Overarching Trends and Concepts

Transcription

1 SWISSMEDIC S PETRA DÖRR ON INTERNATIONAL REGULATORY COOPERATION At EDQM s international conference, held in Tallinn, Estonia in late September 2016, Swissmedic Deputy Executive Director Petra Dörr reviewed the progress the global regulatory community has made in advancing international cooperation and harmonization and the organizations driving the progress. Her talk encompassed: the overarching trends and concepts, including a discussion of the three levels on which international cooperation takes place harmonization of requirements, reliance and work-sharing, and recognition the multilateral initiatives ICH, ICMRA, IDGRP, and IPRF, and the role of EDQM. Thank you [Moderator Jean-Louis Robert, Head of Luxembourg s Official National Laboratory] and also thanks to [Estonian State Agency of Medicines Director General Kristin Raudsepp] and [EDQM Director Susanne Keitel] for inviting me and giving me the opportunity to cover some aspects that go beyond the European Union even beyond the European continent borders. Susanne mentioned in her introduction that we need to set the right priorities in order to make optimal use of our scarce resources. And also Kristin mentioned that the challenges can only be addressed in collaboration. So this sets the theme for my presentation, which I am going to structure in four chapters: I will show you some overarching trends and concepts that, as I said, go beyond Europe. I will give you an update on some of the multilateral initiatives that are ongoing in the area of cooperation, convergence, harmonization, and work-sharing. I will also touch on the role of the EDQM in this context. And I will close with a brief summary. Overarching Trends and Concepts Some of the overarching trends that are my personal observations what I have seen over the years that I have been involved in international cooperation: We are moving from bilateral cooperation to multilateral cooperation. When I started in 2003, many of the arrangements that we have now had not been signed. This has happened in the last ten years. Swissmedic now has around 15 bilateral agreements. For the US FDA, I think it is around 100. And others have been catching up as well. The Chinese FDA has signed, in a short period of time, more than 50 of these bilateral agreements. But what we have found I think all of us is that these bilateral agreements are difficult to manage and implement. You cannot maintain projects bilaterally with one individual authority over time if your numbers are increasing. So regulatory authorities have been moving to multilateral activities, covering specific aspects of international cooperation. I will show you some examples of these.

2 Also the approach that regulatory authorities take towards international cooperation has become more strategic. In many individual agencies, a strategic approach needs to be defined or has been defined already. The initiatives also need to define their strategies, like: How do they position themselves in the global context? What is the vision and mission? What is the business model of any new and existing initiative? And last but not least, what are the benefits they provide for their members? Another trend that we have been seeing is that we are moving from information sharing to worksharing. Another word that is being used in this context is reliance. And this is something that is kind of a buzzword in international cooperation here in the last years. These concepts are adopted by more and more agencies as it becomes obvious that they do not have the capacity to deal with the challenges by themselves. As I mentioned Kristin also said it in her introduction challenges can only be addressed in collaboration. Also some of the international initiatives are moving from information sharing to work sharing in recent years. Three Levels of International Cooperation This pyramid shows you three levels of international cooperation. On the bottom you will find the basis, a foundation, which is built on confidence based on harmonized requirements. And information sharing is often used to build the confidence among regulators. Based on this foundation, regulatory authorities can move to the next level, which is reliance and worksharing. This step requires something that is really important trust. The authorities need to trust each other. You may know that regulatory authorities, the employees, are suspicious by nature. So having trust in what another regulatory authority is doing is not a given. It has to be established. It has to be earned. And the best way to find out if you can trust somebody is to trust them. That is a quote from Earnest Hemingway. Sometimes, the easiest way to start to build trust is to have trust in each other. This is the basis, the requirement, to move into these reliance and cooperative concepts.

3 At this point is when the benefits start for regulators. With the work sharing, with the reliance, they are kind of relieved of part of the work load. The shared work load is still looking at independent decisions. So it is not that the reliance or work sharing means that you have to adopt, to take over, a decision that another regulatory authority has taken. The next, third level is recognition. The European Union has been adopting this concept in the mutual recognition agreements, which they have signed with a number of countries. These are treaties. They are legally binding, and they offer a maximal benefit because they allow you to not do certain things like the Swissmedic inspection team is not required to conduct inspections in European countries, because of the mutual recognition agreement on GMP. But it also has the consequence that these countries, these agencies, partially lose their sovereignty with regard to decision making, because they would have to accept a decision to establish GMP compliance and a GMP certificate that is issued by a regulatory authority that is a partner to a mutual recognition agreement. I would like to briefly touch upon the word benefit for regulators. That may be something that needs a bit more explanation. The benefit of international cooperation activity is something that Swissmedic, as an example, has included in the international cooperation strategy. We had a strategy period from 2011 to 2014 where we set as a goal to intensify international cooperation build more bridges, etc. But now from 2015 to 2018, the goal is that international cooperation should be increasingly focused on the benefits. So we are now looking at focusing our activities on those initiatives and projects that also provide the benefit for Swissmedic. And benefit can be defined as, for example, an activity that helps to avoid duplication of work. It is also an activity that contributes to the quality of the work. An activity that aims at the harmonization of standards would also be considered as a benefit. We also put down as a principle that multilateral activities are prioritized over bilateral activities. So that is the kind of benefit that regulators can see from international cooperation. Examples of the Three Levels On this slide I have put together a number of examples of initiatives and activities that belong to these three levels of international cooperation.

4 You can see here on the bottom, for example, you have IPRF, IMDRF, also ICH ICH is well known in the area of harmonization of requirements for the marketing authorization for human medicinal products VICH as the veterinary. You can also see other initiatives like PIC/S. There are a lot of acronyms here on this slide. At the end of my presentation, you will find a list of all the abbreviations and the explanations, so that you are not confused with what is written here. Some examples on work-sharing: Interestingly, they also include initiatives on the African continent, which I found especially encouraging. The first two that are mentioned here is the East African Community Medicines Regulatory Harmonisation [EAC/MRH], which also includes a project on joint assessments of marketing authorization applications. It means that these five countries come together and jointly look at dossiers. The same thing in the southern African region with ZaZiBoNa that is Zambia, Zimbabwe, Botswana, and Namibia who are small agencies that put together their resources and jointly work in the area of marketing authorization. On the recognition level, I already mentioned the mutual recognition agreements between the European Union and a number of countries. But there is also a similar example in the gulf area [the Gulf Cooperation Council] with the central marketing authorization procedure. And a specific example that I would also like to mention here is the unilateral recognition of marking authorizations that have been adopted by the Mexican regulator COFEPRIS. They accept marketing authorizations basically of innovative medicines that have been issued by a number of established regulatory authorities like the US FDA, the European Medicines Agency, the TGA of Australia, and also Swissmedic, as an example and there are one or two more which I may have forgotten to mention here. Now this concludes the first part of my presentation of showing you some of the overarching trends and concepts. Multilateral Initiatives: ICH, ICMRA, IDGRP, IPRF And now I am going to show you a few slides on each of the four I s, four international initiatives: the International Conference on Harmonization [ICH] the International Coalition of Medicines Regulatory Authorities [ICMRA] the International Generic Drug Regulators Program [IGDRP], and the International Pharmaceutical Regulators Forum [IPRF]. ICH ICH, I think, is the most well-known. It has been around for more than 25 years now, and is working in the area of harmonization of requirements. But it has a new governance structure since autumn The outcome of this new governance structure is also a new model of membership and observership. We have so-called founding regulatory members. These are the European Commission, the MHLW PMDA from Japan, and the US FDA. We have founding industry members the three industry associations from Europe, Japan and the U.S. We have standing regulatory members: Swissmedic and Health Canada. They were the former observers to the old Steering Committee. We have industry members IGBA and WSMI.

5 We also have standing observers and observers. I will show you at the end of this section an overview of the membership and observership of all four initiatives, so you can get an overview of who is involved in which. This is what the structure of the ICH association now looks like: It is an association that has been established in Geneva under Swiss law. The main body is the Assembly. I will show you the responsibilities of the Assembly vs. the Management Committee on the next few slides. There still is the MedDRA Management Committee, which deals with the terminology. And also the ICH Secretariat is involved in all these activities supporting the Assembly, the management committees and the working groups. The Assembly is the overarching body of the association. It is composed of all members. It take positions regarding the articles of the association, the rules of procedures, the admission of new members, observers, and the adoption of ICH guidelines. This is really the decision-making body. The Management Committee is the body that oversees the operational aspects of the association, like the budget, the organization of the meetings, any issues that come up in the discussions, in the working groups, that need resolution. For further information, I included here a link to the new articles of the ICH association [link included below]. One very specific point in this whole discussion about the reforming of ICH was who makes the decision about ICH guidelines? The Management Committee provides recommendations on the selection of new topics and on the adoption, withdrawal or amendments of ICH guidelines. But the Assembly makes the decisions. And these decisions, in the history of ICH, are taken by consensus wherever possible. Only in the absence of consensus, there is a vote. And only the regulatory members have the right to vote, not the industry members. So the keys to success of the ICH initiative: It involves both regulators and industry, but it has an enhanced role for regulators. It is science-based. Involving industry as well as regulators means that we have a broader science base, and it is consensus driven. It has a clear and effectively managed process to develop guidelines.

6 It has close collaboration of parties with comparable regulatory and technical capability. It has the continued commitment of regulators to implement the products of harmonization. And it also looks at broadening its membership and to become a global platform, and also to involve tools that allow access to information more easily. What ICH has achieved is really an enormous task in the international harmonization of technical guidelines. It has a clear governance now with the new model with the Association, the Assembly and Management Committee. And it also has an increasingly global membership following this reform. You have seen the new members that have been listed on one of the previous slides. And we are also now looking at applications from EU regulatory members. And as in the past, in the last 25 years, the five step procedure in the ICH process for guideline development is well known and established, and has proven successful. ICMRA The next initiative is the International Coalition of Medicines Regulatory Authorities. ICMRA has been mentioned by one of the previous speakers, I think it was [Paul-Ehrlich Institute President Klaus Cichutek]. This is a kind of mission statement of ICMRA that I copied from the ICMRA website. One of the new developments in ICMRA is that they have a public website where some information available on the initiative, the membership, and the output of this quite new initiative. ICMRA was established in 2014 as a voluntary, executive-level, strategic coordinating advocacy and leadership entity of regulatory authorities. The membership is really global. It covers all continents. It is about member regulatory authorities, plus the World Health Organization as an observer. Again you will find an overview of the membership on one of the later slides. ICMRA a role is to provide the global architecture to support enhanced communication, information sharing, crisis response and to address regulatory science issues. That is also stated on the ICMRA website as one of the goals and tasks of this initiative. ICMRA also operates a number of so-called strategic initiatives. It was already mentioned that GMP was at the top of the list. Also a working group deals with issues around generic medicines and capacity building. The initial effort was a mapping project to identify initiatives that are working already in the area of regulatory cooperation. In 2015 in the meeting in November in Mexico City, three new topics were adopted: supply chain integrity pharmacovigilance, and crisis management. These are now developed into concrete projects, which will be also discussed at the next meeting of the ICMRA membership, which will be in October in Interlaken, Switzerland. You will find some of the output available on the ICMRA website. You will find an overview of training and capacity building activities for regulators, mainly provided by the ICMRA membership. There was also a statement in the context of the Ebola crisis which was issued by the ICMRA membership. And a press release was issued in the context of the Zika virus. All of this is available on the ICMRA website [link provided below].

7 IGDRP Now moving on to the third initiative, the International Generic Drug Regulators Program. This initiative, as it is mentioned in the name, deals with generic medicines. It has been around for a [few] years now it was established in 2013 and now it is looking at drafting a road map for the future direction towards The most recent meeting was held in Strasbourg in May and was hosted by EDQM, which is a member of IGDRP. This final document of strategic direction of 2020 will be available at the end of this year [2016]. IGDRP operates three working groups or three initiatives: One is on active substance master files or drug master files the ASMF/DMF Working Group the Biowaivers Working Group, and the information and work sharing projects, which involve the European Union decentralised and centralised procedure. It is basically opening up these initiatives to other regulators which are not members of the European Union. The pilot of these projects involves Health Canada, Swissmedic, the Taiwan FDA and the Therapeutic Goods Administration from Australia. Also a new development within IGDRP is on stakeholder engagement. Following the meeting of the steering committee, a stakeholder meeting was held on the 13 th of May also Strasbourg. IPRF Now the number four of four IPRF, the International Pharmaceutical Regulators Forum: This forum has been established in its current form in June of 2013, but it had been around for some time already as the so-called regulators forum. It was a regulators-only initiative a group that met in the margins of the ICH conference. And this is still the case with IPRF. The meetings of the management committee of IPRF are combined with the ICH meetings. IPRF is also looking at the future direction developing a strategy for the years 2016 to This process started the end of last year. The final outcomes will be adopted at the management committee meeting in November 2016 in Osaka, Japan. There was a meeting in June 2016 where interim results were achieved namely the structural analysis was completed and the group developed the future business model for the initiative. From its start in 2013 until June 2016, my colleague Dr. Naoyuki Yasuda and I have been chairing the IPRF management committee. We have decided not to continue with this mandate. In a telephone conference in September, the management committee appointed John Blair from the US FDA as the new chair and Patricia Pereira Tagliari from ANVISA as the new co-chair. They have taken over on September 15, Together with the chairmanship, the secretariat of this initiative is hosted which means by taking over chairmanship, the US FDA will also take over the secretariat. We have committed to support FDA in the transition until October 1, 2016, but the organization of the next management committee meeting in November will then be taken care of by the US FDA. Also IPRF has a number of working groups. They are listed here: We have a working group on biosimilars one on cell therapy products on gene therapy products nanomedicines and in June at the meeting in Lisbon the implementation of identification of medicinal products, or IDMP standards, has been adopted as a new item of work under IPRF. It has been seen as a benefit to share information and to share best practices on the implementation on this important set of standards, which originally also resulted from work that had been done within ICH. Currently experts are being nominated for this group.

8 IPRF is open to membership of any regulatory authority that would like to take part in these activities. It is not necessarily required that these regulatory authorities also send representatives to the management committee, but they can raise their interest in participating in one of the working groups. The biosimilars working group under IPRF is a very active and productive working group. And some of the outcomes of this group are shown here [links provided below]: One of them is a public assessment summary information for biosimilar products. This is the final document that has been consulted with external stakeholders and is now available on the IPRF website. And the same for a reflections paper on extrapolation of indications in authorization of biosimilar products. That is currently under consultation. There is also an analytical tool for regulatory viewers that is being developed to allow better comparability of biosimilar Mabs. The work plan of this working group listing all the activities as well as the work plans for the other working groups are available on the IPRF website. Membership Chart for ICH, ICMRA, IGDRP & IPRF This is slide that I promised you some time ago the overview of the membership of the different initiatives. You can see the dark blue lines are regulatory authorities that participate in one way or another in all four initiatives. O means observer and M means member. You can see the TGA in Australia, ANVISA in Brazil, Health Canada, the European Union, the Japanese regulatory authorities MHLW and PMDA, the Korean MFDS, Cofepris from Mexico they participate in all four activities as well as the HSA in Singapore, Swissmedic, the US FDA, and the World Health Organization. WHO is always, per definition, participating as an observer. Due to their nature as a global body of the United Nations, they cannot be a member of any of these initiatives.

9 I would just like to highlight here also EDQM. You will find them here in this table. They are observers to ICH and also members of IGDRP. In this context, you can see that EDQM is also establishing links with these international initiatives, which surely contribute to their role and to the awareness of other regulatory authorities of EDQM s work. A special feature that I would also like to highlight here is the RHIs Regional Harmonization Initiatives. ICH invited these initiatives in the context of the work they called the Global Cooperation Group, several years ago. They are still coming to ICH. Now under the new governance structure, they are observers to the new ICH. Another specific feature is for ICMRA. You will see that in most of the initiatives, the European Medicines Agency and the European Commission represent the European Union. In ICMRA, the specific issue is that competent authorities of the EU member states also participate in this group. The Role of EDQM I will move onto a very short part of the presentation not because of lack of relevance, but I was asked to briefly touch on the role of the EDQM. It was mentioned already that the EDQM, the European Pharmacopeia especially, has a role that goes beyond the European continent it also has an impact that clearly goes beyond this geographic region. Looking at globalization of manufacturing operations, you can see that the monographs of the European Pharmacopeia are used in more than 100 countries. Obviously, those countries have manufactured products for the European continent, for the countries, which are members to the European Pharmacopeia convention. The work of the European Pharmacopeia and EDQM in general is considered to have very high standards with regards to timeliness and scientific level of work. As I showed you previously, EDQM also establishes links to other international cooperation, harmonization, reliance initiatives. But it is involved also in its own global activity, the global harmonization of pharmacopeias, which is a process that is kind of slow and steady, as I would describe it. Susanne is smiling. I do not know if she agrees with my assessment of the work that is being accomplished together with the USP, JP and also the WHO work in the global pharmacopeia. A few thoughts about the future: I was very relieved when I heard Professor Cichutek talk about innovation and efficiency, because you will find these two terms also on my slides. I think looking at the future of the European Pharmacopeia, and the EDQM in general, is really to constantly look into new activities and tasks to really maintain the role, the importance, the impact of the EDQM. It needs to continue its science-based approach maybe looking at more rapid introduction of new technologies, especially in the monographs of the European Pharmacopeia. The third point I mention here is the relevance of the work and the value for members. EDQM has been very efficient and very active in work-sharing activities in offering also opportunities to its members to adopt projects and work sharing. This should be continued maybe even increased and if possible, some more training activities and possibilities for knowledge transfer should be looked at.

10 Regarding efficiencies, these are just two examples: We have learned from experience within Swissmedic that the use of IT and communications tools can facilitate the work and decision making, because the organization that EDQM operates is quite complex, with a number of working groups, with a huge number of external experts. So it could be that some help could be gained from using IT and communication tools. And also, looking at choosing the most efficient approach: Often in the context of the European Pharmacopeia, maybe creating a new monograph is more efficient than updating an existing one. Summary This being said, I would like to conclude with a few statements to summarize my presentation: As you learned, the multilateral initiatives are increasing in numbers. Most of them have been around for a few years, and now they are gaining momentum. They are creating output, value, benefits for their members. And that is what they need to do. The mandates and work programs should not overlap. Duplication needs to be avoided. Regulatory authorities, as I mentioned, move from information sharing to reliance and work-sharing in order to be able manage their business to address the challenges they are facing all together. Also regulatory authorities are taking a more strategic approach towards international cooperation characterized by looking at increasing benefits and efficiency. With regard to the EDQM: As a multinational organization involved in a number of work-sharing activities, EDQM is well positioned to continue to play an important role in tackling the future challenges of the quality of medicines. Its focus on science and value for members needs to be maintained. The support from members, on the other side, and experts is a key element for the future role and impact of the EDQM as well. It is always, as in real life, give and take. LINKS: ICH ICMRA IGDRP IPRF Articles of Association Public Assessment Summary Information for Biosimilars (PASIB) Draft Reflection Paper on Extrapolation of Indications in Authorization of Biosimilar Products Biosimilars Working Group