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Assessing the Chiral Switch: Approval and Use of Single-Enantiomer Drugs, 2001 to 2011

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Assessing the Chiral Switch: Approval and Use of Single-Enantiomer Drugs, 2001 to 2011 n POLICY n Assessing the Chiral Switch: Approval and Use of Single-Enantiomer Drugs, 2001 to 2011 Walid F. Gellad, MD, MPH; Phillip Choi, BS; Margaret Mizah, PharmD; Chester B. Good, MD, MPH; and Aaron S. Kesselheim, MD, JD, MPH ost physicians, and certainly most patients, have never Objectives: A “chiral switch” occurs in the 1 pharmaceutical market when a drug made up of heard of the “chiral switch.” A chiral drug is a single 2 enantiomer forms is replaced with a purified molecule product that exists in 2 mirror image forms, single-enantiomer version, often in the context of M called enantiomers.2 Despite their similar chemical structures, enan- a patent expiration. We studied the prevalence of chiral switching in the United States over the past tiomers can have different biological properties.3 For example, some decade, including trends in use of, and expendi- enzymatic processes can distinguish between the R- (from the Latin tures on, these products in Medicaid. Study Design: Retrospective analysis. rectus for “right”) and S- (from the Latin sinister for “left”) enantio- 4,5 Methods: We used US Adopted Names pre- mers, such that 1 enantiomer may be responsible for much of the fixes (lev/levo/ar/es/dex/dextro) to identify all pharmaceutical benefit while the other is inactive or even harmful.1,6-9 single-enantiomer drugs approved from 2001 to 2011. From publicly available US Food and Drug The phrase “chiral switch” was coined to refer to the substitution in Administration (FDA) approval documents, we ex- the marketplace of a racemic drug (the name for a 50:50 mixture of 2 tracted the characteristics of the pivotal premarket trials for the single enantiomers. Specifically, we enantiomers) with a single-enantiomer© Managed Care version. & evaluated whether the single enantiomer was One prominentHealthcare example Communications,of a chiral switch occurred LL Cin 2001, when directly compared with the precursor racemic the US Food and Drug Administration (FDA) approved AstraZeneca’s drug and whether there was evidence of superior efficacy. We used quarterly drug expenditure data esomeprazole (Nexium), a proton pump inhibitor (PPI) used to treat from each state Medicaid program to chart trends gastroesophageal reflux disease and erosive esophagitis. At that point, in use of, and spending on, the single-enantiomer products and their racemic precursors during the the PPI marketplace was dominated by AstraZeneca’s omeprazole (Pri- study period. losec), which had been approved in 1989. Marketed as “the purple pill,” Results: From 2001 to 2011, the FDA approved omeprazole earned over $6 billion per year in the United States by 9 single-enantiomer products: dexlansoprazole, levoleucovorin, levocetirizine, armodafinil, arfor- 2000, although the key patents protecting its market exclusivity ended moterol, eszopiclone, escitalopram, dexmethyl- in 2001, opening the door to generic competition.10 Omeprazole is a phenidate, and esomeprazole. Of those 9 drugs, 3 had at least 1 pre-approval randomized trial racemic mixture of R-omeprazole and S-omeprazole, while esomepra- that included the racemic precursor as a direct zole, as its name implies, is isolated S-omeprazole. The S-omeprazole comparator, but there was no evidence of supe- riority of the single enantiomer over the racemic enantiomer was responsible for the drug’s clinical properties while the at comparable doses. Between 2001 and 2011, US R-omeprazole enantiomer was inactive. After FDA approval, esomepra- Medicaid programs spent approximately $6.3 bil- lion on these 9 single-enantiomer drugs. zole was marketed as “the new purple pill” to be used in place of generic Conclusions: Recently approved single-enan- omeprazole. tiomer drugs showed no evidence of superior Chiral switching is a controversial practice. Some claim that single- efficacy over the older racemic precursors in the pivotal trials leading to their approval, and enantiomer drugs offer little clinical advantage and are used by pharma- in a majority of cases, they were not directly ceutical manufacturers to perpetuate revenues as the original racemic compared. pill approaches the end of its market exclusivity. The case of esome- Am J Manag Care. 2014;20(3):e90-e97 prazole, 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 In this article For author information and disclosures, Take-Away Points / e91 see end of text. because of this potential for im- Published as a Web exclusive proved safety or efficacy. Indeed, www.ajmc.com e90 n www.ajmc.com n MARCH 2014 Single-Enantiomer Drugs in guidance originally issued in 1992, and Take-Away Points most recently updated in 2011, the FDA From 2001 to 2011, the US Food and Drug Administration approved 9 single-enantio- identified examples of drug toxicity associat- mer drugs with racemic precursors. Only 3 had pre-approval studies that compared the single-enantiomer with its precursor, and none showed evidence of improved ed with 1 member of a pair of enantiomers.12 patient outcomes. Regardless of the motivation for develop- n US Medicaid programs spent approximately $6.3 billion on these 9 single-enan- ment of a single-enantiomer drug, the FDA tiomer drugs during this period. review and approval process is the same. New n Well-designed comparative trials are needed to clarify, soon after approval, whether a single-enantiomer drug represents a measurable, cost-effective improve- medications are generally approved by the ment over current racemic therapy. FDA on the basis of effectiveness in reaching n Large healthcare organizations that bear the brunt of these costs should use a particular outcome, and an improvement their position to educate prescribers about appropriate use of single-enantiomer products. over placebo is commonly accepted.13 Since the FDA cannot by law require active com- parators in clinical trials leading to drug approvals,14,15 single- mixture were reported on the approved drug label. Since no enantiomer products can reach the market by demonstrating pre-approval studies were powered to assess comparative safe- improvement over placebo, not their closely related racemic ty, we focused on efficacy. precursors. How prevalent is chiral switching in the United States? Medicaid Use and Expenditure To address that question, we identified all single-enantiomer For a more detailed investigation of chiral switching, we medications approved from 2001 to 2011 with racemic mixtures focused on esomeprazole (Nexium) and escitalopram (Lexa- already on the market. We examined FDA documents from the pro), the 2 single-isomer drugs identified in our search with approval of these medications, focusing on their pivotal clini- the largest revenue in the past decade. These drugs were also cal trials and identifying whether the single-enantiomer version approved early in our study period, giving us adequate time to was formally compared with the racemic drug in the course of examine trends in prescription use. Our data source was the FDA approval. Finally, we use national data on prescription Centers for Medicare & Medicaid Services (CMS), which use and expenditures in Medicaid to illustrate the costs associ- provides aggregated quarterly drug expenditure data from each ated with their entry and trends in their use. 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) METHODS (First Data Bank, National Drug Data File, San Bruno, CA: Data Sources Hearst Corporation, 2012). For each drug, we identified the We used the FDA database of drug approvals to identify total number of prescriptions filled and the amount spent on all new single-enantiomer products approved for use be- the drug by state Medicaid programs in each calendar quarter. tween 2001 and 2011 that originated from an already FDA- For 49 states and the District of Columbia (Arizona data were approved racemic mixture. We systematically searched for not available), we analyzed data from 1999 through the most all United States Adopted Names (USAN) prefixes assigned recent quarter of Medicaid data available at the time of the to drugs with a single-enantiomer formulation: lev-/levo- for analysis. the levorotatory, S-isomer form; ar- for the levorotatory, R- isomer form; es- for the dextrorotatory, S-isomer form; and dex-/dextro- for the dextrorotatory, R-isomer form. RESULTS From 2001 through 2011, the FDA approved 9 single- Data Extraction enantiomer versions of racemic products (Table 1). Eight We extracted the manufacturer name and approval year of the drugs had racemic precursors available in the United for each identified drug. We then examined the FDA approval States. The lone exception was eszopiclone (Lunesta), whose letter(s), summary review, and medical review(s) for each of precursor zopiclone (Imovane, Zimovane) was only com- the single-enantiomer drugs, along with the approved label, mercially available outside the United States. Three of the 9 and collected reports of the pivotal trials leading to FDA ap- drugs—levoleucovorin (Fusilev), levocetirizine (Xyzal), and proval. From these reports, we extracted whether the single arformoterol (Brovana)—came from manufacturers other enantiomer was compared with the racemic mixture in those than
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