1 OTC Omeprazole Magnesium (Prilosec 1 TM ) October 20, 2000 Larry Goldkind MD Division of Gastrointestinal and Coagulation Drug Products CDER, FDA

2 Efficacy Pharmacodynamics Review of Efficacy Trials Current Prescription Usage of Prilosec for GERD/Heartburn Definitions of GERD: Heartburn Current OTC template for Heartburn Medications Proposed Prilosec 1 OTC label Summary

3 Pharmacokinetics and Pharmacodynamics Short pharmacokinetic half-life: hour Slow pharmacodynamic onset: Acid inhibition only 50% of maximum at 24 hours Long acting pharmacodynamic effect: acid secretion returns to baseline over 3-5 days

4 Single-Dose Pharmacodynamic Study: Astra Merck Protocol 129 Intragastric pH vs.. time post-dose ??

5 Repeat Dose Pharmacodynamics Reference #44 (mean pentagastrin stimulated peak acid output- mmol H/hour

6 Heartburn Relief Trials: Studies 092 and 095

7 Demographics of Studies 092/095 Mean frequency of heartburn: 60% of days Average heartburn severity: (Scale 0-3: moderate=2) Over 50 % of subjects had heartburn severity > 2

8 Primary Efficacy Endpoint: Sustained Complete Relief First Episode/First Dose

9 Secondary Endpoints First dose Inconsistent results Sustained adequate relief Complete relief within 1 hour Adequate relief within 1 hour Overall assessment

10 Secondary Analysis “All Episodes Analysis” Extent of exposure: almost 90% took more than 3 doses Results beyond first episode are confounded by pharmacodynamic carry-over effect from prior doses No benefit shown for current OTC occasional episodic usage

11 Sustained Complete Relief “All Episodes” Separated by at Least 4 days

12 Additional Heartburn Relief Studies 3 studies : 017, 018 and ,700 subjects enrolled No efficacy at study endpoints: Sustained complete relief Sustained adequate relief Overall assessment of study medication Backup medication

13 Summary of Episodic Heartburn Relief 5 studies of episodic heartburn relief: Primary analyses all failed “All episodes analysis” failed to demonstrate efficacy for occasional episodic usage

14 Prevention of Meal-Induced Heartburn 2 studies : 005 ; 006

15 Primary Efficacy Endpoint Heartburn-Free:4 Hours Post Meal (% subjects heartburn-free)

16 Secondary Endpoints Supportive Results: 20 mg dose Overall assessment of medication Maximum severity score Backup medication use Average symptom severity Reduction of maximum severity score

17 Secondary Endpoints Supportive Results: 10 mg dose Maximum Severity Score Not Supportive Overall assessment Backup medication use Average symptom severity Reduction of maximum severity score

18 Conclusions Prilosec 1 at 20 mg dose may have marginal efficacy for the prevention of heartburn when taken 1 hour before a heartburn inducing meal Prilosec 1 at 10 mg dose lacks replicated efficacy for primary and most meaningful secondary endpoints

19 Conclusions (cont.) Outstanding issues Unreplicated results Small therapeutic gains compared to placebo Consumer confusion due to lack of benefit heartburn relief Pharmacodynamics favor chronic use

20 24-Hour Prevention Studies 171 and 183 New indication: 24 hour prevention of symptoms for up to 10 days Is this management of GERD?

21 Entry Criteria Heartburn of greater than 1 month duration Heartburn at least 2 days per week Antacid or OTC H2-RA responsive heartburn in the past (enriched population)

22 Demographics 80% of subjects: baseline frequency > 50% of days Mean severity 1.5 (2=moderate severity)

23 Primary Efficacy Endpoint Heartburn-Free Day 1 (% subjects)

24 Day 14 Heartburn-Free (% subjects)

25 Summary of Results Replicated statistically significant difference compared to placebo Efficacy both doses Efficacy increases over time Day 1: Therapeutic gain 9-17% Day 14: Therapeutic gain 23-30%

26 Time to Recurrence of Heartburn (% of Subjects Heartburn-Free Post-Treatment)

27 Conclusions: Daily Dose 24-Hour Prevention Studies Successful prevention of heartburn symptoms with 10mg & 20mg doses Increased efficacy over time Benefit lost within 3 days of discontinuation

28 Prescription vs. OTC GERD vs. Heartburn

29 Current Prescription Prilosec Label for GERD Gastroesophageal Reflux Disease (GERD) “The recommended adult oral dose of Prilosec for treatment of patients with symptomatic GERD and no esophageal lesions is 20 mg daily for up to 4 weeks The recommended oral dose for the treatment of patients with erosive esophagitis and accompanying symptoms due to GERD is 20 mg daily for 4-8 weeks "

30 What Is GERD? Sponsor definition: (page 40 of summary volume) “GERD represents a distinct physician-diagnosed chronic disease characterized by acid reflux and attendant symptoms, usually heartburn …... and requires 4-8 weeks treatment with omeprazole” “Episodic treatment of heartburn is different from the treatment of GERD.” Differences not specified

31 Definitions of GERD “GERD may be defined as symptoms and/or tissue injury related to the reflux of gastric contents into the esophagus…….Heartburn is the typical symptom of GERD” (American Society of Gastrointestinal Endoscopy-Guidelines for the Practice of Endoscopy) “ GERD is used to describe any symptomatic clinical or histopathologic alteration resultant from episodes of gastroesophageal reflux” (Gastrointestinal diseases; Sleisenger and Fortran)

32 Definition of GERD (cont.) Entry criteria from published studies: “Patients with a history of heartburn for over 12 months and episodes of moderate to severe heartburn on 4 or more of the seven days before endoscopy” (“Efficacy of omeprazole for the treatment of symptomatic acid reflux disease without esophagitis” Arch Intern Med., June 26, 2000)

33 Summary:Heartburn vs. GERD Heartburn is the cardinal symptom of GERD GERD –Assessment of GERD requires medical judgement –Management of GERD is based on medical judgement Severity Chronicity Frequency

34 Rationale for OTC Treatment of Episodic Heartburn Discrete, episodic, occasional symptoms Symptoms responsive to low-dose therapy (1/8 to 1/4 daily prescription dose of acid suppressive therapies) OTC product is effective at relief and prevention No repeat dose carry-over effects required 2-week limited usage

35 Current Template for OTC Acid Suppressive Agents for Heartburn For relief of episodic symptoms: To prevent symptoms: before eating food or drinking beverages that cause heartburn Note: indication linked to a specific episode of heartburn

36 Proposed Prilosec 1 OTC label For relief of symptoms: No efficacy For 24 hour prevention: take anytime during the day: No data presented

37 Proposed Prilosec 1 OTC label (cont.) or if you prefer, one hour before those events associated with occasional heartburn……. such as consuming food, beverages: M arginal efficacy supported stress, hectic lifestyle, lying down, or exercise: N o supportive data presented

38 Proposed Prilosec 1 OTC Label (cont.) 24 hour prevention is a new indication for OTC heartburn treatment and is not episodic Dose any time of day is an unsupported new dosing instruction and is not episodic Non-meal related symptom prevention is an unsupported new indication Proposed dose is prescription dose for GERD

39 Overall Conclusions Pharmacodynamic properties predict: No efficacy for relief (acute treatment) Progressive improvement in efficacy for prevention over time (delayed PD effect)

40 Overall Conclusions (Cont) Results of clinical studies follow PD predictions : No efficacy at acute treatment of episodic heartburn Marginal efficacy at 1 hour prevention Optimal role in prevention of heartburn over time in the management of GERD, currently “a physician- diagnosed chronic disease requiring 4-8 weeks of therapy”