Publication
Article
Author(s):
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.
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-e97From 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.
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.
METHODSData Sources
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.
Data Extraction
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.
RESULTS
Table 1
From 2001 through 2011, the FDA approved 9 singleenantiomer versions of racemic products (). 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
Table 2
Three of the 9 single-enantiomer drugs had at least 1 preapproval randomized, controlled trial that included the racemic precursor as a direct comparator (). 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
Table 3
Between 2001 and 2011, Medicaid programs nationally spent approximately $6.3 billion on the 9 single-enantiomer drugs we reviewed (). 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.
Figure 1
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 (). 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.
Figure 2
Escitalopram followed a similar pattern. After the introduction of escitalopram in 2002, its use in Medicaid rapidly increased, such that by the second quarter of 2004, over 1 million prescriptions were filled per quarter (). Generic citalopram entered the market in the fourth quarter of 2004, leading to a steep reduction in the use of brand name citalopram, and also a leveling off in the use of escitalopram, although the number of prescriptions for escitalopram continued to outnumber those for generic citalopram until the end of 2009. Prescriptions of all products fell in 2006 due to transition of dual-eligible elderly patients to Medicare Part D.
DISCUSSION
From 2001 to 2011, the FDA approved 9 single-enantiomer drugs, several of which reached blockbuster status in the United States.19,20 Despite substantial spending on enantion mers, most of these drugs were not directly compared with their racemic precursor in the course of FDA approval, and when they were, there was no clear evidence of any improvements in patient outcomes.
In the postapproval period, there has also been little evidence showing any substantial comparative efficacy benefits of these single enantiomers over their racemic precursors. For example, a Cochrane systematic review of escitalopram’s effectiveness identified 6 studies of varying methodological quality (both published and unpublished) directly comparing escitalopram with citalopram. Of the 6 studies, 3 showed a statistically significant advantage of escitalopram in the primary outcome of response to treatment, and each was industry funded.21 The review authors concluded that there was a potential for “overestimation of treatment effect due to sponsorship bias.” The review also found in pooled analyses that escitalopram was no more effective than 3 other antidepressants in the same class (fluoxetine, paroxetine, and sertraline). Evidence of superior effectiveness did not emerge after esomeprazole’s approval, either. The studies reviewed by the Drug Effectiveness Review Project found that comparisons between the enantiomer and racemic precursor uniformly compared esomeprazole at a pharmacologically superior dose (40 mg) with omeprazole (usually at a dose of 20 mg), limiting the possibility of making any conclusions about efficacy.22 The Cochrane review of treatment of gastroesophageal reflux concluded that different PPIs do not show statistically significant differences in effect at comparable dosages.23 Notably, the 2 studies that showed superiority of esomeprazole over omeprazole in the pre-approval RCTs were published within 1 year of approval,24,25 while the 2 studies that showed no superiority were not published until 5 years later,26,27 again raising the concern about publication bias for the postapproval comparative effectiveness studies. Although there is no requirement for comparison of single-enantiomer drugs with their racemic precursors for FDA approval, we found numerous examples in the FDA reviews of experience with the racemic product being invoked to justify the need (or lack of need) for additional testing or guidance prior to approving the drugs. For example, while the FDA does not convene external advisory committee meetings for every drug application, it elected to not do so for dexlansoprazole specifically because the “product is not a new molecular entity. It is the R-enantiomer of a product that was approved in 1995.”28 In another instance, the Division of Pulmonary and Allergy Products did not request audits by the Division of Scientific Investigation because arformoterol “is the active enantiomer of the well-characterized LABA [long-acting beta-agonist], racemic formoterol, which is already approved for treatment of both asthma and COPD, the efficacy data are robust and as would be expected for the product, and the sponsor is not making any novel claims for the product.”29 Regulatory consideration of the safety of single-enantiomer products also benefitted from prior experience with racemic precursors. In the medical review for esomeprazole, the reviewer wrote, “Because Nexium is the S-enantiomer of omeprazole and omeprazole is a PPI that is perceived as safe, Nexium is also considered safe. Omeprazole has been marketed worldwide since 1988 and is presently available in 106 countries for various acid-related gastrointestinal disorders.”17
Although we did not focus on comparative safety or tolerability of the enantiomers, it is conceivable that the benefit of single enantiomers is not in superior efficacy, but superior tolerability or safety. We are not aware, however, of any strong evidence to support that hypothesis for the drugs we studied. For example, in the Cochrane review comparing escitalopram and citalopram, there was no difference between the 2 drugs in study discontinuation due to side effects or number of patients experiencing a side effect.21 Similarly, prior reviews have found no evidence of any difference in adverse events (AEs) or withdrawals due to AEs across trials of PPIs.22 To be sure, there are past examples of chiral switching bringing about important safety benefits, as in the case of levodopa, a key treatment for Parkinson’s disease; initially, the racemic drug caused significant AEs, but shifting to the single enantiomer reduced the AEs and allowed for a higher dose of the active drug.30,31
Despite unclear efficacy or safety benefits, approval of enantiomer drugs over the past decade has had substantial cost implications. In the cases of esomeprazole and escitalopram, the enantiomer rapidly absorbed market share from the racemic precursor and diverted use of generic versions of the racemic product. Increasing the cost of medications with no discernible difference in health outcomes negatively impacts the health of patients taking those drugs. Higher prescription drug costs are associated with lower adherence, higher incidence of serious AEs, greater utilization of healthcare services, and worse health outcomes32-34 These costs must be weighed against any theoretical, or even real, improvement in patient outcomes with use of single-enantiomer formulations.
The case of armodafinil gives further insight into the use of enantiomers to maintain market share in products losing patent protection. Cephalon received approval for modafinil (Provigil) by the FDA in 1998. In 2002, 4 companies filed applications with the FDA for generic modafinil.35 In order to maintain its market exclusivity, in 2006, Cephalon settled with those generic manufacturers for more than $200 million, delaying entry of a generic modafinil until 2012. In 2007, Cephalon’s single-enantiomer armodafinil (Nuvigil) was approved, meaning that the company then had 5 years to “switch” market share away from modafilil.36 In order to encourage transition of modafinil to armodafinil, Cephalon steadily increased the price of modafinil, from $6.80 per pill in 2008 to $13.62 in 2009, by which time armodafinil was launched at $8.98 per pill.37 By 2011, sales of Nuvigil represented 42% of combined armodafinil/modafinil prescriptions in the United States.38
Most patients are probably not aware that the singleenantiomer drugs they are prescribed are so closely related to precursor racemic mixtures. Linguistic similarities between generic names of racemic and enantiomer drugs will likely be missed by most physicians and patients, particularly since most drugs are referred to by their brand name, even after they are being produced by generic manufacturers.39 Thus, naming conventions artificially inflate the differences between the single-enantiomer and racemic drugs.40 If patients (and their physicians) were better educated about the clinical similarities between racemic and enantiomer drugs and were given greater insight into the trials that led to the approval of enantiomers, they may be less likely to pay higher prices for the medication.41-43
A number of measures can be taken to facilitate more rational use of enantiomer drugs by physicians and patients. Although the FDA cannot require comparative efficacy testing prior to approval, the FDA should ensure that single-enantiomer drug labels highlight differences, or the lack of differences, in efficacy and safety from the racemic version.44 Three enantiomer drugs in our sample had direct racemic comparators in approval trials, but only 2 of the labels mentioned the study results (dexlansoprazole and esomeprazole). Special attention should be paid to the single enantiomers when formulary tiering decisions are made by health plans, although heightened attention by insurers to the “chiral switch” may explain, in part, why spending on enantiomers, at least in Medicaid, appears to have slowed for single-enantiomer drugs approved in recent years (Table 3). For another solution, policy makers might look to India, where intellectual property laws prevent patents from regularly being issued on secondary formulations of previously discovered pharmaceutical products that lack substantial clinical benefits.45 In the United States, such a change would require an amendment to the patent law, which does not distinguish between pharmaceutical formulations and other products.
Rapid uptake after approval of single-enantiomer drugs by patients and physicians represents a high financial burden on both the US healthcare system and individuals, without an obvious concomitant gain in patient health. More well-designed and widely disseminated comparative trials are needed to clarify, soon after approval, whether a new 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 and racemic products to slow the adoption of drugs with no real advantage over cheaper alternatives.
Study Limitations
This analysis of single-enantiomer drugs approved since 2001 used publicly available FDA reports, some of which included redacted text. However, such redactions are usually not related to approved-drug indications, so the likelihood that we missed important approval information is not great. We only examined labels at the time of approval, and so did not formally address comparisons between single-enantiomer drugs and their racemic counterparts that may have occurred after approval. Finally, we acknowledge that the FDA does not have legal authority to require comparative efficacy studies for drugs prior to approval and we do not conclude that the FDA erred in approving any of these drugs; there could, in fact, be efficacy or tolerability benefit for individual patients from single-enantiomer drugs that cannot be discerned from population-based randomized trial.46 Nonetheless, our goal was to identify the prevalence of chiral switches and examine whether any comparative effectiveness studies were submitted as part of the approval process.Author Affiliations: Center for Health Equity Research and Promotion, VA Pittsburgh Healthcare System, Pittsburgh, PA (WFG, MM, CBG); Department of Medicine, University of Pittsburgh (WFG, PC, CBG); RAND Health, Santa Monica, CA (WFG); Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA (ASK); Harvard Medical School, Boston, MA (ASK).
Source of Funding: Dr Gellad is supported by a VA Health Services Research & Development (HSR&D) career development award (CDA 09-207). Dr Kesselheim is supported by the Harvard Program in Therapeutic Science, Greenwall Faculty Scholarship in Bioethics, a career development award from the Agency for Healthcare Research & Quality (K08HS18465-01) and a Robert Wood Johnson Foundation Investigator Award in Health Policy Research. None of the funders played any role in the preparation of this article.
Author Disclosures: From 2011 to 2013, Dr Kesselheim acted as an expert witness on behalf of a class of individual plaintiffs in a case against AstraZeneca alleging inappropriate marketing of Nexium. The other authors (WFG, PC, MM, CBG) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article. This work represents the opinions of the authors alone and does not necessarily represent the views of the Department of Veterans Affairs or the United States government.
Authorship Information: Concept and design (WFG, MM, CBG, ASK); acquisition of data (WFG, PC, MM, ASK); analysis and interpretation of data (WFG, PC, CBG, ASK); drafting of the manuscript (WFG, PC, MM, ASK); critical revision of the manuscript for important intellectual content (WFG, PC, MM, CBG, ASK); statistical analysis (WFG); provision of study materials or patients (WFG); obtaining funding (WFG, ASK); administrative, technical, or logistic support (WFG); supervision (WFG, CBG, ASK).
Address correspondence to: Walid F. Gellad, MD, MPH, Center for Health Equity Research and Promotion, VA Pittsburgh Healthcare System, 7180 Highland Dr, Pittsburgh, PA 15206. E-mail: walid.gellad@va.gov.1. Tucker GT. Chiral switches. Lancet. 2000;355(9209):1085-1087.
2. Peter K, Vollhardt C, Schore NE. Organic Chemistry. 5th ed. New York, NY: WH Freeman; 2005.
3. de Carvalho CCCR, da Fonseca MMR. Carvone: Why and how should one bother to produce this terpene. Food Chemistry. 2006;95(3):413-422.
4. Leitereg T, Guadagni D, Harris J, Mon T, Teranishi R. Evidence for the difference between the Odours of the Optical Isomers (4)- and (-)-carvone. Nature. 1971;230(5294):455-456.
5. Leitereg TJ, Guadagni DG, Harris J, Mon TR, Teranishi R. Chemical and sensory data supporting the difference between the odors of the enantiomeric carvones. J Agric Food Chem. 1971;19(4):785-787.
6. Andersson T. Single-isomer drugs: true therapeutic advances. Clin Pharmacokinet. 2004;43(5):279-285.
7. Caner H, Groner E, Levy L, Agranat I. Trends in the development of chiral drugs. Drug Discov Today. 2004;9(3):105-110.
8. Mendelson J, Uemura N, Harris D, et al. Human pharmacology of the methamphetamine stereoisomers. Clin Pharmacol Ther. 2006;80(4): 403-420.
9. Agranat I, Caner H, Caldwell J. Putting chirality to work: the strategy of chiral switches. Nat Rev Drug Discov. 2002;1(10):753-768.
10. Berenson A. Shortage of Prilosec to Persist. New York Times. March 3, 2005.
11. Goozner M. The $800 Million Pill: The Truth behind the Cost of New Drugs. Berkeley: University of California Press; 2004.
12. Development of new stereoisomeric drugs. US Food and Drug Administration website. http://www.fda.gov/drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm122883.htm. Published May 1, 1992. Accessed January 6, 2013.
13. Avorn J. FDA standards--good enough for government work? N Engl J Med. 2005;353(10):969-972.
14. Stafford RS, Wagner TH, Lavori PW. New, but not improved? incorporating comparative-effectiveness information into FDA labeling. N Engl J Med. 2009;361(13):1230-1233.
15. Luce BR, Kramer JM, Goodman SN, et al. Rethinking randomized clinical trials for comparative effectiveness research: the need for transformational change. Ann Intern Med. 2009;151(3):206-209.
16. Centers for Medicare & Medicaid Services. State Drug Utilization Data. http://medicaid.gov/Medicaid-CHIP-Program-Information/By- Topics/Benefits/Prescription-Drugs/Medicaid-Drug-Programs-Data-and- Resources.html. Accessed April 1, 2013.
17. US Food and Drug Administration Center for Drug Evaluation and Research. Esomeprazole (Nexium) Medical Review(s). NDA 21-153.2000.
18. Pharmaceutical Benefits under State Medical Assistance Programs. National Pharmaceutical Council website. http://www.npcnow.org/ system/files/research/download/2005_6%20Pharmaceutical-Benefits- Under-State-Medical-Assistance-Programs.pdf. Published 2006. Accessed June 20, 2013.
19. AstraZeneca. Annual Report and Form 20-F Information. 2011.
20. Forest Laboratories Inc. Annual Report, 2011. New York, NY: Forest Laboratories, Inc.
21. Cipriani A, Santilli C, Furukawa TA, et al. Escitalopram versus other antidepressive agents for depression. Cochrane Database Syst Rev.2009.
22. McDonagh MS, Carson S, Thakurta S. Drug class review: proton pump inhibitors: final report update 5. Portland, OR; Oregon Health & Science University: May 2009.
23. Khan M, Santana J, Donnellan C, Preston C, Moayyedi P. Medical treatments in the short term management of reflux oesophagitis. Cochrane Database Syst Rev. 2007(2):CD003244.
24. Kahrilas PJ, Falk GW, Johnson DA, et al. The Esomeprazole Study Investigators; Esomeprazole improves healing and symptom resolution as compared with omeprazole in reflux oesophagitis patients: a randomized controlled trial. Aliment Pharmacol Ther. 2000;14(10):1249-1258.
25. Richter JE, Kahrilas PJ, Johanson J, et al. Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial. Am J Gastroenterol. 2001;96(3):656-665.
26. Lightdale CJ, Schmitt C, Hwang C, Hamelin B. A multicenter, randomized, double-blind, 8-week comparative trial of low-dose esomeprazole (20 mg) and standard-dose omeprazole (20 mg) in patients with erosive esophagitis. Dig Dis Sci. 2006;51(5):852-857.
27. Schmitt C, Lightdale CJ, Hwang C, Hamelin B. A multicenter, randomized, double-blind, 8-week comparative trial of standard doses of esomeprazole (40 mg) and omeprazole (20 mg) for the treatment of erosive esophagitis. Dig Dis Sci. 2006;51(5):844-850.
28. US Food and Drug Administration Center for Drug Evaluation and Research. Dexlansoprazole (Kapidex) summary review. NDA 22-287.2009.
29. US Food and Drug Administration Center for Drug Evaluation and Research. Arformoterol (Brovana) summary review. NDA 21-912.2006.
30. Cotzias GC, Papavasiliou PS, Gellene R. Modification of Parkinsonism-- chronic treatment with L-dopa. N Engl J Med. 1969;280(7):337-345.
31. Hutt AJ, Velntova J. The chiral switch: the development of single enantiomer drugs from racemates. Acta Facultatis Pharmaceuticae Universitatis Comenianae 2003;50:7-23.
32. Tamblyn R, Laprise R, Hanley JA, et al. Adverse events associated with prescription drug cost-sharing among poor and elderly persons. JAMA. 2001;285(4):421-429.
33. Goldman DP, Joyce GF, Zheng Y. Prescription drug cost sharing: Associations with medication and medical utilization and spending and health. JAMA. 2007;298(1):61-69.
34. Heisler M, Langa KM, Eby EL, Fendrick AM, Kabeto MU, Piette JD. The health effects of restricting prescription medication use because of cost. Med Care. 2004;42(7):626-634.
35. Carrier MA. Provigil: a case study of anticompetitive behavior. Hastings Science & Technology Law Journal. 2011;3(2):441-452.
36. Staton T. How will Cephalon shift patients to Nuvigil? FiercePharma website. http://www.fiercepharma.com/story/how-will-cephalon-shiftpatients- nuvigil/2009-08-07. Published August 7, 2009. Accessed April 1, 2013.
37. Rockoff JD. How a drug maker tries to outwit generics. The Wall Street Journal. November 18, 2008.
38. Cephalon Inc. 10-K Quarterly Report. http://quicktake.morningstar. com/stocknet/secdocuments.aspx?symbol=ceph. Published June 30, 2011. Accessed April 1, 2013.
39. Steinman MA, Chren MM, Landefeld CS. What’s in a name? use of brand versus generic drug names in United States outpatient practice. J Gen Intern Med. 2007;22(5):645-648.
40. Lobo F, Feldman R. Generic drug names and social welfare. J Health Polit Policy Law. 2013;38(3):573-597.
41. Angell M. Excess in the pharmaceutical industry. CMAJ. 2004; 171(12):1451-1453.
42. Elliott S, Ives N. Prescription drug ads come under criticism. New York Times. October 12, 2004.
43. Gladwell M. High prices. The New Yorker. October 25, 2004.
44. Stafford RS, Wagner TH, Lavori PW. New, but not improved? incorporating comparative-effectiveness information into FDA labeling. N Engl J Med. 2009;361(13):1230-1233.
45. Rajkumar R, Kesselheim AS. Balancing access and innovation: India’s supreme court rules on imatinib. JAMA. 2013;310(3):263-264
46. Huskamp HA, Busch AB, Domino ME, Normand SL. Antidepressant reformulations: who uses them, and what are the benefits? Health Aff (Millwood). 2009;28(3):734-745.