Junko Sato
Pharmaceuticals and Medical Devices Agency (PMDA)

he 18th DIA Japan Annual Meeting 2021 featured senior regulatory authorities, industry scientists, and physicians sharing the challenges and their responding adaptations for pharmacovigilance and post-marketing surveillance during the COVID-19 pandemic: Gerald Dal Pan from the US FDA and Kiyohito Nakai from Japan’s Ministry of Health, Labour and Welfare (MHLW) joined DIA board member Peter Honig (recently retired from Pfizer) in a panel discussion chaired by Junko Sato (PMDA) and Stewart Geary (Eisai).

Nakai described how the AEFI (Adverse Event Following Immunization) system for monitoring safety following vaccinations in Japan was enhanced to enable electronic reporting. A special “very early phase” vigilance program surveyed 10,000 healthcare professionals who received COVID-19 vaccinations at the very start of vaccine rollouts in Japan for any adverse health outcomes during approximately one month following vaccination. Additional active surveillance included a post-vaccination health survey targeted to symptoms and conditions which are relatively frequent following vaccinations. Use of the questionnaire allowed calculation of incidence rates of adverse events.

An Expert Advisory Council in the MHLW met at an increased frequency to monitor the ongoing safety information emerging from the vaccination surveillance with additional support from the PMDA and NIID (National Institute of Infectious Diseases). All reports of death in persons who had recently been vaccinated were evaluated to detect unusual patterns outside of normal population mortality. A variety of resources were used to assess whether unusual rates of adverse events were being reported. For example, an observed vs. expected (O/E) analysis was performed for adverse events of pericarditis following vaccination which compared the expected incidence in a national medical billing database to observed events. Performing the analysis by patient age and gender and the vaccine received allowed for comparative analysis of the two mRNA vaccines approved in Japan.

Dal Pan explained that FDA called the entire armament of safety monitoring tools into play during the pandemic. Given the public interest in new therapies approved for COVID-19 under Emergency Use Authorization (EUA), FDA added a COVID-19 EUA tab to the FAERS dashboard showing adverse event reaction reports that FDA received. Unlike products approved through traditional procedures, EUA products come with the requirement for reporting medication errors to the FDA, and some of these reports resulted in revised EUA fact sheets or packaging. He also noted how the use of products and prescription patterns evolved during the pandemic. Poison control centers, for example, reported increases in ingestion of alcohol-containing hand sanitizer. The Sentinel system was used to monitor and evaluate outpatients diagnosed with COVID-19 and subsequent hospitalized thrombotic events, and a Master Protocol was developed to identify real-world data (RWD) related to COVID-19 in the Sentinel database.

Honig noted the importance of scalable business models and strong data systems within a company marketing a COVID-19 vaccine, given the very rapid uptake of the vaccines and intense public interest in their safety. He pointed out that RWD played an important role in the rapid selection of study sites for the vaccine trials (making sure they were in pandemic hotspots), and that arrangements such as the one between Pfizer and Israel to exchange vaccines for data have been invaluable in providing RWD on safety and efficacy.

Panelists also discussed continuing challenges. For example, many approvals for vaccines or medicines during the pandemic relied on special procedures such as the FDA’s Emergency Use Authorization. These differ by country and are not the same as full approval. These differences were sometimes not well-communicated in mass media. A deluge of scientific papers and studies reported small-scale clinical trials with approved medications for various aspects of COVID-19; however, in most cases, these studies were confounded in ways that made them inadequate for regulatory decision making. The pandemic accelerated use of RWD, but work remains to improve linkages between in-patient and outpatient data and the ability to follow patients through the healthcare system in order to maximize the usefulness and completeness of this data.

Panelists also commented on how the shift to remote working has affected work practices. Many organizations were already capable of remote work; FDA, for instance, has had an electronic signature system for years. But the pandemic has ushered in an expansion of flexibility in work arrangements at regulatory agencies as well as private companies. Everyone attending a meeting remotely ensures greater equality in participation than when most participants are together in a room while a few others call in from outside; in a sense, everyone is equal when everyone is remote.

Risk communication during the pandemic has also been challenging despite great efforts in ensuring transparency and access to information. Panelists noted that people tend to have trouble understanding risk and probability when the risk applies to themselves. Their suggestions for effective risk communication included:

• Focus on straightforward, clear messages
• Acknowledge the uncertainties and limits of available knowledge
• Present clear, actionable steps
• Explain the rationale and evidence base for recommendations.

The pandemic has challenged the resources of regulators, private companies, and academia, but it has also emphasized the importance of post-marketing safety and efficacy monitoring of new medical products and accelerated use of RWD in regulatory decision making. The tragedy of the pandemic has changed the public’s perception of pharmaceutical products and vaccines. Citizens’ huge interest in these therapies provides a good opportunity to increase understanding of the benefit-risk of all medical products. It also highlights the need for further work in risk communication and building public trust in science and medicine.