5
Regulatory Science
An effective regulatory process, built on strong regulatory science, is essential to the development and deployment of safe and effective vaccines. It is also necessary for public trust in vaccination.
This chapter addresses the fourth of the four dimensions of vaccine research, development, and manufacturing examined by the committee. It begins by describing the role of regulatory science in the development of COVID-19 vaccines. The chapter then considers how lessons learned from the development of COVID-19 vaccines (shown in Box 5-1) can be applied to both seasonal and pandemic influenza vaccines in the dimension of regulatory science. The final section presents recommendations drawn from these findings.
REGULATORY SCIENCE AND THE DEVELOPMENT OF COVID-19 VACCINES
When SARS-CoV-2 was identified in early 2020, regulators around the world had only modest prior experience with coronavirus vaccines. Not only were there no approved vaccines for this family of viruses, but there were also no established correlates of protection and only minimal experience related to safety. To address these challenges, the U.S. Food and Drug Administration (FDA), the World Health Organization (WHO), and other leading agencies quickly established a process that supported the development of multiple safe and effective vaccines on innovative platforms at unprecedented speed. Key regulatory issues have included guidance for manufacturing, preclinical data, and clinical trials on the pathway to Emergency Use Authorization and licensure; coordination with regulated industry; public communications and transparency; and global collaboration and coordination, particularly with respect to emerging safety issues. Lessons from each of these areas are relevant to the challenge of developing safe and effective vaccines for pandemic influenza.
It should be noted that the starting point for regulators for the development of pandemic influenza vaccines is quite different from the starting point for COVID-19 vaccines. There are already multiple licensed influenza vaccines, established correlates of immunity, and the opportunity to test new seasonal influenza vaccine platforms through phase III trials every year. At the same time, current vaccines and vaccine platforms are insufficient to meet the global need for pandemic influenza, which therefore is the focus of this chapter.
Regulatory Guidance
Soon after the discovery of SARS-CoV-2, as scientists around the world began the research into candidate vaccines, regulators started to plan the regulatory pathway from preclinical data to large trials to establish safety and efficacy. In June 2020, FDA released guidance covering necessary chemistry, manufacturing and controls for vaccine production, nonclinical studies relevant to novel platforms including mRNA, and clinical trials (FDA, 2020). Among the topics covered were how vaccine manufacturers could assess the potential for vaccine-associated enhanced respiratory disease, an early concern of some coronavirus experts.
This document established rigorous standards for phase III clinical trials. It required that vaccines reduce COVID-19 by at least 50 percent, with 95 percent confidence intervals demonstrating at least a 30 percent reduction; as a result, phase III clinical trials had to involve tens of thousands of patients. FDA also required that the studies include a diversity of patients, including large numbers of older adults most at risk of death from COVID-19.
A subsequent FDA guidance, first issued in October 2020, set standards for the Emergency Use Authorization of COVID-19 vaccines. This guidance required substantial evidence of clinical efficacy, consistent with the earlier communication, and added a requirement of at least 2 months of median follow-up time for safety assessment (FDA, 2021). FDA released this guidance after an extraordinary public dispute with the White House, which involved the president of the United States accusing the agency of setting excessively high standards in order to hurt him politically (LaFraniere and Weiland, 2020). Seven former FDA commissioners wrote to defend the agency against such political interference (Califf et al., 2020).
Regulators in other nations overseeing the development of vaccines, including Russia and China, did not publicly release their standards for vaccine development. The Medicines and Healthcare Products Regulatory Agency in the United Kingdom did not require clinical trials to be as large as those for FDA review; however, the small number of older adults in initial trials for AstraZeneca vaccines later led to confusion about whether the vaccine worked in older adults and affected initial country decisions on adoption (Davis, 2021).
The initial U.S. standards had some noticeable gaps. FDA did not require early study of the vaccines in children or people known to be pregnant, which led to gaps in knowledge and public health recommendations in the United States that people who are pregnant make their own decisions with limited evidence (Klein et al., 2021; Mandavilli and Rabin, 2021). Standard setting is a dynamic process, responding to emerging evidence of
safety, efficacy, and immunogenicity. At the time of this report’s publication, for example, the standards for pediatric vaccine development remain in flux, as scientists work to establish the appropriate dose, given the robust immune response to SARS-CoV-2 among children (Johnson, 2021).
Coordination with Regulated Industry
With a novel, deadly virus moving across the planet, regulators altered their usual approach from requiring a single submission to allowing sequential submission and review of information from vaccine developers. Agencies conducted rolling reviews during clinical development, with nearly continuous exchange of data between industry and national regulators (CDC, 2021a). The need for such coordination was heightened by the threat of the pandemic itself. Chemistry, manufacturing, and control (CMC) processes are ideally performed at the manufacturing location. However, this was not always possible because of nationwide stay-at-home orders and mandates to limit face-to-face interaction. During the COVID-19 pandemic, companies and regulators identified ways to conduct the oversight of the CMC online, with regulators inspecting manufacturing facilities at times via video call (Stewart et al., 2021).
Coordination extended to key public statements. In September 2020, for example, nine leading vaccine companies pledged to support high safety standards and to not file for regulatory authorization or approval until established clinical benchmarks had been met (Loftus and Hopkins, 2020).
Public Communications and Transparency
It is not enough to know a vaccine is safe and effective. The public must trust in the process of vaccine development and appreciate the evidence that supports recommendations for use. This distinction reflects the public health wisdom that “vaccines don’t save lives, vaccination saves lives.”
Several communications challenges occurred during the clinical development of SARS-CoV-2 vaccines. In September 2020, U.S. and UK regulators put clinical trials for the AstraZeneca vaccine on hold because of a suspected serious adverse reaction. Information emerged about the situation from the company’s chief executive officer, through his private briefings with investors (Feurstein, 2020). However, regulators provided few details, even as the trials were restarted. Meanwhile, newspaper accounts documented behind-the-scenes disputes between company and government officials (Robbins and Mueller, 2020).
Communications issues intensified around the release of trial results, as companies issued press releases limited to topline data, and politicians extolled the virtues of their own country’s vaccines and debated who won
the “vaccine race.” Public confidence may have been undermined by the perception that political one-upmanship had influenced regulatory decision making.
Transparency supports the credibility of regulatory agencies (Sharfstein, 2020). At the country level, regulators differed in what they revealed publicly about the regulatory process. In the United States, prior to making decisions on Emergency Use Authorization, FDA released its own analyses of company data and convened public meetings of its independent advisory committee. These meetings included presentations from regulatory scientists and company officials, with extensive questions from the committee members and an opportunity for public comment. This process led to robust news coverage of the strong independent endorsements of the vaccines’ safety and efficacy (Sharfstein et al., 2021). China and Russia, by contrast, initially provided little explanation or data to support the use of their vaccines, which has contributed to confusion about these vaccines within and outside of these countries (Cohen and Moutinho, 2021; Sharfstein et al., 2021).
Other transparency issues related to the disclosure of study protocols are the release of clinical trial data and the regulatory pathway to licensure. Under public pressure, several manufacturers released the protocols for their phase III clinical trials, which boosted confidence in their rigorous approach (COVID vaccine confidence requires radical transparency, 2020). Not all manufacturers have committed to making clinical trial data available to independent researchers. In the United States, obscure reasoning behind the delay in licensing vaccines has led to calls for more clarity on timing standards for licensure (Topol, 2021).
Global Collaboration and Coordination
The rapid pace of COVID-19 vaccine development has stressed the global regulatory system. A limited number of experienced and well-resourced regulatory agencies have led in the regulatory review of COVID-19 vaccines, with many other national authorities relying on these assessments and the work of WHO. Over the course of the pandemic, the need for greater global collaboration and coordination has become clear. Opportunities exist for greater regulatory harmonization, improved sharing of data on manufacturing concerns, and a more coordinated response to emerging safety issues. It is challenging for regulatory agencies to scale-up for a pandemic response and then reduce or redistribute resource expenditures after the pandemic response. Addressing this challenge could help in future pandemic responses.
During the pandemic, the COVAX effort played an important role in promoting global coordination in regulatory oversight. COVAX supported
harmonization of certain documents and processes, such as vaccine label requirements for QR codes and fill dates. COVAX also required that vaccines for distribution qualify for an emergency use listing by WHO. Steps to an emergency use listing include an independent assessment of clinical trial data by the technical advisory group comprised of regulatory experts from around the world. Moreover, according to WHO, “as part of the Emergency Use Listing process, the company producing the vaccine must commit to continue to generate data to enable full licensure and WHO prequalification of the vaccine” (WHO, 2021). However, COVAX was limited in its ability to harmonize requirements across leading national regulatory agencies. At the same time, some vaccines were not able to be listed by WHO because of inadequate local standards, and production problems created international shortages. A surge in COVID-19 cases in India disrupted an anticipated global supply, and after a U.S. production plant experienced a variety of production problems, including cross contamination with another vaccine, global distribution of millions of doses came to a halt (Swaine and Rowland, 2021).
The challenge of global regulatory coordination during COVID-19 may be best illustrated by the variety of regulatory response to emerging safety issues. In early 2021, it became clear that two adenovirus-vectored vaccines produced by AstraZeneca and Johnson & Johnson were associated with a rare but severe syndrome of thrombosis with thrombocytopenia (Long et al., 2021; Tsilingiris et al., 2021). In response, some nations suspended use of these vaccines altogether, others limited the vaccines to older adults, and still others added warnings to the vaccine labels (Fox, 2021; Weiland et al., 2021). The European Medicines Agency had recommended continuing the use of the vaccine, and the European Union asked its members to “speak with one voice” on the topic. Nonetheless, every country in the European Union made its own considerations and recommendations for the use of this vaccine (Euronews, 2021). This varied response, and the resulting absence of a cohesive unified public message, may have undermined vaccine confidence.
REGULATORY SCIENCE: APPLYING LESSONS FROM THE DEVELOPMENT OF COVID-19 VACCINES TO VACCINES FOR INFLUENZA
The rapid development of COVID-19 vaccines on novel platforms has important implications for the development of new vaccines against pandemic influenza. For example, the tremendous success of mRNA vaccines has created hope that similar success and scale can be achieved for influenza (Anand and Stahel, 2021). However, limited data are available for mRNA influenza vaccines, and both safety and efficacy will have to be
demonstrated for these platforms (Bever, 2021). Success will require regulators to rethink established practices and expectations for influenza vaccines to support rapid innovation. Just as the time is now to support urgent basic research for vaccines for pandemic influenza, work on a companion regulatory process cannot be delayed. This section considers the application of lessons learned from regulatory experience in the four areas discussed above for COVID-19 vaccines: regulatory guidance, coordination with regulated industry, public communications and transparency, and global collaboration and coordination.
Regulatory Guidance and Coordination with Regulated Industry
The example of COVID-19 demonstrates how regulators can work with the scientific community and the pharmaceutical industry to establish guidance for the development of novel vaccine platforms (including novel adjuvants) for influenza. A logical starting point for this guidance is a pathway for seasonal influenza vaccines, from preclinical studies through licensure, informed by the best practices during COVID-19 of rapid data sharing and review. In formulating this guidance, a key consideration is that the existing hemagglutination inhibition (HI) assay may be potentially insufficient or possibly not relevant to new platforms, and as a result, it may be necessary to conduct clinical trials to generate data related to other potential correlates of protection (van Els et al., 2014). The existence of an accelerated pathway to licensure based on HI can, nevertheless, facilitate development of novel influenza vaccines so this existing pathway must remain in place, to which new pathways can be added.
Turning to the rapid adaptation of seasonal influenza vaccines for pandemic influenza, regulators will want to consider what data can be acquired in the interpandemic period, such as phase I and phase II data for vaccines targeting common pandemic subtypes (Krammer and Palese, 2014). Important as well will be laying out an approach to confirming safety and efficacy as quickly as possible following the recognition of an influenza pandemic. This guidance will need to be dynamic and evolving based on what is learned through the development of these platforms for seasonal influenza.
Conclusion 5-1: An important role for regulators is to formulate and/or update guidance for the development of both seasonal and pandemic influenza vaccines to provide more clarity on expectations for postauthorization/postapproval confirmatory efficacy studies. Ideally, a successful demonstration of safety and effectiveness for seasonal influenza vaccines, combined with the establishment of new correlates of protection, will inform a development pathway for pandemic vaccines that can be accomplished in a matter of months during a pandemic
without requiring full phase III clinical trials. In this case, the guidance will need to establish expectations for postauthorization confirmation of efficacy.
Guidance from regulators will also need to incorporate standards for the inclusion of diverse populations, including pregnant individuals and children, in clinical trials (see Chapter 3). Influenza is known to be a serious threat to people who are pregnant and children, so it is essential that these groups be included early on in clinical trials for influenza vaccines (CDC, 2021b; Poehling et al., 2013). For pandemic vaccine development, guidance can be contingent upon the risk of the infectious agent to each population to stratify the most affected populations for early investigations. Close monitoring of early studies should balance the need for including key populations with the urgency of pandemic response.
Conclusion 5-2: Guidance from regulators can help advance the inclusion in clinical trials of diverse population groups, especially those for whom influenza poses a significant risk, such as children and people who are pregnant.
Public Communications and Transparency
Applying the lessons from COVID-19 vaccine development, regulatory agencies, and WHO can commit to transparency as a key principle in oversight of influenza vaccines. Regulators can provide updates on the status of clinical trials (including basic information about clinical holds), release their own analyses of company data, provide for independent and public review of the data by advisory committees, and offer opportunities for questions and answers from the public and the news media.
For their part, vaccine manufacturers can release the protocols of pivotal clinical trials and make trial data available to qualified researchers, such as through the Yale Open Data Access project (YODA, 2021). The industry can also adopt a code of conduct for announcements of study results that emphasizes the preliminary nature of the findings and the role of independent review by regulators. It will also be important for such a code to support the ability of regulators to rapidly correct misstatements by commercial interests.
Conclusion 5-3: Careful conduct of public communications and transparency can help the public understand the development process for influenza vaccines and counter any misinformation to which they may be exposed.
Global Collaborations and Coordination
Just as for COVID-19 vaccines, international collaboration in regulatory science is essential for the development and safe implementation of vaccines for pandemic influenza. To this end, COVAX and WHO can continue and expand their roles for pandemic influenza, supporting harmonization where possible for vaccine manufacturers. WHO can act as a coordinator of critical areas of data sharing between regulators, including the sharing of data on efficacy and safety, postmarketing surveillance data, and information on product quality. WHO can coordinate with international regulatory agencies to develop core global regulatory standards for Emergency Use Authorization to provide a strong, stable, global vaccine supply in a pandemic. Such broad promulgation of basic standards for production can reduce the chance that vaccines will not receive authorization or will experience serious manufacturing quality problems.
Conclusion 5-4: There is a strong need to develop a robust and coordinated review process for influenza vaccines with consistent standards globally to minimize vaccine development delays and mitigate the credibility issues arising from variable decisions across countries.
National regulatory agencies value their ability to make their own authorization and licensing decisions and fashion their own responses to emerging safety issues and are unlikely to relinquish it. Indeed, risk–benefit analyses for the use of vaccines include multiple country-level factors that affect the results. For example, the prevalence of the virus in a specific region and the availability of other vaccines with a potential different safety and efficacy profile are variables that may lead to a difference in risk–benefit outcomes across countries and regions.
At the same time, when national regulatory agencies make different decisions about the same vaccines, confusion and vaccine hesitancy can result (Petersen, 2021). The committee therefore emphasizes the importance of coordination among regulators in explaining their decisions to the public. Transparency, as discussed above, is an essential element of this coordination. In addition, when explaining the decisions made for their own countries, regulators can acknowledge that circumstances may be different in other countries. Wherever possible, establishing a communication plan will help the public understand different recommendations on the same vaccines in different countries.
Conclusion 5-5: Risk–benefit analyses and regulatory decisions regarding influenza vaccines can be expected to differ across countries and
regions. Explaining such differences to the public is an important part of the communications and transparency discussed above.
RECOMMENDATIONS
Recommendation 5-1: The U.S. Food and Drug Administration and other national regulators (e.g., European Medicines Agency) working with the scientific community and pharmaceutical industry should enhance comprehensive guidance for the development of influenza vaccines on novel platforms through Emergency Use Authorization to full licensure. This guidance should provide pathways for seasonal and pandemic influenza.
Recommendation 5-2: The U.S. Food and Drug Administration and other national regulators (e.g., European Medicines Agency) should commit to transparency in the oversight of clinical trials, review of data, authorization, and approval of pandemic influenza vaccines, including the release of facility inspection findings, clinical trial protocols, and clinical data that are the basis of decision making. Regulators should convene independent advisory committees to systematically review data, make recommendations, and build public understanding and confidence prior to the authorization or approval of novel vaccines.
Recommendation 5-3: The World Health Organization and the International Coalition of Medicines Regulatory Authorities should encourage and support the coordination between regulatory and public health agencies (e.g., the U.S. Centers for Disease Control and Prevention, the European Centre for Disease Prevention and Control, the China Center for Disease Control and Prevention, and the Africa Centres for Disease Control and Prevention) when announcing different decisions on the same or similar vaccines, to explain the different underlying circumstances and judgments.
Recommendation 5-4: Vaccine manufacturers should adopt a code of conduct for press releases and other communications regarding vaccine trial results and other matters that emphasizes the critical role of regulatory review
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