Abstract
BackgroundDrug regulatory agencies (DRA) support prescription of generic products of intravenous antibiotics assuming therapeutic equivalence from pharmaceutical equivalence. Recent reports of deaths associated with generic heparin and metoprolol have raised concerns about the efficacy and safety of DRA-approved drugs.Methodology/Principal FindingsTo challenge the assumption that pharmaceutical equivalence predicts therapeutic equivalence, we determined in vitro and in vivo the efficacy of the innovator product and 20 pharmaceutically equivalent generics of gentamicin. The data showed that, while only 1 generic product failed in vitro (MIC = 45.3 vs. 0.7 mg/L, P<0.05), 10 products (including gentamicin reference powder) failed in vivo against E. coli due to significantly inferior efficacy (Emax = 4.81 to 5.32 vs. 5.99 log10 CFU/g, P≤0.043). Although the design lacked power to detect differences in survival after thigh infection with P. aeruginosa, dissemination to vital organs was significantly higher in animals treated with generic gentamicin despite 4 days of maximally effective treatment.ConclusionPharmaceutical equivalence does not predict therapeutic equivalence of generic gentamicin. Stricter criteria based on solid experimental evidence should be required before approval for human use.
Highlights
There has been a dramatic increase in clinical use of generic medicines since 1980, but there are not systematic evaluations of their therapeutic efficacy compared with innovator products [1,2]
Essential to reduce health budget costs and to promote pharmaceutical competition and employment, generic drugs remain a topic of intense controversy as a result of the accelerated approval process for human use, and sporadic reports of failures and deaths associated with their use [3,4,5]
There is an unsurpassable point in this controversy: forcing the manufacturers of generic drugs to go through the same process required to bring innovator drugs to market implies a cost overrun calculated in 150 to 800 million dollars that would hinder their mainstay objective, i.e., ‘‘to regulate and reduce the medicine’s price’’ [6]
Summary
There has been a dramatic increase in clinical use of generic medicines since 1980, but there are not systematic evaluations of their therapeutic efficacy compared with innovator products [1,2]. Essential to reduce health budget costs and to promote pharmaceutical competition and employment, generic drugs remain a topic of intense controversy as a result of the accelerated approval process for human use (which some disagree with), and sporadic reports of failures and deaths associated with their use [3,4,5]. The solution has been a very short, straightforward and inexpensive process created to approve generic versions of innovator products, which requires no comparative preclinical or clinical safety and/or efficacy studies, hoping that generics would generate results similar to those obtained with the innovator drug [7]. Drug regulatory agencies (DRA) waive the requirement of bioequivalence for pharmaceutically equivalent intravenous solutions because their bioavailability is considered ‘‘self-evident’’ [14]. Drug regulatory agencies (DRA) support prescription of generic products of intravenous antibiotics assuming therapeutic equivalence from pharmaceutical equivalence. Recent reports of deaths associated with generic heparin and metoprolol have raised concerns about the efficacy and safety of DRA-approved drugs
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