Methodological Considerations for Comparison of Brand Versus Generic Versus Authorized Generic Adverse Event Reports in the US Food and Drug Administration Adverse Event Reporting System (FAERS)

Abstract

Background: The US Food and Drug Administration Adverse Event Reporting System (FAERS), a post-marketing safety database, can be used to differentiate brand versus generic safety signals.

Objective: To explore the methods for identifying and analyzing brand versus generic adverse event (AE) reports.

Methods: Public release FAERS data from January 2004 to March 2015 were analyzed using alendronate and carbamazepine as examples. Reports were classified as brand, generic, and authorized generic (AG). Disproportionality analyses compared reporting odds ratios (RORs) of selected known labeled serious adverse events stratifying by brand, generic, and AG. The homogeneity of these RORs was compared using the Breslow-Day test. The AG versus generic was the primary focus since the AG is identical to brand but marketed as a generic, therefore minimizing generic perception bias. Sensitivity analyses explored how methodological approach influenced results.

Results: Based on 17,521 US event reports involving alendronate and 3733 US event reports involving carbamazepine (immediate and extended release), no consistently significant differences were observed across RORs for the AGs versus generics. Similar results were obtained when comparing reporting patterns over all time and just after generic entry. The most restrictive approach for classifying AE reports yielded smaller report counts but similar results.

Conclusion: Differentiation of FAERS reports as brand versus generic requires careful attention to risk of product misclassification, but the relative stability of findings across varying assumptions supports the utility of these approaches for potential signal detection.

Fig. 1. Comparison of known labeled events across two different methods of defining brand, AG, and generic alendronate

ROR- Reporting Odds Ratio NA- Not applicable AG- Authorized Generic a Defined brand, AG, and generics based on the manufacturers name only For alendronate, brand reports were from Merck and Mission Pharma, AG reports were from Watson labs, and generic reports were from all other manufacturers. Although brand vs. generic comparison generated multiple significant RORs, generic vs. AG comparison was significant only for osteonecrosis of the jaw. b Defined brand, AG, and generics based on the manufacturers name and whether reported by brand or generic name A sensitivity analysis was performed where reports were classified as brand, generics, and AG based on both manufacturers' name and the verbatim drug name reported. For example, if the drug name was reported as Fosamax or Binosto and the reporting manufacturers were Merck or Mission Pharma, then it was classified as brand. Similar results were obtained as before.

Fig. 1. Comparison of known labeled events across two different methods of defining brand, AG, and generic alendronate

ROR- Reporting Odds Ratio NA- Not applicable AG- Authorized Generic a Defined brand, AG, and generics based on the manufacturers name only For alendronate, brand reports were from Merck and Mission Pharma, AG reports were from Watson labs, and generic reports were from all other manufacturers. Although brand vs. generic comparison generated multiple significant RORs, generic vs. AG comparison was significant only for osteonecrosis of the jaw. b Defined brand, AG, and generics based on the manufacturers name and whether reported by brand or generic name A sensitivity analysis was performed where reports were classified as brand, generics, and AG based on both manufacturers' name and the verbatim drug name reported. For example, if the drug name was reported as Fosamax or Binosto and the reporting manufacturers were Merck or Mission Pharma, then it was classified as brand. Similar results were obtained as before.

Fig. 2. ROR trend for gastritis with alendronate

ROR- Reporting Odds Ratio AG- Authorized Generic a Cumulative ROR trend, b Annual ROR trend ▴ = The actual value was censored to a value of 13.5 for illustration purpose * = actual ROR, 22.69 Both the cumulative (a) and annual (b) ROR trends were similar which explains minimal influence of temporal variation on reporting trends.

Fig. 3. Sensitivity analysis of report type for gastritis with alendronate

ROR- Reporting Odds Ratio AG- Authorized Generic Although brand vs. generic comparison reached statistical significance for all the cases except for US primary suspect reports, none of the generic vs. AG comparison showed statistical significance. The confidence interval gets wider as the number of reports get smaller.

Fig. 4. Sensitivity analysis comparing reporting patterns for alendronate over all time vs. just after generic entry

ROR- Reporting Odds Ratio AG- Authorized Generic None of the generic vs. AG comparison yielded statistically significant result. Consistent reporting patterns were observed across over all times and just after generic entry.

Fig. 5. Sensitivity analysis comparing reporting patterns for extended release vs. all formulations for carbamazepine

ROR- Reporting Odds Ratio NA- Not applicable AG- Authorized Generic ER- Extended Release No AG report was found for carbamazepine ER. RORs for generics were higher than brand for both the formulations of carbamazepine in case of liver injury; however, none of the generic vs. AG comparison reached statistical significance.