Literature Review of Safety Event Reporting in Observational Studies: Challenges Extrapolating across Comparable Products

: Nirmatrelvir/ritonavir (PAXLOVID TM , Pﬁzer) is an anti-infective inhibiting CYP3A4 indicated for the treatment of COVID-19 in adults at increased risk of severe COVID-19. As a newly approved product, PAXLOVID has limited safety information regarding rare events and serious adverse events (SAEs). This review describes the characterization of the real-world safety proﬁle of products with similar pharmacological properties to PAXLOVID and aims to understand the impact of any drug interaction on the concomitantly prescribed products. A literature search of articles in PubMed published between 2018 and 2023 was conducted to assess the real-world frequency of safety outcomes of interest, speciﬁcally those meeting the criteria of serious adverse reaction. The review was restricted to observational, noninterventional studies and included CYP3A4 inhibitors prescribed for short-term treatment of infections in the outpatient setting. Twenty-one articles were included in the review. Most focused on a small, predeﬁned list of safety outcomes and did not provide insight into the broader range of safety outcomes that might occur for the evaluated products with similar pharmacological properties to PAXLOVID or the impact of any interaction on the concomitant product. The ﬁndings highlight the challenges in obtaining proxy safety outcomes characteristics via a review of products with comparable pharmacological properties and underscore the need to have large, rapidly accessible data sources that can contribute to the safety proﬁle of newly authorized products in the real world.


Background and Rationale
Drug safety profiles, initially developed in clinical trials, continue to evolve as postauthorization data are accrued.Intrinsic elements of clinical trial design (e.g., strict eligibility criteria and limited duration) limit the potential to exhaustively detect rare safety events such as the incidence of serious adverse events (SAEs) or drug-drug interactions.Full characterization of the safety profile of a newly approved product is essential to provide patients and their prescribers comprehensive information on risk-benefit considerations and requires a period of real-world data (RWD) accumulation.The time required for RWD accrual would be impacted by factors such as the health of the indicated population (e.g., younger adults with lower underlying risk for AEs and lower likelihood of comorbidities and comedications) and the size of the patient population (e.g., substantial proportions for vaccinations programs versus smaller patient populations for rarer conditions).
One exploratory method for acquiring proxy information on the safety characteristics of interest during the early post-authorization period is a real-world literature review on products with similar pharmacological properties.This approach was applied to nirmatrelvir/ritonavir (PAXLOVID TM , Pfizer), an anti-infective inhibiting CYP3A4 that is indicated for the treatment of COVID-19 in adults who are at increased risk of progressing to severe COVID-19.The opportunity for drug interactions and potentially related safety outcomes is expected to be greater in a real-world setting than in a clinical trial setting.The purpose of this targeted review was to characterize the interaction profile and the occurrence of safety outcomes of interest among real-world users of products with similar pharmacological properties to PAXLOVID, i.e., short-term anti-infective medications that are CYP3A4 inhibitors that are prescribed in primary care settings regardless of the bacterial, fungal, or viral target.Safety outcomes of interest observed for products with similar pharmacological properties to PAXLOVID were evaluated in the post-marketing primary care setting as proxies for comparable safety outcomes among PAXLOVID users.

Results
The application of predetermined search terms and filters (Supplementary Table S1) yielded 754 abstracts for review; after the application of the additional inclusion and exclusion screening criteria, 21 articles were included in the present review (Figure 1 and Table 1).
Pharmacoepidemiology 2023, 2, FOR PEER REVIEW to severe COVID-19.The opportunity for drug interactions and potentially related safe outcomes is expected to be greater in a real-world setting than in a clinical trial settin The purpose of this targeted review was to characterize the interaction profile and th occurrence of safety outcomes of interest among real-world users of products with simil pharmacological properties to PAXLOVID, i.e., short-term anti-infective medications th are CYP3A4 inhibitors that are prescribed in primary care settings regardless of the ba terial, fungal, or viral target.Safety outcomes of interest observed for products with sim lar pharmacological properties to PAXLOVID were evaluated in the post-marketing pr mary care setting as proxies for comparable safety outcomes among PAXLOVID users.
Drug interactions leading to safety outcomes of interest were a focus of research in three papers [3,9,12].Each was designed with specific pairs of known CYP3A4 inhibitor and substrate drugs or drug classes.None of these studies conducted broad screening and quantification of safety outcomes arising from potential drug interactions.

Discussion
The results of this review indicate that the method of selection of products with similar pharmacological properties to PAXLOVID does not contribute materially to characterizing the safety profile of a new drug such as PAXLOVID.Studies examining safety outcomes secondary to drug interactions were few and were specific to interacting combinations or outcomes.

Outcome Generalizability
Rather than evaluating the frequency of all safety outcomes, several studies were designed to evaluate the selected drug with a specific safety outcome (e.g., clarithromycin association with cardiac events).Other studies selected co-administered drug pairs to evaluate a specific drug interaction event.In the few studies without predefined safety outcomes of interest, either no data were available on the diagnosis related to the hospitalization outcome [3] or no safety outcomes occurred during the study period [4].Accordingly, the results of this literature review cannot be considered representative of all safety outcomes that occur for the short-term CYP3A4 inhibitor anti-infective medications under review.

Patient Representativeness
The demographic and disease characteristics of patients identified in observational studies may not be generalizable to the entire population using the reference drug.For example, some studies gathered specific cohorts of dialysis patients, pregnant patients, patients with diabetes, or elderly patients.While results from special patient cohorts have limited generalizability to a broader patient population, results on products with similar pharmacological properties may still be of interest because they may address the evidence gaps often present in special patient populations; however, the potential for filling evidence gaps depends on the outcomes selected (per point 5.1 above).Similarly, results from patient populations that were selected due to specific infections may have limited potential for generalizability to potential users of PAXLOVID who were infected with COVID-19.The challenge of patient generalizability with respect to the relevant infection could not be avoided in the absence of products that are more directly comparable with PAXLOVID (i.e., an oral treatment indicated for COVID-19).

Setting
Outpatient settings can be highly variable with respect to the burden of illness and patient type.Exposures and behaviors that affect outcomes may not be well documented in this setting.

Exposure Definition
Selection of an appropriate exposure product with similar pharmacological properties to PAXLOVID is challenging.Although the selected anti-infectives are CYP3A4 inhibitors, the level of inhibition may differ, which may affect the outcome, particularly when addressing drug-drug interactions.Differences in chemical structure and product indication would additionally impact the extent to which safety outcomes for products selected for this review could be extrapolated to PAXLOVID.Additionally, other pharmacokinetic and pharmacologic characteristics of the antibiotic and antifungal agents, such as product half-life and mechanism of action, may limit suitability for comparison to the reference antiviral.Lastly, since CYP3A4 inhibition leads to increased exposure to concomitantly prescribed medicines, characterization of the interaction profile associated with CYP3A4 inhibitors would also require collecting a complete list of concomitant medications with well-defined safety profiles.

Methods
This literature search was conducted in PubMed on 16 December 2022 and was restricted to English-language articles published between 2018 and 2023; full details of the search strings are presented in Supplementary Table S1.There were no geographic limits.The review included the following CYP3A4 inhibitors prescribed for patients >11 years old for the short-term (≤14 days) treatment of infections in the outpatient setting: clarithromycin, erythromycin, itraconazole, fluconazole, ketoconazole, posaconazole, ciprofloxacin, levofloxacin, and ofloxacin.To support the objectives of this review, products with CY3A4 inhibition were selected.The focus was on the interaction profile that could lead to the real-world reporting of safety outcomes of interest.This review was restricted to observational, noninterventional studies to assess the real-world frequency of the safety outcomes of interest reported.For this review, safety outcomes of interest were those that met the criteria of "serious", as defined by study authors, or if hospitalization or death was specified in the outcome definition.

Conclusions
In this review, most of the studies focused on a small, predefined list of safety outcomes of interest; therefore, they do not provide insight into the broader range of safety outcomes that might occur for the treatments included in this review.This limited scope, coupled with highly selected patient populations, renders it difficult to extrapolate a general profile of safety outcomes among users of products with similar pharmacological properties to PAXLOVID.
There may be greater potential to gain insight into a new product safety profile via a literature review approach for a product where a more directly comparable treatment can be selected, that is, limiting the search to drugs in the same class, with similar metabolism, indicated for the same condition and similar patient population.However, even under such circumstances, there may be limited potential to further understand the contribution of drug-drug interactions to the observed safety outcomes; in the present review, studies either did not comment on such attribution or were designed specifically to examine safety outcomes in the context of coadministered drug pairs.Because information is not readily available in the literature, an iterative process of search and analysis may be needed to characterize and estimate the rate of potential safety outcomes associated with drug-drug interactions for a new agent such as PAXLOVID.Overall, the results of the present literature review indicate that observational research typically analyzes a prespecified short list of safety outcomes in targeted special patient populations.This suggests that, even for a more limited patient population/more directly comparable product, limitations in the characterization of safety outcomes will occur.
In conclusion, the exploratory method did not yield the proxy information that was of interest.This targeted literature review highlights the challenges in obtaining proxy safety outcome characteristics via comparison with products with similar pharmacological properties to those in the observational setting and underscores the need to have large, rapidly accessible data sources that can contribute to the safety profile of newly authorized products in the real world.

Figure 1 .
Figure 1.Targeted literature review search strategy and articles yielded.

Figure 1 .
Figure 1.Targeted literature review search strategy and articles yielded.

Table 1 .
Characteristics of observational studies identified via a targeted literature review on selected products with similar pharmacological properties to PAXLOVID.