Reliance-Based Regulatory Pathways–The Key to Smart(er) Regulation?
Daniela Drago
Aurion Biotech
Murray M. Lumpkin
Bill & Melinda Gates Foundation
@gatesfoundation
C

OVID-19 exposed many vulnerabilities of our current global healthcare ecosystem. However, it also spurred debate on how to find novel solutions. Examples include the broader use of telemedicine, an increase in decentralized trials, and the provision of timely regulatory guidance. Consensus is growing that reliance pathways are useful in both emergency and routine situations and that more could be done to leverage their benefits. The expert committee members convened by the National Academies of Sciences, Engineering, and Medicine stated in their consensus report that “regulatory reliance is a 21st century best regulatory practice” not only for resource-constrained agencies, but also for better-resourced agencies. This article will 1) define regulatory reliance, 2) discuss national regulatory agencies’ considerations on its use, and 3) outline challenges to implementation and opportunities for fostering this 21st century best regulatory practice.

In the last few decades, several challenges have exacerbated the need for new technical resources and new numbers of technical resources at every national regulatory agency (NRA). These include the trend toward globalization of the life sciences industry, the increased complexity and numbers of products, and the rapid emergence of new technologies. Such challenges also created an increased need for NRAs to improve their cooperation and communication with each other. The concept of regulatory reliance pathways emerged as a potential strategy to bring greater efficiency to the regulatory process by eliminating duplicative work, strengthen regulatory systems, and optimize resource utilization with a focus on value-added activities without sacrificing product quality, safety, or efficacy.

What Is Regulatory Reliance?

The World Health Organization (WHO), in its Good Reliance Practices Guideline, defines regulatory reliance as

The act whereby the national regulatory authority (NRA) in one jurisdiction may take into account and give significant weight to assessments performed by another national regulatory authority or trusted institution, or to any other authoritative information in reaching its own decision. The relying authority remains independent, responsible, and accountable regarding the decisions taken, even when it relies on the decisions and information of others.

In 2019, the National Academies of Sciences, Engineering, and Medicine convened an expert committee to study the role of regulatory reliance in enhancing public health. In the resulting consensus study report, the committee defines two types of reliance activities.

  1. Horizontal (or bidirectional) Reliance Activities: These activities are conducted generally among well-resourced regulators. They share similar requirements and regulatory and scientific competencies, as well as other attributes that can ensure mutual trust and mutual reliance. In this paradigm, regulatory authorities rely on each other’s work for making informed decisions (e.g., using each other’s relevant GMP inspection reports). This kind of horizontal reliance is also apparent in various joint assessment activities, in which agencies pool resources to conduct various regulatory activities.
  2. Unidirectional Reliance Activities: These activities are conducted between a better-resourced and a resource-constrained regulator. The latter can use the work products of a trusted organization to inform its own regulatory decision making. The extent of the reliance can vary, including examining reports and reviews, informing independent national decisions, and accepting other agencies’ decisions without examination other than verification that the product it is receiving is the same as that assessed by the trusted agency.

NRAs’ Considerations on the Use of Regulatory Reliance

The decision of whether an NRA will use a regulatory reliance pathway is often based on several factors. For example, in some situations, the NRA may need access to technical expertise in a specific area which it does not have. A notable example is the recent authorization of COVID-19 vaccines in Africa. The reliance-based mechanism for this was agreed upon by the Africa Centres for Disease Control and Prevention, the African Union, and the WHO and was coordinated by the African Vaccine Regulatory Forum (AVAREF) Secretariat. Once a vaccine received WHO Emergency Use Listing (EUL), a technical session was organized by AVAREF, and all African regulators were invited. The EUL team, which is comprised of WHO personnel and various personnel from NRAs who participated in the EUL assessment, described their assessment and rationale for a positive EUL recommendation. Thereafter, they answered questions from the African NRAs. Each African NRA was able to download the WHO EUL dossier from the WHO SharePoint site to prepare for the meeting and to have the dossier within the agency. After the technical session, each NRA then made its own authorization decision, usually in a matter of days after the technical session.

In other situations, the NRA may need additional capacity in an expertise which it has but does not have enough of at a given time (e.g., inspectors). An example of this type of practice is the exchange of inspection reports for certain products between the US FDA and the EMA. Clearly each agency has the expertise; in this situation, it is a matter of having enough expertise at a given point. Each agency then uses the report from the other to inform its own regulatory decision for the product. This prevents duplicative inspections and frees inspectional resources to focus on other products or public health issues.

Notably, even when an NRA uses a reliance pathway (whether horizontal or unidirectional), it maintains responsibility for the regulatory decision taken in its jurisdiction. In other words, as Analia Porras from PAHO said, “Reliance is not ‘out-sourcing’ of decision making.” It is a tool to add better informed decision making and, as such, does not represent a less robust form of regulation. Regulators utilize the work products of a trusted agency to provide evidence to support their own decision making, avoiding duplication of efforts and encouraging the maximum utilization of technical expertise. The use of regulatory reliance pathways also provides benefits to sponsors and applicants. These include a decreased workload through fewer requests for additional information or repetitive inspections. Additionally, market access for quality new products will likely be faster and more predictable.

One final approach to reliance-based regulatory pathways is using resources in a joint assessment program. An example of this type of practice is Project Orbis, an initiative of the US Food and Drug Administration’s (FDA) Oncology Center of Excellence. Its scope is to provide a framework for simultaneous submission and review of oncology products among partnering international regulatory agencies. Currently, the regulatory agencies of Australia, Brazil, Canada, Singapore, Switzerland, and the United States (US) collaborate in this initiative.

Project Orbis’s first official action occurred in 2019 when NRAs in the US, Australia, and Canada collaboratively reviewed the application for Lenvima (lenvatinib) in combination with Keytruda (pembrolizumab) for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR), and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation. Each country retained its own format and content for the drug label. The regulators exchanged labels to learn about any potential differences, and only minor ones were noted.

Challenges to Implementation and Opportunities for Fostering Regulatory Reliance

Examples of current barriers to the implementation of regulatory reliance practices include:

  1. Different versions of products being marketed in different markets: In instances when a company manufactures different versions of a product at different sites for different markets, inspections of the different sites would be required. This is why it is critical that agencies relying on reports from a trusted agency verify that they are receiving the same version of the product assessed by the trusted agency.
  2. Overly redacted inspection and assessment reports: 20th century confidentiality laws and expectations may hinder communication in the 21st century world of globalized products and regulatory oversight. Sending unhelpful documents does not facilitate reliance pathways and creates unnecessary extra work for the trusted agency sending the reports.
  3. Assessor hesitancy to use these types of pathways: In some countries, regulatory officials may wonder about the implications of reliance for the security of their jobs, raising questions about how to assure that value-added jobs will be available, and whether people will be trained to do them.
  4. National “requirements” that need reassessment: Some countries require redundant lot release, local laboratory testing for authorization vs. importation, and Certificate of Pharmaceutical Products (CoPPs), when the data in the certificate is available online from agency websites.

These and other hurdles might have different origins. Some are internal and derive from the regulatory agency itself or the laws under which it currently operates, while others are external and may be motivated by industry, policy makers, consumers, patient advocacy groups, or other stakeholders.

Numerous opportunities to foster regulatory reliance have been put forward by different stakeholders. In particular, the authors believe that it would be important to address the hurdles discussed previously as well as the following three additional issues:

  1. Need of agreed-upon metrics to determine if these pathways are beneficial: Being able to quantify the impact of regulatory reliance on public health, on economic health, on agency efficiency, and on agency resource utilization would be valuable to help the larger community recognize the value of this approach to regulation.
  2. Transparency on what to do when there is a safety issue (or other issue) and an agency used a reliance pathway: In certain instances, NRAs will likely need to respond to parliament’s questions as to why another agency was trusted and the rationale for relying on them. Having this regulatory practice now enshrined by WHO as a 21st century best regulatory practice and having a systematic process at WHO for assessing the maturity levels of agencies will both help the wider community understand these regulatory practices and will help agencies in their due diligence regarding who their trusted agency partners are.
  3. Incentives for the agency on whom another agency relies: To lessen the burden for the reference regulatory agency, the transparency of decision making could be increased as a routine part of their business practices. NRAs should make their relevant documents accessible and processes straightforward so that the burden on the trusted agency is minimized.

Conclusion

In the last few decades, regulators—as well as industry and other stakeholders—have made significant progress in promoting reliance-based regulatory pathways. However, many challenges still exist. For example, some national requirements need to be reassessed, good pharmacovigilance practices need to be standardized, and public health impacts of reliance need to be evaluated. Fundamental challenges also include the need to verify that the version of a product being considered for a reliance-based regulatory pathway is the same as that assessed by the trusted agency. Overly redacted documents make reliance-based pathways particularly challenging, as it is difficult to “rely” on an inspection report or scientific assessment report if significant parts are redacted. The combined efforts of industry, regulators, physicians, patient advocates, legislators, academia, and others should help build a stronger and more sustainable infrastructure that would produce greater benefits for public health and economic health worldwide.
SUPPLEMENTAL RESOURCES

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

Mutual Recognition Agreements in the Regulation of Medicines: Regulatory Reliance – If Not Now, When? What Are the Current Barriers? National Academies of Sciences, Engineering, and Medicine Webinar

Disclaimer: The content outlined herein represents the individual opinions of the authors and may not necessarily represent the viewpoints of their employers. This article is based on the authors’ book chapter 8 “Regulatory Reliance” in Fundamentals of International Pharmaceutical and Biologics Regulations, Fifth Edition (2021).
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