4

Areas of Need for Harmonized Standards and Barriers to Progress in Addressing the Gaps

Although the morning session of the workshop reviewed the quite extensive harmonization and convergence activities under way around the world, according to Steven K. Galson, Amgen Inc., session chair and workshop co-chair, this session’s focus was on the gaps—how they are identified, how they are dealt with, and what the barriers to progress are.

GAPS FROM THE REGULATOR’S PERSPECTIVE1

Douglas C. Throckmorton, Deputy Director for Regulatory Programs, Center for Drug Evaluation and Research (CDER), FDA, began his presentation by summarizing the current environment for drug regulatory harmonization. He said harmonization is occurring across a wide range of activities, from regulatory policies to technical standard setting. Multiple parties are involved, each with its own skill sets, resources, needs, and values that affect the pace and success of harmonization efforts. Among these interested parties, regulators have an important role to play.

According to Throckmorton, one of the gaps that regulatory agencies face is acquiring the scientific expertise to regulate the cutting-edge products emerging from many scientific specialties, such as pharmacogenomics, metabolomics, antisense therapies, and the development of nanotechnologies. Regulatory agencies need to be able to evaluate such innovative

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1 This section is based on presentation by Douglas C. Throckmorton, Deputy Director for Regulatory Programs, Center for Drug Evaluation and Research (CDER), FDA.



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4 Areas of Need for Harmonized Standards and Barriers to Progress in Addressing the Gaps Although the morning session of the workshop reviewed the quite extensive harmonization and convergence activities under way around the world, according to Steven K. Galson, Amgen Inc., session chair and workshop co-chair, this session’s focus was on the gaps—how they are identified, how they are dealt with, and what the barriers to progress are. GAPS FROM THE REGULATOR’S PERSPECTIVE1 Douglas C. Throckmorton, Deputy Director for Regulatory Programs, Center for Drug Evaluation and Research (CDER), FDA, began his pre- sentation by summarizing the current environment for drug regulatory harmonization. He said harmonization is occurring across a wide range of activities, from regulatory policies to technical standard setting. Multiple parties are involved, each with its own skill sets, resources, needs, and values that affect the pace and success of harmonization efforts. Among these interested parties, regulators have an important role to play. According to Throckmorton, one of the gaps that regulatory agencies face is acquiring the scientific expertise to regulate the cutting-edge prod- ucts emerging from many scientific specialties, such as pharmacogenom- ics, metabolomics, antisense therapies, and the development of nanotech- nologies. Regulatory agencies need to be able to evaluate such innovative 1  This section is based on presentation by Douglas C. Throckmorton, Deputy Director for Regulatory Programs, Center for Drug Evaluation and Research (CDER), FDA. 35

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36 INTERNATIONAL REGULATORY HARMONIZATION products so that their first response to them is not overly conservative. FDA has developed the Voluntary Exploratory Data Submissions (VXDS) meeting to address this need. VXDS provides a mechanism for industry and regulators to discuss potential applications of new science to drug development. The meetings are nonregulatory and sponsor driven, and the discussions are not binding. More than half of the 53 VXDS meetings to date have included EMA participation. Another type of gap has emerged due to improvements in informa- tion management, said Throckmorton. These are gaps in interconnectivity among existing knowledge databases. Here, consistent standards of data collection, access, and storage would enable much greater efficiencies, more robust research, and expanded pharmacovigilance. Gaps in information about how FDA’s regulatory structures work are addressed in CDER’s Forum for International Drug Authorities. In the past 8 years, the forum has met about 15 times. Throckmorton noted that many of the discussions focus on FDA’s perspective on good clinical practices, manufacturing quality, and the like. The educational benefits of this forum also help close the capacity gap, while forging relationships among regulators from around the world, he said. Harmonization initiatives try to fill different sets of gaps, depend- ing on the level of regulatory development in a given country, said Throckmorton. For example: • Nations with well-developed regulatory systems will want to ensure their systems support innovation, and, as suggested, they are always playing catch-up with the science. • Nations with less developed regulatory systems may want to first fill gaps in capacity and bring their system into harmony with other nations (global engagement). • Regulators in all nations want to minimize any differences between their actions, the expectations of the country’s citizens, and the health outcomes they experience. They may ask themselves, “Do our actions result in quality medicines at reasonable costs, effi- ciently produced? To the extent we are not achieving this, there is a gap.” The role for regulators in closing these gaps, said Throckmorton, is to understand the unique role that regulation pays. It is a legal role in that regulations and laws are applied and enforced, and it is a public health role. Regulators are in a unique position to see both needs and opportuni- ties and to understand the changes they might make that not only are the

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AREAS OF NEED AND BARRIERS TO PROGRESS 37 most feasible, but also would have the largest impacts. Throckmorton stated that the five obligations of regulators are to 1. protect the public from harm; 2. preserve maximum individual freedom of choice; 3. promote consistent and dependable rules that are equally appli- cable to everyone; 4. guarantee meaningful public participation; and 5. provide prompt decisions on all regulatory matters. These issues are at the heart of harmonization, he concluded. GAPS FROM THE PERSPECTIVE OF NONGOVERNMENTAL ORGANIZATIONS, FOUNDATIONS, AND PRODUCT DEVELOPMENT PARTNERSHIPS2 Based on his experiences, Vincent Ahonkhai, Deputy Director, Regu- latory Affairs, Bill & Melinda Gates Foundation (BMGF), has a perspec- tive that combines the views of both the private and public sectors. He identified a number of key gaps in the global health regulatory landscape at different stages of new product introduction: product development, registration, and postregistration. During product development, more timely, effective, ethical, and regulatory approvals for trials are needed, he said. For many reasons it may be difficult to conduct the trials in the countries where products will be used. Ahonkhai said one specific need is for the infrastructure and expertise to support and enforce good labora- tory and clinical practices. For a broad array of products, the public health concern and the reg- istration concern is not focused solely on the expeditious development of innovative medicines, vaccines, or diagnostic tools, but also on making those new products affordable. Thus, the entire end-to-end value chain has to be considered, said Ahonkhai. Ahonkhai stated that the countries he is interested in—among the more than 100 low- and middle-income nations around the world—often use products procured by UN agencies, which makes them affordable. These products undergo initial registra- tion, followed by WHO prequalification (WHO PQ) or some other filter of quality assurance, and finally they need to meet the registration require- ments of the purchasing nation. In the postregistration phase, countries need an effective infrastructure to detect and report safety and effective- ness data and then to interpret and act on it, he said. 2  This section is based on the presentation by Vincent Ahonkhai, Deputy Director, Regula- tory Affairs, Bill & Melinda Gates Foundation (BMGF).

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38 INTERNATIONAL REGULATORY HARMONIZATION In terms of regulatory harmonization challenges, Ahonkhai stated that one gap is in the regulation of vector control products. The only group seriously looking at regulatory standards for public health–focused pesti- cides, according to Ahonkhai, is the WHO Pesticide Evaluation Scheme. 3 He said there is little innovation in this area, and no new active ingredi- ents have been developed specifically for this use in the past several years. What has happened instead is a repurposing of agricultural pesticides. The Innovative Vector Control Consortium is a not-for-profit product development partnership working on the issue, but very slowly. Many less developed countries have no pathway to regulate these products; in sub-Saharan Africa, some 30 percent do not, said Ahonkhai. Where capacity does exist, it may be found in the Ministry of Agriculture, either alone or in conjunction with the Ministry of Environment or Ministry of Health. As a result, manufacturers and developers face a complex situ- ation when seeking the necessary approvals. By contrast, according to Ahonkhai, the approval process for drugs and vaccines is very clear, in large part because of the work of ICH. Although following ICH standards is not mandatory, its work is widely used. Ahonkhai described several barriers to closing the gaps in medical product development, including • the diversity of countries, their health problems, and the variability in their standards, capabilities, and aspirations; • a lack of sufficient and sustained financing for critical regulatory activities and the staffing to carry them out; • too few mechanisms for regulators to rely on the work of others— for example, in good manufacturing process inspections; and • asymmetry among the interests of commercial product develop- ers, public health entities, and nonprofit product development partnerships. Yet, at each stage in the product development process, Ahonkhai stated that good examples can be found. In clinical trials, he cited the Afri- can Vaccine Regulatory Forum (AVAREF), the European and Developing Countries Clinical Trials Partnership, and the Critical Path to Tuberculosis (TB) Drug Regimens. In the registration arena, he said the aforementioned WHO PQ programs and the AMRH initiative stand out. Finally, at the postregistration stage, he noted the WHO Global Vaccine Safety Blueprint and the Safety Surveillance Working Group. Moving forward, these initiatives and others can build on past suc- cesses. One example is the vaccine for meningitis A. Developed with 3  See http://www.who.int/whopes/en (accessed April 10, 2013).

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AREAS OF NEED AND BARRIERS TO PROGRESS 39 standards created by the public and private sectors working together, this new vaccine has been registered and is now being administered in Africa’s meningitis belt at a very low cost. Ahonkhai concluded that success such as this comes about because of a solid understanding of the landscape of epidemiologic and drug development challenges facing low- and middle-income countries, comprehensive stakeholder engage- ment, and prioritization of issues where regulatory harmonization can have the most impact. BREAKOUT SESSION REPORTS Following presentations by Throckmorton and Ahonkhai, workshop attendees participated in breakout groups in one of five topic areas to further discuss gaps in harmonization: 1. Qualification of innovative development methods/drug develop- ment tools 2. Clinical development 3. Evaluation and evidentiary requirements 4. Postmarket safety surveillance 5. Manufacturing standards and process The groups’ assignments were to discuss the high-priority gaps in harmonization for that particular area, barriers to achieving harmoniza- tion, and approaches to overcome those barriers. After the breakout ses- sions, a rapporteur from each group reported back to the larger workshop audience on their observations of the key points of discussion. Several rapporteurs related discussions about the need for greater transparency on how standards for decision making are set and interpreted. Even when consistent standards are used, some said, it is not always clear why spe- cific decisions differ across jurisdictions. At the same time, the breakout group participants identified numerous potential opportunities to move forward in resolving gaps. Qualification of Innovative Development Methods and Drug Development Tools4 Martha A. Brumfield, Director, International and Regulatory Pro- grams, C-Path, identified the following key issues discussed by partici- pants in this breakout group: 4  This subsection is based on the presentation by Martha A. Brumfield, Director, Interna- tional and Regulatory Programs, C-Path.

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40 INTERNATIONAL REGULATORY HARMONIZATION • Organizations or sponsors desiring to qualify a drug develop- ment tool, such as an animal model or in vitro test, need to clearly articulate the context of use, including the proposed tool’s specific purpose, its sensitivity and specificity, and how it will be used. • Clinical biomarkers as research tools need special scrutiny and need to be population-specific; researchers need to be clear on whether they are expected to serve as predictive, prognostic, or surrogate endpoints. • At present, FDA, EMA, and PMDA tool qualification procedures are not harmonized and require differing levels of evidence. The FDA’s process requires some degree of predictability about a tool’s performance, whereas EMA uses a more principles-based approach. In addition, their legal structures, fee requirements, and time lines are different. Furthermore, Brumfield noted a willingness among the breakout group participants to consider whether a common technical document might be constructed around areas of agreement in information required by FDA and EMA. From that, she noted, a dossier preparation template could be prepared that would meet the requirements of both agencies, and leave areas of difference to be customized by the respective agencies. Given the staggering number of potential new drug development tools and methods, setting priorities among them is important, said Brumfield. However, not every group’s priorities will be the same. Patients, industry, and regulators may all be deeply interested in different kinds of tools. A prioritization process therefore might start with a gap analysis that would bring to light the priorities of different stakeholder groups, she said. Tool development and qualification take considerable time and energy. To learn whether they are worth the investment, having not just the priorities, but also a set of publicly available performance indicators would allow developers to learn from both successes and failures, Brum- field added. She noted that the breakout group participants did not agree on which entities should be responsible for collecting and reporting this information. Under Europe’s Marketing Authorization Applications process (equivalent to FDA’s NDAs), Brumfield noted that manufacturers may receive scientific advice from the EMA.5 If this advice pertains to use of 5  “Scientific advice is when the [EMA] gives advice to a company on the appropriate tests and studies in the development of a medicine. This is designed to facilitate the development and availability of high-quality, effective and acceptably safe medicines, for the benefit of patients.” See http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/ general_content_000049.jsp&mid=WC0b01ac05800229b9 (accessed April 10, 2013).

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AREAS OF NEED AND BARRIERS TO PROGRESS 41 a biomarker, for example, the dossier needs to include information about how the biomarker was used. Brumfield related the group’s discussions about how extracting this information through some means (undeter- mined) could lead to creation of a helpful compendium of effective appli- cations of various product development tools. U.S. NDAs do not necessar- ily include this information, which means industry would have to divulge it voluntarily for it to be included in a compendium. She added that the group discussed the fact that stakeholders need to better understand more of the nuances of what qualification means in different jurisdictions and what is known and yet to be learned about specific drug development tools. For example, she noted it would be as educational to learn why specific tools were rejected by the regulatory authorities as it would be to know why others were accepted. Similarly, much might be learned by making available both the regulator’s and the industry’s perspective on a specific decision. One way to expand this pool of information, she said, would be to offer incentives for researchers to go through the qualification process. Brumfield noted that breakout group participants suggested a variety of incentives, including a priority review voucher, a commitment to a shortened review time frame, or a waiver of a scientific advice fee. Increasing the number of tools evaluated would benefit learning across the product development enterprise, she said. Evaluation and Evidentiary Requirements6 Lawrence E. Liberti, Executive Director, Centre for Innovation in Reg- ulatory Science (CIRS), identified the following key issues discussed by participants in this breakout group: • Increasing requirements by regulatory authorities of different countries for minimal proportional representation of subjects from the home country in multiregional clinical trials pose difficulties. Liberti said the discussion of the topic centered on whether such requirements reflect real scientific and clinical concerns or whether in some cases they are motivated by political factors or a lack of confidence in other countries’ data. • Development of evidentiary requirements for multiregional clinical research is complicated by a number of additional factors, includ- ing inconsistent ethical oversight, noncomparable standards of care and clinical practice, inconsistencies in good manufacturing prac- tices, and differences in risk tolerance. 6  This subsection is based on the presentation by Lawrence E. Liberti, Executive Director, Centre for Innovation in Regulatory Science (CIRS).

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42 INTERNATIONAL REGULATORY HARMONIZATION • In studying specific diseases and conditions, the local population needs to be able to provide appropriate controls, an issue that affects study design and the selection of endpoints and comparators. • Ideally, study populations in different regions would be aligned with respect to patient needs and patient-focused outcomes. To resolve some of these problems, a way of more effectively com- municating benefits and risks associated with a particular product being tested is needed. Transparency about how decisions are made and the uncertainties that were weighed in the decision is essential, said Liberti. He noted that other ways to increase harmonization that were discussed are through capacity building, especially in making good benefit-risk assessments and employing tools that facilitate a simple, structured, and systematic approach to assessing benefits and risks. Among these tools are a common lexicon and a common format for benefit-risk communica- tion. For example, FDA is now publishing on the web the results of its benefit-risk reviews. A well-structured benefit-risk approach that facili- tates communication can be used by different stakeholders—developers, regulators, patients, and others, he said. Liberti noted that if entities communicate well, then the under- standing of how to interpret evidentiary standards falls into place, and even smaller regulatory entities can apply systematic, well-developed approaches in their decisions. This makes the agency’s position easier to explain in cases where its decision differs (in either accepting or rejecting a product) from those of other regulatory bodies. In this way, said Liberti, local decisions can be informed by global information. Clinical Development7 Leslie Ball, Assistant Commissioner, International Programs, and Deputy Director, Office of International Programs, FDA, stated that the breakout discussion of critical barriers for clinical development focused on two key areas: (1) clinical trials and (2) premarketing safety reporting requirements. Clinical Trials In addition to occasional cultural differences and language barriers that impede the smooth operation of multiregional trials, Ball noted the discussion of numerous bureaucratic obstacles, including 7  This subsection is based on the presentation by Leslie Ball, Assistant Commissioner, International Programs, and Deputy Director, Office of International Programs, FDA.

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AREAS OF NEED AND BARRIERS TO PROGRESS 43 • difficulty identifying specific regulatory requirements; • lack of transparency and gaps in regulatory practices, for example, with respect to time lines; • lack of regulations or organization within regulatory authorities; and • lack of clarity about the oversight responsibilities of regulatory authorities versus ethics committees, which leads to redundant efforts. Ball said the breakout group discussed barriers at three levels. At the level of the regulatory authorities, there are differences in the regulations themselves and in the way that regulators work, she said. For example, the European Union and the United States take different approaches to issues such as choosing active comparators, dose finding, determining treatment effects, and dealing with treatment-effect heterogeneity. Nev- ertheless, expanding ICH beyond the founding members was deemed a positive experience, as were the European Union’s centralized procedures and application process. A second level of barriers arises because of differences from one coun- try to another in how trials are overseen and monitored, said Ball. Third, at the study site level, additional barriers may arise—for example, sites may lack sufficient capacity to carry out the trial, a problem more likely to arise when the trial involves neglected diseases or takes place in develop- ing countries. In addition, she noted there may be specific programmatic complications, such as differing requirements for pediatric drug develop- ment, which may encounter barriers at all three levels. Ball reflected on suggested approaches to reducing these barriers, including an effort to map the regulatory requirements in different coun- tries. For example, the Global Health Technologies Coalition8 has created a description of the regulatory requirements for 10 developing countries, but frequent changes in requirements make this resource difficult to main- tain. As a result, Ball noted one participant suggested that support be offered to countries’ regulators so that they could take responsibility for keeping their websites updated. Joint reviews—particularly for neglected diseases—might be a good place to start in efforts to achieve greater collaboration, noted Ball. Having systems in place that ensure high-quality data would simplify efforts to use trial results across countries. Ball made two final observations based on the discussions: a good candidate for harmonization is consent requirements for participation in clinical trials, and further development of risk communication in clinical 8  See http://www.ghtcoalition.org (accessed April 22, 2013).

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44 INTERNATIONAL REGULATORY HARMONIZATION trials, in the form of a “questions and answers” document, rather than a full guidance, would be desirable. Premarketing Safety Reporting Requirements Lack of harmonization between safety reporting requirements— specifically, between the European Union and FDA—is a problem, Ball stated. One of the fundamental differences is in assessing causality. FDA relies on product sponsors to aggregate adverse events and provide their assessment of the causes. The European Union relies on causality assess- ments by the investigator and by the sponsor. As a result, sponsors have to adapt their reporting to two sets of requirements. An opportunity for convergence might arise, Ball suggested, if the European Union, within the research protocol, listed certain anticipated events that would not have to be reported, thereby greatly reducing the total number of reports. A clearer threshold focusing on patient safety would lead to reporting only serious and unexpected adverse drug reac- tions, she said. Postmarket Safety Surveillance9 Andy Stergachis, Professor of Epidemiology and Global Health, Adjunct Professor of Pharmacy, Director, Global Medicines Program, School of Public Health, University of Washington, identified the follow- ing key needs discussed by participants in this breakout group: • Strengthen capacity around postmarket safety surveillance before attempting harmonization and convergence, but with those factors in mind. • Bring more countries into ICH. • Decrease variability in individual case safety reports and periodic safety updates because even small differences between country requirements are problematic. • Decrease variability in (and in some countries create from scratch) benefit-risk frameworks. • Expand the concept of postmarket safety surveillance to include adverse effects that arise from how medicines are used, as well as product quality (defects, fake products, and substandard manufacturing). 9  This subsection is based on the presentation by Andy Stergachis, Professor of Epidemiol- ogy and Global Health, Adjunct Professor of Pharmacy, Director, Global Medicines Program, School of Public Health, University of Washington.

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AREAS OF NEED AND BARRIERS TO PROGRESS 45 • Increase evaluation efforts and, correspondingly, develop appro- priate metrics. Stergachis suggested that these challenges result in wasted resources that could be used to increase innovation and access to products. Poor regulatory practices and ineffective postmarket surveillance systems may negatively affect population health, he said. More broadly, inadequate monitoring of marketed products can damage public trust in the regula- tory system and threaten public health programs. Regulatory practices that are not evidence based or that lack incremental benefits pose their own risks, he added. Stergachis noted several solutions suggested by the breakout group participants, including the suggestion for a high-level participatory dia- log on a conceptual framework for postmarket surveillance that includes more than adverse events. Achieving greater transparency among regula- tors requires good working relationships and mutual confidence, so that information about problems, as well as best practices, will be shared. Because some countries’ physicians simply do not report adverse events, he noted, the importance of doing so needs to be covered in medical edu- cation and facilitated by easy-to-use reporting systems. Other individual suggestions he noted were to make the case that postmarket surveillance is important to international trade and econo- mies, and to emphasize that low- and middle-income countries have the opportunity to skip some logistical steps in safety reporting and go directly to systems that use mobile technologies. Finally, Stergachis related that several participants emphasized the importance of sustaining what is already working in harmonization. Manufacturing Standards and Process10 Diane Zezza, Vice President, Global Regulatory CMC, Novartis Phar- maceuticals Corporation, stated that the breakout discussion focused on two key areas: CMC reviews and good manufacturing practices. CMC Reviews Zezza stated that members of this breakout group began their identifi- cation of challenging areas of non-harmonization for industry, regulators, and patients with the lack of harmonization of dossier content. While the format may be consistent, she said, the content often varies greatly. CMC 10  This subsection is based on the presentation by Diane Zezza, Vice President, Global Regulatory CMC, Novartis Pharmaceuticals Corporation.

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46 INTERNATIONAL REGULATORY HARMONIZATION guidances, in particular, are not harmonized, and when this section of the dossier goes through review and approval, many changes need to be incorporated to reflect different regulatory authorities’ requirements. As a result, said Zezza, many variations in specifications and control strategies creep in from the beginning. The complexity only increases in the postapproval phase, in attempting to manage supply chain logistics to meet different specifications or when manufacturing processes evolve. Zezza noted that such challenges increase costs and inhibit continuous improvement overall. For a product with a long lifecycle, especially, these multiple requirements are a significant burden. Zezza added that even presumably harmonized guidances, like those of ICH, may be implemented inconsistently across countries, and coun- tries may apply additional standards above and beyond the ICH founda- tion. Some countries require additional import testing, and unexpected results may affect the supply of a product or trigger recalls. Zezza noted that individual suggestions for ways to tackle these prob- lems, short of a centralized global filing procedure, included • development of mutual recognition agreements for dossier review and approval of CMC content; • assessment of whether WHO’s Certificate of Pharmaceutical Prod- uct process might evolve to include CMC reviews; and • application of the fundamental principles of the QBD paradigm in an effort to reduce postapproval changes, acknowledging that the QBD approach has not yet achieved its full potential. Good Manufacturing Practices The good manufacturing practices standards established by differ- ent countries and the way they are interpreted by individual inspectors, even from the same regulatory agency, also are divergent, said Zezza. EU health authorities tend to indicate the significance of their findings, which is deemed helpful, whereas others simply enumerate their observations. Zezza noted that the multiple preapproval inspections that a com- pany must go through, even for a global product manufactured at a single site, can be quite burdensome. For example, the manufacturer of one recent new product underwent 22 preapproval inspections by various groups, she said. While many countries appear to agree on the PIC/S standards, it might be possible for PIC/S to add some criteria from the WHO PQ inspection program, which is well accepted in numerous countries, she said, thereby increasing the number of nations that accept PIC/S inspections. She also noted that significant divergence in regulatory requirements

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AREAS OF NEED AND BARRIERS TO PROGRESS 47 occurs in the postapproval period. Differences in CMC content rules require different categorizations of change. The timing for review of changes may take 24 to 36 months and, in some countries, is completely undefined. The logistical challenges are enormous, requiring, for example, separating projects before and after change. This burden results in higher manufacturing costs and potential product shortages in certain countries. One approach to this problem, Zezza said, might be the broader use of global comparability protocols and implementation of QBD principles. She noted potential opportunities to extend ICH’s success in the manu- facturing arena by persuading all countries to commit to implementing its common data requirements and by linking the ICH guidances to trade agreements. In the developing countries, the existence of multiple, non-harmonized pharmacopeias creates a persistent challenge. The possibility of a global pharmacopeia and development of good pharmacopeia practices is under active discussion, she said. Zezza noted that members of the breakout group acknowledged the shortage of health authorities’ regulatory infrastructure resources in developing countries. Work-sharing options that would preserve those resources were suggested by participants.

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