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Introduction
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The past several decades have been a time of rapid globalization in the development, manufacture, marketing, and distribution of medical products and technologies. Increasingly, research on the safety and effectiveness of new drugs is being conducted in countries with little experience in research regulation. Additionally, biopharmaceutical companies seeking global markets need to submit applications for approval of a given product to the regulatory authorities of many different countries, each of which could introduce scientific requirements discordant with those of the manufacturer’s home market. Differing data requirements across countries may necessitate additional clinical trials and animal studies, increasing the cost of potentially important medicines and slowing patient access to them. In many developing countries, regulatory capacity is insufficient to ensure a smooth process for new drug approval. Even after drugs are approved, international differences in systems to monitor the ongoing safety and quality of approved drugs slow recognition of any safety or manufacturing problems affecting public health. For reasons such as these, demand has been increasing for globally harmonized, science-based standards for the development and evaluation of safety,

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1 The planning committee’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, and are not necessarily endorsed or verified by the Forum or the Institute of Medicine, and they should not be construed as reflecting any group consensus.



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1 Introduction1 The past several decades have been a time of rapid globalization in the development, manufacture, marketing, and distribution of medical products and technologies. Increasingly, research on the safety and effec- tiveness of new drugs is being conducted in countries with little experi- ence in research regulation. Additionally, biopharmaceutical companies seeking global markets need to submit applications for approval of a given product to the regulatory authorities of many different countries, each of which could introduce scientific requirements discordant with those of the manufacturer’s home market. Differing data requirements across countries may necessitate additional clinical trials and animal stud- ies, increasing the cost of potentially important medicines and slowing patient access to them. In many developing countries, regulatory capacity is insufficient to ensure a smooth process for new drug approval. Even after drugs are approved, international differences in systems to monitor the ongoing safety and quality of approved drugs slow recognition of any safety or manufacturing problems affecting public health. For rea- sons such as these, demand has been increasing for globally harmonized, science-based standards for the development and evaluation of safety, 1  The planning committee’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, and are not necessarily endorsed or verified by the Forum or the Institute of Medicine, and they should not be construed as reflecting any group consensus. 1

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2 INTERNATIONAL REGULATORY HARMONIZATION quality, and efficacy of medical products. The goal of such standards is to improve the efficiency and clarity of the drug development and evalua- tion process and, ultimately, to promote and enhance product quality and the public health. Since its inception in 2005, the Institute of Medicine’s (IOM’s) Forum on Drug Discovery, Development, and Translation2 has focused on the need for strengthening the scientific basis of drug regulation, specifically the development of regulatory science as an essential component of the drug discovery enterprise and translational sciences.3 Advancing regula- tory science is a priority for the U.S. Food and Drug Administration (FDA) and provides an avenue for considering the best tools and approaches for international regulatory authorities to harmonize drug regulations and processes. In February 2010, the forum sponsored a workshop and subsequently released the workshop summary Building a National Framework for the Establishment of Regulatory Science for Drug Development: Workshop Sum- mary, which further defined the field of regulatory science and opportuni- ties to create an infrastructure to support its advancement (IOM, 2011). In September 2011, the forum hosted a workshop and subsequently released the workshop summary Strengthening a Workforce for Innovative Regulatory Science in Therapeutics Development: Workshop Summary, which considered opportunities and needs for advancing innovation in the discipline of regulatory science, and examined the development of a workforce within academia, industry, and FDA (IOM, 2012a). The forum maintains a sustained focus on the need for improving the clinical trials enterprise to support more efficient and effective new drug development, including holding two public workshops explor- ing approaches to clinical trial transformation; see Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Sum- mary (IOM, 2010) and Envisioning a Transformed Clinical Trials Enterprise in the United States: Establishing an Agenda for 2020: Workshop Summary (IOM, 2012b). In addition to the work of the forum, in 2012 the IOM released the report Ensuring Safe Foods and Medical Products Through Stronger Regula- tory Systems Abroad, which focused on the increasing globalization of the supply chains for foods and medical products (IOM, 2012c). The com- mittee noted that because of international trade, product safety failures in any one country can have ramifications around the world, and there- 2  Financial support for the forum comes from private foundations, government agencies, industry sponsors, and nonprofit associations. 3  Regulatory science involves the development and application of scientific tools and methodologies to improve the development, review, and oversight of new therapeutics.

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Introduction 3 BOX 1-1 Statement of Task for the Workshop An ad hoc planning committee will plan a 2-day public workshop to address needs for international harmonization of regulatory standards to support the de- velopment, evaluation, and surveillance of biomedical products. Specifically, the topics at the workshop will be defined to help identify principles and potential approaches to the development or evolution of more harmonized regulatory stan- dards. Subject-matter experts will be invited to participate in the workshop to dis- cuss and explore principles, approaches, and strategies to support and advance regulatory harmonization. The workshop will feature invited presentations and discussions that will •  rovide an overview of the current global regulatory landscape. Identify (a) p current organized efforts to promote and evolve harmonized standards, and examples of areas where standards are viewed as adequately harmo- nized; and (b) areas of need for development or evolution of harmonized standards; • identify the characteristics of a well-harmonized regulation; •  iscuss principles to guide the establishment or evolution of harmonized d regulations; •  iscuss options and approaches that could facilitate or underlie systemic d organizational efforts to develop and/or evolve harmonized standards. Dis- cuss potential structures, methodologies, goals, and outcomes. The planning committee will develop the agenda for the workshop, select and invite speakers and discussants, and moderate or identify moderators for the dis- cussions. A single individually authored summary of the workshop will be prepared by a designated rapporteur based on the information gathered and the discussions held during the workshop. fore deemed the regulatory system to be a key factor in public health safety. The committee further noted that the regulatory authorities in low- and middle-income countries often cannot perform all of the neces- sary responsibilities and asserted “The FDA cannot do its job well without substantive improvements in the capacity of its counterpart agencies in emerging economies.” Specifically, the committee called for the sharing of inspection reports as an important first step in mutual recognition and international regulatory harmonization. To follow on these efforts and to explore the need and prospects for greater international regulatory harmonization for drug development, the IOM assembled an ad hoc committee to plan a workshop that would explore a set of questions, described in the committee’s statement of task (see Box 1-1). While harmonization is important in all aspects of interna-

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4 INTERNATIONAL REGULATORY HARMONIZATION tional biomedical research for drugs, devices, and other technologies, this workshop focused on regulatory harmonization in drug development. Regulatory approaches to approval of medical devices and diagnostics are also amenable to harmonization, but often involve different stakeholders, and so their discussion in this workshop was included when relevant. OPENING REMARKS4 Amid all this globalization, the need for consistent science-based r ­ egulations and standards has never been more important. —Thomas J. Bollyky, Council on Foreign Relations The co-chair of the IOM’s Forum on Drug Discovery, Development, and Translation and workshop co-chair Steven K. Galson, Global Regu- latory Vice President, Amgen Inc., emphasized the forum’s function as an ongoing neutral place where stakeholders in government, academia, industry, foundations, consumers, and patient groups meet to discuss and confront issues of mutual interest and concern, including the most press- ing problems in critical areas of drug development. Thomas J. Bollyky, Senior Fellow for Global Health, Economics, and Development, Council on Foreign Relations, and workshop co-chair, reviewed the numerous economic and other trends that have provided the impetus for globalization of the research, development, production, and marketing of biomedical products, including • he quest for lower development costs; t • educed shipping costs; r • etter information and communication technologies; b • owered tariff barriers; l • ising incomes that create new markets; r • ncreased government spending on medical care; and the i • rowing burden of noncommunicable diseases. g In the midst of these many trends, some concerns remain constant: the need for a science-based approach; support for improvements in the effi- ciency and clarity of drug development and evaluation; an emphasis on the safety and quality of biomedical products throughout their lifecycle, throughout the world; and increasing access to safe, effective drugs for all who need them. 4  Thissection is based on the presentations by Steven K. Galson, Global Regulatory Vice President, Amgen Inc., and Thomas J. Bollyky, Senior Fellow for Global Health, Economics, and Development, Council on Foreign Relations.

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Introduction 5 INTERNATIONAL HARMONIZATION: AN INDUSTRY PERSPECTIVE5 In the pharmaceutical industry, said Peter Honig, Global Vice Presi- dent, Regulatory Affairs, AstraZeneca, harmonized standards would • educe costly duplication of effort; r • ncourage sharing of experience and knowledge among regulators e and scientists; • equire fewer clinical trials; and r • ptimize use of limited resources. o From the industry’s perspective, said Honig, harmonization would increase the likelihood that a particular molecule will become a successful drug. Reduced development time, less cumbersome approval processes across countries, and increased speed to market are all important to com- panies. In addition, Honig stated that harmonization would give patients faster access to new medicines and might lower the costs of drug develop- ment, which could lower the price, making new drugs more affordable in many more markets. The need for harmonization has grown up alongside the trend to globalization. Globalization is a boon to industry, and in particular, Honig stated that it offers companies access to scientific talent “emerging in every nook and cranny of the globe”; enables access to more potential recruits for clinical trials and to lower cost suppliers and operational sup- port; and opens new markets in expanding economies. Clinical Trials Until very recently, clinical trial activity has been heavily concentrated in North America and in western and northern Europe. But today, with multiregional clinical trials and global development strategies, the picture is changing. Honig stated that harmonization facilitates the expansion of clinical trial activity. When researchers use clear, shared standards, he said, it is easier for regulators to accept multiregional trial data for their country. Trials can become more efficient. They can better meet the needs of their multinational corporate sponsors. Honig asserted that an ongoing challenge for industry and regulators is to develop shared expectations regarding the use of adaptive trials, conduct of clinical trials, acceptability of endpoints, and data transpar- 5  This section is based on the presentation by Peter Honig, Global Vice President, Regula- tory Affairs, AstraZeneca.

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6 INTERNATIONAL REGULATORY HARMONIZATION ency. A major issue in multiregional clinical trials, especially for a novel therapeutic, is obtaining agreement on appropriate endpoints, including patient-reported outcomes. Furthermore, either rules or common expec- tations may be needed regarding the handling of trial data and when to disclose them. Recent annual growth rates in clinical trial participation in many non- Western countries have been in the double digits. Notable examples of countries where trial participation is increasing rapidly are Japan, China, South Korea, Russia, and Brazil. By contrast, clinical trial participation in the United States has been shrinking. Countries without adequate human subjects protections may be deemed not desirable recruitment targets. The European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) has examined the issue of the accept- ability of foreign clinical trial data, and FDA reportedly is also considering the issue. At present, said Honig, scientists need a better understanding of the regional differences that show up in trial data and what causes them, particularly whether they indicate fundamental population differences or reflect different patterns of medical practice. Persistent Barriers Before clinicians can use a pharmaceutical product in a particular country, it needs to be registered there. Numerous barriers to registration currently exist, said Honig, such as • hina, Korea, and Taiwan require that a new drug be tested in C subsets of their population or in separate studies before it can be approved. • ndia, Mexico, and Vietnam require that specific numbers of their I nationals participate in clinical trials of the proposed drug. Such requirements can create logistical difficulties in multiregional trials, when researchers are required to allocate a certain number or percentage of trial slots to specific groups of patients. “Eventually those percentages add up, and sometimes they add up to more than 100 percent,” said Honig. As challenging, people in some countries are easier to recruit as trial participants than others. In the United States, said Honig, clinical trial recruitment is often slow. The result is that the trial, which has a fixed number of slots divided into specific categories of predetermined size, may fill certain categories much more quickly than others, and the whole process slows down. The industry aim is, of course, to reduce the time involved in subject recruitment.

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Introduction 7 The final composition of the trial population can be “guided by sci- entific insights, proper Phase II dose range, and proper understanding of ethnic sensitivities,” said Honig, but harmonized standards and data requirements would greatly facilitate the process. Before the European harmonization program (see Box 1-2), which has advanced considerably, manufacturers had to seek registration approval for their products in Europe, one country at a time. Now, centralized BOX 1-2 Selected International Harmonization Effortsa • nternational Conference on Harmonisation of Technical Requirements for I Registration of Pharmaceuticals for Humans (ICH) includes regulators and industry representatives from Europe, Japan, and the United States. ICH has produced guidelines on quality, safety, and efficacy and a common tech- nical document. Although some countries have adopted these standards into law, FDA uses them as guidelines only. •  he European Union (EU) has harmonized the European-regulated mar- T ket through EMA, which is a decentralized body of the EU, and its Heads of Medicines Agency, a network of the heads of agencies responsible for regulating human and veterinary medicines in the individual countries of the European Economic Area. •  he World Health Organization (WHO) establishes medicinal, clinical, and T technical standards and promotes regulatory capacity building, training, and work sharing for regulatory authorities. Notable activities are its Certificate of Pharmaceutical Product initiative and its Prequalification of Medicines Programme (WHO PQP), both intended to increase access to essential medicines in resource-limited countries and ensure that they meet accept- able standards of quality, safety, and efficacy. WHO’s International Confer- ence of Drug Regulatory Authorities provides member states with a forum for discussing further collaboration opportunities. •  he Pharmaceutical Inspection Convention and Pharmaceutical Inspection T Co-operation Scheme (PIC/S) encourages mutual recognition of manufac- turing site inspections. •  he European Medicines Agency-U.S. Food and Drug Administration (EMA- T FDA) Quality By Design (QBD) pilot will test a process of parallel review of specific drug development and manufacturing data components, particularly the quality/Chemistry, Manufacturing and Controls (CMC) section of manu- facturers’ marketing applications. •  arious regional harmonization programs, many of which participate in V ICH’s Global Cooperation Group (GCG), include initiatives in Africa, the Asia-Pacific area, Latin America, and the Middle East. a Adapted from the presentation by Peter Honig, Global Vice President, Regulatory Affairs, AstraZeneca.

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8 INTERNATIONAL REGULATORY HARMONIZATION procedures and common labels are all facilitated by harmonized techni- cal requirements. A key underlying factor is having a legal framework in Europe that supports the system, establishing centralized procedures and enabling mutual recognition of each other’s data. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use’s (ICH’s) common technical docu- ment and electronic standards for submission of drug approval requests (dossiers) and individual case safety reports for pharmacovigilance is a major step forward for industry, for the regulators, and for information sharing, said Honig. In addition, Europe has made efforts to facilitate and standardize clin- ical trial applications. New kinds of therapies, biological products, and dosage forms, and an increased industry focus on lifecycle management— from a product’s inception in the laboratory to the end of its patent life— will likely be on the ICH agenda in the future, said Honig. Challenges for Existing Harmonization Initiatives A large gap in regulatory capacity and expertise between emerging and developed countries remains, said Honig. Programs, such as those of WHO, help governments in less developed nations to be sure the drugs and medical devices imported into their countries are safe and effective, without requiring them to divert limited resources to replicate more developed nations’ regulatory infrastructures. This allows them to focus on the issues of greatest local concern, such as the integrity of the supply chain. Honig added that many of the regional harmonization initiatives lack key infrastructure pieces that support the European efforts, notably its legal framework, but may be able to build on region-wide economic interests. The regional interests generally take more of a confederation approach, where they adopt guidelines in spirit, but there is no automatic and infrastructural mechanism to make them binding. Eventually, inter- regional cooperation also may be desirable. Good practice inspections and reinspections of manufacturing and clinical trial sites can become burdensome, said Honig. A global phar- maceutical company will often have multiple inspectors coming in from different countries and from different regulatory authorities in different regions. “One has to wonder about the incremental value of some of these duplicate inspections,” Honig said. At the same time, industry and regulators alike are vitally concerned with maintaining quality standards, having a common understanding of what those are across agencies, and determine whether regulators can assess quality and ensure supply chain integrity. From an industry

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Introduction 9 perspective, Honig argued that harmonization efforts ideally need to aim at simultaneous global development, with near-simultaneous product registration around the world. INTERNATIONAL HARMONIZATION: A REGULATOR’S PERSPECTIVE6 Different countries take different approaches to medical products regulation, depending on a number of factors, said Hubert Leufkens, Chair, Dutch Medicines Evaluation Board, and Division of Pharmacoepi- demiology and Clinical Pharmacology, Utrecht University for Pharmaceu- tical Sciences. This is true even when they are geographically proximate, operate under the same legal framework, and rely on the same scientific processes and the same data to make their decisions. Some regulatory regimes may be more risk-averse, while others may prioritize potential benefits. Whether they emphasize risks or benefits may vary from one instance to another. As a result of these discordant outcomes from regula- tory decision making, said Leufkens, patients in one country may have access to medications that others do not have, which regulators may be hard pressed by patients, providers, politicians, and the media to explain. Leufkens presented an example in FDA’s revocation of approval of Avastin for metastatic breast cancer. Although FDA originally approved the drug for this indication, evidence that it did not extend life or improve the quality of life, while increasing the risk of serious side effects, prompted FDA’s subsequent decision. Yet, Avastin remains approved for metastatic breast cancer in other countries. Such contradictory situations, some of them widely publicized, can erode public trust in the system. However, Leufkens considers FDA’s public report on the reasoning behind its deci- sion a model of balance and perspective. Generally, the way agencies communicate about variance is extremely important and needs greater clarity, he said. Schellekens and colleagues (2011, p. 175) stated that regulatory sys- tems should be assessed “in terms of their ability to ensure patient safety, enhance public health, and stimulate innovation.” Their effectiveness at achieving this latter aim are much in doubt, as the introduction of new and innovative drugs has decreased sharply, despite rapid advances in biomedical research, said Leufkens. Schellekens and colleagues (2011, p. 175) further stated, “Although the reasons for this innovation deficit 6  Thissection is based on the presentation by Hubert Leufkens, Chair, Dutch Medicines Evaluation Board, and Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University for Pharmaceutical Sciences.

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10 INTERNATIONAL REGULATORY HARMONIZATION are not fully understood, many observers see the increasing demands of the regulatory systems as one of the main drivers.” Leufkens asserted that regulators need to answer four important questions in assessing a new pharmacologic product: 1. What is the precise diagnosis it is intended to affect? 2. What endpoints were measured in the research, and are they clini- cally relevant to the disease or condition at issue? 3. What target population will benefit? 4. What kind of comparison is useful, needed, and feasible? Although these questions appear straightforward, addressing each of them presents challenges. Leufkens gave examples for each, keyed to the numbers above, including the following: 1. Diagnosis of psychiatric conditions varies from one country to another 2. In oncology, use of overall survival rates versus progression-free survival as endpoints; or in diabetes, the use of blood glucose levels versus or in addition to other measures, with an increas- ing preference for clinical outcome measures, rather than simple biomarkers 3. Use of biomarkers to identify populations, inasmuch as different nations have different capabilities to conduct a robust biomarker identification effort 4. Divergent views on whether placebo recipients constitute an appropriate comparison group versus active controls (e.g., patients receiving standard treatment), with the trend being for greater emphasis on the latter Regulators use dossiers prepared by manufacturers in determining whether to approve a new drug. Problems associated with these dossiers are not infrequent. Leufkens said typical problems that can contribute to different regulatory decisions include the following: • oor presentation: For example, the dossier presents data in a con- P fusing way or presents too much data, in which case the drug itself often receives a poor assessment. • onversely, some dossiers may mask data shortcomings by the C strength of their presentations. • oping with innovation: It may be difficult for regulators to assess C a new concept, so the default is to request more information, but

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Introduction 11 whether such requests actually produce an improved product is debatable. • Some advanced therapies, including gene therapies, may appear to regulators as too risky. In the end, some of the variance in approval decisions across nations arises through the dynamics of their individual review committees and their decision-making styles and processes. Some nations base their pro- cesses on precise rules, whereas others base them on principles. The latter approach gives greater flexibility to regulators, said Leufkens, but also reduces the system’s predictability. The labeling of a drug, which includes the indications for which its use is approved, can vary among countries and change over time as new information is compiled. Sometimes the number of indications is expanded and sometimes reduced, particularly if complications arise that suggest use needs to be more tightly controlled. A study of approaches used by FDA and EMA in the evaluation and approval of new anticancer indications found real difference in the regulatory agencies’ wording for nearly half (47 percent) of the indications. However, the differences were clinically meaningful in only 10 of these instances (Trotta et al., 2011). Similarly, a study of differences in regulatory actions by FDA and the European Union related to biologicals appeared at first to suggest these differences were quite large, but further analysis indicated that clinically relevant differences were much smaller (Giezen et al., 2008). The more important feature was the timing in the two entities’ actions. FDA was more likely to advise clinicians about potential problems sooner than was the EU, and in some cases even to require a “black box warning” sooner.7 Leufkens concluded that there may always be differences in the ways people look at the data, how they weigh the potential benefit or harm of specific products, and how they try to respond to their populations’ unmet medical needs. 7  An FDA “black box warning” is the most stringent notice of potential side effects from a drug; the notices must be carried on the container to allow the drug to stay on the market.

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