging, in a leaflet or in promotional material. The goal is to have harmonisation across the European agencies, which while worthwhile, creates certain difficulties because not all wordings translate easily from one language to the next.

Other obstacles include Quality Review of Documents templates, which comprise the summary of product characteristics used by health authorities to determine whether the right information has been included before the content gets changed into patient-friendly language. Those issues don’t take into account the new guidelines on how patient information leaflets must be put together, and there are few signs that the health authorities are in a rush to make the changes needed.

Medical Devices

In light of growing pharma interest in delivery systems and because of scandals over breast implants, the European Commission issued a medical devices directive aimed at issuing stricter guidelines around medical devices. The European Union had been trailing its U.S. counterpart, and the directive is an effort to correct that lag. Changes will include stricter rules about how devices get made, sold and distributed; about the conduct of strict clinical trials and the production of evidence; and about pharmacovigilance reporting. However, the guidelines are not expected to be adopted by the European Union until 2014 and will not come into effect until 2015 to 2019.



The U.S. Food and Drug Administration (FDA) has made clear that it is moving toward mandatory electronic (specifically, electronic Common Technical Document [eCTD]) submission over the coming years through phased adoption. This falls under the Food and Drug Administration Safety and Innovation Act (FDASIA) and encompasses both mandatory eCTD drug submissions and acceptance of electronic submissions for medical devices. All New Drug Applications (NDAs) must be filed electronically by 2015, and by 2016 for all Investigational New Drug Applications (INDs). The phased adoption gives companies more time to adapt and reflects the fact that NDAs are being filed largely in eCTD format by drug sponsors, and INDs to a far lesser extent.

In Japan, the eCTD is still not mandatory; and some of the smaller and mid-tier companies have been slower to adopt the format. However, a notice from the Pharmaceuticals and Medical Devices Agency that it plans to shorten the review process has prompted more such companies to adopt the eCTD in the expectation that such adoption will drive an accelerated review process. Larger pharma companies have already been using the eCTD for three to five years.

The CTD has been in place in South Korea for some years and is the required submission standard for all new drug applications. It is anticipated that the KFDA will start requiring eCTD submissions from 2015.

As a department under  China’s SFDA, the Center for Drug Evaluation (CDE) promotes CTD-based dossier submissions, and the SFDA has the intention to make eCTD mandatory by 2015. However, CDE categorises chemical drug products into six groups ranging from a new chemical entity never marketed in any country to a drug substance or preparation involving minimal changes, and it has different policies on what formats are required for each. Fast-track review is generally granted to products involving minimal change. Paper-based submissions are still required.

Clinical Trials

Harmonisation is the European Medicines Agency’s goal with its clinical trials directive as it looks to change to how multi-country clinical trials will be managed. Currently, companies need approval from each European Union country in which they wish to conduct a clinical trial: not only from the national competent authority but also from ethics committees. The agency wants centralised approval of everything; however, companies are still awaiting details on how this will work.

Another aspect to the regulation is the fact that if the authorities neither approve a trial nor respond in a timely way, it implies tacit approval, which, again, aims at driving a streamlined clinical trial process across Europe. There is concern over the introduction of a European portal because of the dearth of information on what the platform will be and how it will be built. Currently there are two platforms in various stages: A common one for centralised procedures, and the CESP, designed for joint access by all of the participating agencies for national, mutual recognition or decentralized procedures,

FDA Module 1

Over the past year, the FDA has been developing guidance for Module 1 version 2. The biggest changes are the ability to submit promotional materials in electronic format and the introduction of grouped submissions, enabling companies to use one submission sequence to update multiple applications.

The biggest difference with the new version lies in how the new items added are structured. Rather than having a complex XML format with hundreds of different elements, there will simply be one element that identifies where forms go, where promotional materials go and so on; then there will be a keyword that states the kind of promotional material or the particular form being sent. This helps FDA and sponsors prepare for the concepts of eCTD 4.

The use of controlled vocabularies is the one other major change to Module 1, though its main impact will be the need for fewer software upgrades, because it should be possible to simply plug in the new version with the controlled vocabularies. These controlled vocabularies are used for metadata about the entire submission (application type, submission type, etc.), and for the keywords for the forms and promotional materials.


The electronic Common Technical Document version 4 (eCTD 4) has at last become a draft standard for trial use, which means the testing process can begin. The eCTD 4 began life as the Regulated Product Submission (RPS) at Health Level Seven International, and it remains based on that standard. The original incentive for RPS was to help the FDA cut costs, as well as simplify and reduce the number of systems it uses. When the ICH wanted to replace the eCTD, it made sense to adopt a standard already in development and simply make it an ISO standard, which it should be within 18 months.

The first country to implement the standard is expected to be the United States because the FDA will be the standard’s biggest beneficiary.


As regulators worldwide continue moving toward greater and greater standardisation and as emphases on patient safety continue, companies will need to pay greater and greater heed to how they manage their processes and to their levels of efficiency in handling submissions regionally and globally.

About the Authors

Joel Finkle is Senior Strategist for Regulatory Informatics within the Global Professional Services division of CSC Life Sciences.

Gillian King is Director of Global Consulting, Project Delivery and Standards, at CSC Life Sciences.

In addition, information on China and South Korea was supplied by Jeanie Kwon, director of Regulatory Operations; Paul Chung,director of Solution Practice, Regulatory Solutions Group; and Haedoe Lee, director of China Operations, all of them at CSC Life Sciences. Insights on Japan’s regulatory developments came from Kiyoshi Goho, senior consultant, Application Development, Health and Life Sciences Industries, Hewlett-Packard Japan Ltd.

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