Regulation in the age of calamity: Changing the regulatory paradigm

We have entered an age of calamity, where the concurrence of disruptive forces, including infectious diseases, will continue in ever accelerating fashion. To better prepare for dealing with "polycrises," the health regulatory paradigm should continue to evolve, with smart and agile regulation as a key enabler proactively guiding the advancement and application of science. How regulators support health innovation will be critical to prevent another cycle of panic and neglect. The Centre of Regulatory Excellence (CoRE) launched an annual lecture series in 2021 to commemorate CoRE's founding Chair, the late Professor Sir Alasdair Breckenridge. Completing a trilogy of lectures on scientific and regulatory issues during the COVID-19 pandemic,1, 2 this perspective piece is based on the 2023 lecture on "Regulation in the Age of Calamity" delivered by Dr Richard Hatchett, Chief Executive Officer of the Coalition of Epidemic Preparedness Innovations (CEPI). "Polycrisis," a term popularized by Adam Tooze and embraced by the World Economic Forum, is the overwhelming concurrence of multiple interconnected global risks. We have entered an age of calamity in which the forces that have disrupted and defined our world in recent decades, not least the force of infectious diseases, will continue in ever accelerating fashion.3 The COVID-19 pandemic was the epitome of a perfect storm of mutually potentiating crises. It could also be the harbinger of an era characterized by increasingly severe and frequent zoonotic spillover events, with the transmission of pathogens from animal reservoir to humans. Data from 1963 to 2019 showed that outbreaks are increasing at an alarmingly accelerating rate, driven by habitat encroachment and climate change.4 On this trajectory, it is estimated that mankind would witness four times as many spillover-driven outbreaks and 12 times as many deaths by 2050, compared with 2020. To be better prepared in this age of calamity, the health regulatory paradigm should continue to evolve, with smart and agile regulation as a key enabler to proactively guide the advancement and application of science. For health product regulators, it is crucial to review the context and way in which regulatory processes and procedures are applied as these may have been fit-for-purpose in the past or in routine situations but could be maladaptive in a crisis. The endeavor should be to go beyond the received wisdom that regulation always follows science, and instead change the paradigm so that regulation proactively helps guide the development and application of science. In the case of COVID-19, the development and emergency authorization of the first vaccine was achieved in just 326 days, when traditionally this would have taken several years. This success was contributed in part by the accelerated regulatory response, and modelers have estimated that vaccines may have contributed to preventing as many as 20 million deaths in the year after they were first authorized.5 However, the question also arises whether the millions of excess deaths that had occurred by December 8, 2020, when the first COVID-19 vaccines became publicly available, could have been moderated had vaccines been available even sooner. Thus, CEPI's call to accelerate the development and ultimately the equitable delivery of a pandemic vaccine within 100 days of the identification of an infectious disease with pandemic potential represents an aspirational and necessary goal. While the same metrics of safety, efficacy, and quality for routine authorization are also applied during emergency authorization of a pandemic vaccine, the risk threshold is very different. Thus, the prompt delivery of a pandemic vaccine and other innovative health products in a public health emergency requires complementary real-world scientific evidence in the post-market phase to better manage risks. In the context of such crises, the challenge for regulators is to recognize their critical, creative, and generative role. Regulators can proactively guide and support the adoption of innovation, through the deployment of smart and agile regulatory strategies that science and industry, properly directed, can provide. These strategies include harnessing real-world data following emergency authorization, promoting international regulatory cooperation, and using advances in immunology to accelerate regulatory decision-making on novel vaccine platforms or pandemic vaccines. For health product regulation, regulatory agility refers to the adoption of risk-based, context-driven innovative approaches and regulatory cooperation based on sound scientific evidence and information.6 Regulatory agility was well demonstrated by regulatory agencies globally in granting conditional approval to novel COVID-19 vaccines from December 2020 onwards. These agencies deployed appropriate risk-based adjustments to their existing national regulatory frameworks, expedited regulatory approvals, and gathered confirmatory real-world scientific evidence post roll-out. However, such agility did not occur in isolation. Major national regulators had been increasing their collaborations in the decades leading up to the COVID-19 pandemic. The International Coalition of Medicines Regulatory Authorities (ICMRA) is a global network of over 30 national regulatory agencies formally established in 2012 after an initial smaller group of agency heads had convened for informal annual summits since 2006 when the US Food and Drug Administration (FDA) had commemorated its centenary. In June 2021, ICMRA convened its members to collectively address regulatory steps to support COVID-19 vaccine development. This resulted in regulatory consensus on innovative strategies to ascertain the effectiveness of second generation COVID-19 vaccines.7 On June 30, 2022, the FDA authorized the BA.4/5 bivalent vaccine booster doses based on preclinical data alone, just 20 months after the first mRNA vaccine was made available, showing a remarkable evolution of regulatory practice. Some of these innovative regulatory strategies have been sustained and further improved on since the COVID-19 pandemic. To better prepare and deal with public health emergencies, sustaining the momentum of continuing innovation in regulatory policy and evolution of regulatory practice is paramount. Some relevant developing domains are discussed below. Immunobridging is a method of inferring the effectiveness of a candidate vaccine using an immune correlate of protection that is reasonably likely to predict efficacy or by using immune markers to compare against an established comparator vaccine. Its application is perhaps best exemplified by the FDA's accelerated approval on November 9, 2023 of the first vaccine against the Chikungunya virus, Ixchiq® (Chikungunya Vaccine, Live), based on achieving antibody levels in human subjects previously confirmed as protective by passive transfer studies in a non-human primate animal model.8 Immunobridging approaches are also being considered to accelerate licensing of future vaccines against viruses of pandemic potential, such as the Nipah virus. For such diseases, outbreaks are often small and sporadic, negating the ability to conduct traditional vaccine efficacy trials. Hence, progressing vaccine development with an immunobridging approach will ensure timely availability of a vaccine should a major outbreak occur. Data from the licensed Ebola Zaire vaccines are now being utilized to identify potential immune markers that might be used for authorizing other vaccine candidates against viruses from the Filovirus family on the same vaccine platform.9 The pandemic also highlighted how minority and marginal groups are disproportionately at risk for severe COVID-19 complications and death. These groups are often under-represented in clinical trials and such lack of diverse representation results in the clinical benefits of vaccines and other health products being less clear in these population segments. However, under pandemic circumstances, diverse representation is not always possible, given the necessity to promptly recruit and conduct clinical trials in relatively homogeneous populations for clear and unequivocal conclusions. One way to address this is to evaluate a vaccine using a particular vaccine platform during peacetime, then extrapolating this on a needs basis to special populations during an emergency for another vaccine on the same platform. During the COVID-19 pandemic, regulators took a pragmatic approach and extrapolated labeling to special populations including in children. Given the paucity of data, these decisions were supported by a combination of prior knowledge of data from the same platform and clinical need, with additional data subsequently being collected in the real-world setting or in specific clinical trials. Similarly, in the recent 2022 to 2023 mpox pandemic, regulators such as those from the United States and the United Kingdom recommended the use of the MVA-BN® (Modified Vaccinia Ankara-Bavarian Nordic) vaccine in pediatric populations, which at that time had been approved for adults only. This was based on the significant need for the vaccine in children during the outbreak and the experience with the same platform in the use of the Mvabea™ (MVA-BN-Filo recombinant) vaccine against Ebola Zaire in children.10 The COVID-19 pandemic played a role in accelerating the adoption of digital health technologies, particularly in the remote monitoring of decentralized clinical trials. This enabled accelerated and broad clinical trial participation under pandemic circumstances, at a time of population movement restrictions. Digital health technologies can also facilitate broader access to trials in previously under-represented population segments. With decentralized trials gaining traction, regulatory guidance such as the recent draft guidance on decentralized trials by the FDA can provide greater clarity for industry, investigators and stakeholders. In his book The Fate of Rome, historian Kyle Harper provides illuminating insights, describing the contributory factors of recurrent pandemics and climate instability on the eventual downfall of the Roman Empire. If there is one key takeaway from COVID-19, it is that pandemic preparedness is a sine qua non in this age of calamity. CEPI has been instrumental in leading global efforts on pandemic preparedness, with prescient investments in the development of vaccines and other biological countermeasures. As a further nudge to propel developments forward in a fragmented vaccine preparedness ecosystem, CEPI is proposing to build a Global Vaccine Library (GVL) to facilitate rapid and equitable information sharing with artificial intelligence integration. This GVL has tremendous potential as an important conduit for international knowledge exchange among scientists and regulators. In tandem with CEPI's efforts, CoRE has been building regulatory capability and promoting policy innovation since it was established in 2014. The Centre continues to evolve with advances in science and build collaborations around fit-for-purpose regulatory approaches and frameworks. Such collaborations among scientists and regulators promote good science and facilitate smart regulation. This is important to help ensure that clinical trials, even in the context of health crises, are well designed and yield informative results leading to good public health outcomes. In this age of calamity, regulators must step up as key collaborators with scientists in guiding the development and application of science to strengthen regulatory systems, prepare for future public health emergencies, and promote regulatory innovation and agility to help prevent future cycles of panic and neglect. No funding was received for this work. The authors declared no competing interests for this work.