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Regulating Medicines in a Globalized World: The Need for Increased Reliance Among Regulators (2019)

Chapter: 5 Removing Impediments and Facilitating Action for Greater Recognition and Reliance Among Regulatory Authorities

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Suggested Citation:"5 Removing Impediments and Facilitating Action for Greater Recognition and Reliance Among Regulatory Authorities." National Academies of Sciences, Engineering, and Medicine. 2019. Regulating Medicines in a Globalized World: The Need for Increased Reliance Among Regulators. Washington, DC: The National Academies Press. doi: 10.17226/25594.
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Suggested Citation:"5 Removing Impediments and Facilitating Action for Greater Recognition and Reliance Among Regulatory Authorities." National Academies of Sciences, Engineering, and Medicine. 2019. Regulating Medicines in a Globalized World: The Need for Increased Reliance Among Regulators. Washington, DC: The National Academies Press. doi: 10.17226/25594.
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Page 54
Suggested Citation:"5 Removing Impediments and Facilitating Action for Greater Recognition and Reliance Among Regulatory Authorities." National Academies of Sciences, Engineering, and Medicine. 2019. Regulating Medicines in a Globalized World: The Need for Increased Reliance Among Regulators. Washington, DC: The National Academies Press. doi: 10.17226/25594.
×
Page 55
Suggested Citation:"5 Removing Impediments and Facilitating Action for Greater Recognition and Reliance Among Regulatory Authorities." National Academies of Sciences, Engineering, and Medicine. 2019. Regulating Medicines in a Globalized World: The Need for Increased Reliance Among Regulators. Washington, DC: The National Academies Press. doi: 10.17226/25594.
×
Page 56
Suggested Citation:"5 Removing Impediments and Facilitating Action for Greater Recognition and Reliance Among Regulatory Authorities." National Academies of Sciences, Engineering, and Medicine. 2019. Regulating Medicines in a Globalized World: The Need for Increased Reliance Among Regulators. Washington, DC: The National Academies Press. doi: 10.17226/25594.
×
Page 57
Suggested Citation:"5 Removing Impediments and Facilitating Action for Greater Recognition and Reliance Among Regulatory Authorities." National Academies of Sciences, Engineering, and Medicine. 2019. Regulating Medicines in a Globalized World: The Need for Increased Reliance Among Regulators. Washington, DC: The National Academies Press. doi: 10.17226/25594.
×
Page 58
Suggested Citation:"5 Removing Impediments and Facilitating Action for Greater Recognition and Reliance Among Regulatory Authorities." National Academies of Sciences, Engineering, and Medicine. 2019. Regulating Medicines in a Globalized World: The Need for Increased Reliance Among Regulators. Washington, DC: The National Academies Press. doi: 10.17226/25594.
×
Page 59
Suggested Citation:"5 Removing Impediments and Facilitating Action for Greater Recognition and Reliance Among Regulatory Authorities." National Academies of Sciences, Engineering, and Medicine. 2019. Regulating Medicines in a Globalized World: The Need for Increased Reliance Among Regulators. Washington, DC: The National Academies Press. doi: 10.17226/25594.
×
Page 60
Suggested Citation:"5 Removing Impediments and Facilitating Action for Greater Recognition and Reliance Among Regulatory Authorities." National Academies of Sciences, Engineering, and Medicine. 2019. Regulating Medicines in a Globalized World: The Need for Increased Reliance Among Regulators. Washington, DC: The National Academies Press. doi: 10.17226/25594.
×
Page 61
Suggested Citation:"5 Removing Impediments and Facilitating Action for Greater Recognition and Reliance Among Regulatory Authorities." National Academies of Sciences, Engineering, and Medicine. 2019. Regulating Medicines in a Globalized World: The Need for Increased Reliance Among Regulators. Washington, DC: The National Academies Press. doi: 10.17226/25594.
×
Page 62
Suggested Citation:"5 Removing Impediments and Facilitating Action for Greater Recognition and Reliance Among Regulatory Authorities." National Academies of Sciences, Engineering, and Medicine. 2019. Regulating Medicines in a Globalized World: The Need for Increased Reliance Among Regulators. Washington, DC: The National Academies Press. doi: 10.17226/25594.
×
Page 63
Suggested Citation:"5 Removing Impediments and Facilitating Action for Greater Recognition and Reliance Among Regulatory Authorities." National Academies of Sciences, Engineering, and Medicine. 2019. Regulating Medicines in a Globalized World: The Need for Increased Reliance Among Regulators. Washington, DC: The National Academies Press. doi: 10.17226/25594.
×
Page 64
Suggested Citation:"5 Removing Impediments and Facilitating Action for Greater Recognition and Reliance Among Regulatory Authorities." National Academies of Sciences, Engineering, and Medicine. 2019. Regulating Medicines in a Globalized World: The Need for Increased Reliance Among Regulators. Washington, DC: The National Academies Press. doi: 10.17226/25594.
×
Page 65
Suggested Citation:"5 Removing Impediments and Facilitating Action for Greater Recognition and Reliance Among Regulatory Authorities." National Academies of Sciences, Engineering, and Medicine. 2019. Regulating Medicines in a Globalized World: The Need for Increased Reliance Among Regulators. Washington, DC: The National Academies Press. doi: 10.17226/25594.
×
Page 66
Suggested Citation:"5 Removing Impediments and Facilitating Action for Greater Recognition and Reliance Among Regulatory Authorities." National Academies of Sciences, Engineering, and Medicine. 2019. Regulating Medicines in a Globalized World: The Need for Increased Reliance Among Regulators. Washington, DC: The National Academies Press. doi: 10.17226/25594.
×
Page 67
Suggested Citation:"5 Removing Impediments and Facilitating Action for Greater Recognition and Reliance Among Regulatory Authorities." National Academies of Sciences, Engineering, and Medicine. 2019. Regulating Medicines in a Globalized World: The Need for Increased Reliance Among Regulators. Washington, DC: The National Academies Press. doi: 10.17226/25594.
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Page 68

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5 Removing Impediments and Facilitating Action for Greater Recognition and Reliance Among Regulatory Authorities Based on its extensive deliberations and input from stakeholders representing regulatory authorities, international organizations, industry, and patient groups, the committee identified key challenges and opportunities that led it to draw one conclusion and offer six recommendations. In the course of its discussions and online searches the committee also came to realize that stakeholder groups other than regulators have an interest in seeing regulatory authorities overcome impediments to greater regulatory cooperation. Because of their motivation, the committee has incorporated each of these groups—industry representatives, patient advocates, policy makers, and regulators themselves—into a proposed strategy in which each has responsibility for helping all regulators across the spectrum of country resources overcome impediments to achieving effective recognition and reliance. This strategy, along with the committee’s conclusion and recommendations, stem from two overarching messages that serve as the lens through which the committee’s conclusion and recommendations should be viewed: • Regulation through recognition and reliance arrangements is now a 21st century best regulatory practice. Accordingly, regulators, regardless of human, technical, and financial resources, should make increased use of reliance and cooperation with other trusted regulators, as no regulator has the resources it needs to meet all of its public health responsibilities. • Impediments to regulators entering into and using such informal and formal recognition and reliance arrangements to help them obtain the information they need for their regulatory decision making should be removed. It is safe to say that virtually all regulatory authorities are motivated by a public health mission to safeguard their populations with respect to the medicines coming into and currently on, the market in their jurisdictions. Additionally, given the rapid movement of people and illnesses across borders in today’s world, it is similarly safe to say that public health is a global concern and that all regulators, regardless of size or financial resources, exercise their responsibilities within that global public health framework as part of a larger global regulatory enterprise. How regulatory authorities carry out their missions and structure their regulatory cooperation activities is often a function of human and financial resources. PREPUBLICATION COPY: UNCORRECTED PROOFS 53

54 REGULATING MEDICINES IN A GLOBALIZED WORLD MEDICINES REGULATION IN A GLOBALIZED WORLD Challenge Every year, billions of people around the world take prescription medicines. The pharmaceutical industry has expanded its production in an effort to meet this massive demand for drugs, while producers of generics and biosimilars are attempting to help meet the demand with lower-priced alternatives. The pharmaceutical industry has looked to reduce its expenses by moving production and manufacturing to locations with lower associated costs. An end result has been the mixing of ingredients from different overseas sources. Today, drug manufacturers rely on vast networks of subcontractors for medicine production, sometimes working with as many as 200 contracted manufacturing organizations covering different functions, such as production of active pharmaceutical ingredients (APIs), bulk production, and finished product packaging (Intelligence, 2018). Other vendors handle additional aspects of providing power, water, and hazardous waste disposal. Challenge: Rapid globalization of drug discovery, research and development, manufacturing, and delivery has significant implications for public health. The resources required to ensure comprehensive oversight of these activities is now an overwhelming task for even the well-resourced national medicines regulatory agencies. All have limited resources to accomplish well all the tasks they are asked to perform. The ongoing evolution of the science and technology associated with drug discovery, research and development, manufacturing, and delivery (e.g., dramatic increases in more complex biological medicines and emerging use of cell and gene therapies) pose additional capacity challenges for regulatory agencies. These challenges underline the need for further cooperation and collaboration among agencies; however, achieving that cooperation is often challenging because individual agencies have different histories, legal frameworks, resources, and areas of expertise. Opportunity It is the responsibility of industry to monitor its own, globalized supply chains and to correct and report any issues that may arise during manufacturing and production processes. Regulatory agencies are expected to ensure that industry takes the proper steps so that people within their jurisdiction have access to safe and effective quality medicines; good manufacturing practice (GMP) is essential to that assurance. According to Patel and Chotai (Patel and Chotai, 2011), GMP diminishes the risk of cross-contamination, labeling errors, and other such inaccuracies that may represent a particular vulnerability given the wide array of international subcontractors with which industry works in deriving a final product. Just as the manufacture and production of medicines now represent a global undertaking, research and development toward the approval of new medicines has expanded in an attempt to capture more of a global market while minimizing costs associated with drug development. Good laboratory practice (GLP) regulations help ensure that nonclinical studies on product safety are adequately planned and performed and reflect sufficiently documented, trustworthy data (Andrade et al., 2016). In the Organisation for Economic Co-operation and Development (OECD) global context—which extends beyond medicines—GLP principles provide “a common PREPUBLICATION COPY: UNCORRECTED PROOFS

REMOVING IMPEDIMENTS AND FACILITATING ACTION 55 basis for cooperation among national authorities and avoid[s] creating non-tariff barriers to trade” (OECD, 2019). The OECD has issued a document on the governance of clinical trials (OECD, 2013a). In that document, the authors note that approximately 25 percent of clinical trial applications involved two or more OECD member states and that roughly two-thirds of all subjects enrolled in clinical trials were part of multinational studies. Conducting such studies is costly. To reduce expenses, among other purposes, trials are increasingly including non-U.S. and non–Western European participants (Ravinetto et al., 2016). Good clinical practice (GCP) guidelines for ensuring the ethical treatment of study subjects are currently being reviewed in light of the high volume of globalized clinical trials and the challenges this poses for all regulatory authorities reviewing multinational studies. As was stated in interviews conducted for this study, the closer a regulatory agency’s framework is to that of another agency, the more likely it is that collaborative efforts will lead toward reliance and recognition. For example, Health Canada and the Therapeutic Goods Administration of Australia (TGA) have equivalent regulatory frameworks and also overlap in language, paving the way for reliance activities and their mutual recognition agreement (MRA). These two medium-sized regulatory authorities teamed up with two other “like-minded” agencies in Singapore and Switzerland for their successful work-sharing initiative, the Australia- Canada-Singapore-Switzerland (ACSS) Consortium. In some ways, the U.S. Food and Drug Administration (FDA) stands alone with regard to its high level of resources, but in many other ways, it shares similarities with other moderately well- and well-resourced regulatory authorities. For example, both the European Medicines Agency (EMA) and FDA struggle with challenges posed by advanced therapeutics such as gene therapy, somatic cell therapy, and tissue-engineered products (Hunter, 2017). These and other innovations in medicine are testing the boundaries of countries’ regulatory processes as the agencies try to stay ahead of the science for ensuring safety without stifling innovation. Given that FDA and EMA align through their commitment to drug development standards and their adoption of International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, these agencies are well positioned to expand upon the information-sharing and collaboration conducted within their confidentiality arrangement (Kashoki et al., 2019). Cluster activities, set up through the EMA, provide regularly scheduled opportunities for sharing on specific topics with other similarly situated authorities. The advanced-therapy medicinal products cluster includes the EMA, FDA, and Health Canada. A biosimilars cluster has representatives from these agencies plus Japan’s Pharmaceuticals and Medical Devices Agency (PMDA). This cluster works toward greater alignment of biosimilar evaluations that could allow for increased acceptance of data across regulatory bodies (EMA, 2019f). Opportunity: In confronting the global challenges of medicines regulation, cooperation and collaboration among regulators offer opportunities to share information and increase the transparency of each other’s activities; to share finite resources and address the growing workload resulting from globalization; and to rely on each other’s processes, work products, and decision-making via both formal reliance arrangements such as MRAs and other, less formal reliance arrangements. PREPUBLICATION COPY: UNCORRECTED PROOFS

56 REGULATING MEDICINES IN A GLOBALIZED WORLD Conclusion: The committee concludes that protecting and promoting public health in a time of globalization and unprecedented advancements in technology and medicines—which are mirrored by the growing complexity of medicines and the supply chains for manufacture and production—is the single greatest challenge facing medicines regulatory authorities today. It is therefore imperative that regulatory authorities at all resource levels—well, moderately well, and lower—find ways to continue or expand upon their ability and willingness to work together to maximize the use of their finite resources so they can ensure the quality, safety, efficacy, and availability of medicines for their jurisdiction in both emergency and non-emergent situations. However, for regulatory authorities to further build upon their current recognition and reliance activities, impediments to entering into and using informal and formal recognition and reliance arrangements, would be removed. Some of these impediments are within the regulatory authority itself while others may be external to the agency and influenced by those within policy, industry, or consumer/patient advocacy groups. Each of these stakeholder groups has a role to play in supporting efforts to enhance cooperation between and among regulatory authorities with the overarching aim of improving public health. The committee therefore recommends that all regulatory authorities and other key stakeholder groups demonstrate their support for formal and informal medicines regulatory recognition and reliance arrangements using a targeted approach. Recommendation 1: The committee recommends a strategy that leverages the support of each stakeholder group in the following manner: • All regulatory authorities, especially those that are well- and moderately well-resourced, should increase information sharing and the transparency of each other’s regulatory activities across the life cycle of medicines in ways that can facilitate more efficient resource allocation and decision making for all regulators and reduce the burden of redundant regulatory activities on regulators, patients, and industry. • All regulatory authorities, especially those that are well- and moderately well-resourced, should be allowed to share their work products in essentially unredacted form (i.e., full reports without parts of the report expunged, except for personal privacy information) with other regulatory authorities so assessment and inspection information can be made available to those other regulators, especially those that are lower-resourced, to enable access to quality, useable regulatory information by a greater number of regulatory authorities for addressing global public health needs. In this respect, policy makers, and the U.S. Congress in particular, should weigh the challenges and opportunities involved with empowering their respective medicines regulatory authorities to PREPUBLICATION COPY: UNCORRECTED PROOFS

REMOVING IMPEDIMENTS AND FACILITATING ACTION 57 share complete unredacted inspection reports (e.g., GMP reports) with other regulatory authorities so as to facilitate learning, aid in decision making, reduce the use of limited resources on redundant inspections, decrease the burden on industry of redundant inspections, and strengthen the overall global public heath infrastructure for safe and effective quality medicines. • Lower-resourced regulatory authorities should consider the risks and benefits of unilateral recognition of the regulatory decisions of trusted regulatory authorities when doing so would facilitates better public health decision making in the context in which the lower- resourced regulatory authority functions. • Industry should support the recognition and reliance efforts of regulatory authorities by encouraging them to share less-redacted or, better, unredacted reports with their trusted regulatory authority partners, and by showing a willingness to share health-related data and/or information relevant to regulatory decision making more publicly for the global public health good and to reduce the sharing authority’s own burden of redundant oversight. • Patient and consumer groups should support the recognition and reliance efforts of medicines regulatory authorities by advocating for a “public health protection and promotion” framing of all such arrangements and for their increased use. The committee further believes, based on its information gathering and expert opinion, that formal and informal recognition and reliance arrangements are very effective tools for facilitating cooperation and reliance on the work of other regulatory authorities, when they are established in ways that emphasize public health, maximize efficiencies, reduce the burden of redundancy, and leverage the potential to benefit both global and national public health by ensuring effective and efficient access to safe and effective quality medicines. To this end, the committee formulated five recommendations in the following areas: • Improving Public Health Through Better-Designed Mutual Recognition Agreements (MRAs) • Responding to Evolving Science and Technology • Better Utilization of the European Union (EU)-US MRA • Information Sharing Among International Medicines Regulators • Evaluating Public Health Impacts of Recognition and Reliance Arrangements for Medicines Regulation PREPUBLICATION COPY: UNCORRECTED PROOFS

58 REGULATING MEDICINES IN A GLOBALIZED WORLD IMPROVING PUBLIC HEALTH THROUGH BETTER-DESIGNED MRAs Challenge Most MRAs reference public health and safety. Article 2 of the EU-US MRA specifically states the following goal: “facilitate trade and benefit public health by allowing each Party to leverage and to reallocate its inspection resources, including by avoiding duplication of inspections, so as to improve oversight of manufacturing facilities and better address quality risk and prevent adverse health consequences.” Thus, while the EU-US MRA has a public health goal, the agreement was developed under the auspices of trade negotiations, with trade facilitation featuring prominently in the discussions. A shift in focus to public health would change the perspective, driving MRAs toward the goal of improved public health with an emphasis on patients. Furthermore, the type of arrangement a regulatory body chose to explore could be guided by public health goals specific to the needs of its jurisdiction. Opportunity The most formal information-sharing arrangements between medicines regulators have typically been legally binding MRAs, in which one agency recognizes the work and actions of another as equivalent to its own and something it can rely on. In discussions regarding MRAs and other regulatory reliance arrangements, it is essential that the goals of international commerce and freer trade not be pursued at the expense of improved public health for either party involved. To the contrary, as discussed above, advancing public health for all concerned must be the focus when these arrangements are designed, developed, and implemented. Opportunity: Ensuring that meeting public health needs is the primary mission of MRAs and other reliance agreements requires that these agreements are designed with goals of advancing public health and these agreements are primarily designed, developed, and implemented by medicines regulators. Recommendation 2: Policy makers, including lawmakers, should explore empowering regulators to expand the scope and substance of future mutual recognition agreements (MRAs) that address issues related to the safety, efficacy, and manufacturing quality of medicines, and to ensure that these MRAs are primarily designed, developed, and implemented by medicines regulators. Policy makers will also need to ensure that regulators have adequate resources for these tasks.1 1 Murray Lumpkin, Lembit Rago and Katherine Bond did not fully concur with this recommendation because they believe it still leaves the negotiation, oversight and finalization of MRAs related to medicines regulation to trade negotiators, rather than empowering medicines regulators to design, develop, conclude, and implement these specific medicines regulatory MRAs on their own. They believe that is the only way to ensure that public health is the sole focus of the negotiation and agreement and that it is negotiated and concluded in the collaborative public health atmosphere that exists between medicines regulators and not the competitive business dynamic that pervades and shades trade negotiations. PREPUBLICATION COPY: UNCORRECTED PROOFS

REMOVING IMPEDIMENTS AND FACILITATING ACTION 59 RESPONDING TO EVOLVING SCIENCE AND TECHNOLOGY Challenge The challenge of responding to evolving science and technology is related to the above challenge regarding the scope of the EU-US MRA. As noted previously, the current EU-US MRA applies to GMP inspections of a limited range of medicine types. In addition, it mandates that the Joint Committee (Art. 20) consider the inclusion of veterinary medicines, vaccines for human use, plasma-derived pharmaceuticals (i.e., albumin, coagulation factors, and immunoglobulins), and clinical trial material for investigational products (FDA, 2019a). However, this expansion would remain limited to GMP inspections. Challenge: As currently designed, MRAs are not sufficiently agile tools to respond to the rapid pace at which science and technology are evolving. Opportunity Both the European Union and the United States have approval pathways for biosimilars. Since the United States first approved the pathway in 2010, 17 biosimilars have been approved, only 7 of which have made it to the market, primarily because of ongoing patent disputes (Zhai et al., 2019). In contrast, since 2006, the EMA has approved 59 biosimilar applications, and it currently has 53 biosimilars available for sale in the EU (Harston, 2019). Opportunity: More agile reliance arrangements would be better suited to meet the challenges posed by rapidly evolving science and technology. Allowing regulators to develop such arrangements would enhance global public health. Thus, to address the public health challenges of the globalized production of medicines, as well as the growing need to address the medicine requirements during public health emergencies, the committee believes that MRAs and other reliance arrangements should be expanded to include new areas. Recommendation 3: The committee recommends that regulators consider increasing the current scope of both formal and less formal reliance arrangements, including mutual recognition agreements (MRAs), and that policy makers encourage regulatory authorities to explore formal and informal opportunities for reliance with other trusted regulatory authorities that give regulators greater flexibility in responding to challenges affecting their responsibility in overseeing the quality, safety, and efficacy of medicines throughout the lifecycle of the medicine. Potential areas identified for scope exploration include GLP, GCP, GPvP inspections reports, pre-clinical assessment reports, bioequivalence assessment reports, and a wider scope of product classes covered by such arrangements. PREPUBLICATION COPY: UNCORRECTED PROOFS

60 REGULATING MEDICINES IN A GLOBALIZED WORLD BETTER UTILIZATING OF THE EU-US MRA Challenge As discussed above, formal and informal (bilateral and multilateral) reliance arrangements have the potential to improve public health protection through increased sharing of information and the reallocation of resources for the inspection of drug manufacturing facilities with potentially higher public health risks (FDA, 2019a). In 2008, following the discovery of contaminated heparin originating from China, the Bush administration announced provisions that would allow U.S. regulators to coordinate certain product manufacturing inspections with Australian and European regulators in China and India, setting the stage for so-called “third- country” inspections (i.e., inspections conducted outside of a regulator’s jurisdiction). This was a critical step in addressing the rapid globalization of medicines production. The 2-year International API Inspection Pilot Program reported overall positive results, having “contributed substantially to a better understanding of regional approaches to inspection and the building of mutual confidence” (EMA, 2011). Sharing the results of inspections carried out in third countries is an integral part of the MRA between the European Union (EU) and Switzerland. That MRA was amended in 2017 to include sharing of results of inspections (conducted by the Parties to the MRA) in third-country and batch certification if a product originates from a third-country manufacturer inspected by either Swiss or European regulators (EMA, 2018b). (See Chapter 3 for information on batch certification.) Such reliance on inspections of manufacturers located in third countries is critical in regions where overseas inspections have proven difficult because of operational challenges, and where the number of facilities needing inspection is very large and historically has exceeded the resources available for such inspections. However, the sharing of information from inspection reports of third-country manufacturers is, at present, inefficient. Efficiency would be improved by the development of better mechanisms for sharing that information; coordination of inspections to avoid duplication; and joint identification and prioritizing of high-risk sites for inspections. Demonstrating the value of such coordination and information sharing could further strengthen trust among regulatory agencies charged with implementing the EU-US MRA, which includes a provision to share results of inspections in third countries. Doing so could potentially expand the range of oversight in countries with less rigorous regulatory oversight. In addition, the EU-US MRA was written to include only nine marketed products in the form of tablets, capsules, ointments, or injectables while excluding human blood and plasma, human tissues and organs, and advanced- therapy medicinal products (EMA, 2019c). (Vaccines and medicines derived from plasma are expected to be added to the MRA list by 2022.) Expanding the scope of the EU-US MRA could make better use of that agreement for purposes of public health protection. Challenge: The EU-US MRA, as currently written, narrowly applies only to areas involving good manufacturing practice (GMP) and only to a limited range of products. Even so, some of its provisions have not been implemented. PREPUBLICATION COPY: UNCORRECTED PROOFS

REMOVING IMPEDIMENTS AND FACILITATING ACTION 61 Opportunity A decade after the heparin scare of 2008, concerns about ensuring the quality of APIs and finished pharmaceutical products from China and India continue. In 2018, FDA announced a voluntary recall of some generic medications used to treat high blood pressure and heart disease (FDA, 2018c; Wilkinson, 2019). Between 2018 and 2019, FDA sent 75 warning letters, roughly half of which went to pharmaceutical manufacturers in China and India. The European Union (EU) also issued notices of noncompliance, roughly two-thirds of which were directed to medicines manufacturers in China and India. MRAs and other reliance arrangements among trusted regulatory authorities would allow them to avoid duplicative inspections at sites demonstrating compliant GMP and to focus on sites that have not been inspected or that are in need of re-inspection following non-compliance. The provision in the EU-US MRA for inspections (conducted by the Parties to the MRA) in third countries, if implemented, could further extend the reach of both agencies. As noted, MRAs cover primarily good manufacturing practice (GMP) and batch certification, although a few also include good laboratory practice (GLP). The inclusion of both GLP and good clinical practice (GCP) represents an opportunity to expand present MRAs to go beyond GMP inspections (i.e., manufacturing and production) to include assessment reports related to generics and biosimilars, as well as new medicines. To progress beyond GMP, however, MRA regulators would likely have to demonstrate high levels of trust and confidence by building a track record of demonstrated equivalence. Opportunity: The provisions in the EU-USA MRA for inspections conducted outside of the respective territories, which have not yet been implemented, could be implemented immediately. The EU-US MRA could be expanded to go beyond GMP to other regulatory activities, together with greater product coverage. If one MRA regulatory authority can trust the other to perform an inspection within the latter authority’s own jurisdiction, the committee could find no reason to doubt the ability of the latter authority to perform a quality inspection outside its own jurisdiction—especially as these inspection are currently limited to surveillance inspections. The EU-US MRA could be expanded to go beyond its currently limited GMP focus to a broader GMP focus and to other regulatory activities, together with greater product coverage. Recommendation 4: Regulatory authorities in the United States and the European Union should immediately implement provisions included in the current MRA (i.e., those regarding so-called “third-country” good manufacturing practice (GMP) inspections). Regulatory authorities also should begin considering the potential for expanding the EU-US MRA to include reliance in areas beyond GMP and a broader scope of products under the current GMP provisions. PREPUBLICATION COPY: UNCORRECTED PROOFS

62 REGULATING MEDICINES IN A GLOBALIZED WORLD FACILITATING INFORMATION SHARING AMONG INTERNATIONAL MEDICINES REGULATORS Challenge The question of how, when, if, and to what extent regulatory agencies can share commercial confidential information and trade secrets is a very real concern for industry. Companies do not want their trade secrets (e.g., product manufacturing processes and chemical formulations) shared, given their fear that this could result in the theft of their intellectual and physical property with no compensation. Accordingly, regulatory authorities sometimes err on the side of excessive caution and redact inspection and other reports so as to protect confidential information and trade secrets and minimize their liability (Schwartz, 2017). While these fears do have a basis in some cases, however, they are not relevant in other cases, when a company has already submitted the same information to another regulator for its review. The usability of a report diminishes significantly if, as a consequence of redaction, one regulator is unable to sufficiently understand another’s report to fully grasp what occurred, what the other agency’s assessments were, and on what they were based. Without such complete understanding, the agency seeking to rely on another agency’s assessment is often left with little choice but to do its own full assessment or inspection to make a truly fully informed regulatory decision. TGA, for example, requires that unredacted reports be submitted by any sponsor seeking rapid approval using TGA’s “comparable overseas regulators” (CORs) processes for prescription medicines. The agencies from which TGA will accept unredacted reports include Health Canada, the Health Science Authority Singapore (HSA), Swissmedic, the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA), FDA, and the EMA (TGA, 2018). In Switzerland, it is up to the companies involved to provide for their medicinal products unredacted reports that are identical to those submitted and authorized abroad. Redacted reports are accepted, but the process is significantly slower, and thus higher fees are often imposed (Swissmedic, Form Information for application Art.13 TPA HMV4, 03.02.2019). The FDA has traditionally shared only heavily redacted reports (Schwartz, 2017), and regulatory partners wishing to rely on FDA inspection reports have been unable to do so because of these numerous redactions (Schwartz, 2017). One of the goals of MRAs and other reliance arrangements is to decrease or eliminate duplicative inspections; heavy redaction impedes this goal. In addition to being costly, unnecessary duplicative clinical research trials pose ethical dilemmas, as patient participants may be exposed to undue distress (physical, emotional, etc.) or be considered ineligible for other clinical trials that could improve their health, while the duplicative trial offers little or no benefit for the public health community (Myles et al., 2014; Paquette et al., 2019). As part of the recent MRA with the European Union, FDA has indicated it will begin sharing unredacted reports with its equivalent, trusted partner through the super confidentiality commitment (Super-CC) (EC, 2017). This shift in thinking for FDA has the potential to pave the way for future pilots with equally trusted regulatory authority partners. How many potential partners this might include is uncertain, but under current approaches, it is not thought to be more than a handful. Whether the current approach to redaction is a relevant good regulatory and good public health practice in a 21st century world of globalized product development, production, distribution, and use is a question worth rethinking. PREPUBLICATION COPY: UNCORRECTED PROOFS

REMOVING IMPEDIMENTS AND FACILITATING ACTION 63 In within the above context, the committee identified the following challenge with respect to open and transparent information-sharing between regulatory partners. Challenge: Regulators with recognized technical capacity and harmonized interests currently experience needless challenges in sharing complete information upon which other regulators can rely to inform their own decision-making. When regulators receive incomplete information from other regulators, they often must use their limited resources to needlessly repeat inspections or data assessments. Opportunity There is great value in reading and being able to use other regulators’ inspection reports (Roth et al., 2018), especially when these reports are from regulators with recognized technical capacity and harmonized interests. First, for those less familiar with inspection processes, knowledge is gained by seeing how an inspection was conducted, what areas were covered, and how the findings were documented. Second, trust is built through the willful sharing of complete information. History shows that trust can lead to reliance pilots, which, if successful, can be elevated even further to more substantive collaborative arrangements. Third, the information gained by reviewing the findings of others’ inspection reports allows regulators to make more informed sovereign decisions, most often without having to use their own limited resources to perform what would be a redundant inspection exercise. Each of these benefits, based on greater transparency and completeness of inspection reports, helps strengthen the global public health infrastructure for safe and effective quality medicines through learning and greater insights into what manufacturers are actually doing. By offering helpful inspection reports that regulators around the world can view, regulatory bodies with recognized technical capacity and harmony of interests can facilitate the robustness of other regulators’ decision making. Currently, the EMA offers a public assessment report with only commercially confidential material redacted,2 and FDA is running a pilot program—with nine companies’ new drug applications—assessing the feasibility of publicly releasing portions of clinical study reports (CSRs). The goal of this pilot is to enhance public “understanding of information about drug approvals to improve the accuracy of discussions about drug approvals in scientific publications, increasing stakeholders' understanding of the basis for FDA’s approval decisions, and informing physicians and other healthcare providers about the clinical trial results on which regulatory decisions are based.”3 Both efforts indicate the willingness by regulators and industry to share information for the public good, although impediments still remain with respect to providing more transparent and complete assessment and inspection reports throughout all phases of a product’s lifecycle. Regulators must balance a desire to provide other regulators with access to unredacted inspection reports against the need to honor the legal requirements for protecting “trade secrets and commercial or financial information which is privileged or confidential.”4 2 .REGULATION (EC) No 726/2004 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 31 March 2004 Laying down Community procedures for the authorisation and supervision of medicinal products. for human and veterinary use and establishing a European Medicines Agency. 3 Federal Register/Vol. 84, No. 124/Thursday, June 27, 2019 / Notices. 4 21CFR20.61 TITLE 21--FOOD AND DRUGS, CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES, SUBCHAPTER A--GENERAL. PREPUBLICATION COPY: UNCORRECTED PROOFS

64 REGULATING MEDICINES IN A GLOBALIZED WORLD Opportunity: Increasing information-sharing and the transparency of each other’s regulatory activities can facilitate medicines regulators’ more efficient resource allocation and decision-making. Making complete/unredacted assessment and inspection information available to other regulators will enable more equitable access to quality regulatory information for a greater number of regulatory authorities to address global public health needs. The Committee identified three areas within this opportunity. Sharing of Inspection Reports • Sharing of complete unredacted inspection reports would facilitate learning, aid in decision making, reduce the use of limited resources on redundant inspections, and strengthen the overall global public heath infrastructure for safe and effective quality medicines. • The benefits of sharing complete unredacted inspection reports could be enhanced by aligning the formats of the reports to facilitate information exchange and increase the reports’ value to the receiving authorities, thereby enabling learning and sovereign decision-making by regulatory authorities with fewer resources. (For example, the Pharmaceutical Inspections Cooperation Scheme (PIC/S) format for inspection reports could be a starting point for such alignment). This benefit is predicated on the sponsor’s intent to market the exact same version of the product that was authorized and inspected by the agency upon which the receiving agency is relying. Shipping an alternative (e.g., “rest of world”) version manufactured in a different plant or on a different manufacturing line would negate the ability to rely on the inspection reports of a reliable counterpart. Sharing of Assessment Reports • Without a unified platform and a standard format for reporting, the sharing of assessment, inspection, and other reports can be challenging. An opportunity exists for regulators to freely share these reports in a standardized format with other regulators with whom legally authorized appropriate confidentiality arrangements exist. • Where the above arrangements do not exist, sponsors could explicitly allow regulators to share full assessment reports on specified products with particular regulators. U.S. FDA Information Sharing • The Super-CC includes medicines, providing a mechanism for the FDA to share unredacted information with regulatory authorities under very specific circumstances. The opportunity exists for the FDA to ensure that current redaction practices optimize information-sharing consistent with current law and for Congress to reevaluate whether existing confidentiality restrictions are still fit-for-purpose in the 21st century globalized environment in which these products exist. PREPUBLICATION COPY: UNCORRECTED PROOFS

REMOVING IMPEDIMENTS AND FACILITATING ACTION 65 Without a unified platform and a standard format for reporting, the sharing of assessment and inspection reports can be challenging. The committee recognized that currently some regulators share assessment, inspection, and other reports with other regulators with whom legally authorized appropriate confidentiality arrangements exist. In instances where they do not exist, sponsors could explicitly allow regulators to share full assessment reports on specified products with particular regulators. Additionally, a recently concluded confidentiality commitment (CC) between the U.S. FDA and the European Union, known as the Super-CC, includes medicines. The Super-CC provides a mechanism for the FDA to share essentially unredacted information with regulatory authorities under very specific circumstances. The committee believes that to best meet the public health goals of reliance arrangements, an opportunity exists for FDA and Congress to ensure that current redaction practices optimize information sharing. To this end, FDA and Congress could reevaluate whether existing confidentiality restrictions are still fit-for-purpose in the 21st century globalized environment in which these products exist and whether modifications are needed to meet the public health goals for these arrangement noted earlier in this report (e.g., protecting and promoting public health; reducing the burden of regulatory redundancy on patients, industry, and regulators; allowing regulators to most effectively and efficiently use the finite human and financial resources they currently have most effectively and efficiently; and helping to bring needed quality medicines to patients domestically and globally as efficiently as possible). Recommendation 5: Regulatory authorities, with guidance by their governmental leaders, should undertake to determine whether current limitations on sharing regulatory work products with other regulatory authorities are still fit-for-purpose to help protect and promote public health; to reduce the burden of regulatory redundancy on patients, industry, and regulators; to allow regulators globally to best utilize the limited technical and financial resources currently available to them to meet their public health mandates; and to bring needed quality medicines to patients domestically and globally as efficiently as possible. EVALUATING PUBLIC HEALTH IMPACTS OF RECOGNITION AND RELIANCE ARRANGEMENTS FOR MEDICINES REGULATION Challenge Recognition and reliance arrangements have been operational over varied timeframes, some for as long as two decades, and in a variety of different contexts. Accordingly, they could offer lessons as to what the most successful such arrangements have in common and their short-, medium-, and long-term benefits. However, such lessons could not be supported by evidence because of a dearth of data. Further, a review of the texts of such arrangements indicates that most do not explicitly call for evaluation of direct or indirect health benefits, although a few do contain language on monitoring the implementation and functioning of the arrangement itself. For example, the Trans-Tasman Mutual Recognition Act (TTMRA) incorporates a “general review” of the arrangement’s operations at given time intervals (TTMRA 12.1.1). This review is intended to “assess the effectiveness of the arrangements in fostering and enhancing trade and workforce PREPUBLICATION COPY: UNCORRECTED PROOFS

66 REGULATING MEDICINES IN A GLOBALIZED WORLD mobility between Australia and New Zealand and an assessment of any amendments or additions.”5 In 1995, the FDA finalized its compliance policy guide pertaining to international agreements (FDA CPG CPG Sec. 100.900 “International Memoranda of Understanding” - updated 3/2/2015). This guide lays out considerations for entering into international agreements and delineates the reasons for doing so, including (1) benefits to health (the potential for “risk reduction associated with products or programs,” prioritization of “products imported into the United States,” risk-based assessment: [“history of compliance problems”]); (2) the “regulatory burden on industry”; and (3) the “U.S. foreign policy objectives and priorities of other U.S. government agencies.” It is worth noting that since the 1990s, Drug Master Files6 from India and China have increased markedly compared with those of the United States and the EU. More broadly, as discussed previously, the supply chain for medicines has become more complex as a result of the globalization of manufacturing and production. Such considerations relevant in 2019 as risks associated with the globalized supply chain and rapidly developing novel treatments and innovative products were not explicitly among the considerations laid out in 1995 (Chace-Ortiz, 2017). Anecdotally, regulators who have had experience with MRAs report benefits to these agreements, but those benefits are not quantified. Informational interviews conducted for this study revealed the potential benefits or pointed to potential measurable outcomes (see the discussion in the “Opportunity” section below). At the time of this writing, the EU-US MRA was too recent to have been evaluated. Nevertheless, the committee was advised by FDA that a benefit/cost analysis of the MRA was planned. Challenge: Evaluating effects of recognition and reliance arrangements on public health, use of resources, and essential regulatory competencies is challenging because of a dearth of frameworks, metrics, and data for use in such evaluations. The texts of existing formal and less formal reliance arrangements fail to incorporate review criteria or frameworks, including specific metrics, by which regulatory authorities and the broader community could evaluate the arrangements’ public health impacts. Opportunity The Government Performance and Results Act (GRPA) of 1993 and successor legislation (GPRA Modernization Act of 2010, S. Rep. No. 111-372 [2010]) mandated that federal agencies set goals, measure results, and report progress.7 Relatedly, the Foundations for Evidence-Based Policymaking Act of 2018 “requires agency data to be accessible and requires agencies to plan to develop statistical evidence to support policymaking.”8 5 TTMRA 12.1.2; The New Zealand TRANS-TASMAN MUTUAL RECOGNITION Act. 6 A Drug Master File (DMF) is a submission to the U.S. Food and Drug Administration (FDA) that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs. See https://www.fda.gov/drugs/forms-submission- requirements/drug-master-files-dmfs. 7 GPRA Modernization Act of 2010, S. Rep. No. 111-372 [2010]. 8 H.R.4174 - Foundations for Evidence-Based Policymaking Act of 2018. PREPUBLICATION COPY: UNCORRECTED PROOFS

REMOVING IMPEDIMENTS AND FACILITATING ACTION 67 Currently, assessment of reliance arrangements globally is generally focused on agreement monitoring rather than on public health objectives per se. Results-based frameworks are utilized increasingly in the public sector and international organizations to shift the focus of monitoring and evaluation from processes to results (Zall Kusek and Rist, 2004). These frameworks reflect a theory of change in a logical fashion (i.e., in the spirit of “What gets measured gets done”) and incorporate planning for results monitoring and measurement into the organization. Within the past decade, FDA has introduced results frameworks to address various aspects of its import safety and inspection programs. The committee anticipates that this focus on public health results rather than agreement monitoring will better further public health goals consistent with the agency’s broader mission. OECD (Correia de Brito, 2016) has identified three potential public health benefits of MRAs: (1) managing risks and externalities across borders, (2) achieving greater administrative efficiency, and (3) improving knowledge flow and peer learning among regulators. OECD (OECD, 2013b) conducted a review of the literature assessing the empirical evidence for these public health benefits and found it comparatively sparse in comparison with the evidence on economic gains. The committee’s interviews with regulators pointed to potential outcome measures that would reflect the public health benefits of recognition and reliance arrangements, although those benefits are not yet being measured. These potential outcome measures included number of inspections in higher-risk areas, number of sites inspected for the first time, redeployment of staff to higher-risk product areas and regions, and rapid response to alerts and incidents involving GMP noncompliance. Regulators noted that such collaborative activities as joint training programs on GMP and GCP were relatively easy to quantify as outputs of agreements. High-quality assessments can prompt substantial improvements in an agency’s ability to fulfill its surveillance duties. For example, the U.S. Government Accountability Office (GAO) has been closely monitoring the overseas work of FDA since having issued its first assessment report on FDA’s international work in medicines regulation in 2008 (GAO, 2008). At that time, policy makers recognized the intense challenges faced by FDA as a result of globalization in ensuring safe and effective medicines for U.S. consumers coming from various parts of the world. FDA responded with a wide array of initiatives, including a joint inspections pilot project with EU regulators and the API Inspection Pilot Program, noted in the previous section, whereby regulators from the European Union and Australia would share plans to inspect, as well as inspection results from API manufacturing sites. Both initiatives were meant to build trust and confidence between regulatory bodies. In particular, the information-sharing activity has helped regulators use their resources more efficiently by minimizing overlap in their inspection scheduling plans. Assessments may also impact the quality and effectiveness of enforcement actions. For example, GAO’s 2016 report on FDA’s overseas progress in drug safety noted two performance measures used by FDA to assess its foreign offices in ensuring drug safety: (1) number of foreign inspections and (2) number of collaborative actions (GAO, 2016).9 GAO identified weaknesses in the latter measure with respect to drug safety, as the annual target of 25 collaborative actions did not specify commodity, was not unique to the foreign offices, and could not easily be tied to an outcome involving drug safety. Furthermore, GAO pointed to activities undertaken that could 9 “FDA defines a collaborative action as concrete regulatory and public health actions, or initiatives that contribute toward supporting OIP objectives and outcomes” ((GAO, 2016), p.26). PREPUBLICATION COPY: UNCORRECTED PROOFS

68 REGULATING MEDICINES IN A GLOBALIZED WORLD surface drug safety outcomes not included in the measures. An example cited by GAO referenced intelligence gathered from FDA’s office in India regarding fraudulent APIs manufactured in that country, resulting in death in another country. FDA staff in India followed up to determine inspection results of the local government, and upon confirmation of noncompliance with clinical GMPs, the agency placed the company and its affiliate on import alert. Recent assessments have highlighted additional opportunities to enhance surveillance through better international reliance. A 2019 GAO High Risk Series report included an update on FDA’s international oversight of medicines (GAO, 2019). In that update, GAO suggested that FDA develop more fully its measures for tracking how overseas offices contribute to drug safety outcomes. The report also applauded FDA’s progress in responding to present-day medicines regulatory challenges through a variety of interventions that included signing the MRA with the European Commission. As discussed earlier, this MRA, which became fully functional in July 2019, includes provisions10 for formally accepting third-country inspections conducted by the other region’s regulatory bodies.11 That is, under the current MRA, the United States and the EU could accept inspection reports accepted by the other agency concerning a manufacturing plant not located in the EU or the United States. Currently, the implementation of the EU-US MRA has in scope only EU inspections performed in the EU and FDA inspections performed in the United States. Recommendation 6: When formal and informal recognition and reliance arrangements are being developed, the regulatory authorities involved should co-create a results framework with clear indicators/metrics and processes for monitoring and measuring the arrangements results and impacts to enhance understanding of their public health and other benefits and associated regulatory efficiencies, and enable benefit/risk and cost- benefit analysis of the arrangements over time. 10 Article 8.3: “A Party may accept official GMPs documents issued by a recognized authority of the other Party for manufacturing facilities located outside the territory of the issuing authority. See http://trade.ec.europa.eu/doclib/docs/2017/february/tradoc_155398.pdf. 11 ANNEX to the Commission Decision on determining the Union position for a Decision of the Joint Committee set up under Article 14 of the Agreement on Mutual Recognition between the European Community and the United States of America, in order to amend the Sectoral Annex on Pharmaceutical Good Manufacturing Practices (GMPs). PREPUBLICATION COPY: UNCORRECTED PROOFS

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Globalization is rapidly changing lives and industries around the world. Drug development, authorization, and regulatory supervision have become international endeavors, with most medicines becoming global commodities. Drug companies utilize global supply chains that often include facilities in countries with inconsistent regulations from those of the United States, perform pivotal trials in multiple countries to support registration submissions in various jurisdictions, and subsequently market their medicines throughout most of the world. These companies operate across borders and require individual national regulators to ensure that drugs authorized for use in their countries are safe and effective, and appropriate for their health care system and their population. This process involves significant resources and often duplicative work. It is important to consider how this process can be improved in order to better allocate resources, time, and efforts to improve public health.

Regulating Medicines in a Globalized World: The Need for Increased Reliance Among Regulators considers the role of mutual recognition and other reliance activities among regulators in contributing to enhancing public health. This report identifies opportunities for leveraging reliance activities more broadly in order to potentially impact public health globally. Key topics in this report include the job of medicines regulators in today’s world, what policy makers need to know about today’s regulatory environment, stakeholder views of recognition and reliance, as well as removing impediments and facilitating action for greater recognition and reliance among regulatory authorities.

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