Introduction

Coronavirus disease 2019 (COVID-19) is an infectious respiratory illness caused by SARS-CoV-2, and was first identified in Wuhan, China in December 2019 before being declared a global pandemic by the World Health Organization (WHO) in March 2020 [1, 2]. In April of 2020, the cumulative case fatality rate of COVID-19 was 8% worldwide, and reached 6% in the US in May of 2020 [3]. The spread of COVID-19 globally required the rapid development of both vaccines and therapeutic agents. In December 2021, nirmatrelvir/ritonavir (Paxlovid™) received emergency use authorization (EUA) in the United States for the treatment of adults and pediatric patients (12 years of age and older weighing at least 40 kg) with mild-to-moderate COVID-19 and who are at high risk for progression to severe COVID-19, including hospitalization or death [4].

Paxlovid consists of nirmatrelvir tablets co-packaged with ritonavir tablets [5]. Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease, which prevents viral replication [5]. Ritonavir does not directly inhibit SARS-CoV-2, it instead acts to inhibit the cytochrome P450 (CYP) 3 A-mediated metabolism of nirmatrelvir, which leads to increased plasma concentration of nirmatrelvir [5]. Due to its potent inhibition of CYP3A, ritonavir is typically prescribed as a booster for drugs that are rapidly metabolized by CYP3A to enhance their bioavailability, as seen in many HIV regimens [6]. The safety and efficacy of nirmatrelvir/ritonavir was initially evaluated in the EPIC-HR study, an international, phase 2/3, double-blind, randomized, controlled trial [7]. The trial reported an 86% relative risk reduction in hospitalization or death in patients treated with nirmatrelvir/ritonavir compared with placebo, with no serious safety concerns [5, 7].

Drug-drug interactions (DDIs) were known to be a potential safety concern for nirmatrelvir/ritonavir due to the inclusion of ritonavir, which has a well-established DDI profile following its initial approval in March 1996 [8]. Indeed, the DDI profile of nirmatrelvir/ritonavir was initially ascertained based on ritonavir labels and supplemented by Pfizer-sponsored DDI studies [9, 10]. Because knowledge of ritonavir-associated DDIs has generally been confined to the HIV healthcare provider (HCP) community, whereas the potential patients and HCPs who would use or prescribe nirmatrelvir/ritonavir were broad and heterogeneous, steps were taken to proactively inform and educate HCPs and patients/caregivers about DDIs.

The EUA for nirmatrelvir/ritonavir was granted in record time; from first synthesis to EUA was approximately 18 months and from first-in-human study to EUA was approximately 10 months [7, 11,12,13]. This compressed development timeline was followed by the rapid uptake of nirmatrelvir/ritonavir during the early days after EUA, since oral outpatient treatment options were urgently needed to prevent hospitalization and death from COVID-19. It was therefore necessary to expeditiously develop a rapid, widespread, and comprehensive strategy to educate HCPs and patients about potential DDIs and the safe use of nirmatrelvir/ritonavir. This unique case study may help to guide best practices for future therapeutics that require timely and comprehensive dissemination of medical information.

Comprehensive Approach to DDI Education

Internal Collaboration

Within Pfizer, several cross-functional teams (including Medical Affairs, Medical Information, Clinical Pharmacology, Regulatory, Safety, and Risk Management) collaborated to identify what educational, non-promotional resources would be required for each stakeholder (e.g., HCPs, patients) to ensure that they had the information and knowledge necessary to anticipate, identify, and manage DDIs when making the decision to utilize nirmatrelvir/ritonavir. Collaboration within the initiative was equally distributed and communication between company teams in various roles and functions was continuous and integrated. The communication between teams avoided the siloing of information and enabled the sharing of ideas and alignment on the most up-to-date data from which to inform compliant content creation and to measure the impact of these efforts. A description of the roles of each Pfizer team in the cross-functional DDI education collaboration is presented in Table 1.

Table 1 Roles of each team in the nirmatrelvir/ritonavir cross-functional DDI education collaboration
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Purposeful and rapid dissemination of information was also a key component of the education initiative. A wider dissemination footprint was enabled by including all of Pfizer Medical, including field medical teams from all business units (i.e., across all therapeutic areas and not limited to those working on nirmatrelvir/ritonavir). Pfizer-wide training across therapeutic areas was conducted so that all relevant colleagues would be able to provide medical education for nirmatrelvir/ritonavir within their specific therapeutic area.

External Collaboration

The initial proactive engagement of the Pfizer Regulatory team with the U.S. Food and Drug Administration (FDA) during nirmatrelvir/ritonavir label development ensured that there was a provision in the EUA to allow for development and dissemination of instructional and educational materials without preclearance [15]. This allowed educational information to be provided on product administration and/or patient monitoring that was consistent with the authorized labeling. The FDA also developed its own patient eligibility screening checklist for prescribers, including a color-coded list of potential DDIs for nirmatrelvir/ritonavir.

In addition to the FDA, Pfizer was involved in multiple simultaneous external collaborations with other institutions (such as the National Institutes of Health [NIH], the University of Liverpool, and the Institute for Safe Medication Practices [ISMP]) on DDI education activities. Pfizer Medical functions were also proactive in subsequent communication with external organizations (such as universities and websites frequently used by HCPs and various healthcare associations) to support the collection of real-time input and insights that helped further develop and adjust the education tactics. Pfizer teams provided guidance to these organizations to help them understand the known DDIs in addition to providing suggestions on how to best represent DDIs to patients and HCPs. An overview of collaboration activities is presented in Fig. 1.

Fig. 1
figure 1

Summary of internal and external collaboration activities supporting nirmatrelvir/ritonavir DDI education. Abbreviations CME = continuing medical education; DDI = drug-drug interaction; HCP = healthcare provider

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Key Materials Developed and Outreach Activities

It was recognized early that, because the EUA fact sheet contained an extensive list of potential DDIs, it would be a challenge to distill this information into an easy-to-read, meaningful format for HCPs while recognizing that they had limited time during patient encounters. A key to the success of the education initiative was specifically tailoring information to educate a variety of providers (e.g., specialists, primary care physicians, and pharmacists) while using a variety of formats and delivery methods to increase the breadth of information dissemination. The information was tailored and varied in both content (including scientific data, case studies, infographics, etc.) and delivery to ensure that the material was comprehensive and relevant to each specific provider group. One example of the unique DDI education materials developed for nirmatrelvir/ritonavir is the ‘DDI Resource’ [16], a quick reference document available online that contains a summary of potentially significant drug interactions (categorized by drug class) in addition to hyperlinks to the EUA fact sheet and external sites such as the NIH and University of Liverpool. It is notable that there were specific classes of drugs that required additional attention due to their widespread use (e.g., statins), and certain materials were targeted for these drug classes and HCP audiences in particular. In addition, some materials were developed specifically to educate patients on DDIs, such as revised packaging that prompted patients to discuss current medications with HCPs and QR codes on packaging to increase access to online materials. Additional examples of DDI educational materials included HCP educational webinars, which discussed important information regarding nirmatrelvir/ritonavir, and Dear Healthcare Provider Letters (DHCPL), which informed providers on important prescribing and dispensing information. An overview of the educational materials that were developed is presented in Fig. 2.

Fig. 2
figure 2

Selected educational materials developed as part of the nirmatrelvir/ritonavir DDI education initiative. Abbreviations DDI = drug-drug interaction; DHCPL = Dear Healthcare Provider Letters; EUA = Emergency Use Authorization; FDA = U.S. Food and Drug Administration; HCP = healthcare provider; PRD = Patient Response Document; SRDs = Scientific/Standard Response Documents [14, 16, 17]

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Omnichannel engagement that disseminated the right information to the right HCP audience was a key strategy of the education initiative. The Pfizer omnichannel strategy for DDI education aims to meet audiences where they are looking for information. This included gaining stakeholder insights to inform the strategy, understanding channel usage and preferences, disseminating medical content, and reviewing data and analytics to continue to adapt the strategy as necessary. Channels used for dissemination included field medical emails, DHCPL, online education (live and recorded), and continuing medical education (CME) programs. Field medical teams across Pfizer also supported proactive education and discussion for nirmatrelvir/ritonavir using the interactive DDI Resource on the Pfizer Medical Portal and shared the DDI checker available on the Pfizer Medical Information website, allowing HCPs to have a concise and useful resources in a high stress work environment.

In addition to developing educational materials internally, Pfizer teams worked with external stakeholders to ensure that accurate information was being relayed to them in a timely manner. This included proactive engagement with HCP media websites to ensure that information on DDIs was accurate and up-to-date, as well as holding regular calls with representatives of HCP associations to allow for bi-directional information sharing on DDIs.

Proactive Signal Monitoring to Inform and Update Ongoing DDI Education Strategy

During the implementation of the DDI education program, the approach was constantly reviewed in light of newly available information and the education strategy was revised as needed. In particular, Pfizer Safety, Regulatory, Medical Information, and Medical Affairs teams worked proactively to identify potential nirmatrelvir/ritonavir safety signals through the use of multi-source data analysis, and materials were updated when new DDIs were identified. While the initial EUA DDI list resembled that of ritonavir DDIs, additional drugs and drug classes were added to the DDI section of the EUA Fact Sheet based on real-world use per FDA request, as use of nirmatrelvir/ritonavir expanded in the wider patient population. The boxed warning on the product label was added at the time of formal FDA approval in May of 2023 (and subsequently added to the EUA Fact Sheet), during which time nirmatrelvir/ritonavir was approved for the treatment of mild-to-moderate COVID-19 in adults who are at risk for progression to severe COVID-19, including hospitalization or death [5]. Educational materials as well as patient and HCP response documents were therefore frequently updated to reflect the most recent DDI information. Pfizer provided continuous proactive education on the risk of DDIs and executed on an ongoing risk management plan to address potential DDIs immediately.

The DDI Resource was shared and tested in-depth with an HCP focus group representative of multiple specialties, who provided feedback and insights. The focus group validated the educational approach and the content, and confirmed the practice real-time use case envisioned for this resource. HCPs reported an increased knowledge and comfort in prescribing nirmatrelvir/ritonavir after reading the document, and agreed they would be highly likely to use it as a personal reference. The feedback received demonstrated that the DDI Resource had a measurable impact for the HCP community. However, it should be noted that it was not possible to compare between an educated and uneducated group of HCPs and, therefore, not possible to conclusively determine the results of the initiative.

External collaborations also enabled the continuous reviewing of metrics to create new content. For example, information gathered through collaboration between the Pfizer Medical and Medical Information teams identified commonly asked questions by HCPs or patients/caregivers, which were used to inform the development of Scientific/Standard Response Documents (SRDs) and Patient Response Documents (PRDs). These SRDs and PRDs are available for HCPs or patients/caregivers as a response to their unsolicited inquiries. In addition, information on adverse events and DDIs that were reported provided insight that helped to tailor and target the messaging of the education efforts.

Key Challenges

Unique to this initiative was the context of a global pandemic, during which timelines were constrained due to the urgency of requirement for therapeutics to treat COVID-19. In addition, the quickly changing environment of the pandemic, frequent guideline changes, and label updates necessitated the creation of additional educational materials or revisions to existing materials. Tight timelines were met by streamlining internal communications and adapting internal review processes to match the pace of the changes. Indeed, new variants and cases of COVID-19, along with hospitalizations and deaths, continue worldwide [18]. As of October 2023, more than 771 million confirmed COVID-19 cases have been reported, with nearly 7 million COVID-19 related deaths globally [19]. Although vaccination continues to be a key part of the prevention strategy, safe and efficacious treatment options are required to address the ongoing high burden of COVID-19 and continuous evolution of SARS-CoV-2, including in cases where Omicron and future variants of concern may have the potential to evade existing immunity [20,21,22,23].

The breadth of HCPs and patients affected by COVID-19 posed a significant challenge. Unlike many therapeutic products that are tailored to a single specialty, nirmatrelvir/ritonavir covered a heterogeneous population of high-risk patients and their providers. As such, the simplification of complex and extensive scientific information into streamlined materials was a considerable challenge given this large population and the extensive DDI profile of ritonavir. This challenge was overcome by compliantly tailoring information for specific audiences, while leveraging subject matter experts within Pfizer to disseminate DDI information to their respective HCPs. The variety of resources that were created using the omnichannel approach helped to share key information across a broad group of providers who had different and individualized preferences, including the use of infographics, case studies, the DDI interaction checker, and medical webinars (Fig. 2). Collectively, these strategies utilized a multipronged approach that focused on each aspect of the medication use process, and enabled outreach and education to a broad range of prescribers and other HCPs.

Conclusions

The collaborative nature of the nirmatrelvir/ritonavir DDI education initiative enabled the strategic dissemination of key DDI resources to HCPs and patients, enabling safer use of nirmatrelvir/ritonavir during the COVID-19 pandemic. Nirmatrelvir/ritonavir DDI education activities are ongoing, including the expanding and refinement of omnichannel engagement, field medical engagement, medical information resources, global medical grants, and the analysis and review of DDI data. The initiative continues to proactively address specific DDIs through the use of multi-analytic data, which allows early intervention and prevention of potential DDIs.