Methods to determine the true rate of side effects caused by medications: A case study with antiretroviral medications and diarrhea.




Bavafa, Azadeh
Killam-Worrall, Lisa
Clay, Patrick G.


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Introduction: There have been discrepancies between the rates of adverse events reported in the medication’s package insert and what have been seen in clinical settings. This difference causes confusion for clinicians and patients and interferes with pharmacists’ attempts to establish the necessary rapport with patient to improve compliance. Hypothesis: The incidence of selected adverse event for a class of medication would not be same as those found the package insert. Goals: The goal of this project is to conduct a systematic review of current literature to identify the true rate of adverse events associated with common Antiretroviral (ARV) medication regimens. Methods: A systematic search of primary literatures was conducted to evaluate the incidence rates of selected adverse events associated with most customary medication regimens recommended by HIV(Human Immunodeficiency Virus)/AIDS (Acquired Immune Deficiency Syndrome) medical practice guidelines. Initially, Inclusion and exclusion criteria were established. The keywords collected were used to search the primary literatures and documents produced during the drug approval process. Finally, the gathered data was tabulated and analyzed to determine “true” rate of adverse events. Results: The incidence rates of diarrhea among HIV infected—treatment Naïve—males and non-pregnant females ages: 18-65, were extracted from various sources including: the medication’s package insert, pertaining briefing document, clinical trials submitted to FDA, and published—unpublished phase III clinical trials. The medication regimens under investigation included: efavirenz (EFV) / emtricitabine (FTC)/ tenofovir( TDF) (Atripla), raltegravir(RAL)/FTC/ TDF, and rilpivirine(RPV)/ FTC/ TDF(Complera). The values reported, varied from one source to another. For example, the rate reported in Atripla’s package insert was 9%, and yet nothing was documented in its briefing document. In addition, the average rates (all causes and grades) extracted from submitted clinical trials—published and unpublished phase III clinical trials, were respectively: 22.9% (10.14%-35.6%) and 13.43% (0%-33.9%). The same method was used for the other two medication regimens, and similar trends were observed. Conclusion: Preliminary results of case study show the rate of diarrhea reported in package insert was different from what was extrapolated from published and unpublished phase III trials. Further analysis will be conducted to confirm this finding.