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Pharmaceutical Technology Europe
EMA has been increasing its interactions with other regulatory agencies across the globe. The agency's most talked about collaboration is with FDA, but EMA has also been intently focused on bolstering its relationship with its counterparts in Japan, India and Russia.
To fulfil its duties, EMA works closely with several European organisations, including the European Commission, the European Parliament, the Council and Presidency of the EU and numerous national bodies in individual member states. EMA also cooperates with decentralised agencies of the EU, such as the European Centre for Disease Prevention and Control, the European Food Safety Authority, the European Environmental Agency and the European Monitoring Centre for Drugs and Drug Addiction. In recent years, however, EMA has placed a growing emphasis on collaborating with international pharmaceutical regulators in areas such as inspections, safety of medicines and exchange of information on issues of mutual concern (1, 2). This focus is to ensure a more global approach for the manufacture and supervision of medicinal products in the long term.
EMA's collaboration with the US FDA tends to receive the most media attention, but the European regulator has also been increasingly interacting with its counterparts in Japan at the Ministry of Health, Labour and Welfare (MHLW) and the Pharmaceutical and Medical Devices Agency (PMDA).
The Japanese regulators have been very committed to improving their relationship with both EMA and FDA following criticism from the pharmaceutical industry regarding a perceived time lag in Japan in the approval of new drugs and medical devices compared with the EU and the US (3). These perceptions have led some manufacturers to delay their submissions to Japanese regulators. For example, applications for an estimated 69 new active substances were submitted between 2002 and 2011 to regulators in the US, EU and Japan. Approximately 77% of these were submitted to PMDA more than one year after submission to EMA or FDA (4). Japanese regulators seem to have realised that it is imperative they improve their international standing.
Confidentiality agreements between EMA and its Japanese partners have been in place since 2007, and were recently extended for a further year in July 2012. Such agreements facilitate the exchange of confidential information between the agencies as part of their regulatory and scientific processes. Shared information may include advance drafts of legislation and regulatory guidance documents, as well as non-public information related to ensuring the quality, safety and efficacy of medicinal products. EMA personnel also meet regularly with their counterparts from the MHLW and the PMDA.
In November 2009, Japan sent a Liaison Official to EMA's offices as a pilot exercise. In July 2012, a report was published by EMA concerning the progress in collaboration that had been made since the appointment (5). The Japanese representative meets weekly with EMA's International Liaison Officer to discuss ongoing activities and areas that need to be addressed. Interactions facilitated by Japan's representative have covered a number of different specialist areas, including advanced therapy medicinal products, pharmacogenomics and biomarkers, paediatrics, orphan drugs and nanomedicines (5–7).
It was concluded that the placement of the Japanese representative at the EMA has been extremely beneficial in terms of education, proactively raising awareness of possibilities for collaboration and the general timeliness of inter-agency communication. Although the EMA has not yet appointed a Liaison Officer to PMDA or MHLW, such a move seems likely in the future.
Cooperation between Europe and Japan has been particularly beneficial in the area of advanced therapy medicinal products. Staff from PDMA attended EMA's Committee on Advanced Therapies (CAT) Workshop on Stem-cell based Therapies, followed by the CAT plenary, in May 2010, and provided input from their perspective on a draft reflection paper on stem cell-based medicinal products. Since then, PDMA has proposed additional collaboration in the area of cell therapy (5). Through a joint EU–FDA–PMDA regulatory mechanism, PMDA has also participated in scientific advice regarding renal toxicity biomarkers.
Rare diseases have also seen much interest from both regulators. MHLW sent an external expert to EMA as part of a visiting expert programme between September 2010 and March 2011 (5). The representative was embedded in the Orphan Medicines Section of EMA and provided information to EMA's Scientific Committees and staff members. This initiative has led to better information exchange between the agencies on the outcomes of orphan medicine designations in each region (7). It has also focused attention on practical measures, such as the provision of information from the Japanese regulator in English. Regular telephone conferences are now held, usually on a quarterly basis, to discuss orphan drug topics.
EMA's most long-standing and well-documented relationship is with the FDA, with which it has had confidentiality arrangements in place since 2003. These arrangements became effective for an indefinite amount of time in September 2010. The increases in interactions between the two agencies have been driven by the Transatlantic Administrative Simplification Action Plan, which was established in 2007 to remove the administrative burden involved in interactions between regulators in Europe and the US (8). The initial plan outlined several projects, including collaborations on inspections (including in third countries), combating counterfeit medicines, safety reporting from clinical trials, exchange of information regarding policies to promote innovation in drug development, the development of biomarkers and joint agency validation of these with respect to product development and recommendations for advanced therapy medicinal products. An additional boost to cooperation was the appointment of a permanent representative from FDA to EMA's office in London in 2009. In 2010, the EMA followed suit with a permanent representative at FDA. One of the most recent initiatives was launched in January 2012 to share work on inspections of manufacturing sites in each other's territories. The general approach will use information exchange for sites and will generally focus on sites that are known to both agencies and that have a history of satisfactory GMP compliance (9).
In addition to the US, EMA also has long-standing agreements with partner regulatory bodies in Canada, Switzerland, Australia and New Zealand, and supports the European Commission's collaboration on pharmaceuticals with China, India and Russia. In 2010, EMA and the Chinese State Food and Drug Authority (SFDA) also agreed to cooperate on GMP and GCP inspections. In addition, EMA provides SFDA with support for training and capacity building activities at their request.
Another important partner for EMA is the World Health Organisation (WHO), with whom it works on projects concerning medicines intended for markets outside of the EU, the quality of medicines and the development of international non-proprietary names (INNs). EMA provides support to WHO to assist in capacity building for regulatory bodies in emerging markets, and also participated in the WHO's "make medicines child size" initiative, which first launched in December 2007 (10). Few essential medicines exist in child-size dosage forms and there is often insufficient information about the paediatric use of such medicines. The EMA-backed initiative has identified certain research, development, regulatory, legislative and supply gaps that need to be addressed to ensure that children receive appropriate medicines, at the right dose and with enough supportive information for the prescriber. The priority areas for the initiative are HIV/AIDS, malaria, pneumonia, tuberculosis and diarrhoea.
In India, EMA works with regulators for the application of international standards in manufacturing and clinical trial activities with Indian regulators are invited to the agency's annual good-clinical-practice (GCP) inspector training. Indian regulators are under considerable domestic pressure to improve clinical trial standards in the country. In 2011, it was estimated that there were 438 deaths associated with clinical trials (11). Indian regulators have been attempting to strengthen their clinical trial regulations as a result, but critics continue to argue that their efforts are insufficient (11). Because many of the clinical trials in India have foreign sponsors, including some of the world's major pharmaceutical companies, Indian regulators are seeking advice from EMA and other bodies with long-standing experience in the field.
The EMA's work with Russia is part of the European Commission's existing arrangements with the country in the area of pharmaceuticals. In 2007, a dedicated EU–Russia regulatory dialogue subgroup on pharmaceuticals was launched and the EMA gets involved when there are scientific or technical issues to discuss.
Looking forward, EMA says that it views international cooperation as a core activity (2). Its current international strategy aims to improve communication and create synergies through collaboration with its partner regulators (2). Important international activities, in particular, include forming mutual-recognition agreements (MRAs) and other complementary arrangements.
As drug development occurs in an international environment, regulatory agencies must collaborate and there is renewed focus on such interactions through dedicated strategies formalising the processes involved. Regulators in all regions are also under increased pressure to improve their performance, but as public bodies they have limited resources at their disposal. Another reason, therefore, for the interest in regulatory collaboration is the ability to learn from the experiences of counterpart agencies, as well as avoiding duplication of work and facilitating synergic activities.
1. EMA website, "Partners & Networks," www.ema.europa.eu, accessed 7 Sept. 2012.
2. EMA website, "Road Map to 2015," www.ema.europa.eu, accessed 7 Sept. 2012.
3. K. Tadano, "PMDA's International Strategic Plan and its Implementation" (PMDA website), www.pharm.kitasato-u.ac.jp, accessed 7 Sept. 2012.
4. Centre for Innovation in Regulatory Science (CIRS) website, "May 2012 Slide of the Month," http://cirsci.org, accessed 7 Sept. 2012.
5. EMA website, "Report on interactions between the Japanese Ministry of Health, Labour and Welfare (MHLW)/Pharmaceuticals and Medical Devices Agency (PMDA) and the European Medicines Agency (EMA)," www.ema.europa.eu, accessed 7 Sept. 2012.
6. Y. Hayashi, "EU, USA and Japan (II)– Reports from Regulators on Exchange Assignments" (PMDA website), www.pmda.go.jp, accessed 7 Sept. 2012.
7. EMA website, "European Union — Japan orphan medicines cooperation". www.ema.europa.eu, accessed 7 Sept. 2012.
8. EC website, "Medicines Regulation: Transatlantic Administrative Simplification Action Plan," http://ec.europa.eu, accessed 7 Sept. 2012.
9. EMA website, "Enhancing GMP Inspection Cooperation Between the EMA and FDA," www.ema.europa.eu, accessed 10 Sept. 2012.
10. WHO website, "Essential medicines for children". www.who.int, accessed 7 Sept. 2012.
11. E. Silverman, "Clinical Trial Deaths In India Dropped" (Pharmalot website, 2012), www.pharmalot.com, accessed 7 Sept. 2012.