Evaluation of Trials Comparing Single-Enantiomer Drugs to Their Racemic Precursors: A Systematic Review.

Journal Article (Systematic Review;Journal Article)

Importance

Chiral switching, a strategy in which drug manufacturers develop a single-enantiomer formulation of a drug to be substituted for a racemic formulation, allows manufacturers to maintain market exclusivity for drugs losing patent protection, even without demonstrating superior efficacy or safety.

Objective

To identify and characterize all randomized clinical trials (RCTs) directly comparing a Food and Drug Administration (FDA)-approved single-enantiomer drug against a previously approved racemic drug for 1 or more efficacy or safety end points.

Evidence review

Drugs were identified using the Drugs@FDA database. Randomized clinical trials were identified using Ovid MEDLINE (1949 to October 22, 2019), Ovid Embase (1974 to October 22, 2019), Web of Science Core Collection (all years), ClinicalTrials.gov, and Cochrane Central Registry of Controlled Trials (CENTRAL, Wiley, Issue 8 of 12, October 22, 2019). Trials were characterized as favoring the single-enantiomer or racemic drugs based on whether the primary efficacy, secondary efficacy, and safety end points achieved each study's defined significance level (eg, P < .05). Trials were characterized as favoring neither drug if no statistically significant differences were reported for any end point or if both drugs were found to be superior for 1 or more separate end points.

Findings

Fifteen FDA-approved single-enantiomer drugs were identified with racemic precursors approved in the US or Europe. For 3 single-enantiomer racemic drug pairs, no RCTs directly comparing the drugs were identified. For the remaining 12 pairs, 185 RCTs comparing efficacy or safety of the drug pairs were identified, 124 (67.0%) of which studied 1 pair (levobupivacaine/bupivacaine). There were 179 RCTs directly comparing drug pairs using efficacy end points, of which 23 (12.8%) favored the single enantiomer based on primary efficacy end point results. There were 124 RCTs directly comparing drug pairs using safety end points, of which 17 (13.7%) favored the single-enantiomer drug. For 9 of the 15 single-enantiomer drugs (60.0%), no RCTs were identified providing evidence of improved efficacy, based on primary end point results, or safety as compared with their racemic precursors.

Conclusions and relevance

The results of this systematic review suggest that most newly marketed FDA-approved single-enantiomer drugs are infrequently directly compared with their racemic precursors, and when compared, they are uncommonly found to provide improved efficacy or safety, despite their greater costs.

Full Text

Duke Authors

Cited Authors

  • Long, AS; Zhang, AD; Meyer, CE; Egilman, AC; Ross, JS; Wallach, JD

Published Date

  • May 3, 2021

Published In

Volume / Issue

  • 4 / 5

Start / End Page

  • e215731 -

PubMed ID

  • 33956134

Pubmed Central ID

  • PMC8103227

Electronic International Standard Serial Number (EISSN)

  • 2574-3805

International Standard Serial Number (ISSN)

  • 2574-3805

Digital Object Identifier (DOI)

  • 10.1001/jamanetworkopen.2021.5731

Language

  • eng