Given the structure of the Statement of Task for this study, much of the committee’s work focused on mutual recognition agreements (MRAs) and thus concentrated heavily on recognition and reliance within good manufacturing practice (GMP). However, the committee recognized the critical importance of other aspects of regulation across the lifecycle of a medicine. In particular, the committee believes public health would benefit greatly from more regulatory cooperation in the area of medicines safety and suggests further exploration by regulatory authorities and other stakeholders within the areas of pharmacovigilance (PV) and post-market surveillance.
PV can be distinguished from post-market surveillance as follows. The World Health Organization (WHO, 2019a) defines PV as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem.” This means monitoring for safety across the entire lifecycle of the medicine. In contrast, as the name implies, post-market surveillance is directed at safety issues occurring only after a medicine has reached the market. Post-market surveillance is an essential step in better ensuring the safety of medicines because, unlike the controlled environment of a clinical trial, it represents “real life” situations in which patients may differ from the populations used in the drug approval study, and in which consumption of other medicines and lifestyle choices could affect how a medicine is metabolized within a person or population. Post-market surveillance also encompasses good
storage and distribution practices (WHO, 2019b) and field surveillance activities to assess the quality of a product on the market.
Given the globalization of the pharmaceutical industry, it stands to reason that greater regulatory cooperation could benefit patients in multiple jurisdictions; however, differences across countries in the areas of PV regulations, systems, and processes place limitations on such cooperation (Hans and Gupta, 2018). A general trend away from reactive (“passive”) PV approaches and toward proactive (“active”) PV approaches may open an opportunity for establishing systems for greater sharing of safety information and data in the post-market phase. The European Union (EU) is an example of this evolution. There is now a unified database, known as EudraVigilance, where manufacturers, patients, and care providers can submit adverse drug reaction reports (EMA, 2019a). In this way, the European Medicines Agency and member states’ regulatory authorities can monitor the safety of medicines for timely detection and assessment of safety signals. The U.S. Food and Drug Administration (FDA) has a similar system—the FDA Adverse Event Reporting System—whereby providers and consumers can submit information directly to FDA, while manufacturers are required to send any adverse event reports they receive (FDA, 2018c). The same is true for the EU.
Countries with well-developed PV systems often engage industry in taking a significant role in reporting to their regulatory authority, whereas other countries with less developed systems may use hospitals or universities as regional PV centers for collecting and analyzing reports on adverse reactions to medicines (Dal Pan, 2014). Monitoring of adverse events is typically supplemented by a process of routine inspections of facilities along with sampling and testing of medicines. In remarks to the committee (July 10, 2019), Emer Cooke, head of medicines regulation at WHO, offered a series of suggestions for adding emphasis on reliance in the post-approval phase that could help stimulate dialogue among stakeholders moving forward. These suggestions included
- proactively sharing post-market safety data;
- establishing standards for timeliness and minimum information content for posting emergent safety issues or regulatory actions;
- standardizing good pharmacovigilance practice (GPvP), including roles and responsibilities of industry in collecting and reporting foreign safety data; and
- encouraging reliance/work sharing throughout a product’s lifecycle, in the monitoring of PV, manufacturing quality, and post-authorization safety and efficacy.
While individual case safety reports, as just described, provide valuable information on adverse events (e.g., potential adverse reactions) experienced by individuals, aggregate safety reports offer a broader profile of the medicine and its use in different populations (Kulkarni and Kulkarni, 2019). Based on these worldwide safety reports, safety signals can be generated, further confirmatory data can be generated if needed, and medicine labels can then be updated in accordance with the findings that optimize the safe use of the medicine. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use-standard Periodic Safety Update Report (PSUR) is a tool used by many agencies and companies around the world for post-authorization benefit/risk analysis of a medicine. PSURs are composed by the marketing authorization holder (i.e., the company/sponsor)—using the Periodic Benefit/Risk Evaluation Reports (PBRERs) format—and submitted to the appropriate regulatory authority at predetermined time points. Like the PSUR, the harmonized PBRER “is intended to promote a consistent approach to periodic postmarketing safety reporting among the ICH regions and to enhance efficiency by reducing the number of reports generated for submission to regulatory authorities” (FDA, 2016, p. 3). In the United States, Periodic Adverse Drug Experience Reports are submitted to FDA for safety monitoring of medicines with market approval in this country, although waivers are given so that global PSURs/PBRERs can be submitted if they contain the information FDA has requested.
In Recommendation 4 in Chapter 5, the committee encourages regulatory authorities in the United States and in the EU to consider “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.” The committee was intentional in this wording. The committee saw no drawbacks in “considering the potential,” nor did it hear negative comments about expanding the scope of recognition and reliance throughout the information gathering for this study. Although the committee initially acknowledged possible fears of reduced human and financial resources and a loss of sovereignty due to greater reliance, none of those fears were substantiated in any of its information-gathering interviews. To the contrary, it became apparent to the committee that even MRAs (and the other, less formal arrangements) preserve sovereign decision making and have not adversely affected resources. At the same time, despite the value of MRAs
for achieving greater reliance between regulators, the committee came to realize that formal trade-orientated MRAs may not be the best vehicle for medicines regulatory activities; rather, formal and informal recognition and reliance arrangements designed, developed, agreed upon, and implemented by medicines regulators would be the most appropriate way forward (see Recommendation 2 in Chapter 5).
In contemplating potential areas for MRA expansion, the committee identified as worthy of consideration GCP reports, GLP reports, GPvP reports, and reviews of PSURs. Consideration might be given to possibilities for sharing of reports or work-sharing arrangements with standardization of both the content and timing (“periodicity”) of reports so regulatory agencies would receive the same reports at the same time. Another possibility for exploration might be in the pre-approval phase, with sharing of bioequivalence reports from generic drug firms submitting the exact same product in both countries—especially if the design is a three-arm design that uses both the EU- and the U.S.-listed reference product along with the test product. Pharmaceutical companies would likely be attracted to the idea of one review used by both agencies, and perhaps this could help alleviate some of the medicines shortages in both jurisdictions.
With regard to other products that the EU-US MRA might expand to encompass, some thought could first be given to biologics, perhaps starting with well-characterized biologics such as monoclonals, and then vaccines. Veterinary products were not part of this committee’s charge, which covered only human medicines, but in considering the expansion of MRA implementation, some thought might go into implementing the existing provision for animal medicines. For more distant consideration, collaborative arrangements between the two regulatory authorities in reviewing such innovations as gene therapies and some newer cutting-edge modalities might also be explored.
The committee looked at its sixth recommendation (see Chapter 5) as an opportunity for regulatory authorities to work together in co-creating a public health results framework and metrics, at the same time an agreement is being developed. However, the committee also recognized the difficulties associated with quantitatively measuring improved public health. At some point, the public health benefit is inferred and/or intuitive. This is not to say that quantitative and qualitative measures should not be collected, however. Rather, public health indicators should be collected based on the up-front, agreed-upon intent of the arrangement. For example, if better utilization of resources is a goal, perhaps there could be some specific metrics around
whether resources were being better utilized. The result of the use of this measure might be to learn that because of this agreement, X number of inspectors had been redeployed from an area of low to high risk, or an increase of X number of manufacturing sites, including new or high-risk sites, had been inspected. These numbers would then be extrapolated to imply a public health impact. Such measurements would go beyond simply affirming that certain activities had been undertaken, to now considering how the undertaking of those activities compared with the status quo before the agreement was implemented.
In the committee’s vision, such measurements would be agreement-specific. While it may be impractical to propose a global framework given the specific nature of recognition and reliance arrangements, the committee was intrigued by the idea of regulators agreeing upon a key set of metrics reflecting a more global public health approach. A global-level conversation could be led by a group such as the International Coalition of Medicines Regulatory Authorities (ICMRA), involving the chief executive officers of the major medicines regulatory agencies globally, that addresses regulatory science issues through enhanced communication and information sharing among regulators. The discussions might include such questions as what “good” looks like under these arrangements, how an agency knows whether the benefits of an arrangement outweigh its (internal) costs, and what parameters might be reported annually so that the agencies and other stakeholders can better understand what is occurring under the auspices of the arrangement.
In addition to ICMRA, WHO—in relation to its planned Good Reliance Practices Guidelines—might be another group to develop some global metrics for these arrangements, particularly if metrics were proposed for measuring the impact of implementing Good Reliance Practices in an annex to the guidelines. The committee believes that even if the proposed metrics were not detailed or comprehensive, some high-level principles and good examples would likely be helpful in structuring future work in this area.
It is the committee’s hope that its landscaping of the medicines regulatory environment will better position regulators, policy makers, and technical and public health experts to address some of the 21st-century challenges facing national leaders around the world in ensuring safe and effective medicines for their countries’ people. As outlined in Chapter 2, these challenges range from ramifications of globalization, to drug shortages, to disease outbreaks. Each of these challenges calls for responses whose central focus is the public’s health. Chapter 5 provides the committee’s conclusion and recommendations based on key opportunities, includ-
ing a strategy for mounting responses that largely reflects messages from a wide array of stakeholders who provided input for this study, as well as the committee’s own knowledge of and expertise in medicines regulation. All of the opportunities outlined in Chapter 5 are built on a foundation of trust, confidence, and reliance within a collaborative dynamic. For example, interactions through working groups and other informal activities often begin the process of building trusted relationships that help establish confidence in the work of other regulators. As trust and confidence grow, they can lead to pilot activities whereby regulators test their ability to rely on each other’s work to inform their own decision making. Such reliance further increases trust and confidence among the partners, who may then agree to acknowledge their reliance more formally, such as through an MRA in which a higher degree of reliance on the partner’s decisions is acknowledged.
As regulators contemplate metrics with a public health focus, it would be wise to consider the views of patients and their desire for access to quality-assured, safe, and effective medicines. Patients are also interested in equity. Persons with rare diseases are acutely aware of the scarcity of study subjects needed for research and development of breakthrough medicines and the importance of working across national boundaries for the testing of new drugs. Speeding this process through greater regulatory cooperation across borders is something patients seek. These issues are what the public cares about, and a public health framing might consider such patient-centered perspectives in the design and evaluation of recognition and reliance arrangements.
Well-resourced regulatory agencies are well positioned to grapple with the challenges posed by continuing innovations in medicine and technology, such as gene therapies and other advanced therapeutics for regulators charged with ensuring the quality, safety, and efficacy of cutting-edge medicines. Nonetheless, shared access to specialists with expertise in highly technical product research, development, manufacturing, and production could help even the well-resourced regulatory agencies stay abreast of the rapidly evolving science of medicines. For lower-resourced authorities also struggling with this challenge—within a context of growing workloads and restricted resources and the limitations thereby imposed—considering the findings of well-resourced agencies and working collaboratively with these agencies might be a mechanism for bringing innovative products into their markets. This does not mean that all countries would automatically accept the findings of other agencies. As is the case today with many regulators, if such information were shared, each medicines regulatory authority could weigh the benefits and risks of approving a medicine for its country’s people.
In the end, medicines regulatory authorities are required to demonstrate their ability to protect and promote the health of the people within
their jurisdiction. Every regulatory authority faces this challenge while at the same time confronting the set of unique circumstances in which it functions. Access to financial and human resources is highly variable, as are population characteristics because of variations in genetics and environmental exposure to health risks, cultural practices, burdens of disease, social perspectives, health care systems, demographics, and societal income levels. Despite all of these differences, however, the tie that binds the work of all medicines regulators is their mandate to facilitate and help ensure the availability of quality-assured, safe, and effective medicines to serve the public health. It is the committee’s firmly held belief that this mandate can be met through effective use of the full range of formal and informal recognition and reliance arrangements that preserve national interests while placing the public’s health at the core of all regulatory efforts.
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