7

Tactics and Strategies for a Way Forward
1

The workshop’s final session involved two brief panels and audience discussion led by workshop co-chairs Steven K. Galson, Amgen Inc., and Thomas J. Bollyky, Council on Foreign Relations. The session offered participants an opportunity to make summative comments as well as suggestions for moving toward more harmonized regulations and regulatory structures.

KEY THEMES

Many Paths to Harmonization

There is no “one size fits all.”—Vincent Ahonkhai, BMGF

Harmonization initiatives worldwide have generated a great deal of multicentric leadership, rather than one overarching, hierarchical organization. Hans V. Hogerzeil, University of Groningen, the Netherlands, suggested that what can be learned from the several multinational networks discussed at the workshop—such as ICH, PANDRH, APEC, and

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1 The first panel consisted of chairs of the previous workshop sessions, as described earlier; the second panel involved Deborah Autor, Deputy Commissioner, Global Regulatory Operations and Policy, FDA; Hans-Georg Eichler, Senior Medical Officer, EMA; and Alan Morrison, Vice President, International Regulatory Affairs and Safety, Amgen Inc.



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7 Tactics and Strategies for a Way Forward1 The workshop’s final session involved two brief panels and audience discussion led by workshop co-chairs Steven K. Galson, Amgen Inc., and Thomas J. Bollyky, Council on Foreign Relations. The session offered participants an opportunity to make summative comments as well as sug- gestions for moving toward more harmonized regulations and regulatory structures. KEY THEMES Many Paths to Harmonization There is no “one size fits all.” —Vincent Ahonkhai, BMGF Harmonization initiatives worldwide have generated a great deal of multicentric leadership, rather than one overarching, hierarchical orga- nization. Hans V. Hogerzeil, University of Groningen, the Netherlands, suggested that what can be learned from the several multinational net- works discussed at the workshop—such as ICH, PANDRH, APEC, and 1  The first panel consisted of chairs of the previous workshop sessions, as described ear- lier; the second panel involved Deborah Autor, Deputy Commissioner, Global Regulatory Operations and Policy, FDA; Hans-Georg Eichler, Senior Medical Officer, EMA; and Alan Morrison, Vice President, International Regulatory Affairs and Safety, Amgen Inc. 67

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68 INTERNATIONAL REGULATORY HARMONIZATION the EAC—is that there are many ways to put networks together. They have independently developed different processes, and they have various scopes. Andreas Seiter, World Bank, added that another commonality is that, although each of these networks exists in a dynamic environment, where many different events and changes occur, similar basic ideas, prin- ciples, and terminology are emerging. While regulators can continue to be encouraged to adopt the broad array of international standards, other initiatives with narrower agendas also have developed and, in some cases, may provide regulatory authori- ties with an initial demonstration of the usefulness of harmonization. Examples of these more focused activities mentioned by individual work- shop participants include the following: • Harmonization with respect to pharmacovigilance is beginning to happen with the aggregation of postmarketing data and use of standard terminology (Deborah Autor, Deputy Commissioner, Global Regulatory Operations and Policy, FDA). • Information-sharing platforms, such as shared inspection reports, are being developed and exchanged internationally (Raymond Chua, Singapore Health Sciences Authority; Fitzgerald, PAHO, WHO; Lembit Rägo, WHO). • Joint review models have developed that have the advantages of pooling capacity, maintaining sovereignty, and moving toward convergence of regulatory approaches. Where these have worked best is with developed country regulators facing a new problem or with regulators in some of the least developed countries where pooling capacity is the most sensible approach (Bollyky; Hans- Georg Eichler, Senior Medical Officer, EMA; Rägo). There will always be a need for this kind of flexibility, said Bollyky, who believes that a single path to international regulatory harmonization is “an impossibility.” All the regulatory issues involved in initial approval, trials, registration, and monitoring cannot be lumped together in the hope of finding a single solution, a participant agreed. Attributes of Successful Networks Numerous workshop participants individually identified various attributes of successful networks, including • a clear vision of what the network wants to achieve, which is vital in establishing a business case that makes sense to stakeholders;

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TACTICS AND STRATEGIES FOR A WAY FORWARD 69 • a dedicated secretariat with dedicated staff (the participating regu- latory authorities also may need staff dedicated to the work of harmonization); • a sufficient budget to support meetings and travel; • high-level political support; and • a bottom-up strategy that starts with the scientists, rather than a top-down strategy that starts with the lawyers. Balancing Competing Regulatory Roles Regulators have two potentially difficult-to-reconcile goals: protec- tion of the public’s health and support for industry. Different metrics would be employed to assess progress toward each goal and to optimize the benefits of regulation for the population and the economy. The drug development and regulation ecosystem is so large and complex that there is enough room to work toward both these goals, as long as the work is prioritized properly, Galson said. Hogerzeil said the need to work toward both these goals ultimately may put a limit on how far harmonization can go, if individual countries’ regulatory systems are sufficiently different in how they balance these two aims. Risk-benefit analysis, done transparently and in a standardized way, can illuminate the balancing process, he said. Such analyses will require both standardized information and standardized ways of presenting it. Some industry representatives are convinced of the potential benefits of harmonization and want to move forward with it, said Seiter, but they are not the same individuals who travel with trade delegations and nego- tiate free-trade agreements. The latter group usually includes lobbyists and lawyers with completely different points of view from the scientific community, he said. This suggests the need for some intracompany edu- cation about how harmonization is good for business and why it is worth investing in building regulatory capacity in countries that have weak systems, so that product sales can continue to grow in these markets. Helping the weaker agencies achieve a higher performance level would be a win-win situation, said Seiter. Often, lower-income countries are plagued with tainted, substandard, or fake medications, and if their regulatory agencies were helped to do a more effective job stemming the tide of illegal medicines, the size of the market for legitimate drugs would increase, and the population would not be exposed to worthless or hazardous products. Eichler said it is therefore not just good industrial policy to increase the efficiency and effectiveness of regulatory agencies; it is also good public health policy.

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70 INTERNATIONAL REGULATORY HARMONIZATION Resource Costs of Harmonization Harmonization is an investment that may not produce immediate monetary savings, even though the long-term savings from increased effi- ciency and reduced duplication of effort is inevitably less costly system- wide. Small agencies that do not have the resources to meet all the current demands on them may have the fewest resources to pursue harmoniza- tion, but, ironically, would likely see its benefits soonest because it would improve their capacity and performance. With all the potential benefits in mind, it is hard to understand why more resources are not being devoted to harmonization. However, there is no single answer to the question of the source of financial support for har- monization. It might come from incremental additions to existing work and budgets; it might derive from nonprofit funding for specific projects; it might be obtained through higher fees from sponsor companies. Or, modest resource increases from each of these sectors might be achievable. According to Seiter, for example, industry is willing to pay higher fees for a better regulated system. Costs of harmonization have to be added to the already strained funding for basic regulatory activities in lower income countries and even some middle-income countries, where sufficient, sustainable funding for training regulators and operating a regulatory agency is a serious and persistent problem. Governments are increasingly under pressure to figure out how to reduce the costs of regulation and avoid duplication of effort, said Galson, whether it occurs in regulatory tool development, clinical trials, amass- ing the evidence base, postmarketing safety, or manufacturing processes. What has to be avoided, said Chua, is the temptation of government leaders to assume that, because harmonization is expected to reduce regulatory costs, the workforce and budgets of regulatory agencies can be reduced immediately—before harmonization is achieved. One partici- pant also suggested that some smaller regulatory authorities may rely on inspections as a source of income, which may serve as a disincentive to move toward harmonization which may involve the use of joint inspec- tions or relying on another another’s inspection. To the extent that disharmonization results in duplication and inef- ficiency, higher industry costs for multiple clinical trials, multiple dossier requirements, or redundant inspections—all of which lead to delays in making effective treatments available—its opportunity costs are high, said Eichler. They are even higher if it means that potential products that will only ever have small markets (e.g., drugs for rare diseases) may not be developed at all. These various opportunity costs are borne by different parties, which make their full impact harder to assess. Regulators bear some; businesses bear others; and patients bear still others, Bollyky noted.

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TACTICS AND STRATEGIES FOR A WAY FORWARD 71 Harmonization and Innovation Seiter noted that one issue the meeting did not fully explore is whether harmonized regulations actually foster innovation in the biomedical prod- ucts field, where regulations are often seen as a barrier to developing new products. Yet, innovation is needed in many areas of disease prevention and treatment, and science is on the cusp of enabling many new types of products. With respect to antibiotics, for example, the lack of new prod- ucts in the face of rising microbial resistance to existing treatments is an increasingly serious problem, he said. Similarly, Seiter added, the cur- rent incentive system does not well support development of innovative products related to the neglected tropical diseases (or orphan drugs in general), and there may be opportunities to shift those incentives. Today’s research and development model is simply not delivering, said Alan Morrison, Vice President, International Regulatory Affairs and Safety, Amgen Inc. The number of new drugs approved per billion dollars invested has approximately halved every 9 years since 1950.2 At present, each new biomedical product costs more than the previous one, and there is a strong imperative to reduce these costs. Harmonization isn’t the total solution, said Morrison, but a more predictable regulatory environment worldwide would be a step in the right direction. Morrison added that harmonization also has to ensure there are no disruptions in the supply chain—a problem of increasing concern. Some of the highly specialized biotechnology products may have a manufactur- ing run only every 2 or 3 years. The supply chain and storage conditions for these products need to be absolutely reliable, otherwise even develop- ing such projects becomes economically untenable. Harmonization and Globalization Harmonization is occurring simultaneously with a homogenization of afflictions facing humanity, said Galson. Although infectious diseases persist, and the biomedical products to prevent and treat them are des- perately needed, the global increase in chronic diseases suggests that, over time, much of the same medications will be needed everywhere, he said. Moreover, the slow rise in the global standard of living will enable more and more people to gain access to health care. Finally, the industry itself is becoming more global, said Galson, with many companies operating in dozens of regions and hundreds of countries. Harmonizing standards for disease-specific entities may be a chal- 2  See http://www.nature.com/nrd/journal/v11/n3/fig_tab/nrd3681_F1.html (accessed April 10, 2013).

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72 INTERNATIONAL REGULATORY HARMONIZATION lenge, posited one workshop participant because of differences in clinical practice and accepted endpoints across regions. Galson responded that for many disease areas (e.g., neglected and tropical diseases), the thinking about their treatment is not that different in different nations. He pointed to the osteoporosis guidance developed for the European Union, noting there is not one in the United States. After a drug is on the market, there are actually two issues, said Eichler: accumulating data on patient experience and deciding whether anything needs to be done about it. The latter depends greatly on the way medicine is practiced locally and the legal systems involved. But with regard to evidence generation for pharmacovigilance, there is much room for harmonization, said Eichler. Recently FDA reorganized so it could rise to the challenges of glo- balization, said Autor. Its Pathway to Global Products Safety and Quality 3 is built on the themes of forming global coalitions of regulators, develop- ing global data systems, using advanced risk analytics, and leveraging the efforts of public and private third parties. Autor asserted these four fundamental ideas demonstrate FDA’s recognition that it needs to work with others, rely on others’ work, and create efficiencies. SUGGESTED PATHS FORWARD Initial Steps The steps needed to move harmonization forward can be undertaken by different stakeholders, and they will not be the same for every stake- holder group. More important, no one group or organization can take on all of them. Numerous specific next steps were suggested by individual workshop attendees as being useful both to understanding harmonization and moving it forward. They included the following: • Articulate the core principles of existing harmonization efforts, which could be used as a framework for developing a common understanding of what harmonization is (Michael J. Brennan, Aeras). • Examine current harmonization initiatives in detail, perhaps through case studies, to find out what contributes to their successes and failures and how they can be developed further (Bollyky). • Strategically map the linkages between existing initiatives and coun- tries and work to establish closer links across efforts (Fitzgerald). 3  See http://www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperations andPolicy/GlobalProductPathway/default.htm (accessed April 10, 2013).

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TACTICS AND STRATEGIES FOR A WAY FORWARD 73 • Invest in economic analysis of the benefits of harmonization (Galson). • Strengthen the rationale for harmonization in countries that are not now fully participating (Fitzgerald). • Analyze why two regulatory agencies can look at exactly the same data and arrive at different conclusions (Galson). • Consider the role of cultural or ethical differences in harmonization efforts (e.g., reporting of adverse events) (Morrison, Toshiyoshi Tominaga, Osaka City University Hospital). • Identify whether harmonized processes are needed when imple- menting harmonized norms and, if so, what those processes should be (Fitzgerald). Workshop participants were divided on the issue of whether to wait until a thorough business case could be developed for harmonization or “just do it.” The truth is probably somewhere in between, suggested Autor. The challenges in harmonization are due to “a combination of inertia and the need for courage and creativity,” said Autor. Working with others globally means giving up some control and learning to do some things in another’s way. This pulls people outside their comfort zone, said Eichler. One tactic to make people more comfortable is to start with noncom- mittal meetings that provide what Eichler called the safe harbor. From there, discussions could move to developing a pilot study, still not very threatening. If the pilot succeeds, one or more additional pilots could be tried, as people become comfortable with and accustomed to doing work differently. Ultimately, a new process can be developed. Postmarketing trials and studies may involve tens of thousands of patients, and many are designed to show that a new treatment is not substantially worse than already available treatments. What is needed in these cases is a better understanding of the criteria by which the study’s outcome will be judged. Ultimately, benefit-risk studies may become useful in facilitating com- munication across regions and with practitioners and patients. The Business Case The conversation about why global convergence is important needs to focus on gains in efficiency, increased coverage and availability, and the complexities of the job that make it impossible to do alone, Autor said. Perhaps the business case should not be written solely by regulators, she said, but by regulators and patients, clinicians, donors, nongovernmental organizations, legislators, consumer groups, and others.

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74 INTERNATIONAL REGULATORY HARMONIZATION Autor added that a solidly constructed business case can be an impor- tant advocacy tool. It can include useful case studies that demonstrate the potential effectiveness of harmonization, discuss the importance of regulatory work, and describe gaps. But what it actually needs to accom- plish is to send the message to stakeholders that drug harmonization is important to everyone. It needs to look separately at the opportunities for harmonization in reviews, versus clinical trials, versus inspections, and versus other areas, said Autor. It needs to separately analyze the needs of the developed world versus the developing world. Business case in hand, the next step is to prepare a proposal and plan for moving to the next level, said Autor, recognizing that this is an evolv- ing field and that continued evaluation of effort will be needed. Bollyky added that focusing on pilot projects in areas where the opportunity costs from different stakeholders line up might be a way to jumpstart efforts, in parallel with building an international secretariat, supporting legal frameworks, and refining the business case. However, he noted that it may be daunting to ask national leaders to make these costly investments in infrastructure before they have seen any benefits from harmonization. An Evolving Global Regulatory Strategy Wood said the tools WHO uses to assess national regulatory authori- ties at present focus on whether systems are in place. The next level of assessment, he said, is to build in performance indicators, but how to do that is not yet clear. Performance assessment also is needed at the multinational network level. In some cases, going to a regional network may not actually save time in the approval process, but several workshop participants gave examples that review times have been substantially shorter than usual. In one instance, where delays occurred, they were actually on the side of the manufacturer. For example: • In Latin America, countries sharing inspection schedules and reports are finding that good manufacturing practice inspections by each individual nation are not necessary. Sharing has produced monetary savings, and the quality of the inspections has improved as well (Fitzgerald). • The prequalification of a new antimalaria drug facilitated its reg- istration in a number of African countries within 2 years—likely much faster than the norm (workshop attendee Nathalie Strub Wourgaft, Drugs for Neglected Diseases initiative [DNDi]). • DNDi sought a joint ethical review for a new sleeping sickness medication that brought together scientists and people knowledge-

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TACTICS AND STRATEGIES FOR A WAY FORWARD 75 able about ethics in the relevant countries. Each country’s repre- sentatives returned to their own institutions’ ethics committees for further review. The process facilitated meeting all the requirements for both a scientific and ethical review while maintaining the sov- ereignty of each country, and also promoted mutually beneficial sharing of information (Strub Wourgaft). Another topic needing discussion is who should pay for these reviews, said Strub Wourgaft, because she suggested the sponsor may not be the best candidate due to conflicts of interest. Risk management and risk mitigation strategies also could be har- monized, added one participant. The European Union, for example, has a risk management plan, and the United States uses a risk evaluation and mitigation strategy template. Harmonizing these two approaches would be an improvement. The many specific ideas put forward provide a starting point for mul- tiple subsequent actions. All told, the meeting projected “an overwhelm- ing sense of optimism” that harmonization can happen and is happening, said Galson, and he closed the meeting by admonishing the group to “go forth and converge.”

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