Current Regulatory Standpoint on Evaluating the Bioequivalence of Different Classes of Generic Drugs - Is the Evaluation in the Right Direction?

Abstract

Background: The concept of evaluating bioequivalence has changed over a period of time. Currently, the Average Bioequivalence approach (ABE) is the gold standard tool for the evaluation of generics. Of late, many debates had arisen about employing ABE approach for the appraisal of all drug categories. This review aims to examine the limitations of ABE approach and the significances of Population Bioequivalence (PBE) and Individual Bioequivalence (IBE) approach, current regulatory thinking for assessing different categories of the drug, whether they are adequately assessed, and the evaluation is in the right direction. Methods: We carried out an organized search of bibliographic databases for peer-reviewed research literatures, regulatory recommendations, guidance documents using a focused review question and eligibility criteria. The standard tools were used to appraise the quality of retrieved documents and to make sure the authenticity of the data. Results: In total 73 references were used in the review, the majority of the references (guidance documents) were from the different regulatory agencies and product-specific guidance. There were 29 product-specific guidance from USFDA and EMA. The limitations of the ABE approach were discussed in detail along with the significances of Population Bioequivalence (PBE) approach and Individual Bioequivalence (IBE) approaches. Conclusion: It is apparent from the review that IBE approach is a precise method for evaluating the drugs as it answers drug interchangeability (prescribability and switchability). IBE approach is followed by PBE approach and ABE approach for the evaluation of different categories of drugs in terms of precision.

Decrease in Antidepressant Efficacy After Change in Generic Formulation

“…These research participants are not representative of the patients who will eventually take the medication 14 . Moreover, current regulations do not require BE studies comparing different generic versions, so variability in the dose of the active pharmaceutical ingredient (API) can be greater between these formulations than between each generic and the brand-name drug 11 …”

“…Several clinical trials and many case series in various fields of medicine demonstrate differences in therapeutic efficacy between branded and generic medications. 10,11 Antidepressant medications are no exception with published cases involving selective serotonin reuptake inhibitors, 12 serotonin-norepinephrine reuptake inhibitors, 4 and bupropion. 13 In fact, the latter study of a specific generic form of bupropion XL 300 mg tablets lead to the Food and Drug Administration's recommendation of non-BE and withdrawal of that specific product.…”

“…14 Moreover, current regulations do not require BE studies comparing different generic versions, so variability in the dose of the active pharmaceutical ingredient (API) can be greater between these formulations than between each generic and the brand-name drug. 11 In addition, active ingredients make up a very small proportion of what is contained in most medications. Instead, the majority of the drug is made up of other ingredients, collectively known as excipients.…”

Simultaneous Determination of Loratadine and Its Metabolite Desloratadine in Beagle Plasma by LC-MS/MS and Application for Pharmacokinetics Study of Loratadine Tablets and Omeprazole‑Induced Drug–Drug Interaction

“…A commonly accepted evaluation method is the study of the preparation’s pharmacokinetic properties. 19 , 20 It is necessary to preliminarily investigate whether LTD tablets with different dissolution rates have influence on pharmacokinetic behaviors of LTD and DL.…”

Generic substitution of antidepressants

“…However, proof of bioequivalence does not necessarily establish equivalence in clinical outcomes (efficacy and/or toxicity) of generic and brand‐name drugs, including psychotropics 1 , 2 . The following case describes a clinical problem that appeared to be associated with a change in generic formulations of an antidepressant in an elderly patient 3 …”