UNITED STATES DISTRICT COURT 

FOR THE DISTRICT OF NEW JERSEY 

ASTRAZENECA AB, ASTRAZENECA LP, 

KBI INC, and KBI-E INC. 

 

 Plaintiffs and 

Counterclaim Defendants, 

v. 

HANMI USA, INC., HANMI 

PHARMACEUTICAL CO., LTD., HANMI 

FINE CHEMICAL CO., LTD, and HANMI 

HOLDINGS CO., LTD., 

 Defendants 

and Counterclaim Plaintiffs

Civil Action No. 3: 11-cv-00760-JAP-TJB 

DECLARATION OF NIMISH VAKIL, M.D. AGAF, FACG, FACGE 

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I, Nimish Vakil, M.D., declare: 

I. PROFESSIONAL BACKGROUND AND QUALIFICATIONS 

1. I am a board-certified gastroenterologist and am also board certified in Internal 

Medicine. I went to Medical School at the University of Bombay where I earned the M.B.B.S. 

and M.D. degrees. I completed an Internal Medicine Residency at New York Medical College 

Affiliated Hospitals (Lincoln Medical and Mental Health Center) in New York City and a 

Gastroenterology Fellowship at Northwestern University School of Medicine in Chicago, IL. 

Following my fellowship, I received specialized endoscopy training at the University of Munich, 

Munich, Germany. 

2. I have been teaching gastroenterology for my entire career. I have served on the 

faculty of the University of Texas, Houston and the University of Rochester in Rochester, New 

York. Currently, as Clinical Professor of Medicine at the University of Wisconsin School of 

Medicine and Public Health, I have responsibilities in teaching medical students 

gastroenterology including the appropriate evaluation of patients with gastro-esophageal reflux 

disease and their treatment. I lecture medical students and act as their preceptor on 

Gastroenterology rotations. I also teach trainees in gastroenterology as core faculty of the 

Aurora Health Care Fellowship in Gastroenterology. I teach gastroenterology fellows the 

evaluation and management of gastro-esophageal reflux disease and I am in charge of the 

research training program of fellows. In this capacity, I have supervised among other research 

studies on the appropriate utilization of proton pump inhibitors in the hospital setting.1

 

 

1

Guda NM, Noonan M, Kreiner MJ, Partington S, Vakil N. Use of intravenous proton pump inhibitors in community 

practice: an explanation for the shortage? Am J Gastroenterol. 2004 Jul;99(7):1233-7. 

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3. Moreover, I have periodically conducted courses on gastroenterology for primary 

care providers in which we discuss the treatment of gastroenterological disorders including 

gastro-esophageal reflux disease. As Clinical Associate Professor of Medicine at the Marquette 

University College of Health Sciences in Milwaukee, Wisconsin, I have been responsible for an 

annual lecture series in gastroenterology to students who are training to become physician 

assistants. I have also served as preceptor for their elective clinical rotation in gastroenterology. 

In this capacity, I taught the pathophysiology and treatment of gastro-esophageal reflux disease 

to physician assistant students. I have given more than 200 invited lectures throughout the world 

and been a regular participant in national and international educational meetings concerning 

gastroenterology, with a particular focus and expertise in gastro-esophageal reflux disease 

(“GERD”) and complications of acid reflux disease. For example, I have lectured at national 

meetings of Gastroenterology societies in Argentina, Brazil, Chile, China, Japan, Singapore, 

Indonesia, Russia, UK, France and a number of other countries. 

4. I have had extensive involvement with clinical research throughout my career and 

continue to maintain a very active role in research. This involvement includes research studies in 

the field of reflux disease, dyspepsia and Helicobacter pylori infection. For example, in the area 

of reflux disease, I have performed studies that evaluate the impact of combining H2 receptor 

antagonists with proton pump inhibitor therapy.2

 I have performed studies on the outcome of 

surgery for the management of reflux disease.3

 I have evaluated the impact of proton pump 

 

2

 Vakil N, Guda N, Partington S. The effect of over-the-counter ranitidine 75 mg on night-time heartburn in patients 

with erosive oesophagitis on daily proton pump inhibitor maintenance therapy. Aliment Pharmacol Ther. 2006 Mar 

1;23(5):649-53.

3

 Vakil N, Kirby R, Shaw M. Clinical effectiveness of laparoscopic fundoplication in a US community. Am J Med 

2003 Jan;114(1):1-5 

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inhibitors on complications such as a stricture.4

 I have performed studies on the impact of 

GERD on sleep disorders.5

 I also have consulted on the design of clinical trials, including trials 

to support regulatory approval. I have served as a consultant for the design of trials of acid 

inhibitors for the treatment of GERD and have served as a principal investigator for studies on 

novel mechanisms for treating reflux disease (inhibition of transient lower esophageal sphincter 

relaxations)6

 and in the design of trials for functional dyspepsia and GERD.7 In this role, I have 

appeared as an external consultant in meetings with the FDA to discuss trial design and 

endpoints for clinical trials.8 

5. I also have led an international consensus group with members from 18 countries 

that defined and classified reflux disease and provided a definition and classification that are 

novel, patient-centered, and global in perspective.9

 I have co-authored studies that examine how 

proton pump inhibitors are used in clinical practice.10 I have performed meta-analyses of trials, 

 

4

 Guda N, Vakil N. Proton pump inhibitors and the time trends for esophageal dilation. Am J Gastroenterol. 2004 

May;99(5):797-800. 

5

 Guda N, Partington S, Vakil N. Symptomatic gastro-oesophageal reflux, arousals and sleep quality in patients 

undergoing polysomnography for possible obstructive sleep apnoea. Aliment Pharmacol Ther. 2004 Nov 

15;20(10):1153-9. 

6

 Vakil NB, Huff FJ, Bian A, Jones DS, Stamler D. Arbaclofen placarbil in GERD: a randomized, double-blind, 

placebo-controlled study. Am J Gastroenterol. 2011 Aug;106(8):1427-38. 

7

 Dent J, Kahrilas PJ, Vakil N, Van Zanten SV, Bytzer P, Delaney B, Haruma K, Hatlebakk J, McColl E, Moayyedi 

P, Stanghellini V, Tack J, Vaezi M. Clinical trial design in adult reflux disease: a methodological workshop. 

Aliment Pharmacol Ther. 2008 Jul;28(1):107-26. 

8

 Vakil N, Laine L, Talley NJ, Zakko SF, Tack J, Chey WD, Kralstein J, Earnest DL, Ligozio G, Cohard-Radice M. 

Tegaserod treatment for dysmotility-like functional dyspepsia: results of two randomized, controlled trials. Am J 

Gastroenterol. 2008 Aug;103(8):1906-19. 

9

 Vakil, N, van Zanten, S., Kahrilas P, Dent J & Jones R. The Montreal Definition and Classification of 

Gastroesophageal Reflux Disease: A Global Evidence-Based Consensus. American Journal of 

Gastroenterology 2006;101(8):1900-1920. 

10 Guda N, Noonan M, Kreiner M, Partington S, Vakil N. Use of intravenous proton pump inhibitors in community 

practice: an explanation for the shortage. Am J Gastroenterol. 2004 Jul;99(7):1233-7. An editorial accompanies this 

paper. 

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including a meta-analysis on the efficacy of PPIs for laryngeal symptoms attributed to GERD.11 

I have also performed cost-effectiveness studies that evaluate the cost and effectiveness of 

different alternatives for the management of gastroenterological disorders.12, 13 As set forth in 

my CV, which is attached as Exhibit A, I have authored or co-authored 221 papers, including 

papers which have been published in the New England Journal of Medicine, Annals of Internal 

Medicine, Journal of the American Medical Association and the American Journal of Medicine, 

as well as in leading journals in the field of gastroenterology, such as Gastroenterology and the 

American Journal of Gastroenterology and Gut.

14, 15, 16, 17

6. I am familiar with the methods of evidence-based medicine and have received 

training in meta-analysis and cost analysis, including the Cochrane courses on meta-analysis. I 

have performed several systematic reviews, meta-analyses and cost-effectiveness analyses, 

which have been published in the peer-review literature.18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 I also have 

 

11 Gatta L, Vaira D, Sorrenti G, Zucchini S, Sama C, Vakil N. Meta-analysis: the efficacy of proton pump inhibitors 

for laryngeal symptoms attributed to gastro-esophageal reflux disease. Aliment Pharmacol Ther 2007 Feb 

15;25(4):385-92. 

12 Vakil N. The cost-effectiveness of treating GERD. Eur J Gastroenterol and Hepatol 2001;13:S10-3 

13 Vakil N, Ashorn M. Cost-effectiveness of non-invasive testing and treatment strategies for H pylori infection in 

dyspeptic children. Am J Gastroenterol 1998;93:562-8. 

14 Vakil N, Schwartz S, Buggy B, Brummitt C, Kherellah M, Letzer D, Gilson I, Jones P. Biliary cryptosporidiosis 

in people with HIV infection following the waterborne outbreak of cryptosporidium infection. New Engl J Med, 

1996;334:19-23. 

15 Talley N, Vakil N, Ballard C, Fennerty B. Effect of eradicating Helicobacter pylori in patients with non-ulcer 

dyspepsia. New Engl J Med 1999;341:1106-11.. 

16 Moayyedi P, Talley NJ, Fennerty MB, Vakil N. Can the clinical history distinguish between organic and 

functional dyspepsia? JAMA. 2006 Apr 5;295(13):1566-76. 

17 Vaira D, Zullo A, Vakil N, Gatta L, Ricci C, Perna F, Hassan C, Bernabucci V, Tampieri A, Morini S. 

Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized trial. Ann 

Intern Med. 2007 Apr 17;146(8):556-63. 

18 Moayyedi P, Talley NJ, Fennerty MB, Vakil N. Can the clinical history distinguish between organic and 

functional dyspepsia? JAMA. 2006 Apr 5;295(13):1566-76. 

19 Inadomi J, Sampliner R, Lagergren J, Lieberman D, Fendrick M, Vakil N. Screening and Surveillance for Barretts 

esophagus in High-Risk Populations: A Cost-Utility Analysis. Ann Intern Med 2003 Feb 4;138(3):176-86. 

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participated in evidence based training programs for gastroenterologists in clinical practice. In 

2010 and in 2011, I served on the American Gastroenterological Association’s review panel for 

meta-analyses being submitted to the annual meeting of the association. I have reviewed metaanalyses and systematic reviews submitted for publication for a number of journals including 

Gut, American Journal of Gastroenterology and Annals of Internal Medicine. I regularly teach 

medical students concerning literature searches, publication bias, and meta-analysis, and since 

1993, I have conducted a regular journal club for gastroenterology trainees where the literature is 

evaluated using evidence-based medicine principles. Therefore I am qualified to comment on 

literature searches, publication bias, meta-analysis and related topics concerning the review and 

analysis of scientific and medical literature. 

 

20 Ford AC, Talley NJ, Veldhuyzen Van Zanten SJ, Vakil NB, Simel DL, Moayyedi P. Will the history and physical 

examination help establish that irritable bowel syndrome is causing this patient's lower gastrointestinal tract 

symptoms? JAMA. 2008 Oct 15;300(15):1793-805. 

21 Moayyedi P, Delaney BC, Vakil N, Forman D, Talley NJ. The efficacy of proton pump inhibitors in nonulcer 

dyspepsia: a systematic review and economic analysis. Gastroenterology. 2004 Nov;127(5):1329-37. 

22 Spiegel BM, Ofman JJ, Woods K, Vakil NB. Minimizing recurrent peptic ulcer hemorrhage after endoscopic 

hemostasis: the cost-effectiveness of competing strategies. Am J Gastroenterol. 2003 Jan;98(1):86-97. 

23 Spiegel BM, Ofman JJ, Woods K, Vakil NB. Minimizing recurrent peptic ulcer hemorrhage after endoscopic 

hemostasis: the cost-effectiveness of competing strategies. Am J Gastroenterol. 2003 Jan;98(1):86-97. 

24 Vakil N, Rhew D, Soll A. Ofman J. The Cost-Effectiveness of Diagnostic Testing Strategies for H. Pylori. Am J 

Gastroenterol 2000;95:1691-8. 

25 Rubenstein JH, Vakil N, Inadomi JM. The cost-effectiveness of biomarkers for predicting the development of 

oesophageal adenocarcinoma.Aliment Pharmacol Ther. 2005 Jul 15;22(2):135-46. 

26 Moayyedi P, Delaney BC, Vakil N, Forman D, Talley NJ. The efficacy of proton pump inhibitors in nonulcer 

dyspepsia: a systematic review and economic analysis. Gastroenterology. 2004 Nov;127(5):1329-37. 

27 Vakil N, Moayyedi P, Fennerty MB, Talley NJ. Limited value of alarm features in the diagnosis of upper 

gastrointestinal malignancy: systematic review and meta-analysis.Gastroenterology. 2006 Aug;131(2):390-401. 

28 Gatta L, Vaira D, Sorrenti G, Zucchini S, Sama C, Vakil N.Meta-analysis: the efficacy of proton pump inhibitors 

for laryngeal symptoms attributed to gastro-oesophageal reflux disease.Aliment Pharmacol Ther. 2007 Feb 

15;25(4):385-92. 

29 Vakil N, Ryden-Bergsten T, Bergenheim K. Systematic review: patient-centred endpoints in economic 

evaluations of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2002 Aug;16(8):1469-80. 

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7. I have held a number of leadership positions in various gastroenterology societies. 

I have served as Chairman of the Practice Parameters Committee of the American College of 

Gastroenterology, as a member of the Research Committee of the American Society of 

Gastrointestinal Endoscopy, a member of the research committee of the American College of 

Gastroenterology, Chairman of the ad hoc Committee on networking of the American Society of 

Gastrointestinal Endoscopy and a member of the Global Guidelines Committee of the World 

Organization of Gastroenterology. I have served as a member of the publications committee of 

the American College of Gastroenterology. I also currently serve on the editorial boards of 

several journals: Alimentary Pharmacology and Therapeutics, Evidence-based 

Gastroenterology, Folia Gastroenterologica, Best Practice and Research in Gastroenterology. I 

was Associate Editor of the American Journal of Gastroenterology from 2003-2013 and in this 

capacity regularly (approximately weekly) evaluated and discussed papers with my co-editors 

regarding the treatment of gastrointestinal disorders. I am currently the U.S. Editor of 

Endoscopy, the official journal of the European Society of Gastrointestinal endoscopy and in this 

capacity regularly receive papers for potential publication, manage their peer-review and make 

decisions regarding their suitability for publication. I am therefore familiar with the process of 

selection and review of research papers for publication. I am an active reviewer for 12 medical 

journals at the present time. 

8. In addition, I co-author content for UptoDate, an on-line resource supported by 

the American Gastroenterological Association, used by physicians on recommendations for 

upper gastrointestinal disorders. I also serve on advisory boards to organizations that are 

devoted to gastrointestinal disease, including the Advisory Board of the International Foundation 

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for Functional Gastrointestinal Disorders, a patient organization for individuals with irritable 

bowel syndrome, dyspepsia, functional heartburn and other disorders. 

9. I was President of a private practice (Digestive Disease Specialists of Wisconsin) 

and in that role negotiated contracts with managed care and developed practice managed plans. I 

served on the Gastroenterology advisory board for Anthem (formerly Blue Cross of Milwaukee 

WI). I have served as a reviewer for United Health Care for cases that did not meet criteria for 

approval of certain procedures in which the decision was appealed by physicians or patients. 

10. I have expertise in how treatments are selected and used in clinical practice. In 

addition to my research studies related to studies in clinical practice settings described above, at 

a national level, I have been a member and also the Chairman of the Practice Parameters 

Committee of the American College of Gastroenterology, a committee which develops practice 

management guidelines for the management of gastroenterological disorders. I have served on 

an international committee that develops guidelines for use around the world. I have also coauthored national guidelines for the treatment of gastroenterological disorders. For example, I 

co-authored the American College of Gastroenterology guidelines on treatment of dyspepsia, the 

World organization of Gastroenterology guideline on Helicobacter pylori, and the Asia Pacific 

consensus on GI bleeding .30,31, 32, 33 I was also a member of the American Gastroenterological 

Association’s eight-member expert panel that generated a practice guideline for reflux disease, 

 

30 Talley NJ, Vakil N. Practice Parameters Committee of the American College of Gastroenterology. Guidelines for 

the management of dyspepsia. Am J Gastroenterol. 2005 Oct;100(10):2324-37. 

31 World Gastroenterology Organisation. World Gastroenterology Organisation Global Guideline: Helicobacter 

pylori in developing countries. J Clin Gastroenterol. 2011 May-Jun;45(5):383-8. 

32 Talley NJ, Vakil NB, Moayyedi P. American gastroenterological association technical review ont eh evaluation 

of dyspepsia. Gastroenterology. 2005 Nov; 129(5):1756-80.

33 Sung JJ, Chan FK, Chen M, Ching JY, Ho KY, Kachintorn U, Kim N, Lau JY, Menon J, Rani AA, Reddy N, 

Sollano J, Sugano K, Tsoi KK, Wu CY, Yeomans N, Vakil N, Goh KL. Asia-Pacific Working Group consensus on 

non-variceal upper gastrointestinal bleeding. Gut. 2011 Sep;60(9):1170-7. 

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entitled “Improving the Management of GERD: evidence-based therapeutic strategies.34 I have 

served as one of two U.S. representatives on the Maastricht European Consensus guidelines on 

H. pylori that form the basis of all international guidelines.35 I represented the USA at the last 

consensus conference in Florence Italy in November 2010. I have participated in invited 

conferences on H. pylori at the National Institute of Health in Washington DC. I have been an 

invited expert on the Asia Pacific consensus on gastrointestinal bleeding. 

11. From 1993-2009, I was in private clinical practice with affiliations to the 

University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin, and the 

Marquette University College of Health Sciences in Milwaukee, Wisconsin. I am currently a 

full-time gastroenterologist at the Aurora Wilkinson Clinic, a part of Aurora Health Care. As a 

clinician, I see patients in consultation at least 5 days a week and perform endoscopic procedures 

5 days a week. As a gastroenterologist, I am frequently asked to evaluate patients who have tried 

and failed to respond to one or more PPIs for treatment of their GERD, as well as patients with 

the most severe cases of GERD and complications of GERD. In 2009 and again in 2010,2011 

and 2013, I was elected to Best Doctors in America by my peers. In 2011,2012 and 2013 I was 

also selected by Marquis Who’s Who for inclusion in their reference in Medicine and Health 

Care for 2011-2012. In 2009, I was featured in the New York Times in an interview with the 

 

34 Peterson W and the American Gastroenterological Association Consensus Development Panel. Improving the 

Management of GERD: evidence based therapeutic strategies. Monogram published by the American 

Gastroenterological Association. Available on-line at: http://www.gastro.org/userassets/Documents/GERDmonograph.pdf. 

35 Malfertheiner P, Megraud F, O'Morain C, Bazzoli F, El-Omar E, Graham D, Hunt R, Rokkas T, Vakil N, Kuipers 

EJ. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut. 

2007 Jun;56(6):772-81 

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expert on H. pylori entitled Holding Back the Ulcer Bug (available at 

http://www.nytimes.com/ref/health/healthguide/esn-ulcers-expert.html). 

12. Based on my training; my clinical practice; my experience teaching medical 

students, physician assistants, internal medicine residents, and fellows in gastroenterology; and 

my extensive involvement in research and guidelines concerning treatment of gastroenterological 

disorders, I feel qualified to speak to standards of care, best practice strategy, criteria on which 

prescribing physicians select gastroenterological treatments they use in their clinical practice, the 

qualities and relative benefits of the various treatment options for GERD and other acid-related 

conditions, and the studies and other data supporting the use of those treatment options. 

13. A true and correct copy of my curriculum vitae is attached as Exhibit A. 

II. CLINICAL BACKGROUND 

A. What Is Gastroesophageal Reflux Disease (GERD) 

14. GERD develops when the reflux of stomach contents into the esophagus causes 

troublesome symptoms and/or complications. The disorder, which is increasing in prevalence, is 

primarily caused by abnormal regulation of the sphincter muscle at the lower end of the 

esophagus. The sphincter muscle opens to allow food to enter the stomach and then closes to 

prevent stomach contents from refluxing back into the esophagus. In a patient with GERD, the 

sphincter muscle operates abnormally and permits the acidic stomach content to reflux up into 

the esophagus. Unlike the stomach, the esophagus is not equipped to withstand acid, and the 

reflux of stomach acid up into the relatively delicate and unprotected tissue of the esophagus is 

frequently uncomfortable and painful. 

15. The most common symptom of GERD is frequent and persistent heartburn. Some 

patients also may experience regurgitation of gastric contents into the mouth and difficulty 

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swallowing. Reflux disease can also cause disorders outside the esophagus (extra-esophageal 

disorders). These disorders include laryngitis, asthma, chest pain and dental erosions. 

16. GERD is a very common disorder. In the US alone, 65% of the total adult 

population experiences heartburn at some point in their life. It is also estimated that GERD 

affects 10-15% of the population of the western world at any one time. It has also been reported 

that, in Western populations, 40% of patients report that they experience symptoms on a monthly 

basis and 7% on a daily basis36. 

17. Carefully performed studies have repeatedly shown that GERD can have a major 

impact on a patient’s quality of life, including the ability to sleep, work and eat. Mild symptoms 

that occur twice a week or severe symptoms that occur just once a week are associated with a 

measurable decrease in the quality of life. I also know from my own experience with patients 

that, at its worst, GERD is a debilitating chronic disorder that affects quality of life to an 

enormous extent. I have seen many patients in consultation who report almost unbearable 

symptoms. Some have to spend almost every night sitting upright in a chair, trying to sleep in 

that position, because they are unable to sleep lying down as their symptoms become intolerable 

when they do. 

18. It is also important to note in this context that severe GERD is extremely 

prevalent. When we conduct clinical trials in large groups of patients with esophagitis, we 

generally see that one third of all untreated patients come to us presenting severe disease. Thus, 

as an illustration of this, if, say, 10% of the European population has GERD, of which one third 

(33%) has disease at the severe end of the spectrum, I would expect this to amount to in the 

region of between 3% and 4% of the entire European population at any one time. 

 

36Kulig et al, “Quality of life in relation to symptoms in patients with gastro-oesophageal reflux disease – an 

analysis based on the ProGERD initiative”, Aliment. Pharmacol. Ther., 2008; 18:767-76 (Attachment 5) 

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19. For patients with severe GERD, there is also a greater risk of development of 

organic diseases. When reflux occurs, the lining of the esophagus is injured, which may result in 

esophagitis. The refluxed contents can cause visible damage to the lining of the esophagus by 

creating breaks in the skin lining the esophagus. These breaks are referred to as erosions; when a 

person has these breaks, the condition is referred to as erosive esophagitis (EE). 

20. EE is not present in all patients with GERD, but it is a complication of GERD. 

EE cannot be diagnosed by symptoms alone, and symptoms do not correspond to the severity of 

the disease in the individual patient. EE is instead diagnosed by endoscopy. Erosions in the 

esophagus are graded based on severity using an international classification called the Los 

Angeles Classification. There are four grades of severity in the Los Angeles Classification 

corresponding to the severity of injury seen at endoscopy: Grade A: One or more mucosal 

breaks confined to the mucosal folds, each not more than 5 mm in maximum length; Grade B: 

One or more mucosal breaks confined to more than 5 mm in maximum length but not continuous 

between the tops of the mucosal folds; Grade C: Mucosal breaks that are continuous between the 

tops of 2 or more mucosal folds but which involve less than 75% of the circumference of the 

esophagus; Grade D: Mucosal breaks which involve at least 75% of the esophageal 

circumference. 

21. There is a correlation between the amount of acid entering the esophagus and the 

degree of esophagitis, providing an approximate correlation between the severity of the 

abnormalities in regulation of the esophageal sphincter and the abnormalities seen at endoscopy. 

Published data suggest that the severity of EE is associated with the extent and time that the 

esophageal tissue is exposed to refluxed stomach acid, with greater acid exposure resulting in 

more severe damage to esophageal tissue. The degree of acidity of the refluxate is measured in 

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terms of pH. Stomach refluxate that has a pH less than 4 is associated with esophageal injury as 

well as with acid-related symptoms, like chronic heartburn. 

22. Other serious, long-term complications of GERD include esophageal bleeding, 

esophageal stricture resulting in obstruction, ulcers, and a pre-cancerous change in the esophagus 

called Barrett’s esophagus and esophageal cancer. Chronic reflux disease is the leading risk 

factor for adenocarcinoma of the esophagus, a cancer with a high mortality rate and a growing 

incidence. Effective treatment of EE by complete healing of the damaged tissue, and then 

maintaining that healing, generally is recommended as a possible means of avoiding many of 

these serious complications. 

B. Treatment of GERD 

23. Only 30 years ago, the treatment options for patients suffering from GERD were 

limited and frequently unsatisfactory. The primary treatment was administration of antacids to 

neutralize stomach acid, but this treatment typically offered only temporary relief. The 

alternative was surgery. In another procedure, a fundoplication, the surgeon wrapped a portion 

of the patient’s stomach around the junction of the patient’s esophagus to reinforce the natural 

barrier between the stomach and the esophagus. These surgeries, while effective in reducing the 

experience of heartburn pain or the amount of refluxate, carried the risk of significant 

complications.37

24. Medical therapy for treatment of reflux disease has evolved from the frequent use 

of antacids to drugs that decrease acid secretion. These agents decrease the volume of acid 

secretion in the stomach and thereby decrease the amount of material that refluxes up into the 

 

37 Vakil N, Shaw M, Kirby R. Clinical effectiveness of laparoscopic fundoplication in a U.S. community. Am J 

Med. 2003 Jan;114(1):1-5. 

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esophagus. By decreasing acid production, the acidity of the refluxate is also decreased. Any 

material that refluxes up into the esophagus is therefore less injurious than it would have been 

without treatment. Treatment through acid inhibition results in an improvement in symptoms 

and healing of erosions in the esophagus. 

25. Two major classes of acid-inhibitory drugs are widely used for the treatment of 

reflux disease. The first class is called Histamine 2 receptor antagonists (H2RAs), which 

includes drugs such as ranitidine (Zantac) and famotidine (Pepcid). Some of these drugs are 

available by prescription, and some are also available over-the-counter (e.g., Zantac, Pepcid, 

Tagamet, and combination drugs such as Pepcid Complete, which combines an H2RA and an 

antacid). Generic versions of several H2RAs are also available (e.g., ranitidine (generic version 

of Zantac), cimetidine (generic version of Tagamet)). 

26. The second class of acid-inhibitory drugs is proton pump inhibitors (PPIs). A 

meta-analysis of many trials published on the efficacy of these two classes of drugs has shown 

that proton pump inhibitors are more effective than H2RAs in the treatment of esophagitis.38

27. Prilosec® (omeprazole) was the first PPI on the market, followed by Prevacid® 

(lansoprazole), Aciphex® (rabeprazole), Protonix® (pantoprazole), Nexium® (esomeprazole), 

and Dexilant® (Dexlansoprazole).39 Generic versions of omeprazole, pantoprazole, and 

lansoprazole are now available. In addition, omeprazole is available over-the-counter as Prilosec 

OTC, which is FDA-approved for treatment of frequent heartburn as part of a 14-day course of 

therapy, after which consultation with a doctor is recommended; omeprazole is also is available 

over-the-counter in a generic version. Lansoprazole also is available over-the-counter as 

 

38 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 Apr 18;(2):CD003244. Review. 

39 Another branded product called Zegerid is an immediate release preparation of omeprazole combined with 

bicarbonate, approved at 20 mg for healing EE. 

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Prevacid® 24HR. Pantoprazole also is available as a generic drug. Each proton pump inhibitor 

has been approved by the FDA for different indications and at different recommended doses for 

GERD-related indications. For example the highest approved doses for healing of erosive 

esophagitis are 20 mg for Prilosec® (omeprazole), 20 mg for Aciphex®, 30 mg for Prevacid®, 

40 mg for Protonix® (pantoprazole), 40 mg for Nexium®, and 60 mg for Dexilant® 

(dexlansoprazole). 

28. Notwithstanding the significant benefits patients and doctors enjoyed with 

omeprazole over prior therapies, not all patients are helped with omeprazole (or other PPIs). In a 

Gallup poll in the USA, only 49% of patients were completely satisfied with GERD therapy.40 

Similar data were reported in a US study of 11,064 users of medication for heartburn in the USA. 

In that study, conducted prior to the availability of Nexium®, only 46% of heartburn sufferers 

were completely satisfied with their therapy.41 Professor Tytgat wrote about the unmet needs of 

patients with GERD.42 He suggested that full 24-hour control of gastric acid secretion should be 

available with medical therapy to fine-tune acid suppressant therapy to the individual clinical 

needs. He also pointed out that “for ordinary GERD, full symptom control and patient 

satisfaction is often lacking, necessitating additional over-the-counter medication for control of 

remaining symptoms.” He also suggested that the available PPIs were suboptimal for “ondemand” therapy in Non-Erosive Reflux Disease (NERD)/GERD. Some of these unmet needs 

were addressed by the creation of Nexium®. 

 

40 Shaker R, Castell DO, Schoenfeld PS, Spechler SJ. Nighttime heartburn is an under-appreciated clinical problem 

that impacts sleep and daytime function: the results of a Gallup survey conducted on behalf of the American 

Gastroenterological Association. Am J Gastroenterol. 2003 Jul;98(7):1487-93. 

41 Crawley J, Schmitt C. How satisfied are chronic heartburn sufferers with their prescription medications?Results of 

the patient unmet needs study. J Clin Outcomes Management 2000;7:29-34. 

42 Tytgat GNJ. Are there unmet needs in acid suppression? Best Practice & Research Clinical Gastroenterology 

Volume 18, Supplement, 2004, Pages 67-72. 

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29. It thus is clear that a substantial number of patients were dissatisfied with existing 

treatment options, including omeprazole. In addition, in assessing whether Nexium® offers 

advantages over omeprazole, one needs to evaluate the room available for improvement in 

comparison to omeprazole, one needs to evaluate the results previously obtained with 

omeprazole. For example, the FDA approved labeling for omeprazole states that the healing rate 

for erosive esophagitis in its approved dose of 20 mg/day was 74%.43 Therefore any new drug 

that hopes to achieve better results has only 26% room for improvement. Similarly the FDA 

approved label for omeprazole states that complete relief of GERD symptoms was achieved in 

84% of patients in the erosive esophagitis trials leaving only 16% of patients who could improve 

compared to existing treatment with a new agent.44 

C. Nexium® 

30. Nexium® (esomeprazole magnesium) addresses the patient needs that are left 

unmet by omeprazole by improving acid inhibition, leading to more predictable and better acid 

control and therefore improved outcomes in patients, as is described below. 

31. Nexium® and omeprazole are different drugs, with different pharmacokinetic and 

pharmacodynamic properties. By way of background, many drugs are a mixture of two 

molecules, called isomers, that have the same molecular formula, but have a different 

arrangement of the atoms in space. These isomers are mirror images of each other, called 

enantiomers. The mixture is called racemic when there are equal amounts of the two 

compounds. Omeprazole is an example of a racemic mixture of two mirror-image molecules, 

called enantiomers: S-omeprazole and R-omeprazole. 

 

43http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory. 

Accessed October 9, 2011. 

44http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory 

accesed October 9, 2011 

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32. Each isomer of omeprazole can produce acid inhibition. However, the S-isomer, 

esomeprazole, is metabolized more slowly than the R-isomer and omeprazole (the mixture). The 

S-isomer therefore produces higher plasma concentrations for longer and, as a result, inhibits 

gastric acid production more effectively and for longer. Thus, esomeprazole has the 

pharmacological properties of a more effective form of treatment for disorders related to gastric 

acid secretion. As described below, clinical studies have confirmed the anticipated increased 

efficacy. 

33. Although Nexium® and omeprazole are related compounds, they plainly are not 

the “same,” as their metabolism makes clear.45, 46 The R-isomer of omeprazole and 

esomeprazole (the S-isomer) are both metabolized by the liver. After passing through the liver a 

portion of the active drug is metabolized and inactivated (all metabolites of omeprazole and 

esomeprazole are inactive), while the remaining molecules are circulated in the bloodstream to 

the parietal cells of the stomach lining, where they bind to the acid secretory pumps to suppress 

the production of stomach acid. The more quickly the molecules are metabolized, the more 

quickly they are inactivated, and fewer molecules remain to circulate to the stomach to act to 

suppress the production of stomach acid.47

34. Omeprazole and its isomers are metabolized and inactivated by two metabolic 

pathways known as the cytochrome P450 enzymes CYP2C19 and CYP3A4. CYP2C19 is a 

more rapidly metabolizing pathway than CYP3A4. The metabolism of R-omeprazole is more 

 

45 Creutzfeldt W. Chiral switch, a successful way for developing drugs: example of esomeprazole. Z Gastroenterol 

2000; 38: 893–7. 

46 Andersson T, Hassan-Alin M, Hasselgren G, Röhss K, Weidolf L. Pharmacokinetic studies with esomeprazole, 

the (S)-isomer of omeprazole. Clin Pharmacokinet 2001; 40: 411–26. 

47 Dent J. Review article: pharmacology of esomeprazole and comparisons with omeprazole. Aliment Pharmacol 

Ther 2003; 17(Suppl. 1): 5-9. 

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dependent on the CYP2C19 pathway, whereas a substantial portion of esomeprazole is 

metabolized by the slower CYP3A4 pathway. As the CYP3A4 metabolizes more slowly, less 

esomeprazole is metabolized on each pass through the liver and more unmetabolized 

esomeprazole reaches the parietal cells of the stomach than in the case of omeprazole. 

35. Because esomeprazole is metabolized at a lower rate, it results in higher plasma 

levels – also described as greater bioavailability – of esomeprazole, which is frequently 

measured as the “area under the curve,” or “AUC.”48 In the study displayed below, after 5 days 

of dosing, the bioavailability – measured as the AUC – of esomeprazole (Nexium®) 20 mg was 

almost twice that of omeprazole (Prilosec) 20 mg, while the bioavailability of 40 mg 

esomeprazole was more than 5 times greater than 20 mg omeprazole:49 

Figure 13 

 

48 Andersson T, Rohss K., Bredberg E., Hassan-Alin T. Pharmacokinetics and pharmacodynamics of esomeprazole, 

the S-isomer of omeprazole. Aliment Pharmacol Ther 2001; 15(10): 1563–1569. 

49 Lind T, Rydberg L, Kylebäck A, Jonsson A, Andersson T, Hasselgren G, Holmberg J, Röhss K. Esomeprazole 

promotes improved acid control vs. omeprazole in patents with symptoms of gastro-oesophageal reflux disease. 

Aliment Pharmacol Ther. 2000 Jul; 14 (7): 861-7.

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36. There was less inter-patient variability in AUC and gastric acid suppression with 

Nexium® than with omeprazole in this study.50

37. The metabolism of esomeprazole is not only slower but more consistent in 

different individuals than the metabolism of omeprazole or its R-isomer.51 First, the CYP2C19 

pathway has more genetic variability than the CYP3A4 pathway. In about 15% of the Asian 

population and about 3% of the Caucasian population, the CYP2C19 system is absent. Because 

the metabolism of omeprazole occurs so significantly in the CYP2C19 pathway, there is 

corresponding variation among individual patients in how much omeprazole reaches the target 

cells. 

38. Second, Nexium® maintains the area under the curve (AUC) in a therapeutic 

range in a larger proportion of patients. An AUC greater than 2 (uμol + h/L) provides peak acid 

inhibition; once the AUC is higher than 2, there is almost complete inhibition of acid secretion.52, 

53 The AUC with Nexium® 20 mg and 40 mg has been shown to be consistently above 2 

compared to omeprazole 20 mg.54 In a study by Lind et al., the steady state AUC for omeprazole 

20 mg in 36 patients with GERD ranged from 1.83 to 3.00 [mean 2.34]; with Nexium® 20 mg, 

the range was 3.27 to 5.35 [mean 4.18], and with Nexium® 40 mg, the range was 9.89 to 16.17 

[mean 12.64]. 55 Therefore, the AUC with Nexium® was consistently well above the peak acid 

 

50 Id. 

51 Kendall MJ. Review article: esomeprazole – the first proton pump inhibitor to be developed as an isomer. Aliment 

Pharmacol Ther 2003; 17( Suppl. 1): 1– 4. 

52 Andersson et al. (2001), supra n. 48. 

53 Lindberg P, Keeling D, Fryklund J, Andersson T, Lundborg P, Carlsson E. Review article: esomeprazole – 

enhanced bio-availability, specificity for the proton pump and inhibition of acid secretion. Aliment Pharmacol Ther 

2003; 17: 481-488. 

54 Lind et al. (2000), supra n.49.

55 Lind et al. (2000), supra n.49.

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inhibitory AUC threshold of 2. In addition, there was less inter-patient variability in AUC with 

Nexium®.56 

39. These differences in metabolism provide one explanation for the greater acid 

suppression seen with Nexium®. For example, in a double-blind, crossover study, 40-mg and 

20-mg Nexium® maintained mean gastric pH higher than 4, an important marker (see infra), for 

16.8 hours (P < 0.001) and 12.7 hours (P <0.01), respectively, versus 10.5 hours for omeprazole, 

as displayed below:57

Figure 14 

40. Compared with the 24-hour mean gastric pH for omeprazole (3.6), mean pH 

levels were significantly higher for Nexium®: 40 mg (4.9, P < 0.001) and 20 mg (4.1, P < 0.01). 

41. The pharmacological data provide a scientific basis for the greater efficacy of 

Nexium® in clinical trials. Further, as described above, Nexium® has demonstrated less interpatient variability in AUC and gastric acid suppression than omeprazole, and thus may provide 

 

56 Lind et al. (2000), supra n.49. 

57 Lind et al. (2000), supra n.49. 

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doctors and patients with a more predictable response, which offers doctors additional reasons to 

prescribe Nexium® in addition to the clinical data described below. 

(1) Nexium® Has Demonstrated More Effective Acid Suppression 

42. As noted above, there is a correlation between the amount of acid entering the 

esophagus, the contact time of the refluxate with the esophageal lining, and the degree of 

esophagitis, providing a correlation between the severity of the abnormalities in regulation of the 

esophageal sphincter and the abnormalities seen at endoscopy.58 Studies suggest that the severity 

of EE is associated with the extent and time that the esophageal tissue is exposed to refluxed 

stomach acid, with greater acid exposure resulting in more severe damage to esophageal tissue.59 

43. The degree of acidity of the refluxate is measured in terms of pH. Stomach 

refluxate with pH less than 4 is associated with greater esophageal injury60, 61, 62, 63, as well as 

with acid-related symptoms, like chronic heartburn, although symptoms may occur with 

refluxate that has a pH greater than 4 as well.64, 65 The pH of gastric juice is generally between 1 

and 2. Meals temporarily increase intra-gastric pH, but acid secretion then resumes and intra-

 

58 Lundell LR, Dent J, Bennett JR, Blum AL, Armstrong D, Galmiche JP, Johnson F, Hongo M, Richter JE, 

Spechler SJ, Tytgat GN, Wallin L. Endoscopic assessment of oesophagitis: clinical and functional correlates and 

further validation of the Los Angeles classification. Gut. 1999 Aug;45(2):172-80. 

59 Holloway RH, Dent J, Narielvala F, et al. Relation between oesophageal acid exposure and healing of 

oesophagitis with omeprazole in patients with severe reflux oesophagitis. Gut 1996;38:649-54. 

60 Orlando RC. Why is the high grade inhibition of gastric acid secretion afforded by proton pump inhibitors often 

required for healing of reflux esophagitis? An epithelial perspective. Am J Gastroenterol 1996;91:1692-6. 

61 Berstad A. A modified hemoglobin substrate method for the estimation of pepsin in the gastric juice. Scand J 

Gastroenterol 1970;5:343-8. 

62 Fiorucci S, Santucci L, Chiucchiu S, et al. Gastric acidity and gastroesophageal reflux patterns in patients with 

esophagitis. Gastroenterology 1992;103:855-61. 

63 Roberts NB. Review article: human pepsins – their multiplicity, function and role in reflux disease Aliment 

Pharmacol Ther 2006;24(2):2-9. 

64 Smith JL, Opekun AR, Larkai E, et al. Sensitivity of the esophageal mucosa to pH in gastroesophageal reflux 

disease. Gastroenterology 1989;96:683-9. 

65 Joelsson B, Johnsson, F. Heartburn—the acid test. Gut 1989;30:1523-5. 

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gastric pH falls again. All PPIs offer some measure of 24-hour acid control compared to no 

medication66, and Nexium® is no exception. As pH is a logarithmic scale, small changes in pH 

correspond to large changes in acid secretion. 

44. The figure below shows a trial comparing omeprazole and esomeprazole and 

demonstrates the differences in effects of these two PPIs on inhibiting gastric acid during a 24 

hour period.67

Figure 2 

45. Because proton pump inhibitors work by inhibiting stomach acid secretion, one 

way to assess their potency is by quantitatively evaluating their ability to inhibit acid secretion. 

Such studies are relevant to the comparison of PPIs, because GERD is an acid-related disease 

and there is evidence to suggest that greater acid control may effectively provide more reliable 

treatment of reflux disease and healing of erosive esophagitis.68

 

66 Tutuian R, Katz P, Castell D. A PPI is a PPI is a PPI: lessons learned from longterm intragastric pH monitoring. 

Gastroenterology 2000;118 (suppl 2 part 1):A17 abstract 332. 

67 Lind T, Rydberg L, Kylebäck A, Jonsson A, Andersson T, Hasselgren G, Holmberg J, Röhss K Esomeprazole 

provides improved acid control vs. omeprazole In patients with symptoms of gastro-oesophageal reflux disease.

Aliment Pharmacol Ther. 2000 Jul;14(7):861-7. 

68 Hunt RH. Importance of pH control in the management of GERD. Arch Intern Med. 1999 Apr 12;159(7):649-57. 

Review. 

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46. Acid inhibition studies are performed by placing an electrode in the stomach 

which measures gastric pH over a 24-hour period. In comparative studies, the same group of 

patients is treated with one proton pump inhibitor after another, with a wash-out period between 

treatments. Gastric pH is measured in each patient on each PPI. The conventional measure of 

acid inhibition is to determine the number of hours out of 24 that the gastric pH is maintained 

above 4, because the gastric juice becomes less injurious at a pH greater than 4. 

47. Acid control over a 24-hour period refers to a change in the pH curve of the 

stomach as shown in Figure 2 (above). It is important to recognize that the time pH is controlled 

above 4 is a different but related concept. A pH of 4 is a threshold that has been developed 

based on the knowledge that pepsin, an enzyme secreted by the stomach, is activated at a pH that 

is less than 4. The material that refluxes into the esophagus is less damaging to the esophageal 

lining if the pH is greater than 4.69 

48. The time that gastric acid is controlled above pH 4 may be related to healing in 

patients with erosive esophagitis, and published data suggest that failure to control gastric pH 

may play a role in treatment failure. For example, in a study of 103 patients with Los Angeles 

Classification Grade C and D esophagitis – the most severe grades of EE – patients in whom 

esophagitis healed with PPI therapy had gastric pH greater than 4 for 61% of the 24-hour period, 

while patients in whom esophagitis did not heal with PPI therapy had poorer control of gastric 

acid (gastric pH>4 for 42% of the 24 hour period; P=0.0002). Thus, in patients with Grade C 

 

69 See Roberts et al. (2006), supra n. 63..

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and D disease, patients with healed esophagitis had longer periods with a pH > 4 than patients 

who failed to have healing of esophagitis, as reflected in Figure 3, below:70

Figure 3 

49. Given this understanding as to the role of acid suppression in treatment of acid 

reflux disease and the basic fact that all PPIs work by suppressing acid, a physician reasonably 

could consider the ability of the various PPIs to suppress acid in the physician’s prescribing 

decisions. Doctors understand that acid suppression studies measure the pharmacodynamics, or 

action, of PPIs rather than their clinical effect on a particular disease or condition. This 

distinction is apparent on the labeling for Nexium® and all other PPIs, and it is a basic concept 

that doctors learn as part of their medical training. Acid suppression studies also provide doctors 

with useful information to help them care for patient subpopulations who may not be represented 

in randomized controlled clinical trials, for example: the very elderly, patients with other serious 

health care problems, and those who cannot undergo endoscopy. It is appropriate for doctors to 

 

70 Katz PO, Ginsberg GG, Hoyle PE, Sostek MB, Monyak JT, Silberg DG. Relationship between intragastric acid 

control and healing status in the treatment of moderate to severe erosive oesophagitis. Aliment Pharmacol Ther. 

2007 Mar 1;25(5):617-28. 

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consider this relevant, objective measure of the effect of PPIs when considering the treatment 

options available to their patients. 

50. Published studies have demonstrated that Nexium® provides more effective 

gastric acid suppression compared to other PPIs. In a randomized, open-label, comparative, 5-

treatment, 5-way crossover study that compared the potency of 5 different PPIs, Nexium® 

(esomeprazole) provided a significant increase in the number of hours out of 24 that intragastric 

pH was greater than 4, compared with the other PPIs studied.71, 72 The day 5 results of this study 

are reflected in the figure below: 

Figure 4 

 

71 Miner P Jr, Katz PO, Chen Y, Sostek M. Gastric acid control with esomeprazole, lansoprazole, omeprazole, 

pantoprazole, and rabeprazole: a five-way crossover study.Am J Gastroenterol. 2003;98:2616-2620. 

72 Miner P Jr, Katz PO, Chen Y, Sostek M. Reanalysis of intragastric pH results based on updated correction factors 

for Slimline and Zinetics 24 single-use pH catheters. Am J Gastroenterol. 2006;101:404-405. The data used in the 

study published in 2003 were re-analyzed in 2006, as were many other pH studies, when it was discovered that the 

Slimline catheter used in pH studies of this type had an error in its calibration curves. The correction did not alter 

the conclusions of the study or affect the results meaningfully. 

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51. Similar results were seen in a series of carefully performed studies that measured 

intra-gastric pH compared with all the currently available proton pump inhibitors in their 

approved doses. In healthy volunteers and in patients with reflux disease, esomeprazole 40 mg 

demonstrated better acid control than rabeprazole 20 mg, lansoprazole 30 mg, pantoprazole 40 

mg and omeprazole 20 mg.73, 74 Similar studies have also been performed for maintenance doses 

of esomeprazole comparing it to the approved maintenance doses of other proton pump 

inhibitors, once again demonstrating more effective suppression of gastric acid with 

esomeprazole.75

52. Nexium® 40 mg and omeprazole 40 mg also have been compared in a pH study 

of 114 patients with GERD, in which Nexium® 40 mg was shown to maintain gastric pH above 

4 significantly longer than omeprazole 40 mg (both administered once a day for five days).76 

The mean percentage of the 24-hr. period with intragastric pH > 4 was significantly greater (P < 

0.001) with esomeprazole 40 mg than with omeprazole 40 mg on days 1 (48.6% vs. 40.6%) and 

5 (68.4% vs. 62.0%). Inter-patient variability was significantly less with esomeprazole than 

omeprazole. 

53. The effect is also seen across ethnic groups. For example in another study of 

Hispanic individuals with GERD, Nexium® was more effective in controlling gastric acid 

 

73 Röhss K, Lind T, Wilder-Smith C. Esomeprazole 40 mg provides more effective intragastric acid control than 

lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg in patients with gastrooesophageal reflux symptoms. Eur J Clin Pharmacol. 2004 Oct;60(8):531-9 

74 Wilder-Smith CH, Röhss K, Nilsson-Pieschl C, Junghard O, Nyman L.Esomeprazole 40 mg provides improved 

intragastric acid control as compared with lansoprazole 30 mg and rabeprazole 20 mg in healthy volunteers. 

Digestion. 2003;68(4):184-8. Epub 2003 Dec 19 

75 Röhss K, Wilder-Smith C, Nauclér E, Jansson L. Esomeprazole 20mg provides more effective intragastric Acid 

control than maintenance-dose rabeprazole, lansoprazole or pantoprazole in healthy volunteers.Clin Drug Investig. 

2004;24(1):1-7 

76 Röhss K, Hasselgren G, Hedenström H. Effect of esomeprazole 40 mg vs omeprazole 40 mg on 24-hour 

intragastric pH in patients with symptoms of gastroesophageal reflux disease. Dig Dis Sci. 2002 May;47(5):954-8. 

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compared to lansoprazole and pantoprazole. This study was important because it measured acid 

in the lower part of the stomach and also measured acidity in the acid pocket close to the gastroesophageal junction where much of the acid-related injury occurs. 77

54. Thus, doctors reasonably may consider this acid suppression data demonstrating 

Nexium®’s better acid control compared to all other PPIs a reason to prescribe Nexium® instead 

of omeprazole or any other PPI, because acid suppression is a key aspect of the treatment of 

GERD and its complications. 

(2) Nexium® Has Demonstrated Higher Rates of Healing Erosive Esophagitis 

55. Regulatory studies concerning proton pump inhibitors and H2RAs have focused 

on healing of erosive esophagitis as a therapeutic end-point of clinical trials, and healing of 

erosive esophagitis has been one of the primary endpoints for many trials involving all of the 

available PPIs. This end-point is used in clinical trials because: (a) the presence of erosions 

confirms the presence of reflux disease; (b) healing of erosions is an objective end-point that can 

be measured by different endoscopists with good accuracy; and (c) healing of esophagitis 

prevents serious complications, making it a valid measure of treatment efficacy. 

56. Nexium® has demonstrated higher rates of healing erosive esophagitis in studies 

compared to omeprazole. In four studies that are reported in the FDA-approved Nexium® 

labeling, healing of erosive esophagitis was evaluated in double-blind, randomized, controlled 

trials that compared two doses of Nexium® (esomeprazole) with the FDA-approved 20 mg dose 

 

77 Morgan D, Pandolfino J, Katz PO, Goldstein JL, Barker PN, Illueca M. Clinical trial: gastric acid suppression in 

Hispanic adults with symptomatic gastro-oesophageal reflux disease - comparator study of esomeprazole, 

lansoprazole and pantoprazole. Aliment Pharmacol Ther. 2010 Jul;32(2):200-8. 

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of Prilosec (omeprazole) for healing erosive esophagitis.78, 79, 80, 81 In all four studies, patients 

with erosive esophagitis were randomized to treatment with esomeprazole or omeprazole. 

Healing was assessed endoscopically, and the principal end-point of the trial was to determine 

the proportion of patients who had complete healing of esophagitis at 8 weeks; week 4 healing 

data and symptom data were secondary end-points. 

57. In two of these studies, esomeprazole 40 mg provided statistically significant 

higher rates of healing EE than omeprazole 20 mg.82 In a third study, Nexium® 40 mg showed 

numerically higher healing rates, but the results did not reach statistical significance.83 These 

results can be displayed as follows: 

 

78 Richter JE, Kahrilas PJ, Johanson J, Maton P, Breiter JR, Hwang C, Marino V, Hamelin B, Levine JG; 

Esomeprazole Study Investigators. Efficacy and safety of esomeprazole compared with omeprazole in GERD 

patients with erosive esophagitis: a randomized controlled trial. Am J Gastroenterol. 2001;96:656-665. 

79 Kahrilas PJ, Falk GW, Johnson DA, Schmitt C, Collins DW, Whipple J, D'Amico D, Hamelin B, Joelsson 

B.Esomeprazole improves healing and symptom resolution as compared with omeprazole in reflux oesophagitis 

patients: a randomized controlled trial. The Esomeprazole Study Investigators. Aliment Pharmacol Ther. 2000 

Oct;14(10):1249-58. 

80 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;51:844-850 

81 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 May;51(5):852-7. Epub 2006 Jun 14. 

82 See Richter, et al. (2001), supra n. 78; Kahrilas, et al. (2000), supra n. 79. 

83 See Schmitt, et al. (2006), supra n. 80.

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Figure 584

58. Nexium® 20 mg also showed numerically higher 8-week healing rates than 

Prilosec 20 mg in two studies, and the results were statistically significant in one of the two 

studies.85 The results can be displayed as follows: 

Figure 6 

 

84The Study number in the chart refers to the corresponding number for the study used on the Nexium labeling, as 

reflected in Figure 7, below. Thus, Study 1 on the labeling is the study by Lightdale, et al., supra n. 81; Study 2 on 

the labeling is the study by Kahrilas, et al., supra n. 79; Study 3 on the labeling is the study by Schmitt, et al., supra 

n. 80; Study 4 on the labeling is the study by Richter, et al., supra n. 78. In his declaration, Dr. Abramson also 

refers to these studies as 172, 173, 174, and 222. Study 1 on the labeling is Study 173; Study 2 on the labeling is 

Study 172; Study 3 on the labeling is Study 174; and Study 4 on the labeling is Study 222. 

85 See Kahrilas, et al. (2000), supra n. 79; Lightdale, et al. (2006), supra n. 81.

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59. The results of these four trials are shown in tabular form in the labeling, or 

package insert, for Nexium®, as reproduced below: 

Figure 7 

60. In the same four trials, resolution of heartburn was assessed as well. The 

controlled trials for Nexium® introduced a new and more rigorous end-point into clinical trials 

for GERD. This end-point was complete resolution of symptoms (rather than improvement of 

symptoms) lasting for 7 consecutive days. In two studies, Nexium® 40 mg provided statistically 

significantly more rapid and complete heartburn control in EE patients than omeprazole 20 mg.86 

The results of the comparisons of Nexium® 40 mg and omeprazole 20 mg are displayed below: 

 

86 See Richter et al. (2001), supra n. 78; Kahrilas et al. (2000), supra n. 79. 

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Figure 8 

61. The results of the comparisons of Nexium® 20 mg and omeprazole 20 mg, which 

were not statistically significant, are displayed below: 

Figure 9 

62. A summary of the results of symptom resolution also was provided on the FDAapproved Nexium® labeling, as reproduced below: 

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Figure 10 

63. Further, as stated on the labeling, in these four studies of EE patients, “the range 

of median days to the start of sustained resolution (defined as 7 consecutive days with no 

heartburn) was 5 days for Nexium® 40 mg, 7-8 days for Nexium® 20 mg, and 7-9 days for 

omeprazole 20 mg.” 

64. Other randomized controlled trials have compared Nexium® 40 mg to other 

agents in the PPI class for healing of EE across all grades.87, 88 , 89, 90, 91 All were randomized 

 

87 See Richter et al. (2001), supra n. 78. 

88 See Kahrilas et al. (2000), supra n. 79. 

89 See Schmitt et al. (2006), supra n. 80. 

90 Castell DO, Kahrilas PJ, Richter JE, Vakil NB, Johnson DA, Zuckerman S, Skammer W, Levine JG. 

Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis. Am J 

Gastroenterol. 2002;97:575-583. 

91 Labenz J, Armstrong D, Lauritsen K, Katelaris P, Schmidt S, Schütze K, Wallner G, Juergens H, Preiksaitis H, 

Keeling N, Nauclér E, Eklund S; Expo Study Investigators. A randomized comparative study of esomeprazole 

(Footnote continued)

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controlled trials with healing of erosive esophagitis as the primary end-point. The results of 

these trials are summarized graphically below: 

Figure 11 

65. These data thus demonstrate Nexium®’s higher rates of healing in erosive 

esophagitis, and its demonstrated symptom resolution in EE patients. A doctor might reasonably 

consider these data a reason to prescribe Nexium® over omeprazole or other PPIs. 

(3) Nexium® Has Demonstrated Greater Efficacy in Healing Severe 

Esophagitis 

66. The ability of a PPI to heal severe esophagitis (Los Angeles Grade C and D 

disease) is important because patients with more severe EE tend to have greater esophageal acid 

exposure and tend to be more difficult to heal. They are also at the highest risk for serious 

complications, such as major bleeding, stricture, and ulceration. Moreover, patients with GERD 

 

40 mg versus pantoprazole 40 mg for healing erosive oesophagitis: the EXPO study. Aliment Pharmacol Ther. 2005 

Mar 15;21(6):739-46. 

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frequently are treated without performing an endoscopy. However, when an endoscopy is 

performed, the endoscopy reveals esophagitis in some patients, 92 which for some patients is 

severe (Grade C or D). Physicians thus may elect to prescribe a PPI with proven ability in 

comparative clinical trials to more effectively heal the most severe erosions.93

67. Furthermore, the results of a drug that is more effective for more severe disease 

may not be as apparent in trials where large proportions of patients with mild disease are 

enrolled. In contrast, the advantages of a drug may be more readily apparent in patients with 

more advanced disease. Therefore, it is reasonable to evaluate improvements in treatment 

response by evaluating a group of patients with more severe disease. 

68. The greater healing ability of Nexium® is most apparent in more severe 

esophagitis. For example, Nexium® was compared to lansoprazole in patients with Los Angeles 

Grades C and D disease in one trial in which healing was the primary objective of the trial.94 In 

this trial, healing rates at week 8 with Nexium® 40 mg were 82.4% compared to 77.5% with 

lansoprazole 30 mg (p=0.007, comparison of the time-to-healing using a log rank test). A 

significantly greater proportion of patients had resolution of their symptoms at week 4 with 

Nexium® (72% versus 63.6%, p=0.005). In addition, post hoc analyses of six other studies, 

including studies against omeprazole, showed a statistically significant difference favoring 

Nexium® in the healing of Grades C and D esophagitis in 5 of the 6 studies. 95, 96, 97, 98, 99, 100, 101 

 

92 Ruigómez A, Rodríguez LA, Wallander MA, Johansson S, Dent J. Endoscopic findings in a cohort of newly 

diagnosed gastroesophageal reflux disease patients registered in a UK primary care database. Dis Esophagus. 

2007;20(6):504-8. 

93 Gralnek IM, Dulai GS, Fennerty MB, Spiegel BM. Esomeprazole versus other proton pump inhibitors in erosive 

esophagitis: a meta-analysis of randomized clinical trials. Clin Gastroenterol Hepatol. 2006 Dec;4(12):1452-8. 

94 Fennerty MB, Johanson JF, Hwang C, Sostek M. Efficacy of esomeprazole 40 mg vs. lansoprazole 30 mg for 

healing moderate to severe erosive oesophagitis. Aliment Pharmacol Ther. 2005 Feb 15;21(4):455-63. 

95 Richter et al. (2001), supra n. 78. 

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Furthermore, as described below, a meta-analysis of randomized controlled trials confirms that 

Nexium® provides higher healing rates in Grade C and D disease. Doctors might reasonably 

consider this data concerning Nexium®’s greater efficacy in healing severe esophagitis a reason 

to prescribe Nexium® over omeprazole and other PPIs. 

(4) Efficacy of Nexium® 40 mg Is Confirmed in Meta-Analysis of Clinical 

Trials 

69. The efficacy of Nexium® versus other PPIs has been confirmed in a metaanalysis of clinical trials. Meta-analysis is a statistical procedure that integrates the results of 

several independent studies considered to be “combinable.”102, 103 Well-conducted metaanalyses allow a more objective appraisal of the evidence than traditional narrative reviews, 

provide a more precise estimate of a treatment effect, and may explain heterogeneity between the 

results of individual studies.104 A well-conducted systematic review precedes a quantitative 

meta-analysis and utilizes measures of study quality that are used to select studies for inclusion 

into the quantitative aspect of the study. 

70. The relative benefit of an active treatment over a control is usually expressed as 

the relative risk, the relative risk reduction, or the odds ratio. For clinical decision making, 

however, it is clinically meaningful to use a measure called “number needed to treat.” This 

 

96 Kahrilas et al. (2000), supra n. 79. 

97 Schmitt et al. (2006), supra n. 80. 

98 Lightdale et al. (2006), supra n. 81. 

99 Castell et al. (2002), supra n. 90. 

100 Labenz et al. (2005), supra n. 91. 

101 Fennerty, et al. (2005), supra n. 94. 

102 Egger M, Davey Smith G. Meta-analysis: potentials and promise. BMJ 1997;315:1371-4 

103 Egger M, Smith GD, Phillips A. Meta-analysis: Principles and procedures BMJ 1997;315:1533-1537 

104 See Egger, et al., supra n. 102, 103. 

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measure is calculated on the inverse of the absolute risk reduction. It has the advantage that it 

conveys both statistical and clinical significance to the doctor.105 In the case of proton pump 

inhibitors, the number needed to treat is the number of patients you need to treat to create one 

additional better outcome (i.e., healing of erosive esophagitis). 

71. A meta-analysis was performed to calculate the pooled effect of esomeprazole on 

healing rates, symptom relief, and adverse events versus competing PPIs in patients with erosive 

esophagitis.106 The authors identified 10 studies that evaluated 15,316 patients. These 10 studies 

included 8 peer-reviewed, full-text manuscripts, 1 published abstract, and 1 manufacturer 

package insert. At 8 weeks after initiation of therapy, there was a 5% (Relative risk= 1.05; 95% 

confidence interval, 1.02–1.08) relative increase in the probability of healing of erosive 

esophagitis with esomeprazole compared to all other PPIs, yielding an absolute risk reduction of 

4% and number needed to treat of 25 (number of patients needed to be treated with esomeprazole 

to get one additional responder compared to other proton pump inhibitors). 

72. If the results are broken down by grade of esophagitis, the number of patients that 

need to be treated with esomeprazole 40 mg to get an additional responder compared to other 

proton pump inhibitors were: Los Angeles Grade A=50 patients, Los Angeles Grade B=33 

patients, Los Angeles Grade C=14 patients and Grade D=8 patients, as reflected in the following 

figure reproduced from the publication: 

 

105 Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect. BMJ 1995; 

310: 452-454. 

106 Gralnek IM, Dulai GS, Fennerty MB, Spiegel BM.Esomeprazole versus other proton pump inhibitors in erosive 

esophagitis: a meta-analysis of randomized clinical trials. Clin Gastroenterol Hepatol. 2006 Dec;4(12):1452-8. 

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Figure 12 

73. This meta-analysis confirms the superiority of Nexium® in healing the most 

severe disease. Based on this meta-analysis, a reasonable gastroenterologist or other physician 

may therefore conclude that Nexium® 40 mg offers a significant advantage to patients, 

especially those with more severe disease. 

(5) Nexium® Is Effective in Maintenance of Healing of Erosive Esophagitis 

74. Erosive esophagitis is chronic in the majority of cases; GERD is a chronic 

disorder and most patients who cease treatment are likely to relapse. Therefore, long-term 

studies of the maintenance of healing of erosive esophagitis are an important consideration in 

GERD therapy. 

75. Two randomized controlled trials have demonstrated that Nexium® is effective 

versus placebo in maintaining the healing of EE. These trials evaluated patients who had been 

treated with either esomeprazole or omeprazole and had complete healing of erosive 

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esophagitis.107, 108 After healing of erosive esophagitis, patients were randomized to placebo, 

esomeprazole 10 mg, esomeprazole 20 mg, or esomeprazole 40 mg. The primary endpoint was 

endoscopic relapse of mucosal breaks and/or study discontinuation due to symptomatic relapse. 

Both studies demonstrated that esomeprazole 20 mg and 40 mg are effective in maintaining 

healing of EE. Like the results of the trials for healing EE, the results of these studies are shown 

on the FDA-approved Nexium® package insert, and the FDA approved 20 mg Nexium® as the 

recommended dose for maintenance of healing of EE. 

76. In addition, two randomized controlled trials compared Nexium 20 mg to 

lansoprazole 15 mg (both FDA-approved maintenance doses of the medication) for maintenance 

of healing of erosive esophagitis. In the first trial, patients treated with Nexium® 20 mg once 

daily consistently maintained statistically significantly higher remission rates than those treated 

with lansoprazole 15 mg once daily, regardless of baseline disease severity (83% vs. 74%, 

p<0.0001).109 Similarly, in the second trial, patients receiving Nexium® 20 mg evidenced 

statistically significantly better maintained healing compared with lansoprazole 15 mg. 

(endoscopic and symptomatic remission, 84.8% vs. 75.9%, p=0.0007).110

 

107 Johnson DA, Benjamin SB, Vakil NB, Goldstein JL, Lamet M, Whipple J, Damico D, Hamelin B. Esomeprazole 

once daily for 6 months is effective therapy for maintaining healed erosive esophagitis and for controlling 

gastroesophageal reflux disease symptoms: a randomized, double-blind, placebo-controlled study of efficacy and 

safety. Am J Gastroenterol. 2001 Jan;96(1):27-34. Erratum in: Am J Gastroenterol 2001 Mar;96(3):942. 

108 Vakil NB, Shaker R, Johnson DA, Kovacs T, Baerg RD, Hwang C, D'Amico D, Hamelin B. The new proton 

pump inhibitor esomeprazole is effective as a maintenance therapy in GERD patients with healed erosive 

oesophagitis: a 6-month, randomized, double-blind, placebo-controlled study of efficacy and safety. Aliment 

Pharmacol Ther. 2001 Jul;15(7):927-35. 

109 Lauritsen K, Devière J, Bigard MA, Bayerdörffer E, Mózsik G, Murray F, Kristjánsdóttir S, Savarino V, Vetvik 

K, De Freitas D, Orive V, Rodrigo L, Fried M, Morris J, Schneider H, Eklund S, Larkö A; Metropole study results. 

Esomeprazole 20 mg and lansoprazole 15 mg in maintaining healed reflux oesophagitis: Metropole study results. 

Aliment Pharmacol Ther. 2003 Feb;17(3):333-41. 

110 Devault KR, Johanson JF, Johnson DA, Liu S, Sostek MB. Maintenance of healed erosive esophagitis: a 

randomized six-month comparison of esomeprazole twenty milligrams with lansoprazole fifteen milligrams. 

Clin Gastroenterol Hepatol. 2006 Jul;4(7):852-9. Epub 2006 May 6. 

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(6) Nexium® Works When Other Therapies Have Failed 

77. Pragmatic studies are studies that are performed in real life conditions and provide 

an important glimpse into how drugs work in real life, outside the carefully controlled conditions 

that exist in a randomized controlled trial. 

78. Many patients on proton pump inhibitors other than Nexium® are unhappy with 

their therapy and continue to experience symptoms that affect their quality of life. In many 

instances, when they are switched to Nexium® treatment, their satisfaction with treatment 

increases significantly. This is something I have observed in my own practice. It also has been 

demonstrated in published studies. 

79. For example, in a large Dutch study of 4929 patients, only 21.9% of patients 

reported that they were satisfied with their PPI treatment at consultation (i.e. prior to switching to 

esomeprazole). Following switching to esomeprazole therapy, 88.0% of patients reported that 

they were satisfied with therapy and only 26.9% of patients were still experiencing symptoms 

(vs. 84.0% at consultation); 71.3% reported that they were more satisfied with esomeprazole than 

with their previous PPI, most frequently because they had fewer or no symptoms. Among 

patients who had been using an additional therapy to control GERD symptoms, 62.0% were no 

longer using any such medication. Of the 1069 patients who had been satisfied with their 

previous PPI therapy, 39.4% were even more satisfied with esomeprazole.111 

80. Another study from the United Kingdom found similar results. Patients who did 

not have adequate control of their symptoms on other proton pump inhibitors improved 

 

111 Hoogendoorn RJ, Groeneveld L, Kwee JA, Patient Satisfaction with Switching to Esomeprazole from Existing 

Proton Pump Inhibitor Therapy for Gastro-Oesophageal Reflux Disease Clin Drug Investig 2009; 29 (12): 803-810. 

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significantly when they were switched to Nexium®.112 Patients with GERD in a general practice 

setting who were dissatisfied with their current proton pump inhibitor therapy were offered entry 

into a trial where they were switched to Nexium® 40 mg/day. The mean frequency of heartburn 

was reduced by 78% from 4.4 days a week to 1 day a week at the end of the 8-week treatment 

period (p < 0.0001). Other GERD symptoms were also significantly reduced following of 

treatment with esomeprazole (all p < 0.0001). 

81. In a practice setting in Canada, patients who were still symptomatic on other 

proton pump inhibitors had a significant improvement in quality adjusted months when switched 

to esomeprazole, and the treatment was cost-effective. The majority of patients were receiving 

antisecretory therapy other than esomeprazole (rabeprazole, 24.7 % ; pantoprazole, 20.5 % ; 

lansoprazole, 12.9 % ; omeprazole, 12.5 % ; or ranitidine, 16.8 % ). After 4-week follow-up, 

there was a statistically significant benefit of esomeprazole vs. usual care in terms of participants 

symptom rating, with 563 / 973 (58 % ) recording their symptoms as none or minimal over the 

previous 2 days compared with 170 / 591 (29 % ) in the control group ( P < 0.0001, intention to 

treat (ITT) analysis). There was also a statistically significant improvement in symptom score at 

4 weeks in the esomeprazole arm compared with the control arm (difference in GOS score = −

0.9; 95 % confidence interval. This study in a real-life setting demonstrates that Nexium® is 

superior to other agents in routine practice settings and the improved outcomes are costeffective.113 

 

112 R. Jones, T. Patrikios, The effectiveness of esomeprazole 40 mg in patients with persistent symptoms of gastrooesophageal reflux disease following treatment with a full dose proton pump inhibitor Int J Clin Pract, December 

2008, 62, 12, 1844–1850. 

113 Moayyedi P, David Armstrong, Hunt R, Lei Y, Bukoski White R. The Gain in Quality-Adjusted Life Months by 

Switching to Esomeprazole in Those With Continued Reflux Symptoms in Primary Care: EncomPASS — A 

Cluster-Randomized Trial. Am J Gastroenterol 2010; 105:2341–2346. 

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82. A study of 1,564 patients recruited from primary care centers across Canada has 

also demonstrated a statistically significant benefit versus control when patients were switched to 

Nexium® from their existing PPI therapies (including rabeprazole, pantoprazole, lansoprazole 

and omeprazole).114 Additional data from this study show that switching to esomeprazole 

improved the sleep disturbance caused by night time reflux in these patients.115

83. Nexium® is the only PPI that has been shown to be superior to surgery for reflux 

disease.116 

(7) Nexium® Is More Effective in Inhibiting H Pylori at Once-Daily Dosing 

84. H pylori is an organism that causes peptic ulcer disease and gastric cancer. 

Nexium® is more effective in inhibiting H pylori than omeprazole. In a study of isolates of H 

pylori, Gatta et al. reported that the MIC50 and MIC90 (measures of how the drug inhibits the 

growth of H pylori) of esomeprazole were 16 and 32 mg/L.117 In contrast the MIC of 

omeprazole was twice as high at 32 and 64 mg/L, reflecting less inhibition of growth of H pylori 

with omeprazole. Overall, 63.5% of isolates showed the same susceptibility to both drugs; 17 

isolates were two- to 64-fold more susceptible to esomeprazole and two isolates were two-fold 

more susceptible to omeprazole. The authors concluded that the increased antimicrobial activity 

in vitro of esomeprazole against H pylori could contribute to improving the outcome of the 

 

114 Moayyedi et al, "The gain in quality-adjusted life months by switching to esomeprazole in those with continued 

reflux symptoms in primary care EncomPASS - a cluster-randomised-trial", American Journal of Gastroenterology,

(2010), 105, 2341-2346. 

115 Moayyedi et al, “The impact of intensifying acid suppression on sleep disturbance related to gastro-oesophageal 

reflux disease in primary care” Aliment Pharmacol Ther, (2013), 37(7):730-7. 

116 Galmiche JP et al, "Laparoscopic antireflux surgery vs esomeprazole treatment for chronic GERD: the LOTUS 

randomized clinical trial", JAMA, (2011), 305(19), 1969-77. 

117 Gatta L, Perna F, Figura N, Ricci C, Holton J, D'Anna L, Miglioli M, Vaira D. Antimicrobial activity of 

esomeprazole versus omeprazole against Helicobacter pylori. J Antimicrob Chemother. 2003 Feb;51(2):439-42. 

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eradication treatment of such an infection. This is borne out in clinical studies, as Nexium® is 

the only proton pump inhibitor to be approved in a triple therapy regimen as a once-a-day 

treatment on 10 days dosing. All other PPIs must be given twice a day, or for a longer period of 

time, to achieve efficacy.118 This is reflected in the approvals for proton pump inhibitors for H 

pylori treatment with triple therapy. Omeprazole, pantoprazole, lansoprazole and rabeprazole are 

all approved by the FDA for treatment of H pylori infection in combination with amoxicillin and 

clarithromycin but all need to be administered twice a day. In contrast, esomeprazole is 

approved in the same treatment regimen using the same doses of amoxicillin and clarithromycin, 

with esomeprazole administered only once a day. 

85. In an analysis of 3 randomized, controlled trials of therapy for H pylori, 

esomeprazole administered once a day achieved eradication rates that were virtually identical to 

that of other twice-daily proton pump inhibitor-based triple therapies. 119 In my opinion, this is 

another demonstration of the superiority of this drug. 

III. SUMMARY OF CLINICAL ADVANTAGES OF NEXIUM® 

86. Nexium® provides more predictable treatment response and has demonstrated 

advantages over omeprazole and other PPIs that support the use of Nexium® over omeprazole or 

other PPIs for appropriate patients in the treatment of acid reflux disease. 

87. Clinical studies demonstrate advantages with Nexium® over omeprazole and 

other PPIs and that Nexium® offers a superior treatment option for appropriate patients. 

 

118 Anagnostopoulos GK, Tsiakos S, Margantinis G, Kostopoulos P, Arvanitidis D. Esomeprazole versus 

omeprazole for the eradication of Helicobacter pylori infection: results of a randomized controlled study.J Clin 

Gastroenterol. 2004 Jul;38(6):503-6. 

119 Laine, L., Fennerty, M. B., Osato, M., Sugg, J., Suchower, L., Probst, P. et al. Esomeprazole-based Helicobacter 

pylori eradication therapy and the effect of antibiotic resistance: results of three US multicenter, double-blind trials. 

American Journal of Gastroenterology 2000; 5, 3393-8. 

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• Better acid control in the stomach

Medical treatment of acid reflux disease focuses on suppression of gastric acid, and 

published studies have demonstrated that Nexium® provides more prolonged gastric 

acid suppression compared to omeprazole and other PPIs. 

• More predictable bioavailability and less inter-patient variability

Nexium® has demonstrated more predictable efficacy in healing of all grades of 

erosive esophagitis (“EE”) – damage to the lining of the esophagus caused by reflux 

of stomach contents into the esophagus – compared with omeprazole. Nexium also 

has demonstrated less inter-patient variability in AUC (bioavailability) and gastric 

acid suppression than omeprazole and thus may provide doctors and patients with a 

more predictable response. 

• Higher rates of healing erosive esophagitis

Nexium® has demonstrated higher rates of healing EE and faster time to start of 

sustained symptom resolution in EE patients when compared to the standard 20 mg 

dose of omeprazole approved by FDA for treatment of EE. Nexium® also has 

demonstrated higher healing rates in studies against Prevacid® (lansoprazole) and 

Protonix® (pantoprazole), and it has been shown to be more effective than other 

PPIs in healing the most severe grades of EE. 

• Better efficacy in maintenance of healing compared to lansoprazole

In addition, Nexium® has been demonstrated to be safe and effective in maintaining 

the healing of EE, and more effective than lansoprazole in its approved doses in 

maintaining the healing of EE, an important criterion as GERD is a chronic disease. 

• Better symptom control

Nexium® address the needs of patients who are still symptomatic on omeprazole and 

other PPIs, further demonstrating its superiority. Patients are concerned with the 

control of their symptoms, but many patients continue to report persistent reflux 

symptoms even on PPI therapy. Peer-reviewed studies have demonstrated that 

patients with such persistent symptoms on other proton pump inhibitors, including 

but not limited to omeprazole, improve after being switched to Nexium®. 

Moreover, in a cost-constrained environment, the use of Nexium® has been shown 

to be cost-effective for patients dissatisfied with the symptom relief accorded by the 

other proton pump inhibitors they were taking. 

• Better activity against H pylori

Nexium® has better anti-bacterial activity against H. pylori. It is the only PPI 

approved for eradication of H. pylori in a single daily dose in combination with 

antibiotics (clarithromycin and amoxicillin); all other proton pump inhibitors 

approved for H. pylori eradication need to be administered twice a day. Proton 

pump inhibitors are a major component of the cost of H. pylori treatment, and 

reducing the dose by 50% may offer significant cost-savings. 

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88. Together, these data show that Nexium® (esomeprazole magnesium) has a unique 

place in the management of patients with GERD particularly the management of difficult 

patients and those who have failed other forms of therapy. 

IV. INTRODUCTION OF A NEW BRANDED PPI 

89. During my career, I have witnessed the launch of multiple proton pump inhibitors 

(Prevacid®, Aciphex®, Protonix®, Nexium®, Zegerid®). I have witnessed these launches as a 

practicing gastroenterologist and as an expert in reflux disease. I have participated in educational 

activities related to each of these agents. I served on advisory boards for Prevacid®, Aciphex®, 

Protonix® and Nexium® and participated in post-launch educational activities related to each of 

these drugs. I have been a member of small groups of experts who assessed and interpreted 

clinical data associated with each of these agents prior to their launch. I am therefore familiar 

with the process for the release of a new drug in the United States, and new PPIs, in particular. 

90. The process for release or launch of a new PPI comprises several steps, which I 

discuss below in the usual order in which they occur. 

91. When Phase II clinical studies (designed to evaluate clinical efficacy) show 

promising results, experts are consulted to plan Phase III studies (Phase III studies are also called 

regulatory studies and consist of two large randomized controlled trials conducted in multiple 

centers in the United States to demonstrate efficacy of the drug. These have been conducted with 

esomeprazole magnesium). It is at this point, when the relevant scientific community becomes 

aware of a potential new therapeutic agent. When Phase III trials are conducted, practicing 

gastroenterologists and experts perform the study, which further increases awareness of the drug. 

Other physicians also participate in the large Phase III trials and also become aware of the 

studies and data. As the data of the Phase III trials become available and are prepared for 

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submission to the FDA, the study data are presented at major U. S. scientific meetings (e.g. 

American Gastroenterological Association or American College of Gastroenterology) and the 

broader gastroenterology community becomes aware of the data. Prior to launch, advisory board 

meetings are scheduled with groups of gastroenterologists to obtain their opinions and to prepare 

a marketing strategy for the new Drug. At this time, a brand name is chosen for the drug, tested 

in focus groups and reviewed by the FDA (to avoid l similarities with other approved agents). 

Speaker bureaus are also established to educate primary care physicians, physician assistants and 

others regarding the new drug in advance of the launch and shortly after launch. 

V. HANMI’S ESOMEPRAZOLE STRONTIUM 

92. Counsel for AstraZeneca has informed me that Hanmi received approval for 

Esomeprazole Strontium delayed release capsules on August 6, 2013. I have received a copy of 

the FDA approval letter.120 I was unaware of the approval of Hanmi’s product by FDA or a 

planned launch of a new PPI, prior to being informed by AstraZeneca’s counsel and receiving 

the FDA approval letter. I have not heard or seen any information about the Hanmi product or 

esomeprazole strontium. I have also not heard any discussion of this agent among my colleagues 

and fellow gastroenterologists. 

93. I find news of an imminent launch121 of this esomeprazole product highly 

unusual. My colleagues and I would expect to have had significant knowledge about this 

product well before launch. None of the typical steps associated with the launch of a new PPI 

have taken place and I have no knowledge that anyone in the scientific community, in particular 

 

120 FDA Approved Drug Products with Generic Equivalence Evaluations (“Orange Book”), available at 

http://www.fda.gov/Drugs/InformationOnDrugs/ucm129662.htm

121 http://www.globalpost.com/dispatch/news/yonhap-news-agency/130807/us-fda-oks-sale-s-koreas-improvedversion-nexium 

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gastroenterologists and the leaders in our community, has any awareness of this product. I am 

not aware of any presentations at scientific meetings and meetings of gastroenterologists, where I 

would expect news of a new therapeutic product to be prescribed by gastroenterologists to be 

announced. I attended the 2013 Digestive Disease Week (“DDW”) conference in Orlando, 

Florida., which is a major annual conference drawing gastroenterologists from all over the world, 

leaders in the field, along with representatives from pharmaceutical companies and healthcare 

organizations. I acquired no awareness of Hanmi or an esomeprazole strontium product at that 

meeting. In view of an expected launch, I would have expected high exposure of a new product 

at this highly prominent meeting. 

94. To my knowledge, there have been no clinical studies of esomeprazole strontium, 

publications of these studies and no expert panels or advisory boards related to this drug. 

95. I note from the FDA approval letter that Hanmi’s drug has been approved as a 

new brand but has no brand name. I understand from the FDA approval letter that Hanmi’s 

product will be marketed as esomeprazole strontium delayed release capsules. 

VI. EFFECT OF ESOMEPRAZOLE STRONTIUM LAUNCH 

96. Switching patients from a drug that is working for them can have consequences 

for the patient and for society. In accordance with managed care formulary guidelines, 

Nexium® has occasionally been excluded by managed care organizations and a switch has been 

forced to other agents, to save the managed care organization money. When one of the largest 

managed care providers in the USA attempted this, it had the opposite effect paradoxically 

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raising costs because the new treatment was ineffective in treating the patient.122 Therefore the 

arrival of any new agent that could change existing therapies either deliberately due to a forced 

managed care change or accidentally due to confusion with pre-existing therapy (with Nexium® 

in this case) is a cause for concern on the part of patients and the physicians treating them. 

A. Physicians 

97. The lack of clinical study data for esomeprazole magnesium, the lack of prelaunch education of leaders of the gastroenterology community and the lack of pre-launch notice 

to physicians demonstrates that a great majority of physicians will not become aware Hanmi’s 

esomeprazole strontium product until it reaches the market. 

98. An unpublicized introduction of esomeprazole strontium or any new drug will 

likely be upsetting to many clinicians. The lack of pre-launch communication with physicians 

and the lack of published scientific information makes it likely that clinicians will first learn of 

esomeprazole strontium from a pharmacist or patient. 

99. Given the lack of information Hanmi has disseminated about its product, the risk 

of confusion here is very high. Patients and clinicians are likely to be caught off-guard by the 

presence of an esomeprazole alternative particularly because we do not know its clinical efficacy 

related to Nexium®. 

100. The lack of pre-launch information about Hanmi’s esomeprazole strontium 

product combined with its lack of a brand name will create confusion about the relationship 

between esomeprazole magnesium (Nexium®) and esomeprazole strontium. Without any 

clinical data or information on esomeprazole strontium, most physicians (and 

 

122 Alemayehu et al, "Esomeprazole formulary exclusion: impact on total health care services use and costs", 

Postgraduate Medicine, (2012), 124(3), 149-63. 

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gastroenterologists) will not know the difference between Nexium® and esomeprazole strontium 

and are likely to confuse the two. As noted above, switches in agents can have unfortunate 

effects on clinical outcomes in patients and a deterioration in their condition. The absence of a 

brand name may create the perception that esomeprazole strontium is generic Nexium® or that 

AstraZeneca is either involved or responsible for the new PPI.

101. I performed an online search on August 18, 2013 to identify any information 

relating to the launch of esomeprazole strontium. I identified several press reports 

characterizing esomeprazole strontium as an “improved Nexium” while Hanmi’s website states 

that it is a generic drug. Although not all these reports appear to be statements directly from 

Hanmi, I do believe that the public representations of esomeprazole strontium are indicative of 

the mixed message that will be delivered to patients and physicians, when Hanmi’s esomeprazole 

strontium enters the market. 

102. Many physicians will also consult the product insert (label) when they first 

encounter a new drug. Under these circumstances, the label for Hanmi’s esomeprazole strontium 

capsules will likely enhance the confusion. 

103. Hanmi’s esomeprazole strontium label contains only limited pharmacological 

study of esomeprazole strontium. Hanmi’s label does not contain any study evaluating 

esomeprazole strontium in patients with GERD. The only studies in Hanmi’s label directed 

toward clinical endpoints use esomeprazole magnesium (Nexium®). The data presented in 

Hanmi’s label therefore cannot demonstrate whether the drug is equivalent, superior or inferior 

to Nexium®. The label states “Because clinical trials are conducted under widely varying 

conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly 

compared to rates in the clinical trials of another drug and may not reflect the rates observed in 

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practice. The safety of esomeprazole strontium has been established from adequate and wellcontrolled studies of esomeprazole magnesium. “ To a clinician and scientist, this is both 

confusing and lacks transparency. As this is a new drug and approved under a new drug 

application, we would want to see safety and efficacy data of that drug before making any 

prescribing decision 

104. Hanmi’s pricing of its esomeprazole strontium capsules will likely increase 

confusion. If Hanmi prices its esomeprazole strontium capsules as a generic and gains a 

favorable position on managed care formularies compared to Nexium®, pharmacies and 

healthcare plans will use various cost-control mechanisms to shift prescriptions from Nexium® 

to the lower-cost Hanmi product. These mechanisms will likely emphasize “esomeprazole” or 

the “similarities” of esomeprazole strontium to Nexium® (esomeprazole magnesium) which 

remain unproven. This will further enhance the incorrect perception that Nexium® and 

esomeprazole strontium are either the same (Pharmaceutically Equivalent) or Therapeutically 

Equivalent. 

105. There is therefore a high likelihood that a launch of esomeprazole strontium 

delayed release capsules will create confusion among practicing physicians and 

gastroenterologists who are likely to prescribe PPIs. 

B. Patients 

106. Given the lack of information Hanmi has disseminated about its product, the risk 

of patient confusion regarding the two compounds is certain. Patients will likely confuse 

esomeprazole strontium with esomeprazole magnesium (Nexium®), because both products will 

contain “esomeprazole” on their labeling, Patients will not know that the two compounds have 

not been compared and have not been shown to be clinically equivalent. They will also not know 

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that the rigorous clinical trials conducted with Nexium® have not been conducted with 

esomeprazole strontium and that safety and efficacy are inferred from the extensive research 

conducted on Nexium® but are not demonstrated for the new compound. To make an informed 

decision to choose a pharmaceutical agent, patients need to be aware of this. 

107. As discussed above, Nexium® provides a number of clinical advantages 

compared to omeprazole or other PPIs. Many patients receiving Nexium® have previously 

failed on other PPI. Patients successfully treated on Nexium® would have no reason to switch to 

esomeprazole strontium, particularly if those patients had been switched to Nexium® after one 

or more treatment failures. A forced switch of these patients from Nexium® to esomeprazole 

strontium could upset the patients’ established course of treatment and lead to recurrent 

symptoms and clinical problems as have occurred with other mandated switches by managed 

care organizations in the past. 

108. I declare under penalty of perjury under the laws of the State of Massachusetts 

that the foregoing is true and correct and that this Declaration was executed this 20th day of 

August, 2013, at Milwaukee, Wisconsin. 

_____________________________________ 

NIMISH VAKIL, M.D. FACG, AGAF, FASGE 

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