Submitted:
26 January 2025
Posted:
28 January 2025
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Abstract
Objective: This study introduces the Denominator-Adjusted Rate Estimates of Substance Adverse Events Frequency Evaluation (DARE-SAFE) method to analyze pharmacovigilance reporting rates for vaccines and common pharmaceuticals. Methods: We calculated reporting rates for the top 250 most prescribed drugs in the US FDA Adverse Event Reporting System (FAERS) and common vaccines in the Vaccine Adverse Events Reporting System (VAERS). For vaccines, we used CDC dose data and OpenVAERS reports. For pharmaceuticals, we utilized prescription data from ClinCalc and FAERS reports for 2022. Results: VAERS reporting rates varied significantly across vaccine types. COVID-19 vaccines showed a 63.0±0.6 times higher rate of VAERS deaths per dose and an 18.95±0.02 times higher rate of total adverse event reports compared to influenza vaccines. The ratio of total VAERS reports to deaths for vaccines was approximately 70:1 (R²=0.966). For pharmaceuticals, the ratio of total adverse event reports to deaths was about 43:1 (R²=0.697), with a strong correlation between serious adverse events and deaths (ratio 11:1, R²=0.768). Conclusion: DARE-SAFE provides a standardized method for comparing reporting rates across different medical products. The observed differences between vaccines and pharmaceuticals, as well as among different vaccine types, warrant further investigation into reporting practices, actual safety profiles, and potential biases in surveillance systems.
Keywords:
Pharmacovigilance
; Vaccine Adverse Event
; Drug Safety
; Vaccine Adverse Event Reporting System
Introduction
Post-marketing surveillance utilizing passive reporting carries the caveat that lacking knowledge on the number of people administered a drug, raw numbers of reports do not reflect actual safety risk. This analysis calculates the reporting rates for the top 250 most prescribed drugs in the US FDA Adverse Event Reporting System, as well as common vaccines in the Vaccine Adverse Events Reporting System. While reporting rates and incidence rates are two different quantities, this data may be valuable as a resource in pharmacovigilance to identify changing trends in reported drug and vaccine adverse events (AEs), while remaining agnostic to the source of the trend, be it in reporting behaviour or actual risk.
The use of pharmacovigilance systems has come with caveats to the use of said systems, that one is unable to assign causality or to determine rates of adverse events from reporting frequencies. The use of any dataset comes with caveats, and VAERS is no different, requiring care in analysis and reporting. While we cannot calculate incidence rates from VAERS reports, it is possible to calculate the reporting rates, given a suitable denominator (number of doses). We make this clarification at the outset. Adverse events are typically underreported, where more serious and temporally associated events are more likely to be reported, and minor events with a less salient association with vaccination tend to be more underreported (less likely to be reported) [1].
The Problem of Inferring Rates in the Vaccine Adverse Event Reporting System
Pharmaceutical drugs are commonly understood to have side effects associated with them. These side effects are measured against their benefits to determine if it is in the patient’s best interest to take a prescription for a drug. By comparison, vaccines are understood to have side effects, ranging from site pain and cold and flu symptoms to severe impairments and death, yet outside of special cases of allergy to a component, are almost unanimously determined by medical professionals to be in the patient’s best interest.
This promotion by medical professional belies significant financial incentives for physicians to promote vaccines, which includes bonuses up to tens of thousands of dollars [2,3].
While vaccines can lower the incidence and severity of infectious diseases, they may not be appropriate in every case. For a proper comparison of utility with downsides, it is important to quantify levels of risk to compare with benefits. Promotion of vaccines is often laden with absolute statements. For example, official messaging on Covid-19 vaccines often included the words “Safe and effective”, without reference to what these meant quantitatively. Without a quantitative measure, “safe” communicates to the audience that the product is without risk, and “effective” communicates that the vaccine prevents the disease that the vaccine is targeted against. For the case of Covid-19 and all vaccines, neither is absolutely true.
It is commonly said that VAERS cannot be used to infer adverse event rates. While this is technically true, it can provide a helpful estimation. If the number of doses is known, than it is possible to provide the reporting rate per a constant number of doses. This should be considered only a proxy measurement for risk, and not an absolute measure, as it does not account for the reporting rate, which may differ between vaccines due to increased salience of pharmacovigilance reporting.
Many factors influence the reporting rate of VAERS reports, though it is widely accepted to be underreported, with reporting rates differing by condition, severity, and salience of the connection with vaccination. While caveats need to be accounted for, this does not mean that VAERS reports per dose is a useless measure, as is often implied. It may be informative of the relative safety of vaccines, and should importantly be corroborated with active surveillance tools. In principle, researchers are allowed to access active surveillance data; but in practice, requests can be declined by the agencies acting as custodians for the data.
Some AE rates for vaccines are reported, though our literature search has not revealed data on VAERS reports per dose for major vaccines as a resource. We include this data as a means of comparison of relative reporting rates between vaccines. Two analyses have compared reporting rates of Covid-19 vaccines with Influenza [4,5]. We expand this analysis to more vaccines in the CDC schedule.
If there is a large difference in VAERS reporting rates per dose between vaccines which does not correspond with an actual increased risk of adverse events for a given vaccine, it becomes informative to study the factors resulting in the discrepancy. As vaccine adverse event underreporting is a significant challenge, studying the factors behind greater reporting (as long as reports are truthful) can help pharmacovigilance efforts for current and future vaccines. In the case where differential reporting rates correspond to discrepancies in actual risk, it is important to study the factors driving the increased risk, as this may improve the safety of the vaccination program as a whole.
Pharmacovigilance Reporting for Pharmaceutical Drugs
It is less controversial that pharmaceutical drugs have side effects and potential adverse events associated with them. However, awareness of pharmacovigilance programs are limited, and adverse events are underreported for drugs as well as vaccines [6]. In the below analysis, we report the crude rates of drug associated adverse events per prescriptions. We wish to emphasize that the dataset for VAERS reporting rates is different from the dataset we provide for pharmaceutical adverse event reporting rates, and we provide these by prescription, instead of per dose, as is the case for vaccine adverse events, i.e. the rates are not directly comparable.
Methods
VAERS Reporting Rates by Vaccine Type
Using numbers of doses in CDC data, we search the number of VAERS reports for a given vaccine type using the resource OpenVAERS.com, which aggregates reports and provides the numbers of reports for given search terms. Additional filters can filter for deaths. We report both the total number of reports, as well as the deaths for a given vaccine type for the time period specified by the CDC data, ranging from Jan.1, 2022 to Dec.31, 2022, available at https://www.hrsa.gov/sites/default/files/hrsa/advisory-committees/vaccines/vicp-stats-01-01-25.pdf, accessed 9 January, 2025.
VAERS Reporting Rate by COVID-19 Vaccine Manufacturer
We delineate the VAERS reporting rates by Covid-19 vaccine manufacturer, using numbers of doses (Up to December 31, 2022) from https://ourworldindata.org/grapher/covid-vaccine-doses-by-manufacturer?country=~USA, and VAERS reports using the OpenVAERS search by vaccine manufacturer, for reports up to and including 2022.
FAERS Reporting Rates by Drug
Data on the number of prescriptions for a given drug per year are obtained through the website https://clincalc.com. The number of FAERS reports for the year 2022 is found for that same year using the FDA database, available at https://www.fda.gov/drugs/fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard. FAERS reports are also delineated by serious adverse events and deaths. Prescription rates for the year 2022 are obtained from https://clincalc.com/DrugStats/Drugs.
Results
VAERS Reporting Rates by Vaccine Type
Calculating the VAERS reporting rate per dose produces significant variation in the reporting rates for AEs across vaccine type. Given the possible variation in AE rates, especially for common and non serious events like site pain and cold/flu symptoms, we examine deaths, finding significant variation per dose as well, with Covid-19 vaccines being considerably more dangerous than other commonly administered vaccines, such as influenza.
Since influenza is one of the relatively safer vaccines with a large number of doses distributed, we express VAERS reporting rates as multiples of influenza, and do the same for VAERS deaths. For Covid-19 vaccines, we observe a 63.0±0.6 times higher rate of VAERS deaths per dose than influenza. For total AEs, Covid-19 vaccines have a rate of VAERS reports 18.95±0.02 times the influenza rate. These findings suggest differences in vaccine safety and/or reporting practices between the two vaccines.
Using a fixed intercept model, and weighting by the number of VAERS reports, the ratio of total reports to deaths is 70 (R2=0.966).
Table 1.
VAERS reporting rates per doses administered for vaccines in VAERS.
| Vaccine Name | Number of Doses Distributed (2006-2022) | Number of VAERs reports | VAERS reporting rate per dose | VAERS deaths | VAERS deaths reporting rate |
| DT | 794,777 | 462 | 0.000581 | 2 | 2.51643E-06 |
| DTaP | 122,237,653 | 25629 | 0.00021 | 656 | 5.3666E-06 |
| DTaP-Hep B-IPV | 94,331,585 | 9990 | 0.000106 | 419 | 4.44178E-06 |
| DTaP-HiB | 1,135,474 | 380 | 0.000335 | 1 | 8.80689E-07 |
| DTaP-IPV | 40,456,384 | 9818 | 0.000243 | 8 | 1.97744E-07 |
| DTaP-IPV-HiB | 89,568,786 | 8906 | 9.94E-05 | 224 | 2.50087E-06 |
| DTaP-IPV-HiB-Hep B | 2,021,770 | 526 | 0.00026 | 3 | 1.48385E-06 |
| DTP | 0 | 556 | N/A | 3 | N/A |
| DTP-HiB | 0 | 57 | N/A | 2 | N/A |
| Hep A+Hep B | 19,811,507 | 2893 | 0.000146 | 8 | 4.03806E-07 |
| Hep B-HiB | 4,787,457 | 1000 | 0.000209 | 18 | 3.75982E-06 |
| Hepatitis A (Hep A) | 231,034,565 | 30930 | 0.000134 | 85 | 3.6791E-07 |
| Hepatitis B (Hep B) | 248,816,802 | 19737 | 7.93E-05 | 222 | 8.92223E-07 |
| HiB | 159,451,493 | 21526 | 0.000135 | 435 | 2.7281E-06 |
| HPV | 158,878,541 | 42464 | 0.000267 | 109 | 6.86059E-07 |
| Influenza | 2,407,000,000 | 149512 | 6.21E-05 | 650 | 2.70046E-07 |
| IPV | 85,815,525 | 16104 | 0.000188 | 93 | 1.08372E-06 |
| Measles | 135,660 | 118 | 0.00087 | 2 | 1.47427E-05 |
| Meningococcal | 152,565,553 | 31050 | 0.000204 | 54 | 3.53946E-07 |
| MMR | 134424338 | 35743 | 0.000266 | 88 | 6.54643E-07 |
| MMR-Varicella | 42936444 | 15668 | 0.000365 | 20 | 4.65805E-07 |
| Mumps | 110749 | 65 | 0.000587 | 0 | 0 |
| OPV | 0 | 188 | N/A | 5 | N/A |
| Pneumococcal | 517159908 | 83537 | 0.000162 | 810 | 1.56625E-06 |
| Rotavirus | 150866652 | 19899 | 0.000132 | 476 | 3.1551E-06 |
| Rubella | 422548 | 98 | 0.000232 | 0 | 0 |
| Td | 79443263 | 3322 | 4.18E-05 | 9 | 1.13288E-07 |
| Tdap | 358134237 | 39153 | 0.000109 | 59 | 1.64743E-07 |
| Tetanus | 3838993 | 1226 | 0.000319 | 4 | 1.04194E-06 |
| Varicella | 143906028 | 48863 | 0.00034 | 84 | 5.83714E-07 |
| Covid-19 | 663000000 [7] | 781075 | 0.001177 | 11288 | 1.70154E-05 |
Table 2 includes the analysis for Covid-19 by vaccine manufacturer, showing higher levels per dose for Johnson&Johnson, with comparable levels of risk when taking into account that Pfizer/BioNTech and Moderna vaccines are a two dose series compared to one dose for Johnson&Johnson.
VAERS Reporting Rates by COVID-19 Vaccine Manufacturer
Using a fixed intercept model, and weighting by the number of VAERS reports, the ratio of total reports to deaths is 59 (R² = 0.989).
FAERS Reporting Rates for 250 Most Prescribed Pharmaceuticals in 2022
For the sake of brevity, we have included only the top 10 most prescribed medications in 2022 in Table 3. The full dataset is available in Supplementary Table 1.
For the sake of brevity, we have included only the top 10 most prescribed medications in 2022 in Table 3. The full dataset is available in Supplementary Table 1.
We observe a strong correlation between the reporting rates of serious adverse events and the reporting rates for deaths. Using a fixed intercept model, and weighting by the number of adverse event reports, the ratio of adverse event reports to deaths is 43±2 (R2=0.697).
Using a fixed intercept model, and weighting by the number of serious adverse event reports, the ratio of serious adverse event reports to deaths is 11.217 ± 0.002 (R2=0.768).
Discussion
This work presents Denominator-Adjusted Rate Estimates of Substance Adverse Events Frequency Evaluation (DARE-SAFE) for pharmaceuticals and vaccines, which provides values for the pharmacovigilance reporting rates for vaccines and common pharmaceuticals. The DARE-SAFE analysis provides a comprehensive examination of adverse event reporting rates for both vaccines and pharmaceuticals, offering valuable insights into pharmacovigilance data. This study calculates reporting rates for the top 250 most prescribed drugs in the US FDA Adverse Event Reporting System and common vaccines in the Vaccine Adverse Events Reporting System (VAERS).
A key finding of the analysis is the significant variation in VAERS reporting rates across different vaccine types. Notably, COVID-19 vaccines showed considerably higher reporting rates compared to other commonly administered vaccines, such as influenza. The study found that COVID-19 vaccines had a 63.0±0.6 times higher rate of VAERS deaths per dose than influenza vaccines, and an 18.95±0.02 times higher rate of total adverse event reports.
The analysis also revealed a consistent ratio of approximately 70:1 for total VAERS reports to deaths for vaccines. This ratio was determined using a fixed intercept model weighted by the number of VAERS reports, with an R2 value of 0.966, indicating a strong correlation.
For pharmaceuticals, the study examined the FDA Adverse Event Reporting System (FAERS) data for the year 2022. The analysis found a lower ratio of about 43:1 for total adverse event reports to deaths, compared to the 70:1 ratio observed in vaccines. Additionally, a strong correlation was observed between serious adverse events and deaths in pharmaceutical reporting, with a ratio of approximately 11:1.
These findings underscore the importance of context when interpreting pharmacovigilance data. While DARE-SAFE provides a standardized method for comparing reporting rates, it's crucial to remember that these rates do not directly equate to incidence or causality. The observed differences between vaccines and pharmaceuticals, as well as among different vaccine types, warrant further investigation into reporting practices, actual safety profiles, and potential biases in surveillance systems.
References
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Table 2.
VAERS reporting rates per doses administered for Covid-19 vaccines in VAERS.
| Covid-19 Vaccine Manufacturer | Doses (cumulative to 2022-12-31 in USA) | Number of VAERS reports | Number of VAERS death reports | VAERS reporting rate per dose | VAERS death reporting rate per dose |
| Pfizer/BioNTech | 395801679 | 398,648 | 6530 | 0.001007 | 1.64982E-05 |
| Moderna | 248752253 | 371,774 | 6056 | 0.001495 | 2.43455E-05 |
| Johnson&Johnson | 18953653 | 61,262 | 1093 | 0.003232 | 5.7667E-05 |
| Novavax | 69623 | 627 | 0 | 0.009006 | 0 |
Table 3.
FAERS reporting rates per prescription and patient for the top 10 most prescribed drugs in USA in 2022.
Table 3.
FAERS reporting rates per prescription and patient for the top 10 most prescribed drugs in USA in 2022.
| Drug Name | Total Prescri-ptions (2022, Millions) | Total Patients (2022, Millions) | Total AEs | Serious AEs | Deaths | AEs per prescription | Serious AEs per prescription | Deaths per prescription | AEs per patient | Serious Aes per patient | Deaths per patient |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Atorvastatin | 109.583 | 27.936 | 3834 | 3601 | 305 | 3.4987E-05 | 3.2861E-05 | 2.7833E-06 | 0.00013724 | 0.0001289 | 1.0918E-05 |
| Metformin | 86.748 | 19.536 | 5164 | 4631 | 663 | 5.9529E-05 | 5.3385E-05 | 7.6428E-06 | 0.00026433 | 0.00023705 | 3.3937E-05 |
| Lisinopril | 82.514 | 20.314 | 2564 | 1387 | 286 | 3.1074E-05 | 1.6809E-05 | 3.4661E-06 | 0.00012622 | 6.8277E-05 | 1.4079E-05 |
| Levothyroxine | 82.432 | 18.130 | 1756 | 1370 | 252 | 2.1302E-05 | 1.662E-05 | 3.0571E-06 | 9.6854E-05 | 7.5564E-05 | 1.3899E-05 |
| Amlodipine | 70.766 | 17.790 | 3903 | 3682 | 726 | 5.5153E-05 | 5.203E-05 | 1.0259E-05 | 0.0002194 | 0.00020697 | 4.081E-05 |
| Metoprolol | 65.245 | 15.543 | 2360 | 2096 | 400 | 3.6171E-05 | 3.2125E-05 | 6.1307E-06 | 0.00015184 | 0.00013485 | 2.5735E-05 |
| Albuterol | 59.075 | 19.265 | 2305 | 2073 | 109 | 3.9018E-05 | 3.5091E-05 | 1.8451E-06 | 0.00011964 | 0.0001076 | 5.6578E-06 |
| Losartan | 53.556 | 13.150 | 1194 | 980 | 157 | 2.2295E-05 | 1.8299E-05 | 2.9315E-06 | 9.0798E-05 | 7.4525E-05 | 1.1939E-05 |
| Omeprazole | 52.133 | 13.802 | 4844 | 4405 | 536 | 9.2916E-05 | 8.4496E-05 | 1.0281E-05 | 0.00035096 | 0.00031915 | 3.8835E-05 |
| Gabapentin | 40.141 | 9.890 | 5263 | 4149 | 1195 | 0.00013111 | 0.00010336 | 2.977E-05 | 0.00053218 | 0.00041953 | 0.00012083 |
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