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Principles and Definitional Considerations

Andreas Seiter, Senior Health Specialist, Pharmaceuticals, Health, Nutrition, and Population, World Bank, introduced the session by noting that pharmaceutical regulation is “the place where hard science meets cognitive complexity,” where people of different backgrounds in terms of geography, education, professional training, and habits of mind come together to make vital scientific decisions. Therefore, clarity in definitions is essential, he said, and helps overcome the problem that words may have different meanings in different contexts.

THE TERMINOLOGY LANDSCAPE AND OPTIONS FOR REGULATORS1

Mike Ward, Manager, International Programs, Health Canada, began his presentation by emphasizing that the lack of commonly accepted definitions in drug regulation is a stumbling block to harmonization. Lack of clarity exists, he said, even around such deceptively obvious concepts as regulatory cooperation. Other examples Ward gave of terms that all countries may not use the same way include

• International: Does it mean more than one or two countries, regional, beyond regional?

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1 This section is based on the presentation by Mike Ward, Manager, International Programs, Health Canada.



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2 Principles and Definitional Considerations Andreas Seiter, Senior Health Specialist, Pharmaceuticals, Health, Nutrition, and Population, World Bank, introduced the session by noting that pharmaceutical regulation is “the place where hard science meets cognitive complexity,” where people of different backgrounds in terms of geography, education, professional training, and habits of mind come together to make vital scientific decisions. Therefore, clarity in definitions is essential, he said, and helps overcome the problem that words may have different meanings in different contexts. THE TERMINOLOGY LANDSCAPE AND OPTIONS FOR REGULATORS1 Mike Ward, Manager, International Programs, Health Canada, began his presentation by emphasizing that the lack of commonly accepted defi- nitions in drug regulation is a stumbling block to harmonization. Lack of clarity exists, he said, even around such deceptively obvious concepts as regulatory cooperation. Other examples Ward gave of terms that all coun- tries may not use the same way include • International: Does it mean more than one or two countries, regional, beyond regional? 1  This section is based on the presentation by Mike Ward, Manager, International Pro- grams, Health Canada. 13

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14 INTERNATIONAL REGULATORY HARMONIZATION • Regulatory versus regulation. • Cooperation versus collaboration. Putting these albeit imprecise notions together, Ward suggested that a working definition of international regulatory cooperation could be “inter- country activities carried out with a view to improving national regula- tory outcomes and promoting convergence.” The current lack of common understandings can lead to confusion and, more important, can set unre- alistic or varying expectations in the minds of central agencies, regulators, industries, consumers, and other stakeholders. This working definition could involve any number of countries, is applicable at all stages of the regulatory life cycle, from assessment of new or existing regulations through program implementation, and, finally, to review and evaluate regulatory programs. Inherent in the definition are many potential activi- ties, Ward said, including • information sharing; • collaborative scientific work; • common standards; and • work sharing. Ward described the history of international efforts in the harmoni- zation of products. The quest for international harmonization, he said, began with the Industrial Revolution and the need to standardize even humble products like screws so they had identical thread sizes. With the expansion of trade in the 20th century, products crossed borders and many people around the world depended on goods made in other countries. After World War II, the Geneva-based International Organiza- tion for Standardization (ISO) was created and the General Agreement on Tariffs and Trade (GATT) was adopted, both of which furthered the push for common standards. GATT was not put in place until 1995, when the World Trade Organization (WTO) began its work. Most recently, the development of the European Union has been an important driver for harmonization of standards not only within Europe, but more broadly, starting with creation of the European Economic Community in 1957, the European Communities a decade later, and, in 1993, the European Union. In the pharmaceutical field, the leading international body for stan- dards harmonization is the ICH, said Ward. Many drivers led to its creation in 1990—globalization of the pharmaceutical industry; a rapid increase in the diversity of technical requirements; increasing workloads for regulators; the complexity of products, processes, and technology; ris- ing drug development costs; and a more informed and risk-averse public. Trade agreements and the globalization of many aspects of drug

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PRINCIPLES AND DEFINITIONAL CONSIDERATIONS 15 research and production have pushed regulators to look at the drug approval process as not something confined to their own nations, but rather an activity that requires international regulatory cooperation. Harmonization or Convergence? Perhaps most relevant in the current context, said Ward, is the WTO Sanitary and Phytosanitary Agreement related to food safety and animal and plant health. It defines harmonization as “the establishment, recog- nition and application of common sanitary and phytosanitary measures by different members (jurisdictions)” (WHO, 2010). An example can be seen by looking at pharmacopeial harmonization: The U.S., European, and Japanese pharmacopeias have engaged in harmonization efforts for some time. This does not mean that their texts are exactly the same, but they are harmonized because, when they are tested, they yield the same result. Harmonization applies to work like that of ICH, where people develop together the same standard or even joint processes: one example is the Gulf Cooperative Council’s work on joint drug registration and procurement. Convergence, by contrast, takes a broader outlook and is becoming a more widely used term. Convergence goes beyond the development of common standards and processes to take into account how regulatory authorities actually use them. For example, while review practices are not the same across countries, they often produce the same outcome. Many aspects of regulatory review—templates, operating procedures, competency-based training, and so on—are part of good review practices, but they are not necessarily standardized or harmonized. However, if they produce similar results, they are converging. Regulatory convergence also considers the disparate capabilities of regulatory authorities across nations. Inherent in the term is the impli- cation that the process is moving forward. Essentially, convergence is dynamic and catalyzed by workload, globalization, technology, and pub- lic expectations, said Ward. Harmonization and Convergence in Action Operationally, what does harmonization imply? Its benefits are evi- dent, said Ward. It is a key enabler for enhanced international cooperation; it can expand from technical requirements to procedures and processes; then, in certain circumstances, it can evolve into laws and regulations. But while simple in concept, harmonization is difficult in execution. Key to the success of ICH’s operations is the involvement of both regulators and industry, said Ward. Its approach is well managed, sci-

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16 INTERNATIONAL REGULATORY HARMONIZATION ence based, and consensus driven. Most important, it involves a limited number of players that have comparable regulatory and technical capa- bility, and the regulators are committed to implementing the products of harmonization. Countries may adopt a harmonized standard or guidance without change or adapt it in any number of ways—good or bad—to meet local circumstances, but true harmonization cannot be measured until the stan- dard’s actual implementation is assessed, said Ward. The implementa- tion process may encounter numerous stumbling blocks. A new standard needs to fit into existing laws and regulatory frameworks, which may mean collateral changes are needed with respect to filing documents, policy work, and so on. Regulators may need training to carry out the new standard, or industry may not be prepared to respond to it. Thus, even though a harmonized standard is in place, the implementation phase contains many variables that may result in divergent results. Finally, as explored earlier in the workshop, no matter how well harmonized stan- dards and processes are, different regulatory agencies may reach different conclusions. Ward noted that the Pan American Network for Drug Regulatory Harmonization (PANDRH), established to promote pharmaceutical regu- latory harmonization and capacity building within the Americas, recog- nized at the outset that asymmetries within the regulatory capacities of the hemisphere’s nations might impede implementation. In PANDRH, harmonization connotes a search for common ground within a framework of recognized standards. PANDRH’s approach more closely approximates the concept of regulatory convergence, whereby regulatory requirements across economies or countries become more aligned over time as a result of the adoption of internationally recognized technical guidance, stan- dards, and best practices. Importantly, it does not require the harmoniza- tion of different countries’ laws and regulations. Where a political and economic directive exists, such as in the Euro- pean Union and other regions, the issue of different laws is not a problem, asserted Ward. But, worldwide, “if we had to wait for laws to be harmo- nized, nothing would happen,” Ward added. Regulations and technical requirements translate a country’s laws into practice and, ideally, these laws would contain some flexibility. Canada and the United States may not go so far as to harmonize their laws and regulations, but they can adopt good review practices that pro- duce an equivalent result. Two or more systems are said to be equivalent if they produce the same outcomes, regardless of internal system differ- ences. Equivalence can be established and documented through objective means. Examples are mutual recognition agreements related to good manufacturing practices.

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PRINCIPLES AND DEFINITIONAL CONSIDERATIONS 17 Although many nations appear to be on the path to standards har- monization and regulatory convergence, increasingly sophisticated and innovative biopharmaceutical products pose new challenges. Perhaps foremost is that they may require health care settings capable of using them effectively and safely on patients. At present, this final implementa- tion step is not part of the process, except in an after-the-fact way through postmarketing surveillance. In U.S. medicine today, professional organizations are working to put together standards of care that are consensus driven and evidence based. But the practice of medicine is simply not regulated in the same way as the drug market, and variability in care delivery is outside the domain of drug regulators, Ward argued. STANDARDS SETTINGS IN THE CONTEXT OF REGULATORY HARMONIZATION2 A drug manufacturer today may need to produce multiple versions of the same product to accommodate differences in standards and regula- tions that exist from one nation to another. The pharmaceutical industry is a global business, and these varying rules cause delays, impede access to needed medicines, and increase the costs of health care. Unless different standards have some scientific justification, they are both medically and ethically suspect, according to Carolyn Compton, President and Chief Executive Officer, Critical Path Institute (C-Path). Regulatory convergence is a vital strategy for reducing the time and costs required to make new drugs available to patients. Bringing one new drug to market now takes at least a decade and costs more than a billion dollars, said Compton, although one recent analysis estimated the real cost at nearly $11 billion (Herper, 2012). Streamlining the current process will require collaborative, global approaches to standardization that include the public, regulatory bodies, and the private sectors in industry and academia. That will be difficult because, even within a single company, much less between companies and across countries, there is currently much heterogeneity—a lack of common standards—in the way products are developed, tested, and assessed, said Compton, because • data to demonstrate efficacy and safety are defined and collected differently; 2  This section is based on the presentation by Carolyn Compton, President and Chief Executive Officer, Critical Path Institute (C-Path).

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18 INTERNATIONAL REGULATORY HARMONIZATION • measurements of efficacy and safety are based on different criteria; and • methods for designing clinical trials for new drugs differ widely. Conceptually, a good standard is one that saves time, money, and problems in the long run.3 Compton asserted that standards require cer- tain foci—all of which need to be achieved simultaneously—to ensure that the standard is • widely accepted; • freely available (not proprietary or exclusionary); • applicable cost-effectively; • endorsed by standards development organizations; • enforced by regulators; and • globally applicable. The ISO defines a standard as “a document that provides require- ments, specifications, guidelines or characteristics that can be used con- sistently to ensure that materials, products, processes and services are fit for their purpose” (ISO, 2013). Among the benefits of international standards cited by ISO are that they ensure products and services are safe, reliable, and of good quality. In the case of drug development, standards are strategic tools and reduce costs by minimizing waste and errors and increasing productivity. Measurement and Methods Standards C-Path primarily develops measurement and methods standards. Its multistep, iterative development process brings together the best sci- entists from industry, academia, and government, including FDA, for precompetitive data sharing. Measurement and methods standards may be distinguished as follows: • Measurement standards, for example, cover use of molecular or imaging biomarkers for efficacy and patient classification, molec- ular biomarkers for toxicity testing, and patient-, observer-, or clinician-reported outcomes. • Methods standards cover topics like the use of disease models, clini- cal trial simulation tools, and in vitro models. 3  Global good standards have been achieved in many other industries. For example, a person possessing a credit card or bank card can visit any ATM anywhere in the world and extract money in the local currency or in U.S. dollars.

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PRINCIPLES AND DEFINITIONAL CONSIDERATIONS 19 FDA, EMA, and PMDA (Pharmaceuticals and Medical Devices Agency [Japan]) have rigorous, formal processes for review and accep- tance of proposed standards. Once approved, the new standard can be used by any company to develop drugs with the assurance that the sci- entific basis of their data collection will be acceptable to these regulators. C-Path organizes its standards development collaborations into consortiums that are generally focused on a single disease process or on a methodology, such as the generation of patient-reported outcomes instruments. It has established seven consortiums involving more than a thousand scientists and 41 companies around the world.4 According to Compton, the process of working together on the standards and sharing precompetitive information is improving the culture of drug develop- ment. The process also fosters compliance with the standard, she said, as manufacturers develop a sense of ownership that reduces the need for active enforcement. Meanwhile, the regulatory agencies themselves do not have a har- monized process for qualifying these standards. Some have fees, some do not; FDA has twice the number of minimum steps (24) as EMA and PMDA; and FDA takes about four times as long to decide whether to qualify a new standard, said Compton. So far, only a few standards devel- oped under C-Path’s process have been qualified—three by FDA, six by EMA, and one by PMDA.5 According to Compton, initial conversations are under way between FDA and EMA regarding bringing their tool qualification processes more into alignment. Also, as the process becomes more familiar, she said, the pace of qualification may accelerate. Data Standards The challenge of developing data standards is similar to that of developing the scientific standards just described, said Compton. A data standard does not mean a common data element such as the patient’s birth date, which can be written many ways: January 20, 1946; 1-20- 46; 01/20/46; 20 Jan 46; and so on. This diversity in the ways data are reported creates enormous problems when researchers want to query 4  The seven consortium and the issues they are working on [in brackets] are coalition against major diseases [understanding diseases of the brain]; critical path to tuberculosis (TB) drug regimens [testing drug combinations]; multiple sclerosis (MS) outcome assess- ment consortium [drug effectiveness in MS]; polycystic kidney disease consortium [new imaging biomarkers]; patient-reported outcome consortium [drug effectiveness]; electronic patient-reported outcome consortium [drug effectiveness]; predicting safety testing consor- tium [drug safety]. 5  The review and analytic process for qualifying these drug development tools is separate from that for new product approval.

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20 INTERNATIONAL REGULATORY HARMONIZATION across datasets, pool and share data, or analyze multiple trials. Adher- ing to data standards makes clinical trials more efficient; trials that use them can save as much as 60 percent of the time required to analyze and report results and from 70 to 90 percent of the time needed to start up and conduct the trial. At FDA, the extreme variability and unpredictability of data format and content present major obstacles to performing timely, consistent, and efficient data reviews, said Compton, which ultimately hamper innova- tion. In order for FDA staff to work efficiently, they need standardized and well-organized data, they need to understand the basis of the data collection, and they need to understand the scientific basis on which those data were collected. According to Compton, data management and review preparation consume about 40 percent of regulatory review time. Compton argued that implementing data standards would allow FDA to focus on more significant questions relevant to market approval. Its work would be transformed from the “doing steps” of data aggregation and analysis to the “thinking steps” of analysis planning, interpretation, communication, and decision making. Moreover, the sophisticated ana- lytical tools FDA is trying to build cannot be used, at least not efficiently, without these data standards, argued Compton. According to Compton, C-Path is working collaboratively with the Clinical Data Interchange Standards Consortium to address the 58 thera- peutic or disease-specific standards FDA has indicated it urgently needs within the next 5 years. The U.S. Food and Drug Administration Safety and Innovation Act (FDASIA), signed into law in 2012,6 gives the agency authority to require data standards and electronic submission of market approval applications, which it must do by 2017. Requiring and imple- menting U.S. data standards through regulation may create efficiencies domestically, but regulatory bodies around the world will have the added challenge of working within this additional set of standards. Measuring Harmonization The true extent of global harmonization and convergence is difficult to assess because each country’s system also continues to evolve on its own, and major system changes, such as the new U.S. law, periodically occur. Compton suggested that the assessment of progress toward har- monization could be based on achieving standards in a set number of identified technical areas, or specific metrics could be used to assess dif- ferent aspects of harmonization. Measuring the process improvement in 6  FDA Safety and Innovation Act of 2012, P.L. 144, 112th Congress, 2nd session (January 3, 2012).

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PRINCIPLES AND DEFINITIONAL CONSIDERATIONS 21 one regulatory system in one country may not require the same yardstick needed in another. Some greater effort to measure the true extent of har- monization would reveal whether only some aspects of drug regulation are harmonizing or converging, while others—and perhaps the whole international system—are becoming more divergent. Citing Lord Kelvin’s well-known admonition, Compton said, “If you cannot measure it, you cannot improve it.”

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