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Omeprazole Magnesium. Keith C. Triebwasser, Ph.D. Senior Director Regulatory Affairs Procter & Gamble. Rx to OTC Switch. Omeprazole for the Prevention of Frequent Heartburn Symptoms. Target Population: People with Frequent Heartburn.

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Omeprazole Magnesium

Keith C. Triebwasser, Ph.D.

Senior DirectorRegulatory AffairsProcter & Gamble


Rx to OTC Switch

Omeprazolefor the Prevention ofFrequent Heartburn Symptoms


Target Population: People withFrequent Heartburn

  • Heartburn symptoms 2 or more days per week (40 million people)

  • Affects their daily lives

  • Goal: to prevent vs. treat symptoms


Target Population Tries to Manage Frequent Heartburn

  • 77% use OTC medications

  • OTC product use

    - 80% use antacids

    - 48% use OTC H2RAs

    - 38% use both

  • Only 19% report satisfaction


Current OTC Therapies Not Well-Suitedfor People with Frequent Heartburn

  • Pharmacology limits effectiveness

    • Short duration of action

    • Intended for episodic heartburn

  • Current therapies lack all day efficacy


Omeprazole Ideally Suited for Target Population

  • Pharmacology provides for

    • Prolonged acid suppression

    • 24 hour prevention of symptoms

    • Once daily dosing


Omeprazole Ideally Suited for Target Population

  • Omeprazole’s excellent safety profile

    • 15 years

    • 125 countries

    • 450 million patient treatments


OTC Label

Label clearly directs consumers:

  • How to select the product

  • How to use the product

  • What to do if symptoms continueor return


OTC Label Elements

  • Target population

    • Frequent heartburn sufferers (2 or more days/week)

  • Indication

    • Prevention of the symptoms of frequent heartburn for 24 hours


OTC Label Elements

  • Target population

    • Frequent heartburn sufferers (2 or more days/week)

  • Indication

    • Prevention of the symptoms of frequent heartburn for 24 hours

  • Dose

    • 20 mg of omeprazole as omeprazole magnesium


OTC Label Elements

  • Target population

    • Frequent heartburn sufferers (2 or more days/week)

  • Indication

    • Prevention of the symptoms of frequent heartburn for 24 hours

  • Dose

    • 20 mg of omeprazole as omeprazole magnesium

  • Directions for use

    • Take 1 tablet in the morning


OTC Label Elements

  • Target population

    • Frequent heartburn sufferers (2 or more days/week)

  • Indication

    • Prevention of the symptoms of frequent heartburn for 24 hours

  • Dose

    • 20 mg of omeprazole as omeprazole magnesium

  • Directions for use

    • Take 1 tablet in the morning

    • Take every day for 14 consecutive days


OTC Label Elements

  • Target population

    • Frequent heartburn sufferers (2 or more days/week)

  • Indication

    • Prevention of the symptoms of frequent heartburn for 24 hours

  • Dose

    • 20 mg of omeprazole as omeprazole magnesium

  • Directions for use

    • Take 1 tablet in the morning

    • Take every day for 14 days

  • Instructions to see a doctor

    • If you have warning signs

    • If heartburn continues or returns


Omeprazole, properly labeled, can be safely and effectively used in an OTC setting


Presentation Agenda

OTC Omeprazole for Frequent Heartburn

David Peura, M.D.Professor of MedicineAssociate Chief of Gastroenterology, University of Virginia

Efficacy and Consumer Use

Douglas Bierer, Ph.D.Director, OTC Drug Development, The Procter & Gamble Co.

Safety

Douglas Levine, M.D.Chief Medical Officer, AstraZeneca LP

Safe Use in OTC Setting

Nora Zorich, M.D., Ph.D.Vice President, Pharmaceuticals, The Procter & Gamble Co.

Summary

Keith Triebwasser, Ph.D.Senior Director, Regulatory Affairs, The Procter & Gamble Co.


Proposed OmeprazoleRX to OTC Switch:A Clinician’s Perspective

David Peura, M.D. FACP FACG

Professor of MedicineAssociate Chief of Gastroenterology and HepatologyUniversity of Virginia


Gap in OTC Therapy for Frequent Heartburn

  • Heartburn frequency varies

  • Current OTC meds are inadequate therapy for frequent HB

  • Condition does not require intensive physician involvement

  • Consumers could self-manage frequent HB with effective OTC therapy


Current Physician ExperienceWith PPIs and Frequent Heartburn

  • More than 50% GI patients on PPIs

  • Primary care physicians comfortable prescribing PPIs for frequent heartburn

  • Endoscopy/diagnostic tests unnecessary for uncomplicated frequent heartburn

  • Symptom management/prevention is current practice


OTC Omeprazole Consistent withCurrent Practice Guidelines

Therapy should be aimed at treating or preventing heartburn symptoms with acid-reducing medications


Frequent Heartburn Can Be Self-Managed With OTC Omeprazole

  • Label encourages people to see their doctor

  • People will continue to see doctors

  • Low risk/high benefit to consumer


OTC Omeprazole Would Benefit Consumers

  • Symptom prevention is key

  • PPI best therapy to prevent frequent heartburn symptoms

  • Proposed dose and duration appropriate

  • Omeprazole safe and effective


Efficacy and Consumer Use

Douglas Ws. Bierer, Ph.D.

Director, OTC Drug DevelopmentProcter & Gamble


Efficacy and ConsumerBehavior Program

  • Pivotal efficacy studies

  • Consumer understanding and behavior studies

    • Label comprehension

    • Appropriate OTC use


Efficacy Trials

  • Two efficacy trials

  • Study populations

    • Heartburn symptoms > 2 days a week

    • No physician diagnosis of GERD or erosive esophagitis

  • Dosing

    • One tablet in the morning for14 consecutive days

  • Endpoint

    • % subjects heartburn-free

    • % days heartburn-free


Percent of Subjects Heartburn Free For24 Hours: Time Course Over 14 Days

Study 183 20 mg OME

Study 17120 mg OME

Study 183Placebo

Study 171Placebo

90

80

70

60

50

% Subjects With No Heartburn

40

30

20

10

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Time (days)

* p < .001 (day 1, day 14, across 14 days)


Conclusion: Efficacy Studies

  • 20 mg provides prevention of heartburn symptoms for 24 hours

  • Uses:For the prevention of the symptoms offrequent heartburn for 24 hours

  • Dose:20 mg

  • Directions:1 tablet in the morning for 14 consecutive days


Consumer Understanding and Behavior Program

  • Objectives

    • Correct self-selection

    • Understand how to use product

    • Understand and adhere to product warnings

  • Studies

    • Label comprehension

    • Actual use


Subjects recruited from 12 sites across U.S.n=684

Study population

Infrequent or no heartburn

Frequent heartburn

Low-literacy with frequent heartburn

Potential drug-drug interactions

Pregnant/nursing

Label Comprehension Study Design


Label Comprehension Study ResultsWho Should Use the Product

Infrequent/No Heartburn

22%

78%Chose Correctly

n=229


Label Comprehension Study ResultsWho Should Use the Product

FrequentHeartburn

1%

99%Chose Correctly

n=200


Frequent heartburn situations79%

Infrequent heartburn situations49%

Label Comprehension of Low LiteratePeople with Frequent Heartburn

% CorrectResponse(n=162)


1 tablet per day95%

Take for 14 consecutive days91%

Contact healthcare professional before using beyond 14 days92%

Subjects Understood How to Usethe Product


Subjects Understood When Not toUse/Ask a Health Professional

  • General warning signs81%

  • Drug-drug interactions

    • Generic + brand names82%

    • Generic names alone50%

  • Pregnant/nursing91%


Actual Use Study: Objectives

  • Evaluate consumer use in naturalistic OTC setting

    • Correct self-selection

    • Appropriate use

    • Complied with label instructions


Actual Use Study Design

  • Design mimicked consumer purchase decisions:

    • Mall kiosk site – not clinical site

    • No health care professional on site

    • No subject contact in use phase

    • Purchase product

    • Product repurchase allowed


Study Phases

Self Selection Decision

At Mall Kiosk

Product Use/Repurchase

8 Week Period

Follow-UpInterview

4 Weeks After Usage Period


Disposition of Subjects

Population Approached at Mall

n = 5060

No Heartburn/Not Interested

Not Appropriate to use

n = 3809

Said They Could Use Product

n = 1251

Would Not Purchase

n = 385

Agreed to Purchase Product

[Self-Selection Population]

n = 866


Demographics of Self-Selection Population

Characteristic

Gender (% female) 58%

Race

% Caucasian68%

% African American16%

% Hispanic11%

Mean age/range 48/18-91

Low reading ability (REALM Test) 8%

Heartburn symptoms  2days/wk 90%

Use OTC heartburn medications 90%

Use Rx heartburn medications40%

n=866


Results of Self-Selection

Correct self-selection ofall 6 selection criteria: 81%

  • Heartburn  2 days per week

  •  18 years of age

  • Not allergic to omeprazole

  • Not pregnant or nursing

  • No general warning signs

  • No drug-drug interactions

    n=866


< 18 years of age3

Pregnant/nursing 1

Allergic to omeprazole 0

General warning signs 82

Drug-drug interactions 8

Infrequent heartburn 86

People Who Did Not CorrectlySelf- Select

n=866

Numberof Subjects


Disposition of Subjects WhoPurchased Product

Agreed to Purchase Product

[Self-Selection Population]

n = 866

No Diary

n = 96

WithdrewConsentn = 4

Did Not MeetStudy Criterian = 8

Used Product and Returned Diary

[Use Population]

n = 758


Subjects Are Compliant WithDosing Directions

  • No more than 1 tablet per dose96%99%

  • No more than 1 tablet per day91%98%

Per Subject

Per Dosing Occasion


Compliance With the 14-DayDosing Regimen

  • Definition of compliance

    • 80-100% of the product within14 ± 3 days

    • Physician consultation if exceeded 14 doses

  • (11-14 doses within 11-17 days)


Compliance With the 14-DayDosing Regimen

People achieved high compliance withdosing directions

9% 11-14 doses in > 17 days

9% < 11 doses

< 1% Multiple daily doses

3% > 14 doses w/o doctor contact

79%Accordingto label directions


Return of Frequent HeartburnFour Weeks After Trial

No Medication

8%

Antacids

No FrequentHeartburn

22%

43%

H2RA

9%

Antacids + H2RAs

3%

Rx Therapy

15%


Actual Use Study: Conclusions

  • Consumers appropriately self-select

  • Consumers understood the label

  • Consumers used product for prevention of frequent heartburn

  • Consumers used omeprazole according to label directions


Summary

  • Indication

    • Prevention of the symptoms of frequent heartburn for 24 hours

  • Dose

    • 20 mg of omeprazole as omeprazole magnesium

  • Directions for use

    • Take 1 tablet in the morning

    • Take every day for 14 days


Our proposed label, the efficacy data and the consumer’s abilityto understand and use this product safely and appropriately are congruent


OTC OmeprazoleUpdate on Safety

Doug Levine, M.D.

Chief Medical OfficerAstraZeneca LP


OTC Omeprazole Product Safety

Product safety is defined as adverse events occurring in relation to product use during short or long term

Safety of omeprazole is established based on:

  • Clinical trials with Rx product

  • Rx post-marketing surveillance

  • OTC clinical trials

    Adverse event profile of omeprazole is established, and is acceptable for OTC


OTC Omeprazole Product Safety

  • Sponsor intent = short term use

  • If unintended long-term use occurs without medical supervision, product adverse event profile is acceptable (based on Rx product experience)


Long-term Safety Issues Not Directly Related to the Product

  • Potential consequences of consumer behavior without medically supervised use

  • Involves medical diseases other than acid reflux disease

  • Involves the natural history of acid reflux induced damage to the esophagus

  • Not directly linked to omeprazole


Long-term Safety Issues Not Directly Related to the Product

  • Not likely with alarm symptoms (labeled)

    • Dysphagia (trouble swallowing food)

    • Frequent chest pain

    • Unexplained weight loss

    • Frequent wheezing, chronic cough

    • Chest pain with shortness of breath; sweating; pain spreading to arm, neck or shoulders; or lightheadedness


Long-term Safety Issues Not Directly Related to the Product

Possible with responders who do not seek medical advice (despite label instructions):

  • Non-neoplastic upper GI condition

    • Esophageal erosions

    • Gastric/duodenal ulcers

  • Upper GI malignancies

  • Upper GI conditions with risk of malignancy


Long-term Safety Issues Not Directly Related to the Product

Unlikely with upper GI malignancy (esophagus, stomach)

  • Different symptoms (e.g., dysphagia, nausea, vomiting, early satiety, weight loss) do not respond to omeprazole

  • Malignancy usually present at first presentation for medical care, without antecedent heartburn, other symptoms

  • Malignancy is unusual in endoscoped populations with frequent heartburn


Long-term Safety Issues Not Directly Related to the Product

Possible with upper GI conditions with risk of malignancy

Barrett’s esophagus (complication of acid reflux induced esophageal damage)

  • Common, but rare progression to malignancy

  • Difficult to effectively manage cancer risk

  • Omeprazole does not increase cancer risk

  • Omeprazole does not induce regression


Heartburn and Esophageal Cancer

  • Increasing incidence of esophageal adenocarcinoma is not related toacid reducers

  • Afflicted patients generally present without heartburn or Barrett’s esophagus

  • Presently, incidence rate approximately equals mortality rate for this cancer, suggesting lack of clinical “signal” to draw medical attention

  • No evidence that acid reducers mask such “signals”

  • Cancer development is rare

  • Omeprazole does not increase cancer risk


Conclusions

  • Product-related safety profile of omeprazole is acceptable

  • The natural history of esophageal acid reflux damage can involve rare, serious consequences

  • Omeprazole does not directly increase the risk of esophageal adenocarcinoma

  • Based on overall safety considerations, omeprazole is acceptable for OTC use


Benefit/Risk Assessment of Omeprazole in the OTC Market

Nora Zorich, M.D., Ph.D.

Vice President Pharmaceuticals Procter & Gamble


Considerations of Chronic Use of Omeprazole Without Physician Involvement

  • What proportion of consumers may use OTC omeprazole on a regular basis?

  • Do consumers with FHB go to their physicians? Will OTC omeprazole change that?

  • What benefits and risks might result from use without physician involvement?


What Proportion of Consumers May Use OTC Omeprazole on a Regular Basis?

NDC Prescription Database: PPI Use

Rx Dispensed/Year

Patients (%)

1

44.3

2

15.4

3

9.0

4

6.2

5

4.4

6+

20.7


What Proportion of Consumers May Use OTC Omeprazole on a Regular Basis?

Bardhan Study Design

  • Patients with frequent heartburn

  • Controlled study to assess omeprazole usage pattern over 1 year period

  • Omeprazole 20mg daily for 14 days

  • If FHB returned (in 1 year) patients selfmanaged additional courses of therapy

Bardhan et al., BMJ, 1999, 18:502-507


What Proportion of Consumers May Use OTC Omeprazole on a Regular Basis?

Bardhan Study Results

  • 72% used intermittent 14-day regimens

    • Of these, 68% requested 3 or fewer treatment courses over the year

    • Symptom control after 2 weeks was a strong predictor of outcome

  • 28% required maintenance therapy at some point during the year

Bardhan et al., BMJ, 1999, 18:502-507


What Proportion of Consumers May Use OTC Omeprazole on a Regular Basis?

Antacids/

H2RAs/No

No Frequent

Medicine

Heartburn

42%

43%

Rx Therapy

15%

Actual Use Trial Results


What Proportion of Consumers May Use OTC Omeprazole on a Regular Basis?

  • Administrative claims database

    • 21% used chronically

  • Published literature

    • 28% required maintenance therapy

  • Actual Use Trial

    • 15% returned to prescription PPI

    • An additional 4% took two or more14 day regimens

Most of the people who use omeprazole don’t use it chronically


Considerations of OTC Chronic Use of Omeprazole Without Physician Involvement

  • What proportion of consumers may use OTC omeprazole on a regular basis??

  • Do consumers with FHB go to their physicians? Will OTC omeprazole change that?

  • What benefits and risks might result from use without physician involvement?


Do Consumers With FHB Go toTheir Physicians?

Oliveria Study Design

  • Survey of 2000 people with heartburn

  • How they understand their heartburn

  • How they manage their symptoms

  • How often they have physician contact

Oliveria et al., Arch Intern Med. 1999;159:1592-1598


Do Consumers With FHB Go toTheir Physicians?

Oliveria Study Results

  • Over 90% were taking therapy for symptoms

  • Physician contact directly correlates to the frequency of symptoms

    • People with frequent HB were 4 times more likely to see their physician

    • 78% of people with most frequent HB had physician contact

Oliveria et al., Arch Intern Med. 1999;159:1592-1598


Do Consumers With FHB Go to Their Physicians? Will OME Change That?

OTC H2RA’s Effect on Physician Visits

  • Fallon Community Healthcare System

    • 2000 patients with acid-related diseases

  • Minneapolis Cross-Sectional Survey (1993-1997)

    • 3400 consumers

  • MEDSTAT Marketscan data base (1995-1998)

    • Database of >7 million people


Do Consumers With FHB Go to Their Physicians? Will OME Change That?

Fallon Community Healthcare SystemPre & Post OTC H2RA

7/94-7/95

7/95-7/96

GERD-related clinic visits/yr (mean)

0.72

0.67

3SE Andrade et al, Med Care; 1999; 37:424-430


Do Consumers With FHB Go to Their Physicians? Will OME Change That?

Minneapolis Cross-Sectional Survey:Physician Visits in Past Year

1993

(n=1141)

%

1997

(n=1238)

%

Heartburn

23.6

21.9

Dyspepsia

22.0

23.5

MJ. Shaw et al, Am J Gastroenterol 2001, 96(3):673-6


Do Consumers With FHB Go to Their Physicians? Will OME Change That?

MEDSTAT Marketscan Data Base1995-1998

1995

1996

1997

1998

UGIEndoscopy(% of pop)

0.14

0.16

0.18

0.16

Visits/UGIDx Code (mean)

2.04

2.00

2.12

2.09


Do Consumers With FHB Go to Their Physicians? Will OME Change That?

Actual Use Trial Results

  • Rate of physician consultation for heartburn doubled during the study

  • 20% contacted a doctor for the first time about their heartburn duringthe study

  • 53% of people taking more than14 doses, talked to their physician during or just after the study


Do Consumers With FHB Go to Their Physicians? Will OME Change That?

  • The majority of people with FHB see a doctor for their symptoms

  • Physician visits stayed the same after H2RA’s were available OTC

  • The Actual Use Trial suggests that physician visits will not decrease and may increasewith OTC omeprazole


Considerations of OTC Chronic Use of Omeprazole Without Physician Involvement

  • What proportion of consumers may use OTC omeprazole on a regular basis?

  • Do consumers with FHB go to their physicians? Will OTC omeprazolechange that?

  • What benefits and risks might result from use without physician involvement?


Considerations of OTC Chronic Use of Omeprazole Without Physician Involvement

Benefit to User

  • The label is clear - see physician if FHB returns

  • OTC omeprazole a better option than current OTC therapies


Short-term PPI Superior to Long-Term H2RA for Healing of Esophagitis

Chiba et al., Gastroenterology 1997, 112:1798-1810


Considerations of OTC Chronic Use of Omeprazole Without Physician Involvement

  • The majority of consumers won’t use chronically

  • Consumers who use chronically will involve their physician

  • The risks of use without physician involvement are minimal and the benefits are substantial


Summary

  • Omeprazole will fill a critical gap in OTC for frequent heartburn

  • The target population is those people with frequent heartburn

  • The label is understood and it is congruent with OTC omeprazole use

  • The label should specify a 14-day regimen

  • Omeprazole is acceptable for use OTC


Conclusion

Omeprazole can be safely and effectively used OTC


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