This chapter draws heavily on information-gathering sessions conducted by the committee between April and August 2019. In these sessions, current and former regulators and representatives of international harmonization initiatives, industry, and patient advocacy groups gave presentations and answered questions from the committee. These speakers brought numerous challenges, benefits, and opportunities associated with recognition and reliance arrangements to light. Appendix D includes the agendas for the public where key stakeholders informed the work of this committee by providing views and perspectives that were considered in preparing this report. To the extent possible, points raised by stakeholders about issues related to regulatory challenges and opportunities entailed in recognition and reliance arrangements were compiled into listings presented in this chapter. Content for these listings was supplemented by stakeholder written responses to committee questions, a questionnaire administered by the World Health Organization (WHO), the published literature, and publicly available government reports. The final section of the chapter presents the committee’s synthesis of the challenges and opportunities thus derived.
To simply say “the world is changing rapidly” hardly captures the conditions under which medicines regulators are currently working. This was a subtle message expressed by stakeholders throughout all of the committee’s information-gathering work. As of this writing, there was uncertainty about the future of the United Kingdom as part of the European Union (EU) and
what that would mean for the Medicines & Healthcare products Regulatory Agency and its colleagues within the European Network. There was also more offshore manufacturing of drugs taking place than ever before. Such a shift requires that more regulators spend time in those countries where the manufacturing is taking place—in 2019, that was China and India (see Chapter 3). This was not the case just two decades earlier, and whether these two countries will remain the dominant producers of generics a decade from now is yet another uncertainty.
Just as the global landscape is changing, so too are medicines regulatory bodies’ recognition and reliance arrangements, the staff that design them, and the parties involved. Therefore, it must be emphasized that what is presented in this chapter represents a snapshot in time. The committee recognizes that circumstances may have changed even by the time this report is published. In an effort to present relevant material in a constantly changing environment, this chapter is organized around themes intended to help guide the discussion of a core set of challenges and opportunities associated with reliance arrangements in the following chapter.
Impediments and Challenges
Presented in Box 4-1 is a list of impediments that could stall or inhibit communication and collaboration among medicines regulators, thereby preventing any type of meaningful recognition or reliance. This is followed by more targeted messages captured in Box 4-2 about challenges specific to reliance in conducting good manufacturing practice (GMP) inspections, as well as more general challenges that could be faced with any type of reliance used within medicines regulation.
Benefits and Opportunities
The potential contribution of improved decision making to protecting the public health was a clear message from the regulators who provided input for this study, as was the potential to facilitate focusing limited resources on higher-risk issues. It is critically important to understand these points given that ensuring safe and efficacious quality medicines for the health of society is key to the mission of medicines regulatory authorities. For example, greater information sharing between national regulators and national health systems in the form of early-stage notification could help limit the effects of a public health event caused by a medicine. Currently, the Pharmaceutical Inspection Co-operation Scheme (PIC/S) has a procedure for alerting other authorities about recalls arising from quality defects in medicinal products (PIC/S, 2017), and WHO has a system for notifying authorities about products found to be substandard or falsified. The system
also includes a rapid notification procedure for alerting regulatory authorities of counterfeit or tampered products when urgent action is required to protect public health. The system is dependent on the submission of this information by regulators. According to the regulators who provided input for this study, the system works fairly well, although there is room for improvement. Currently, this system is dependent primarily on external resources, and staffing is limited relative to the system’s mandate.
Benefits of Reliance
and international communication and collaboration, respectively. Because so much of the discussion with stakeholders involved mutual recognition agreements (MRAs) and thus GMP, Box 4-5 lists separately the perceived and real benefits of reliance in the area of GMP based on the sources described previously. It must be emphasized that “perceived” does not mean the benefits are not real, without ex post evaluations; however, it is impossible to know whether the benefits describing greater regulatory efficiency, for example, have actually been attained. Nonetheless, for this particular example, there are indications of expected cost savings from the
recently activated US-EU MRA. The European Commission estimates that 100 inspections in the United States will be waived by the end of 2019. One inspection takes roughly 16 person-days for the regulatory authority and 160 person-days for industry (at an estimated cost for industry of €352,000 or $389,493) (EFPIA, 2018). The benefits listed in Box 4-5 include those associated with a regulatory authority’s relying, to some extent, on other regulatory agencies for GMP inspection information instead of performing such inspections itself.
Opportunities for Reliance
Whereas benefits represent gains stakeholders perceive as having accrued to them through reliance arrangements, opportunities represent gains they hope to realize through greater reliance in regulatory environments. Box 4-6 lists opportunities identified by stakeholders, both those related specifically to reliance within GMP and those that might go beyond GMP. Discussions of good laboratory practice (GLP) and good clinical practice (GCP) during the committee’s information-gathering sessions were more limited than those of GMP; however, they yielded some outlook that the expansion of the EU-US MRA into areas beyond GMP and batch certification would require political will. Reliance for market authorization—the approval process for medicinal products—would entail sharing of robust data that could be analyzed extensively and completely so that all parties would understand the conclusions reached, which could be difficult for complex medicinal products. However, the situation is different for variations in marketing authorizations of medicines. In this case, the source product is already on the market, so that verification of the risks and benefits for its use in patients already exist. The EU system does accept “do-and-tell” whereby companies make some changes after a product is on the market and then inform the regulators. Because this process does not require an assessment, companies are expected to make the necessary changes, and these reports could easily be shared. The situation is different for companies seeking changes in medicines that could modify their risk/benefit profile (e.g., a new indication, a change in dosing, or the addition of new elements in the safety profile). Because this situation requires an assessment, sharing in this space would require political will. Therefore, one way forward would be to start small and evolve toward this outcome.
The committee’s focus on GMP does not indicate less importance for GLP or GCP, just relatively less input from stakeholders. This limited input may reflect time restrictions for the committee’s interviews, or a potential gap in the shared work of regulators and a potential opportunity for future reliance arrangements. For example, given that most drug development employs multiregional clinical trials to provide the clinical evidence for
marketing authorization, such trials are fairly common for both the United States and the EU (EMA, 2009a); therefore, citizens from both jurisdictions may be participants in the same global clinical trial. Both U.S. and EU regulators are required to verify that any study under their jurisdiction—whether in-country or abroad—has followed GCP, was conducted in an ethical manner, and reported accurate and complete data. Given globalization and resource limitations, inspection of all clinical trial sites is virtually impossible. One answer to this challenge is to create greater efficiencies through collaboration in GCP inspections and the exchange of information and inspection reports. Indeed, the European Medicines Agency and the U.S. Food and Drug Administration tested this possibility under their arrangement. The pilot test ended in 2011 and could provide the founda-
tion for future expansion of the recently activated EU-US MRA. Other regulators might also consider exploring the feasibility of reliance in this area.
A Patient-Centered Regulatory Framework
Virtually all of the regulators who provided input for this study supported the notion that each reliance arrangement either does now or would in the future enable medicines regulatory agencies to improve their efficiency. The regulators also agreed that such arrangements allow them to redirect resources to areas of greater need, although none had data from their agency to support that claim. However, that lack of data may change with the EU-US MRA, as the partners agreed to establish performance
indicators with which to demonstrate that implementing the agreement would deliver what had been promised. Information on the specific metrics were not shared with the committee, although a patient advocate from the International Alliance of Patients’ Organizations expressed his interest in what might be measured through the development of a framework that put the patient or consumer at its core. He stressed that in such a framework, patient safety would have to be paramount. He also highlighted the importance of ensuring faster access to innovations, particularly gene therapies and biotherapeutics, through MRAs or other reliance arrangements, so that patients who needed these innovative medicines would have access to them. Furthermore, he stressed the need for measuring increased equity, especially in the area of rare diseases, where patients stand to benefit most from increased reliance and access to new medicines. Lastly, his patient-centered framework would include metrics for affordability. He encouraged policy makers to invite patients into debates about regulatory reliance in general and MRAs in particular, emphasizing that patients can offer a real-life perspective that is often missing from policy-driven conversations. He also believes patients could bring a unique view to GMP inspections.
The pharmaceutical industry has benefited from recognition and reliance arrangements, as the collaboration that takes place provides guidelines for industry. In other words, it becomes clearer to all parties what is needed to facilitate market authorization across multiple jurisdictions. There are many agreed-upon technical requirements; however, when a consensus is lacking as to all of the information to be relied on, the approval process decelerates. Applications for different regulatory authorities have different requirements and these inconsistencies diminish their ability to rely on each other’s work products. Moreover, as medicines continue to become more complex, the burden of duplicative inspections on industry will increase, and the benefit to multiple jurisdictions will be small, as the expertise necessary to examine complex medicines effectively may be limited to a few individuals.
Acknowledging the complications associated with initiating and implementing MRAs, industry still sees opportunities for MRAs to expand reliance beyond GMP. Attention focuses on product review and first approval inspections; however, a large percentage of industry work occurs in the post-approval and lifecycle management spaces, which are as important to public health as initial approvals. Regulatory authorities have limited capacity, resulting in backlog such that several years may pass before they are able to review post-approval changes, hindering multinational distribution. Regulatory reliance has potential utility across the medicines life-
cycle; examples include registration, inspections, variations, post-approval changes, import testing, and lot release. For example, MRAs and other reliance arrangements used for post-approval changes to vaccine supply would motivate industry because expedited market penetration would be secured. The opportunity to reduce the time and effort put forth to keep essential medicines on the market parallels regulatory authorities’ goal of reducing supply shortages.
Understanding the Value of Reliance
Of particular note from the committee-developed supplemental information-gathering questionnaire and information-gathering sessions was the importance of helping all stakeholders understand that increased reliance is not an opportunity simply to reduce the resource needs or fees of participating regulatory authorities. Rather, reliance presents opportunities for ensuring that agencies can avoid duplication and focus their resources on key activities that bring value to the populations they serve instead of repeating redundant regulatory tasks. If full trust is built, the result may be greater public health protection. Currently, the overwhelming perception of all the stakeholders whose views were gathered for this study is that greater recognition and reliance in all their forms will, in both the short and long terms, strengthen public health across the globe.
Among the challenges associated with reliance arrangements, particularly in the case of MRAs, are the costs of setting them up. In most cases, these costs are short term, as they are related to the high degree of administrative and programmatic effort needed to develop, negotiate, and maintain the arrangement. The financial benefits are believed to be realized once the arrangement has been fully implemented. Expected gains in financial and time efficiencies may be modest in the initial phases of trust and knowledge building, but what must be emphasized is the improved decision-making process that is realized when two or more sets of national regulators work together. The stakeholders interviewed by the committee reported their view that this benefit more than compensates for the initial investment of time and resources (see the opportunities listed in Box 4-6). In addition to regulators, these arrangements provide benefits to both industry and consumers. Industry stands to benefit through improved market access, fewer duplicative inspections, and batch retesting waivers upon importation, each of which could translate into greater financial return for
companies and indirectly generate public health benefits (e.g., a reduction in redundant regulatory processes expedites the availability of products to populations in need). For patients and consumers, reliance arrangements can provide access to a wider array of medicines at potentially lower cost, as was expressed by the speaker discussing the work of Mexico’s Comisión Federal para la Protección contra Riesgos Sanitarios in recognizing generic approvals of trusted authorities (see Chapter 2). The overall outcome of these benefits is improved public health protection.
As was discussed with stakeholders, a potentially more sustainable model than unilateral reliance might involve greater transparency of the work of well- and moderately well-resourced regulatory bodies that are performing at an international level of regulatory oversight. Increased information sharing along with efforts—such as those of WHO and PIC/S—at capability and capacity building among lower-resourced regulatory authorities could improve overall global public health while opening the door to better-informed sovereign decision making in all countries, regardless of national income status. The availability of unredacted reports would allow both well- and lower-resourced regulatory authorities to perform their regulatory activities in an ever-improving manner. One of the issues for lower-resourced regulators is that the medicines involved may be different, so it is important for them to understand the details provided in a shared report. In some cases, it is not possible to truly rely on the work product of another agency unless the receiving agency obtains a full report. The availability of such unredacted reports would both allow other countries to use these reports to reach their own sovereign decisions on market access and help build needed capabilities in review capacity among regulatory authorities.
Public Health Imperative
The public health imperative drives some countries to expand their participation in reliance arrangements. In the case of New Zealand, for example, the population is relatively small and thus may be a lower marketing priority for multinational drug companies compared with larger markets. An MRA with Australia, however, has enabled the New Zealand authority to incentivize sponsors to submit for marketing authorization in that country. This mechanism will contribute to bringing new drugs to New Zealand in a timely manner despite the country’s limited market size and population. It should be noted that many countries ensure access to innovative medicines without mutual arrangements—they just unilaterally recognize
marketing authorizations issued by other regulatory authorities with the capacity to assess such products. Without such unilateral arrangements, new medicines would not reach many countries in the world. It is speculated that such a process, if built on a foundation of trust, might even be a faster mechanism for approving medicines and getting them to these markets relative to using an MRA.
As discussed previously, informal arrangements that facilitate decision making through reliance on the exchange of trusted information include Memoranda of Understanding, confidentiality commitments, regularly scheduled discussions, and agreed-upon work-sharing programs. In these situations, agencies are gaining access to trusted information that they can then use to decide whether further action on their part is needed prior to making a regulatory decision, or they can make their sovereign regulatory decision informed, in part or in whole, by the information received through these informal arrangements.
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