3

Overview of the Current Global Regulatory Landscape

The session, introduced by Hans V. Hogerzeil, Professor of Global Health, University of Groningen, the Netherlands, described in more detail several current regulatory harmonization initiatives around the world and what is being learned from them.

ICH1

Toshiyoshi Tominaga, Professor and Director, Food and Drug Evaluation Center, Osaka City University Hospital, began by describing ICH, an initiative cosponsored by the drug regulatory agencies and pharmaceutical manufacturing associations of the following organizations:

• Europe (EU/EMA, EFPIA [European Federation of Pharmaceutical Industries and Associations]);

• Japan (MHLW (Ministry of Health, Labor, and Welfare)/PMDA, JPMA [Japanese Pharmaceutical Manufacturers Association]); and

• The United States (FDA, PhRMA [Pharmaceutical Research and Manufacturers of America]).

ICH’s mission is “to make recommendations towards achieving greater harmonisation in the interpretation and application of techni-

___________________

1 This section is based on the presentation by Toshiyoshi Tominaga, Professor and Director, Food and Drug Evaluation Center, Osaka City University Hospital.



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3 Overview of the Current Global Regulatory Landscape The session, introduced by Hans V. Hogerzeil, Professor of Global Health, University of Groningen, the Netherlands, described in more detail several current regulatory harmonization initiatives around the world and what is being learned from them. ICH1 Toshiyoshi Tominaga, Professor and Director, Food and Drug Evalua- tion Center, Osaka City University Hospital, began by describing ICH, an initiative cosponsored by the drug regulatory agencies and pharmaceuti- cal manufacturing associations of the following organizations: • Europe (EU/EMA, EFPIA [European Federation of Pharmaceutical Industries and Associations]); • Japan (MHLW (Ministry of Health, Labor, and Welfare)/PMDA, JPMA [Japanese Pharmaceutical Manufacturers Association]); and • The United States (FDA, PhRMA [Pharmaceutical Research and Manufacturers of America]). ICH’s mission is “to make recommendations towards achieving greater harmonisation in the interpretation and application of techni- 1  This section is based on the presentation by Toshiyoshi Tominaga, Professor and Director, Food and Drug Evaluation Center, Osaka City University Hospital. 23

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24 INTERNATIONAL REGULATORY HARMONIZATION cal guidelines and requirements for pharmaceutical product registration, thereby reducing or obviating duplication of testing carried out during the research and development of new human medicines” (ICH, 2013). The governing body of ICH is a steering committee that includes the organizations noted above, with the addition of WHO, Health Canada, and the European Free Trade Association as observers. The International Federation of Pharmaceutical Manufacturers and Associations is a non- voting member. Additional interested organizations may be invited to participate in expert working group activities, as appropriate. To produce harmonized guidelines, ICH has a five-step process: 1. Building scientific consensus among members of an expert work- ing group 2. Agreement on draft text 3. Consultation with regional regulatory agencies and solicitation of comments from other regulatory agencies, GCG members, and the public 4. Revision and adoption of harmonized guidelines 5. Implementation guidelines in ICH regions ICH has produced numerous guidelines in four major categories: qual- ity, safety, efficacy, and multidisciplinary. In addition, it has developed elec- tronic standards, a common technical document for electronic submission of data on new drug applications (NDAs), and other helpful products. The common technical document includes guidance on formatting trial datasets and data elements, which facilitates review and enables industry to submit its data to different regulatory authorities in a single format. As an example of a completed guideline, Tominaga described guide- line Q1A, “Stability Testing of New Drug Substances and Products,” which specifies the temperature and humidity conditions under which a drug should be stored in order to demonstrate its stability over different time periods. If this guideline is followed, any of the three ICH regula- tory agencies—EMA, PMDA, or FDA—will accept the test data (although sometimes with a requirement for country-specific testing), as will many other regulatory authorities that also have accepted the guideline. ICH promotes the implementation of guidelines worldwide under its GCG. Involved are the regional harmonization initiatives, as well as individual countries that have implemented ICH guidelines or have major pharmaceutical production and clinical research activities. They are • Asia-Pacific Economic Cooperation (APEC)2 2  The organizations listed in bold are discussed later in this chapter.

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OVERVIEW OF THE CURRENT GLOBAL REGULATORY LANDSCAPE 25 • Association of Southeast Asian Nations Pharmaceutical Product Working Group • East African Community (EAC) • Gulf Central Committee for Drug Registration • PANDRH • Southern African Development Community • Individual countries, including Australia, Brazil, China, Chinese Taipei, India, Republic of Korea, Russia, and Singapore As part of its efforts, GCG also coordinates training and capacity building for regulators in non-ICH member countries. Tominaga asserted that the benefits of ICH adoption for industry are fewer duplicate tests, reports, and submissions. For regulators, he said, data submitted for review are more consistent, which enables more con- sistent reviews and facilitates cooperation with other regulatory agencies. For the public, he added, the benefits are quicker access to safe and effec- tive new drugs and (as taxpayers and purchasers) lower costs. Speaking specifically about the benefits to his home country of Japan, Tominaga said the ICH experience has helped Japan update and improve its clinical trial system. Furthermore, the pattern of cooperation across countries has laid the groundwork for multinational studies of ethnic factors in drug development. According to Tominaga, the keys to ICH’s success have been its well-defined process and effective management, the commitment on the part of the three founding members to implement ICH guidelines, and its concentration on technical requirements. It does not delve into what regulators need to do or how they develop their decisions. In terms of difficulty, technical guidance is the low-hanging fruit and is an excel- lent place to start harmonization efforts. Remaining challenges are to achieve mutual recognition of regulations or procedures and mutual recognition of regulatory decisions, with this last the most difficult, said Tominaga. PANDRH3 Drug regulatory harmonization initiatives in Latin America cannot be discussed without reference to broader harmonization initiatives in the Americas and the broader global context. Many regulators in the Latin American region participate in these broader efforts, according to James 3  This section is based on a presentation by James Fitzgerald, Coordinator, Medicines and Technologies, Area of Health Systems based on Primary Health Care, Pan American Health Organization (PAHO), WHO.

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26 INTERNATIONAL REGULATORY HARMONIZATION Fitzgerald, Coordinator, Medicines and Technologies, Area of Health Sys- tems based on Primary Health Care, Pan American Health Organization (PAHO), WHO. PANDRH was established in 2000 by the directing council of PAHO, based on the findings of a conference on harmonization hosted by FDA 2 years earlier. According to Fitzgerald, the agency is working on a number of fronts, including efforts to strengthen national regulatory ­ uthorities, a improve the capacity for regulating medicines and biologicals, and moni- tor trends in regional cooperation and collaboration. At the time of PANDRH’s formation, its purpose was to promote “technical agreements on drug regulation among the member states, including multilateral, bilateral, and subregional agreements, with the participation of all sectors and interest groups” (PANDRH, 2000). Since then, the mission has evolved, and the organization now also takes into account some of the asymmetries within the region of the Americas, rec- ognizing that there are many well-established national regulatory authori- ties and some strongly developing ones, as well as some low-income countries that do not have robust regulatory capacity and are not priori- tizing harmonization efforts at present. The network sets its agenda and promotes technical cooperation under the direction of a Steering Committee that includes members from the subregional economic and trade integration mechanisms of Caribbean Community (CARICOM) (in the Caribbean), Mercado Común del Sur (MERCOSUR) (in the south), Sistema de la Integración Centroamericana (SICA) (in Central America), and the North American Free Trade Agree- ment (NAFTA) (in North America), as well as representation from indus- try. The economic development and trade orientation of these bodies is exemplified by one particular instance, where the drug industry harmoni- zation initiative is led by customs officials from the economic ministries, not health officials. While drug regulators and trade officials often have the same objectives, experience has shown that the best outcomes occur when drug regulators, the regulated industry, and academia are in the lead, said Fitzgerald. Once their recommendations are made, they can work through other relevant regional committees, including the trade committees. PANDRH’s technical working groups tackle the requirements and pri- orities set by the steering committee, which presents the working groups’ results to the Pan American Conference. The conference has additional participation by consumers, academics, and professional associations. So far, PANDRH has completed 15 technical documents, including the following 5: 1. Harmonized requirements for the licensing of vaccines

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OVERVIEW OF THE CURRENT GLOBAL REGULATORY LANDSCAPE 27 2. Harmonized guidelines for preparation of an NDA 3. Guidelines for good clinical practices 4. Guidelines for clinical trials in pediatrics 5. Considerations about the use of placebos Additional working group documents are forthcoming. The impact of this work cannot be truly measured until some years in the future, when the extent to which the guidelines have been adopted, adapted, and implemented can be measured, said Fitzgerald. At pres- ent, however, there is some empirical evidence regarding impact. For example, Fitzgerald pointed out that Technical Document 6, which covers self-evaluation of good laboratory practices, has been implemented by 21 countries; 20 countries have adopted the norms in the document covering pharmacovigilance; and the vaccine common technical document is being implemented partially in 14 countries and completely in 7. The impact of the documents on actual regulatory practice has not been assessed yet, and there is no legal framework within the region to ensure that technical documents are implemented in similar ways. Nevertheless, according to Fitzgerald, PANDRH believes they are having considerable influence. Certainly, they have facilitated capacity building and development of regulatory networks within the region. For example, there is now a regional network of 25 Official Medicine Control Labora- tories working together, and a 12-country network for sharing pharmaco- vigilance information has been formed. The vaccine document specifically has proved to be a useful tool in increasing efficiencies in the vaccine reg- istration process. PANDRH is defining a method to measure and evaluate how countries are implementing these documents to date. In the discussion period at the end of this panel session, participants focused on how successful implementation depends in large part on a country’s approach to policy. Workshop attendee Peter Barton Hutt, Covington & Burling, LLP, described three levels of legal structure: man- datory implementation, guidance, and voluntary convergence. The most stringent, Hutt said, is mandatory implementation, which is usually estab- lished through statute or, in most countries, regulations. Bilateral or mul- tilateral agreements and treaties can make requirements mandatory across countries and may be essential for true harmonization in the long run, he said. The next strongest level of policy is guidance, said Hutt. While guid- ances, like those developed by ICH, are neither mandatory nor binding on either industry or governments, because industry takes them so seriously, they may be considered de facto mandatory. However, if a manufacturer or regulatory agency diverges from a guideline, there is no enforcement capability. When countries and regions get together and propose voluntary convergence, they are using the weakest policy approach, said Hutt. Volun-

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28 INTERNATIONAL REGULATORY HARMONIZATION tary efforts often are frustrating because they take a long time, and there is no guaranteed outcome. Mike Ward, Health Canada, and Fitzgerald argued that classifications for a country’s efforts at harmonization could be simplified further to mandatory or non-mandatory. Although voluntary convergence may be slow, negotiations over the legal language in mandatory regulations also can stall. In one case cited by Fitzgerald, legal language was being hashed out over a period of years, but meanwhile, the regulators convened, agreed on basic principles, and moved forward into implementation. Achieving mandatory regulations requires more than the support of the health sector, added Ward. It also needs the backing of political leaders, and it needs to be compatible with economic drivers, such as the thrust toward single-market economies. The number of entities working on economic integration in the Amer- icas creates a complex situation. The same country may be involved in bilateral and multilateral agreements, each with its distinct politi- cal mandates and trade policies. For example, Fitzgerald noted that in recent years, Brazil has signed 13 bilateral agreements among regulators. PANDRH has studied how to move forward with implementation of its harmonization initiatives in this environment and begun a dialog with some of the more well-established national regulatory authorities to that end. These regulators have suggested that PANDRH begin to look at convergence by linking its normative processes, which focus on technical harmonization, while building on established capacity within the national regulatory authorities. Accordingly, noted Fitzgerald, PAHO member states adopted a reso- lution in 2010 to strengthen national regulatory authorities for medi- cine and biologicals. Essentially, member states are to develop regulatory capacity with respect to critical functions within their health systems, and then link into and support the harmonization work of PANDRH. Currently, PANDRH is assessing and evaluating regulatory systems of individual countries, as well as supporting the implementation of insti- tutional development plans of a number of them. The process has brought countries together to work on joint proj- ects. For example, Fitzgerald recognized that Argentina, Brazil, Colombia, Cuba, and Mexico are meeting biannually and making progress, par- ticularly with respect to sharing reports on good manufacturing pro- cess inspections. Cooperation also is increasing between FDA and Health Canada and countries in the southern hemisphere, he said. As drug regis- tration processes are linked, confidence is building among regulators. To ensure regulators have a secure environment for dialog, last year PAHO, with FDA assistance, launched an online platform for access and innova- tion in health technology. What PANDRH has learned from all these efforts, said Fitzgerald, is

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OVERVIEW OF THE CURRENT GLOBAL REGULATORY LANDSCAPE 29 that regulatory harmonization depends on political, economic, and trade agreements as well as the policies within particular regional initiatives; that implementation of harmonized norms requires well-functioning reg- ulatory systems; that convergence is achievable within short- to mid-term time frames; and that modern communications technologies can facilitate the process. According to Fitzgerald, in the future, PANDRH will not abandon the normative guidance and technical document development that have been its core work for 15 years, but will move more generally toward good regulatory and review practices and mechanisms to support broadly defined network development. APEC MEMBER ECONOMIES4 APEC was created in 1989 and includes 21 member economies, which account for 40 percent of the world’s population, 54 percent of its gross domestic product, and 44 percent of its trade. APEC includes Australia, Canada, China, Japan, Korea, Russia, the United States, and many smaller economies. APEC’s goals are to promote trade, sustainable economic growth, and the prosperity of member economies through policy align- ment and economic and technical cooperation. APEC is still relatively new compared to some of the other more well- established regional organizations, but, according to Ward, its experience speaks to how such an organization needs to • be clear on what it wants to achieve, with whom, and why; • develop a business case; and • create a strategy or roadmap describing how it will work toward desired outcomes. Such a plan needs to be practical and proceed one step at a time, taking into account what is already going on within the region and internation- ally, said Ward. According to Ward, APEC’s annual work plan is developed around senior officials’ meetings, culminating in a leaders’ declaration that endorses policy and sets the agenda for the subsequent year. The chair- manship rotates annually among member countries. An understandably complex organization, APEC has more than 40 task forces and committees working on a broad range of issues—from investment banking to food safety. The Life Sciences Innovation Forum, where drug regulatory har- 4  This section is based on presentation by Mike Ward, Manager, International Programs, Health Canada.

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30 INTERNATIONAL REGULATORY HARMONIZATION monization fits, has as its underlying premise that a healthy population is necessary to a healthy economy. Thus the forum is concerned with pro- moting both public and economic health, said Ward, and from its outset, saw regulatory harmonization as a prerequisite to fostering innovation. Unlike other harmonization initiatives, the forum does not produce harmonized guidances. Rather, it promotes the use of existing interna- tional guidelines and best practices. The forum can access APEC funds to undertake projects, although, because country participation is volun- tary, only those economies interested in and committed to cooperation participate in a particular activity. Another difference is that APEC has a tripartite structure, with government, industry, and academia playing complementary roles. Initially, APEC efforts were not sufficiently coordinated or robust and were deemed unlikely to achieve results, said Ward. In 2009, a Regulatory Harmonization Steering Committee (RHSC) and the APEC harmonization center were inaugurated. The RHSC mandate is to promote a more strate- gic, effective, and sustainable approach to harmonization by • proactively identifying and prioritizing projects considered to be of greatest value to regulators and regulated industries; • strengthening linkages with harmonization initiatives both region- ally and internationally; and • persuading key players such as WHO to promote complementary actions and most effective use of resources. As a result, Ward said, APEC has become a good example of intercon- nectivity among initiatives. It concerns itself with medical products, nota- bly pharmaceuticals, including biologics, medical devices, and advanced therapies, including cell and tissue therapies. A growing number of senior regulators from APEC economies partici- pate in the RHSC, as do research-based industry coalitions representing pharmaceuticals, medical devices, generic drugs, and, most recently, the biotech products sector. Also involved is the director of the Seoul-based APEC Harmonization Center, an organization-wide resource to enhance and sustain regulatory convergence and capacity building. APEC is work- ing to establish official liaisons with other international harmonization initiatives, said Ward, because of the belief that it needs to act as a catalyst for international action on issues that demand a global approach, such as supply chain integrity. APEC’s strategic framework outlines a multiyear approach for achieving greater regulatory convergence by 2020; describes guiding prin- ciples and the steps necessary to achieve that end; and accommodates different countries’ pace. The strategic framework outlines a coordinated

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OVERVIEW OF THE CURRENT GLOBAL REGULATORY LANDSCAPE 31 approach to promoting regulatory convergence. From there, APEC moved to identify priority work areas and develop implementation roadmaps that would bring best practices to light. The result is a move from ad hoc, individual country actions to collective efforts. Two examples of the prior- ity work areas in which projects are completed are multiregional clinical trials (led by Japan) and supply chain integrity (United States). Under way are projects in good review practices, biotech products, pharmacovigilance, good clinical practice inspection, and cellular thera- pies. Much of this work builds on the standards developed by ICH, using its GCG and ICH Regulators Forum as the interface. APEC plays an enabling role, supporting the uptake and broader understanding of these international standards and best practices, Ward concluded. HARMONIZATION INITIATIVES IN AFRICA5 The African Union (AU) comprises 54 member states, with 900 mil- lion people and 8 regional economic communities that undertake most of the continent’s economic development activities. AU’s New Partnership for Africa’s Development (NEPAD) has the mandate to • facilitate and coordinate implementation of continental and regional programs and projects; • mobilize resources and partners in support of the implementation of priority programs and projects; • conduct and coordinate research and knowledge management; and • advocate for the AU and NEPAD vision, mission, and core prin- ciples and values. Margareth Ndomondo-Sigonda, Pharmaceutical Coordinator, AU-NEPAD Planning and Coordinating Agency, said the African Medi- cines Regulatory Harmonization (AMRH) initiative has developed as an essential step in reaching the vision of the approximately 6-year-old Pharmaceutical Manufacturing Plan for Africa, developed within the NEPAD framework. The plan’s aim is to contribute to a sustainable sup- ply of quality essential medicines to improve public health and promote industrial and economic development on the continent. Regulatory har- monization is seen as a critical factor in facilitating local production of pharmaceuticals, said Ndomondo-Sigonda, ensuring a sound regulatory environment, and encouraging intra- and intercontinental trade. To this end, Ndomondo-Sigonda asserted that AMRH encourages 5  This section is based on presentation by Margareth Ndomondo-Sigonda, Pharmaceutical Coordinator, AU-NEPAD Planning and Coordinating Agency.

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32 INTERNATIONAL REGULATORY HARMONIZATION increased use of harmonized policies and regulatory frameworks by AU member states. It also works to increase the human and institutional capacity for regulating medical products and technologies and to create knowledge assets on medicines regulation at the country, regional, and continental levels. One such activity is the development of a community of practice. In addition, AMRH is planning a scientific conference to bring together regulators, industry, and research organizations to discuss issues of common interest. According to Ndomondo-Sigonda, the first of these will be held in late 2013. The sum of these activities, she said, is creating an enabling environment for harmonization through coordination across regional activities, measurement of impact, and developing an account- ability framework. The consensus of a broad range of stakeholders—funders, interna- tional development agencies, United Nations (UN) agencies, and others, as well as regional economic communities—is that the time is right for attempting regulatory harmonization in Africa, said Ndomondo-Sigonda. Setting priorities for action has taken into account that 54 national regu- latory agencies are involved in this effort: each of them works indepen- dently and may lack adequate medicines policies and laws; have differ- ent requirements and formats; vary in regulators’ capacity; operate with minimal transparency; have no clear time lines; and make little to no use of reference evaluations conducted by more stringent national medica- tions review authorities. Because of the severe challenges regulators face, AMRH’s first priority for action is to harmonize medicines registration requirements and stan- dards. This activity is seen as not only protecting and improving public health, but also contributing to economic development. To overcome the current fragmented efforts across countries, Ndomondo-Sigonda stated that AMRH hopes to have five to seven regional economic blocks work- ing together to create a single, clear set of guidelines that will drastically limit the number of dossiers that manufacturers need to submit. Achiev- ing more transparent and coordinated regulatory processes will enable pooling of resources and information sharing, and a quality management system will enable more robust research, but will require investments in information management. In the EAC6 specifically, a treaty among the partner states provides for cooperation on health issues. Decisions at the ministerial level of the five EAC member nations have enabled their regulatory agencies to develop a proposal for regional harmonization of medicines. The relevant stake- holders have agreed to a governance structure to oversee the project, and 6  The EAC comprises Burundi, Kenya, Rwanda, Tanzania, and Uganda. It has a population of 133 million and an annual gross domestic product of $79 billion.

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OVERVIEW OF THE CURRENT GLOBAL REGULATORY LANDSCAPE 33 technical working groups have been established with different countries having different responsibilities. For example, leadership of the technical working group on registration was assigned to Tanzania, supported by Burundi. By the end of this year, some of this group’s guidelines will be ready for review and approval by relevant stakeholders. As another exam- ple, the technical working group on good manufacturing processes—led by Uganda, supported by Rwanda—has produced a number of draft documents. Additional technical working groups are focused on informa- tion management and quality management systems. EAC’s progress is considered a model for other African regions. At the continental level, AMRH working groups also have formed, for example, around regulatory capacity development, medicines policies, and regulatory reforms. In July 2012, the AU assembly endorsed a road- map for shared responsibility on key infectious diseases that emphasized the need to accelerate and strengthen harmonization initiatives and, more important, laid the foundation for a single African medicines agency. According to Ndomondo-Sigonda, in 2013 stakeholder consultations are planned to discuss a draft model law for medicines regulation harmoni- zation in Africa.

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