From 2001 to 2011, the US Food and Drug Administration approved 9 single-enantiomer drugs with racemic precursors. None showed pre-approval evidence of improved efficacy over the racemic precursor.
Published Online: March 14, 2014
Walid F. Gellad, MD, MPH; Phillip Choi, BS; Margaret Mizah, PharmD; Chester B. Good, MD, MPH; and Aaron S. Kesselheim, MD, JD, MPH
Objectives: A “chiral switch” occurs in the pharmaceutical market when a drug made up of 2 enantiomer forms is replaced with a purified single-enantiomer version, often in the context of a patent expiration. We studied the prevalence of chiral switching in the United States over the past decade, including trends in use of, and expenditures on, these products in Medicaid.
Study Design: Retrospective analysis.
Methods: We used US Adopted Names prefixes (lev/levo/ar/es/dex/dextro) to identify all single-enantiomer drugs approved from 2001 to 2011. From publicly available US Food and Drug Administration (FDA) approval documents, we extracted the characteristics of the pivotal premarket trials for the single enantiomers. Specifically, we evaluated whether the single enantiomer was directly compared with the precursor racemic drug and whether there was evidence of superior efficacy. We used quarterly drug expenditure data from each state Medicaid program to chart trends in use of, and spending on, the single-enantiomer products and their racemic precursors during the study period.
Results: From 2001 to 2011, the FDA approved 9 single-enantiomer products: dexlansoprazole, levoleucovorin, levocetirizine, armodafinil, arformoterol, eszopiclone, escitalopram, dexmethylphenidate, and esomeprazole. Of those 9 drugs, 3 had at least 1 pre-approval randomized trial that included the racemic precursor as a direct comparator, but there was no evidence of superiority of the single enantiomer over the racemic at comparable doses. Between 2001 and 2011, US Medicaid programs spent approximately $6.3 billion on these 9 single-enantiomer drugs.
Conclusions: Recently approved single-enantiomer drugs showed no evidence of superior efficacy over the older racemic precursors in the pivotal trials leading to their approval, and in a majority of cases, they were not directly compared.
Am J Manag Care. 2014;20(3):e90-e97
From 2001 to 2011, the US Food and Drug Administration approved 9 single-enantiomer drugs with racemic precursors. Only 3 had pre-approval studies that compared the single-enantiomer with its precursor, and none showed evidence of improved patient outcomes.
US Medicaid programs spent approximately $6.3 billion on these 9 single-enantiomer drugs during this period.
Well-designed comparative trials are needed to clarify, soon after approval, whether a single-enantiomer drug represents a measurable, cost-effective improvement over current racemic therapy.
Large healthcare organizations that bear the brunt of these costs should use their position to educate prescribers about appropriate use of single-enantiomer products.
Most physicians, and certainly most patients, have never heard of the “chiral switch.”1 A chiral drug is a single molecule product that exists in 2 mirror image forms, called enantiomers.2 Despite their similar chemical structures, enantiomers can have different biological properties.3 For example, some enzymatic processes can distinguish between the R- (from the Latin rectus for “right”) and S- (from the Latin sinister for “left”) enantiomers, 4,5 such that 1 enantiomer may be responsible for much of the pharmaceutical benefit while the other is inactive or even harmful.1,6-9 The phrase “chiral switch” was coined to refer to the substitution in the marketplace of a racemic drug (the name for a 50:50 mixture of 2 enantiomers) with a single-enantiomer version.
One prominent example of a chiral switch occurred in 2001, when the US Food and Drug Administration (FDA) approved AstraZeneca’s esomeprazole (Nexium), a proton pump inhibitor (PPI) used to treat gastroesophageal reflux disease and erosive esophagitis. At that point, the PPI marketplace was dominated by AstraZeneca’s omeprazole (Prilosec), which had been approved in 1989. Marketed as “the purple pill,” omeprazole earned over $6 billion per year in the United States by 2000, although the key patents protecting its market exclusivity ended in 2001, opening the door to generic competition.10 Omeprazole is a racemic mixture of R-omeprazole and S-omeprazole, while esomeprazole, as its name implies, is isolated S-omeprazole. The S-omeprazole enantiomer was responsible for the drug’s clinical properties while the R-omeprazole enantiomer was inactive. After FDA approval, esomeprazole was marketed as “the new purple pill” to be used in place of generic omeprazole.
Chiral switching is a controversial practice. Some claim that singleenantiomer drugs offer little clinical advantage and are used by pharmaceutical manufacturers to perpetuate revenues as the original racemic pill approaches the end of its market exclusivity. The case of esomeprazole, in fact, has been cited as an example of “corporate waste” of healthcare resources.11 However, in some cases, single enantiomers may offer benefit to patients, particularly if the inactive enantiomer may also be responsible for unwanted side effects; manufacturers may pursue single-enantiomer development because of this potential for improved safety or efficacy. Indeed,in guidance originally issued in 1992, and most recently updated in 2011, the FDA identified examples of drug toxicity associated with 1 member of a pair of enantiomers.12
Regardless of the motivation for development of a single-enantiomer drug, the FDA review and approval process is the same. New medications are generally approved by the FDA on the basis of effectiveness in reaching a particular outcome, and an improvement over placebo is commonly accepted.13 Since the FDA cannot by law require active comparators in clinical trials leading to drug approvals,14,15 singleenantiomer products can reach the market by demonstrating improvement over placebo, not their closely related racemic precursors.
How prevalent is chiral switching in the United States? To address that question, we identified all single-enantiomer medications approved from 2001 to 2011 with racemic mixtures already on the market. We examined FDA documents from the approval of these medications, focusing on their pivotal clinical trials and identifying whether the single-enantiomer version was formally compared with the racemic drug in the course of FDA approval. Finally, we use national data on prescription use and expenditures in Medicaid to illustrate the costs associated with their entry and trends in their use.
We used the FDA database of drug approvals to identify all new single-enantiomer products approved for use between 2001 and 2011 that originated from an already FDAapproved racemic mixture. We systematically searched for all United States Adopted Names (USAN) prefixes assigned to drugs with a single-enantiomer formulation: lev-/levo- for the levorotatory, S-isomer form; ar- for the levorotatory, Risomer form; es- for the dextrorotatory, S-isomer form; and dex-/dextro- for the dextrorotatory, R-isomer form.
We extracted the manufacturer name and approval year for each identified drug. We then examined the FDA approval letter(s), summary review, and medical review(s) for each of the single-enantiomer drugs, along with the approved label, and collected reports of the pivotal trials leading to FDA approval. From these reports, we extracted whether the single enantiomer was compared with the racemic mixture in those trials and whether there was any evidence of superior efficacy. We also identified whether these comparisons to the racemic mixture were reported on the approved drug label. Since no pre-approval studies were powered to assess comparative safety, we focused on efficacy.
Medicaid Use and Expenditure
For a more detailed investigation of chiral switching, we focused on esomeprazole (Nexium) and escitalopram (Lexapro), the 2 single-isomer drugs identified in our search with the largest revenue in the past decade. These drugs were also approved early in our study period, giving us adequate time to examine trends in prescription use. Our data source was the Centers for Medicare & Medicaid Services (CMS), which provides aggregated quarterly drug expenditure data from each state Medicaid program categorized by National Drug Code (NDC).16 We used the NDC code to link the drugs and their racemic counterparts to the National Drug Data File (NDDF) (First Data Bank, National Drug Data File, San Bruno, CA: Hearst Corporation, 2012). For each drug, we identified the total number of prescriptions filled and the amount spent on the drug by state Medicaid programs in each calendar quarter. For 49 states and the District of Columbia (Arizona data were not available), we analyzed data from 1999 through the most recent quarter of Medicaid data available at the time of the analysis.
From 2001 through 2011, the FDA approved 9 singleenantiomer versions of racemic products (Table 1). Eight of the drugs had racemic precursors available in the United States. The lone exception was eszopiclone (Lunesta), whose precursor zopiclone (Imovane, Zimovane) was only commercially available outside the United States. Three of the 9 drugs—levoleucovorin (Fusilev), levocetirizine (Xyzal), and arformoterol (Brovana)—came from manufacturers other than the one that applied for approval of the racemic drug. The drugs covered a range of indications from depression to chronic obstructive pulmonary disease (COPD).
Comparative Efficacy of Single-Enantiomer and Racemic Drugs
Three of the 9 single-enantiomer drugs had at least 1 preapproval randomized, controlled trial that included the racemic precursor as a direct comparator (Table 2). Esomeprazole 40 mg demonstrated statistically significant efficacy over omeprazole 20 mg in 2 studies, although it was not superior in 2 other studies. However, pharmacologically equivalent doses of the racemic and enantiomer medications were not compared in these studies, as 40 mg of the single-enantiomer product would contain at least 3 times as much of the active S-isomer as 20 mg of racemic omeprazole on a per milligram basis.17 Dexlansoprazole (Dexilant) and levocetirizine (Xyzal) demonstrated efficacy similar to that of their racemic predecessors in the pre-approval studies. Two additional drugs—escitalopram (Lexapro) and dexmethylphenidate (Focalin)—included the racemic as an active control in pre-approval studies but compared the 2 arms with placebo, not with each other.
Trends in the Use of Esomeprazole and Escitalopram
Between 2001 and 2011, Medicaid programs nationally spent approximately $6.3 billion on the 9 single-enantiomer drugs we reviewed (Table 3). The 2 greatest contributors to this total were esomeprazole ($3.5 billion) and escitalopram ($1.8 billion), each representing over 60% of total Medicaid spending on the single-enantiomer and racemic precursor over that time period. Dexmethylphenidate spending was $678 million from 2001 to 2011, while the single enantiomers approved after 2004 generated substantially lower Medicaid spending.
After esomeprazole’s approval in 2001, its use in Medicaid quickly surpassed omeprazole's and peaked at over 1 million prescriptions per quarter in the second half of 2005 (Figure 1). Generic omeprazole entered the market in the fourth quarter of 2002, became available as an over-the-counter drug in June 2003, and peaked in the third quarter of that year with almost 400,000 prescriptions. However, generic omeprazole did not surpass esomeprazole in number of prescriptions until early 2010. The data show an increase in the use of omeprazole between 2009 and 2011, potentially signifying enhanced coverage of over-the-counter omeprazole in Medicaid programs, which had largely excluded this version of the product in the mid-2000s.18 Esomeprazole represented almost one-third (32.7%) of prescriptions even at the end of the study period in the third quarter of 2011.
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