# Presentation: 834099

## Omeprazole Magnesium

**Keith C. Triebwasser, Ph.D.**
**Senior Director****Regulatory Affairs****Procter & Gamble**

**Notes:**
Good morning.  Mr. Chairman, ladies and gentlemen of the advisory committees.

I’m Keith Triebwasser with Procter & Gamble

## Rx to OTC Switch

**Omeprazole****for the Prevention of****Frequent Heartburn Symptoms**

**Notes:**
We are here today to discuss the Rx to OTC switch of omeprazole for the prevention of frequent heartburn symptoms.  

Some of you may recall that we came before the joint NDAC/GDAC Advisory Committees in the fall 2000.  At that time, the Chairman of that committee, Dr. Brass, noted that omeprazole may be suitable for switch to OTC, but we needed to define a suitable target population and labeling that was congruent with our data and with the safe and effective use of omeprazole by this population.

Since that time we have worked with the FDA to identify this target population and to develop new OTC labeling.  We have conducted label comprehension and actual use studies with this new label.

We are here today to show you how these data support our proposed OTC label and to show that the known benefits of omeprazole will outweigh any potential risks associated with use in the OTC setting.

Our presentation will address the questions posed to you by the FDA.  

## Target Population: People withFrequent Heartburn

**Heartburn symptoms 2 or more days per week (40 million people)**
**Affects their daily lives**
**Goal: to prevent  vs. treat symptoms**

**Notes:**
Our OTC target population is those people with frequent heartburn, defined as heartburn symptoms two or more days a week.  This is 40 million people in the United States. 

Their heartburn affects their daily lives. 

It limits what they can eat, what they can do at work and at leisure, and often their sleep.   

It is not surprising that the goal of people with FHB is to prevent these symptoms rather than treat each occurrence.  

## Target Population Tries to Manage Frequent Heartburn

**77% use OTC medications**
**OTC product use**
**	****	****- 80% use antacids**
**	****	****- 48% use OTC H****2****RAs**
**	****	****- 38% use both**
**Only 19% report satisfaction**

**Notes:**
Right now, most people with frequent heartburn – 77 % of them - are using OTC medications.   These medications are not indicated for prevention of frequent heartburn.

The OTC medicines they use are antacids and H2 receptor antagonists, and they frequently use them together.

Most people aren’t satisfied with the OTC medications they’re taking. 

In fact, only 19% say they are completely satisfied with the heartburn relief they achieve with OTC medications.

Just why is satisfaction with current OTCs so low among people with frequent heartburn?

## Current OTC Therapies Not Well-Suitedfor People with Frequent Heartburn

**Pharmacology limits effectiveness**
**Short duration of action**
**Intended for episodic heartburn**
**Current therapies lack all day efficacy**

**Notes:**
One of the reasons is that current OTC therapies are not well-suited to prevent frequent heartburn symptoms.

The pharmacology of these OTC products limits their effectiveness against frequent heartburn. Their duration of action is limited.  Antacids last for 1-2 hours, and H2  receptor antagonist effectiveness is only 8-12 hours.  

As a result of these limitations, these medications lack all day efficacy.  Often more than one dose per day is needed to control heartburn and people with frequent heartburn symptoms find themselves using these therapies repeatedly, often without complete satisfaction or adequate acid control. 

OTC omeprazole can be the solution these people are seeking.

## Omeprazole Ideally Suited for Target Population

**Pharmacology provides for**
**Prolonged acid suppression**
**24 hour prevention of symptoms**
**Once daily dosing**

**Notes:**
Omeprazole is ideally suited for prevention of frequent heartburn symptoms.

Simply stated, omeprazole has the right pharmacology to meet the unmet needs of this target population.

The mechanism of action provides for prolonged acid suppression, which reaches a maximum at 3-5 days. 

The prolonged acid suppression means a single daily dose prevents heartburn symptoms for 24 hours.  

The onset of action profile and long duration of action of omeprazole match very well with the needs of the target population, and are ideally suited for prevention of symptoms.

## Omeprazole Ideally Suited for Target Population

**Omeprazole’s excellent safety profile**
**15 years**
**125 countries**
**450 million patient treatments**

**Notes:**
In addition Omeprazole has an excellent safety profile.  This drug has been marketed for 15 years in more than 125 countries with more than 450 million patient treatments.  This extensive experience with this drug has revealed no safety concerns. 

## OTC Label 

**Label clearly directs consumers:**
** ****How to select the product**
** ****How to use the product**
** ****What to do if symptoms continue****or return**

**Notes:**
Since our previous Advisory Committee meeting, we have had several productive discussions with the FDA and have developed a label that is simple, direct and, as you will see, adhered to by the consumer. 

This label  provides clear instructions to the consumer on how to select and use the product and what course of action to take if their symptoms continue or 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**

**Notes:**
As I’ve mentioned, we’ve identified a specific target population and indications which are appropriate for omeprazole use in this target population.

## 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**

**Notes:**
.
We believe omeprazole should be available over the counter at 20 mg, the current Rx dose.  This dose provides superior acid suppression and shows both clinical and statistical significance in our efficacy trials.

## 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**

**Notes:**
The label’s directions for use call for 1 tablet/day, taken in the morning.  This is the dosing in  our clinical efficacy trials and ensures 24 hour prevention of heartburn symptoms

## 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**

**Notes:**
Since omeprazole is indicated for prevention of frequent HB symptoms, in the OTC setting it should be labeled to be taken on consecutive days.  

This is consistent with both the pharmacology of omeprazole, and with the needs of people with frequent heartburn to prevent heartburn symptoms from occurring.

We believe the OTC label should specify that this regimen be 14 consecutive days. 

A 14-day regimen is a conservative application of clinical guidelines and it is an appropriate period after which people should see a doctor before continuing to use omeprazole. 

Our Actual Use study demonstrates that people understand and comply with a 14 day label. 

And, this is the duration of our clinical trials which support our application.

## 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**

**Notes:**
We have included instructions to see a doctor if warning signs of more serious conditions are present, and we have been very clear that if symptoms continue or return to seek physician attention before continuing to use the product.

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

**Notes:**
Today, we will show you how omeprazole, properly labeled, will be safely and effectively used in an OTC setting.

## Presentation Agenda

**OTC Omeprazole for Frequent Heartburn **

**David Peura, M.D.****Professor of Medicine****Associate Chief of Gastroenterology, University of Virginia**

**Efficacy  and Consumer Use**

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

**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.**

**Safety**

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

**Notes:**
With this as background, here is today’s presentation flow. 

First, Dr. David Peura, from the University of Virginia will provide his views on how OTC omeprazole can fill a crucial gap in existing heartburn therapy and how this fits with current clinical practice.

Dr. Doug Bierer, will present the results of the efficacy program and the results of the studies showing that consumers use the product appropriately and according to label instructions.

Dr. Douglas Levine and Dr. Nora Zorich will discuss product safety and safe use of omeprazole in the OTC setting. 

Their presentations will address the risk benefit analysis for anyone who may use omeprazole chronically without physician  involvement.

And finally, I will summarize how the data support the safe and effective use of OTC omeprazole for the prevention of frequent heartburn symptoms.   

Housekeeping note: Please note that there is a number on each slide in the upper right hand corner for you to use if you have questions regarding the slides.

Let me introduce Dr. David Peura

## Proposed OmeprazoleRX to OTC Switch:A Clinician’s Perspective

**Proposed Omeprazole****RX to OTC Switch:****A Clinician’s Perspective**

**David Peura, M.D. FACP FACG**
**Professor of Medicine****Associate Chief of Gastroenterology and Hepatology****University of Virginia  **

**Notes:**
Good morning. 

As a practicing Gastroenterologist for almost 30 years, I’ve treated thousands of patients with all kinds of heartburn. My clinical and research experience extends back to the B.C. era...before Cimetidine. I’ve been involved in the evolution of all classes of heartburn medication...from the 1970’s when we used to dispense antacids by the caseloads...to the 1980’s when I was involved in early trials for H2 receptor antagonists....and finally  the 1990’s with the latest generation of heartburn meds, proton-pump inhibitors or PPIs. 

Today, PPIs are the class of drugs that my GI and primary care colleagues and I most frequently prescribe. Because of their unique pharmacology and duration of action, they are by far the preferred medication for the prevention of frequent heartburn.

My purpose today is to give you a clinical perspective on the proposed Omeprazole RX to OTC switch. I will talk about how the switch will fit into established medical practice and how it will benefit people in the OTC setting. 

## 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**

**Notes:**
In considering this proposed switch of Omeprazole to OTC, first it’s important to understand the condition of frequent heartburn. 

Just as the severity of heartburn symptoms ranges from relatively mild to very severe, frequency of heartburn varies as well. Some people get heartburn only once in awhile, when they eat pizza for example. Omeprazole is probably not the right drug for them -- they can get immediate relief from current OTC products like antacidsand H2s.  

But larger numbers of people get heartburn two or more times a week, with varying degrees of severity.  Some of them have this frequent heartburn every week... others experience it intermittently.  It is a very common condition, yet, there is currently no effective over the counter option to help these people prevent their symptoms. The H2s don’t last long enough and the antacids just aren’t strong enough. While these medications are adequate for treating symptoms of occasional heartburn, for making you feel better after that pizza, clinical experience has taught us that only PPIs can prevent the symptoms of frequent heartburn.

We’re talking about 40 million people in the US.   I don’t think that all consumers with frequent heartburn need to see a doctor before they begin treatment. I do think that with the proper OTC medication, consumers can safely and effectively self-manage their symptoms, including deciding when to go see a doctor.

## 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

**Primary care physicians comfortable prescribing PPIs for frequent heartburn**
**Endoscopy/diagnostic tests unnecessary for uncomplicated frequent heartburn**
**Symptom management/prevention is current practice**

**Current Physician Experience****With PPIs and Frequent Heartburn**

**Notes:**
To explain why, let’s talk about how physicians use PPIs to prevent frequent heartburn. 

Conservatively, I’d say that more than half the patients I currently see take PPIs, and that would also be true for most of my GI colleagues. Many of these patients failed H2s.

Primary care physicians are also very comfortable prescribing this class of medication for their patients with frequent heartburn...in fact, in the US most PPI prescriptions are written by primary care physicians.

When patients come to me with frequent heartburn symptoms, and there are no warning signs of other conditions, I give them a short course of a PPI like Omeprazole.  Neither my colleagues nor I routinely do diagnostic tests unless a patient has severe or refractory symptoms.  In fact, few doctors would recommend initial endoscopy for a patient who complains only of frequent heartburn. This is what the professional society guidelines currently recommend...a therapeutic trial before endoscopy.  

When I start a patient on a PPI, they usually get better very quickly, I’m confident of the diagnosis and I simply follow their clinical progress.    

## OTC Omeprazole Consistent withCurrent Practice Guidelines

**OTC Omeprazole Consistent with****Current Practice Guidelines**

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

**Notes:**
This treatment approach to frequent heartburn that I have just described and the sponsor’s proposal for OTC Omeprazole are very consistent with current practice guidelines. In fact, the most recent published guidelines specify that therapy should be aimed at treating or preventing heartburn symptoms with acid-reducing medications. If acid-reducing therapy prevents symptoms, nothing further needs to be done. Therefore, symptom management is really the first stage in patient management.

Today’s patients are quite knowledgeable. They can recognize their frequent heartburn for what it is.  They know when they need to see a doctor. Given these factors, and since symptomatic management and prevention would be the doctor’s initial approach, I believe that with a safe and effective OTC medication, consumers will successfully self-manage their frequent heartburn. 

## Frequent Heartburn Can Be Self-Managed With OTC Omeprazole

**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 **

**Notes:**
Let me elaborate on this. 
First, the sponsor’s proposed label educates consumers to take Omeprazole for 14 days, and not to take it for longer without first contacting their doctor. I remember, there was concern when H2s went over the counter that people would stop going to their doctors. But, studies show that didn’t happen...people continued to see their physicians about their heartburn.  

I expect it’ll be the same with OTC Omeprazole.  In fact the sponsor’s data would suggest that consumers will follow instructions and will ask their doctor about their frequent heartburn if they haven’t already done so.       

Undoubtedly there will be some consumers who will take the drug for longer periods of time without talking to their physician. This does not concern me, because it’s likely that’s what their doctor would have told them to do anyway.  We know that when patients with frequent heartburn are treated with PPIs they do much better than those who are treated with any current OTC heartburn medication -- primarily because PPIs are more effective at reducing acid. 

Some of you might have concerns that OTC Omeprazole might mask or delay a diagnosis. I’m comfortable that’s not going to be the case.   It didn’t happen when H2s were first released OTC.   And as far as masking a more serious condition, while it’s conceivable, in almost fifteen years of using these drugs in thousands of patients -- I’ve not seen it.   
In my opinion the risk/benefit ratio here is very favorable. 

## OTC Omeprazole Would Benefit Consumers

**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**

**Notes:**
In conclusion:  The best way to manage frequent heartburn is to prevent symptoms and taking a PPI is the best way to do that. Doctors know that, and that’s why doctors use PPIs for their patients with frequent heartburn. 

Certainly physicians have a role in the management of these patients, but that involvement does not have to be intensive. This is a common condition, and consumers who have it understand it.  They know when it’s appropriate to go to the doctor.  They can safely and effectively self-manage their own frequent heartburn symptoms, and I believe they should be empowered to do so.

The proposed dose and duration of therapy is appropriate, effective and consistent with current medical practice.

From my thirty years of clinical experience I know omeprazole is safe, and it works – and more importantly, so do my patients with frequent heartburn.

Thank you for your attention.

## Efficacy and Consumer Use

**Douglas Ws. Bierer, Ph.D.**
**Director, OTC Drug Development****Procter & Gamble**

**Notes:**
Good morning and thank you for the opportunity to present the results of our clinical efficacy and consumer behavior program that supports the use of omeprazole for the prevention of frequent heartburn symptoms.

## Efficacy and ConsumerBehavior Program

**Pivotal efficacy studies**
**Consumer understanding and behavior studies**
**Label comprehension**
**Appropriate OTC use**

**Notes:**
Our program consists of efficacy and consumer understanding and behaviour studies. 

First, pivotal efficacy studies that show omeprazole prevents the symptoms of frequent heartburn for 24 hours and over a 2 week dosing period. 

Second, consumer understanding and behaviour studies that show consumers understand the product label and use the product appropriately in a naturalistic OTC setting.  

Our entire program supports that the product is efficacious and that consumers will use omeprazole safely and according to label directions.

## 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 for****14 consecutive days**
**Endpoint**
**% subjects heartburn-free**
**% days heartburn-free**

**Notes:**
We conducted two well controlled efficacy trials in which we evaluated the efficacy of omeprazole–magnesium for the prevention of the symptoms of frequent heartburn over a 14 day period.  As you know, these studies were presented at our previous Advisory Committee meeting and they support our proposed dose and the dosing duration.

The study population included subjects who had heartburn symptoms two or more days a week and did not have prior physician diagnosis for GERD or erosive esophagitis. 

Subjects in the study were instructed to take one tablet every morning for 14 consecutive days. 

The endpoints that support our label directions are the percentage of subjects who were heartburn free after the first dose and the percentage of heartburn-free days over the 14 days of dosing.

Let’s look at the results of these studies.

## Percent of Subjects Heartburn Free For24 Hours: Time Course Over 14 Days 

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

**Notes:**
This slide shows the percentage of subjects who were heartburn free for the entire day, over 14 days of consecutive dosing. 
In both studies, we achieved our primary endpoint -- prevention of heartburn symptoms for 24 hours after the first dose of product. A higher percentage of subjects taking 20 mg omeprazole were heartburn free as compared to placebo.  

As can be seen from this graph, heartburn prevention increases over the first few days of dosing.  This is consistent with the pharmacology of the drug and this prevention effect remains consistently high over the 14 days of dosing. The effect is both clinically and statistically significant for both studies on day 1 , on day 14 and when analyzed across all 14 days.  

## Conclusion:  Efficacy Studies

**20 mg provides prevention of heartburn symptoms for 24 hours**
**Uses:****For the prevention of the symptoms of****frequent heartburn for 24 hours**
**Dose:****20 mg**
**Directions:****1 tablet in the morning for 14 consecutive days**

**Notes:**
In summary, our studies show that :
20 mg omeprazole provides clinical and statistical significance in the prevention of heartburn symptoms..  

These studies support our proposed OTC label indication for the prevention of symptoms of frequent heartburn for 24 hours. 

They also support our dose of 20 mg and the label directions to take one tablet in the morning for 14 consecutive days.  

Now let’s look at our consumer understanding and behavior program.

## 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 **

**Notes:**
For our OTC target audience of people with frequent heartburn, our program objectives were to demonstrate that consumers correctly self-selected this was a product they were willing to use, understood how to use the product,  and adhered to the product warnings.  

In our consumer understanding and behaviour program we conducted two types of studies:  Label comprehension and an actual use study to understand how the general population will use this product in an OTC setting. All of these studies met our objectives in that the vast majority of the people understood the product label, used the product appropriately and adhered to the warnings.

## Label Comprehension Study Design

**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 ****	****	****	**

**Notes:**
In our first label comprehension study, we recruited 684 subjects from 12 geographically and socio-economically diverse sites across the US.  The study population included: people with infrequent or no heartburn; people from our OTC target population with frequent heartburn; low literate people with frequent heartburn who had less than an 8th grade reading ability as measured by the REALM test which evaluates understanding of medical terminology; people with a potential drug-drug interaction; and finally, those who were pregnant or nursing.

In general, all five groups scored very well on label comprehension. Let’s take a closer look

## Label Comprehension Study ResultsWho Should Use the Product

**Infrequent/****No Heartburn**

**22%**

**78%****Chose Correctly**

**n=229**

**Notes:**
First, lets look at subjects with infrequent or no HB.  78% with infrequent or no heartburn correctly chose this was a product they should not use for episodic or acute heartburn of 1 day a week or less.  

## Label Comprehension Study ResultsWho Should Use the Product

**Frequent****Heartburn**

**1%**

**99%****Chose Correctly**

**n=200**

**Notes:**
99% with frequent heartburn correctly chose this was a product they could use. These data demonstrate high understanding of who should and should not use the product.  

We were also interested in low literate subjects’ comprehension of the label.

## Label Comprehension of Low LiteratePeople with Frequent Heartburn

**Frequent heartburn situations****	****79%**
**Infrequent heartburn situations****	****49%**

**% Correct**_** **_**Response****(n=162)**

**Notes:**
For this portion of the study, we gave each person in the low literate group descriptions of situations involving either frequent or infrequent heartburn and asked them whether they should use the product in these situations. In situations involving frequent heartburn, 79% answered correctly. In situations involving infrequent heartburn, 49% answered correctly. Initially these results concerned us, but as you will see later, in our Actual Use Study the low literate group score much higher for appropriate self-selection. 

Now let’s look at how well all subjects understood the dosing directions.

## Subjects Understood How to Usethe Product

**1 tablet per day****	****95%**
**Take for 14 consecutive days****	****91%**
**Contact healthcare professional ****before using beyond 14 days****	****92%**

**Notes:**
Here we found high comprehension of the label dosing directions.  Subjects clearly understood how much omeprazole to take, how often to take it, and to contact their healthcare professional before taking it more than 14 days.

We then looked at other circumstances which require healthcare provider involvement.

## Subjects Understood When Not toUse/Ask a Health Professional

**Drug-drug interactions****	**
**Generic + brand names****	****82%**
**Generic names alone****	****50%**
**Pregnant/nursing****	****91%**

**Notes:**
In our proposed label, we include a warning for people who may have symptoms that could be mistaken for, or occur with any heartburn of any severity.  These include chest pain, trouble swallowing food, frequent wheezing, unexplained weight loss. It is important to note that these symptoms are not related to the use of any kind of heartburn medication. Because these symptoms can be signs of more serious conditions, we advise people, in the label, to talk to their doctor about these symptoms, if they have not already done so. After testing several versions, we achieved labeling that was understood by 81% of people with these general warning signs. As you will see shortly in our Actual Use Study, people were compliant with this warning. 

Regarding drug-drug interactions, we found that people were much more likely to understand the nature of the drug-drug interaction when shown brand names in addition to generic drug names.  As you see, 82% responded correctly when shown both the brand name and the generic name, as opposed to 50% when shown just the generic name. Because of regulatory and policy considerations, we believe it’s most appropriate to discuss this labelling issue with the agency at a later date.

More than 90% of the pregnant or nursing women correctly selected that they shouldn’t use this product without consulting their doctor.
Now let’s look at our Actual Use Study.

## Actual Use Study:  Objectives

**Evaluate consumer use in naturalistic OTC setting**
**Correct self-selection**
**Appropriate use**
**Complied with label instructions**

**Notes:**
As you know, label comprehension studies indicate whether people understand what is written on the label.  But, what is even more important, is how people will use the product in a real world setting.  

Our actual use study had three major objectives:  To evaluate 
---whether consumers correctly self-selected  
---whether they used the product appropriately: to prevent the symptoms of frequent heartburn
---whether they complied with the label.  

In our Actual Use Study we found consumers correctly self-selected and used the product appropriately for prevention and used it  according to label directions.

## 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**

**Notes:**
We designed our Actual Use Study to mimic real world purchase experience using both traditional methods and some new features.  

The study was conducted at a mall kiosk that was freely accessible to subjects, rather than at a clinical site.  To ensure subjects were able to correctly self-select based on the product label alone, there were no health professionals on site. There was no contact with the subjects during the use portion of the study. And, as with any OTC medication, subjects were free to contact their own doctor at any time during the study. 

We also incorporated a couple of new features, designed to mimic real-world consumer purchase decisions. Subjects purchased the product at a realistic market price and they were free to return to the mall kiosk to buy additional product. We were also careful not to present barriers for repurchase. The kiosk was highly accessible, open during regular mall hours and was close to where the study subjects lived.  Subjects were told numerous times they could return to buy more product. 

Now let’s take a closer look at the study.  

## Study Phases

**Study Phases**

**Notes:**
We recruited subjects through local advertising and spontaneous mall intercept at 5 malls across the US. At the mall kiosk, subjects made a self-selection decision -- to determine whether this was a product they could use and also, whether they would be willing to purchase the product.  

Our product is intended to be used for a regimen of two weeks, and not to be used for more than 2 weeks unless directed by a doctor.  So, it was especially important to find out whether people would incorrectly use the product on an extended basis without physician involvement.

Therefore, we made the product available for a total of 8 weeks. During that period, people could have bought as much product as they wanted...and theoretically, they could have taken 4 courses of product.    

Four weeks after the use period, we contacted participants by telephone and asked whether their frequent heartburn returned and, if so, what they did about it.  

Before I describe the results of this study, let’s first look at the disposition of subjects.

## Disposition of Subjects

**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**

**Notes:**
We approached 5060 subjects at the mall and asked “Do you get heartburn?” Of these,  3809 said they did not get heartburn, were not interested in being interviewed, or the drug was not appropriate for them to use.

Of the 1251 people who said they could uses the product, 385 were not willing to buy the product, mostly because they were not interested in participating in a clinical study or they wanted to check with their doctor before taking a new medication.  866 people said that this was a product they could use, and they were willing to buy the product and participate in the study. 

This 866 constitutes our self-selection population since they not only identified omeprazole as a drug they could use, but they were also willing to buy it and use it.  When people are asked a hypothetical question: could you use this product, they may say yes.  But in the real world, the key differentiator is whether they will actually buy the product.    

Now let’s look at the demographics of of our self–selection population.

## Demographics of Self-Selection Population

_**Characteristic**_**	****	****	****	**
**	****Gender (% female) ****	****	****	****	****58%**
**	****Race **
**	****	****% Caucasian****	****	****	****	****68%**
**	****	****% African American****	****	****	****16%****	**
**	****	****% Hispanic****	****	****	****	****	****11%**
**	****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 medications****	****	****40%**
**	****	****	****	****	****	****	****	****n=866**

**Notes:**
Slightly more than half were women, 68% were Caucasian, and 16% were Black and 11% were Hispanic.  The average age was 48 years with a range of 18 to 91 years old and 8% had a low reading ability as measured by the REALM test of medical literacy.  

Importantly, 90% of the subjects who purchased product had frequent heartburn 2 or more days a week.  This indicates that the label is well understood by the intended OTC target population.

More than 90% of these people used OTC heartburn medications to control their symptoms and 40% reported using prescription medications.  

Now, let’s look at whether the people correctly self-selected.

## Results of Self-Selection 

**Correct self-selection of**_**all 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**

**Notes:**
As I will show you, 81% met all 6 self-selection criteria.

These criteria, as specified in our label are: heartburn 2 or more days a week, 18 years or older,  not allergic to omeprazole, not pregnant or nursing, no general warning signs and no drug-drug interactions as listed on the label.  

In order to correctly self-select for this trial, subjects had to meet all six selection criteria. That is, if they did not correctly answer any one of these criteria, there were counted as a self-selection failure.  Again, of the 866 people who said they could use this product and wanted to buy the product, 81% met all six self-selection criteria. 

When we looked specifically at the low literate people, we found that almost 70% met all six self-selection criteria.  

Now let’s look at the people who did not correctly self-select.

## People Who Did Not CorrectlySelf- Select

**	**
**< 18 years of age****	****3**
**Pregnant/nursing****	****    1**
**Allergic to omeprazole****	****   0**
**General warning signs****	****  82**
**Drug-drug interactions****	****    8**
**Infrequent heartburn****	****  86**

**Number**_**of Subjects**_

**n=866**

**Notes:**
Four subjects who incorrectly self selected weren’t allowed to buy the product.  Three of them were under 18 years of age, and another was pregnant.  There were no subjects allergic to omeprazole. 
However, we did allow subjects who were in the last three groups on this slide to purchase and use the product, even though these people we were counted as a self-selection failure.  This is consistent with the FDA’s guidance to include self-selection failures when the risk is minimal. 
There were 82 subjects who had not talked to their doctor before the study about a general warning sign listed on the label.We found that during the trial none of these subjects had a serious adverse event. 
There were 8 subjects who were taking a drug listed in the drug-drug interactions on the label. While these 8 subjects did not initially contact a doctor or pharmacist, we found that 5 of them did contact a doctor about concomitant use with omeprazole during  the study. Again, none had a serious adverse event.
Finally, there were 86 subjects who had infrequent heartburn.  Half of these people took the product in compliance with the 14 day regimen, and the other half took it sporadically, as you would expect of people with infrequent heartburn.  None exceeded 14 doses.
Now, let’s move to the use and repurchase phase of the study.

## Disposition of Subjects WhoPurchased Product

**Disposition of Subjects Who****Purchased Product**

**Agreed to Purchase Product**
**[Self-Selection Population]**
**n = 866**

**Withdrew****Consent****	****n = 4**
**Did Not Meet****Study Criteria****	****n = 8**

**No Diary**
**n = 96**

**Used Product and Returned Diary**
**[Use Population]**
**n = 758**

**Notes:**
Of the 866 subjects in our self-selection population, 96 people did not return a diary despite several contacts.  Four subjects withdrew consent and 8 were not allowed to purchase product.  This includes the 3 subjects who were under 18, the one pregnant woman, and 4 others who had participated in a previous use study with this product.  Importantly, 90% of our self-selection population, 758 people, used the product and returned a diary.

Our use directions call for taking 1 tablet per day.  Let’s look at whether people complied with this label direction.  

## Subjects Are Compliant WithDosing Directions

**No more than  ****1 tablet per dose****	****96%****	****99% **
**No more than ****1 tablet per day****	****91%****	****98%**

**Per Dosing**_** Occasion**_

_**Per Subject**_

**Notes:**
We found excellent compliance with the dosing directions. 96% of the subjects took no more than 1 tablet per dose and 91% of the subjects took only 1 tablet per day. Again, people clearly understood these label instructions.

One of our key questions was whether people with frequent heartburn would take the product as a regimen for 14 consecutive days.     

## Compliance With the 14-DayDosing Regimen

**Definition of compliance**
**80-100% of the product within****14 ****± 3 ****days**
**Physician consultation if exceeded 14 doses**

** ****(11-14 doses within 11-17 days)**

**Notes:**
In the protocol we defined compliance to the 14 day dosing regimen based on two criteria:
First, they had to take 80-100% of the product and take it for 14 plus or minus  3 days. This is a range of plus or minus 20%.  That is they had to take 11-14 doses within 11-17 days.  This criteria is similar to the industry convention of patients taking at least 80% of the medication in a clinical trial. It is also consistent with the long lasting pharmacology of the drug.

 Second, if subjects took more than 14 doses of product – that  is, they took even one more dose than 14 doses --  they had to consult their physician to be defined as compliant.

With this definition in mind, now let’s look at how people were compliant with the 14 day regimen.

## Compliance With the 14-DayDosing Regimen

**Compliance With the 14-Day****Dosing Regimen**

**79%****According****to label directions**

**Notes:**
This slide shows the compliance to the 14 day dosing regimen of all 758 subjects who used the product and returned a diary. 
79% of the people were compliant. That is, they took 11 – 14 doses in 11 to 17 days, or they contacted their doctor if they exceeded 14 doses. 64% took exactly 14 doses in 14 days. These data demonstrate high compliance with the dosing regimen of 14 consecutive days and use of the product for the prevention of frequent heartburn. 

9% took the right amount of drug (that is 11-14 doses) but over a longer period of time (more than 17 days).  
9% took fewer than 11 doses. As expected many of these people had infrequent heartburn.
Note, that none of these people -- this group of 18%. – took more than 14 doses.

Fewer than 1% took multiple daily doses of the product.  There were only 3 people and none exceeded 3 tablets/day. There were no significant AE’s

We found that only 3% of the subjects took more than 14 doses without healthcare professional contact. And it is important to note that 75% of these people had either talked to their doctor about their heartburn before the study began or soon after the study ended.

In summary, the label was clearly understood.  People understood they were to use the product for prevention of heartburn symptoms and they achieved high compliance with the dosing directions. 

Now, as I explained earlier, 4 weeks after the study ended, we wanted to find out whether people’s frequent heartburn returned and if so, what they were doing about it.

## Return of Frequent HeartburnFour Weeks After Trial

**Return of Frequent Heartburn****Four Weeks After Trial**

**Notes:**
We were able to follow up by phone with about 85% of the people who used the product and returned a diary.  

43% said their frequent heartburn had not returned.
Of those who said their frequent heartburn had returned.
8% were not taking any medication. 
22% reported taking only antacids.
9% were taking OTC H2RAs.
 3% were taking a combination of both antacids and H2RA’s.
Finally, 15% had returned to their previous Rx medication or started a new prescription. This physician involvement is consistent with the habits and practices of people with frequent heartburn.

## 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**

**Notes:**
So, our actual use study showed that consumers appropriately self-selected, they understood the label instructions, they   took the product on a regimen basis for the prevention of frequent heartburn and they used the product 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**

**Notes:**
In summary, our efficacy and consumer behaviour data supports the proposed product label:

The efficacy data supports:  
The indication: for the prevention of the symptoms of frequent heartburn for 24 hours
It supports our proposed dose:  20 mg
And it supports our dosing directions: take 1 tablet in the morning every day for 14 days

Our consumer understanding and behaviour program shows compliance with these use directions and generally adherence to label warnings when this product is used  in a naturalistic OTC setting.

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

**Notes:**
Thus, we have demonstrated that our proposed label, the efficacy data and the consumer’s ability to understand and use this product safely and appropriately are all congruent!!!!!!

## OTC OmeprazoleUpdate on Safety

**Doug Levine, M.D.**
**Chief Medical Officer****AstraZeneca LP**

**Notes:**
Thank you, and good morning. I would like to present a perspective on safety issues related to OTC omeprazole.

## 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**

**Notes:**
One type of safety consideration is product safety ...

... which is defined as adverse events occurring in relation to product use during the short or long term.

Omeprazole has an excellent safety profile. The product-related adverse event profile is very well-established, based on data from clinical trials with the Rx product, Rx post-marketing surveillance, and the OTC clinical trials.

This profile of omeprazole makes it acceptable for OTC use.

## 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)**

**Notes:**
The use of OTC omeprazole ...

... is intended to be short term, as per the proposed label instructions.

However, if unintended long-term OTC use were to occur without medical supervision, the product adverse event profile for this situation is considered acceptable, based on extensive experience with omeprazole in the Rx setting.

## 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**

**Notes:**
Another type of safety consideration would include ...

... potential consequences of consumer behavior involving long-term use of the product without medical supervision, but such consequences would not be directly linked to omeprazole.

This type of safety issue involves considerations of medical diseases other than acid reflux disease ...

... as well as of the natural history of acid reflux induced esophageal damage, which is not completely understood from an epidemiologic perspective.

Again, the sequelae of these diseases are 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**

**Notes:**
First, use of the OTC product for alarm symptoms would most likely be self-limiting because these symptoms would not be expected to subside with omeprazole use.

The proposed label instructs NOT to use the product and to seek medical attention if these symptoms are present.

## 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**

**Notes:**
However, there are a variety of conditions with symptoms that could ...

... respond to OTC omeprazole, and might lead to some consumer behavior involving long-term use without seeking medical supervision (despite label instructions).

The most common, non-neoplastic upper GI conditions resulting from acid-peptic injury would be well-managed with chronic omeprazole therapy, with little chance of adverse consequences.

However, it is important to address medical diseases that include either overt malignancy ...

... or conditions that predispose to malignancy of the upper GI tract.

## 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**

**Notes:**
Individuals ...

... with a malignancy of the esophagus or of the stomach might have frequent heartburn.

However, such tumors more typically produce different symptoms, such as dysphagia, nausea, vomiting, early satiety, and weight loss, which do not respond to treatment with omeprazole and would likely lead to seeking of medical attention.

Unfortunately, these types of tumors are commonly diagnosed as part of initial presentations for medical care, suggesting that they commonly evolve without producing significant heartburn or other symptoms during their precancerous stages.

Additionally, in endoscopic survey studies of individuals with heartburn, cancer of the esophagus or stomach is rarely identified.

## 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  **

**Notes:**
Another area of concern ...
... is a condition associated with cancer risk.

Barrett’s esophagus is a complication of chronic acid reflux disease with resulting esophageal damage.

While Barrett’s esophagus is common, its progression to esophageal adenocarcinoma is rare.

It is, in fact, the inconsistent correlation between frequent heartburn and the presence of Barrett’s, plus the rarity of progression from Barrett’s to esophageal cancer that makes it difficult for the medical community to manage this risk. If desired by the advisory committee, we can provide additional data on this topic during the question and answer period.

In the context of OTC treatment of heartburn, available data show that omeprazole is a neutral factor – it does not increase cancer risk ...

... and it does not reliably induce regression of Barrett’s esophagus.

## Heartburn and Esophageal Cancer

**Increasing incidence of esophageal adenocarcinoma is not related to****acid 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**

**Notes:**
To summarize the current situation on heartburn and esophageal adenocarcinoma:

 The increasing incidence of esophageal adenocarcinoma in the US since the 1970s is not related to acid reducers
     but research continues to evaluate many other factors that may contribute to this.
 Patients afflicted with esophageal adenocarcinoma generally present without a prior history of heartburn or a prior diagnosis of Barrett’s esophagus
 The status of esophageal adenocarcinoma in 2002 is as medically challenging as it is sobering. Presently, the incidence rate for esophageal adenocarcinoma is about the same as the mortality rate, reflecting the fact that these cancers are discovered at late, incurable stages, without antecedent clinical “signals” that might lead to diagnosis of earlier stage cancers or precancerous lesions.
 There is no evidence to suggest that acid reducers are masking such “signals.”
Fortunately, the development of this cancer is rare among individuals with heartburn, or among those with documented Barrett’s esophagus
 Omeprazole, specifically, does not increase the risk of this cancer

## 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**

**Notes:**
In conclusion, I have tried to frame today’s discussions on safety related to OTC omeprazole use.

The product-related safety profile of omeprazole is acceptable for OTC use.

The natural history of acid reflux damage to the esophagus can involve rare, serious consequences, however ...

Omeprazole does not directly increase the risk of esophageal adenocarcinoma.

Based on the overall safety considerations I have presented today, omeprazole is acceptable for OTC use

Thank you for your attention to my remarks.

## Benefit/Risk Assessment of Omeprazole in the OTC Market

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

**Notes:**

Good morning.. And thank you Dr. Levine.  Building on both Dr. Levine’s and Dr. Peura’s  comments and the data presented by Dr. Bierer, I am going to address in more depth, the question of whether long term use of omeprazole without physician involvement is acceptable.

In order to do this, I will consider three key factors important to the benefit/risk assessment.

## Considerations of Chronic Use of Omeprazole Without Physician Involvement 

**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?**

**Notes:**

These three key factors are:

First we’ll look at data that provides insight into what people do now and what they might do in the future; specifically addressing what proportion of consumers might use the product on a more regular basis.

Then I will discuss data that examines physician involvement by people with FHB and specifically address the concern that once omeprazole is available people with HB won’t seek physician counsel about their condition.

and finally I will recap the issue of potential risks and discuss the known benefits that might result for consumers who use this product even without physician oversight. 

Before we can discuss how often consumers might use OTC omeprazole in the future it is worth looking at how people use it now.  Let’s start with the 40,000 foot view by looking at a very large administrative claims database of prescription drug use.  

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

**NDC Prescription Database:  PPI Use**

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

**20.7**

**6+**

**4.4**

**5**

**6.2**

**4**

**9.0**

**3**

**15.4**

**2**

**44.3**

**1**

_**Patients (%)**_

_**Rx Dispensed/Year**_

**Notes:**

We conducted an analysis of the NDC Database, which collects and analyzes the prescription data from multiple managed care organizations,  covering million of lives.  We examined the drug records of almost 100,000 people who were prescribed a Ppi for the first time in January of 2001 and then we followed whether they had any further omeprazole dispensed over the next year.
These data represent people who had HB symptoms that were significant enough that they contacted a physician and prescribed a Ppi.  Logically, this would not be a population of people with episodic HB.

As you can see, almost 1⁄2 of the people were dispensed only one treatment course over the year.
At the other end of the range of use, about 20% of these people took 6 or more treatment courses in the year.  Looked at from this perspective, chronic users  are those people taking the drug on more days than not over the year. Chances are that these same people will continue with this pattern of chronic use.
So that is the big picture of omeprazole use.  
Let’s look a little further into understanding how this drug is used within a population specifically diagnosed as having GERD.

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

**Bardhan Study Design**

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

**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 self****managed additional courses of therapy **

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

**Notes:**

This study, published by Bardhan was a randomized clinical trial in which people with symptomatic frequent heartburn were evaluated on how often they required omeprazole to manage their symptoms.  The reason I selected this particular study to discuss, is that this study captures the use-decision behavior we would expect to see in the OTC setting, the patients decided if and when they needed more drug in response to their symptoms. 
The most relevant group for our discussion was those individuals who took an initial course of 20 mg omeprazole for 14 days.  They then self-managed their frequent heartburn by requesting additional courses of therapy throughout the year if and when their FHB symptoms returned.  

Now, let’s look at the results.

(NORA NOTES. . .NOT TO BE DELIVERED)
( Moderate heartburn was described as discomfort sufficient to interfere with usual activities. Severe heartburn was defined has heartburn that left people unable to perform normal activities. HB for more than 2 days in each of the previous 2 weeks.) 
(relapse defined as the return of moderate or severe FHB)

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

**Bardhan Study Results**

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

**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**

**Notes:**
Of the 704 patients who were randomized, there were 526 in whom final outcome was available.
Bardhan found that 72% of these individuals were able to self-manage their FHB symptoms by taking additional 14 day regimens of omeprazole intermittently.

Of this group, 68% requested 3 or fewer treatment courses over the year. To put that in perspective, this is only 42 days of therapy in one year.  This pattern of use is quite similar to what we saw in the NDC prescription database, where we saw a about 70% of drug use being 3 or fewer treatment courses a year.

Bardhan found that symptom control after two weeks of therapy was a powerful prognostic indicator of future need for therapy, with about 30% of the subjects requiring no further therapy during the year if they had a good response to that first 14 days of therapy.

Only 28% of the study participants had ongoing symptoms which required maintenance therapy at some point during the year.

Let’s compare these data with what we saw in our Actual Use Trial.

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

**Actual Use Trial Results**

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

**Notes:**

Remember, in our Actual Use Study we found that very few people took more than the 14 day regimen  of omeprazole. In fact, well over 90% of the participants purchased only one box of 14 day omeprazole during the 2 months the product was available. 

And when we contacted them three months after they entered the study, 43% of consumers reported that their FHB did not return.
42% stated that they were having FHB, but over half of them had elected to manage their symptoms with antacids.
15% of the participants were taking a prescription therapy;  with half of them going back to what they had been taking prior to the study and the other half went to see a physician and most of them were prescribed a PPI.

So after 3 months of observation, we found that very few people had used more than one, 14-day regimen, of the OTC omeprazole when they had the opportunity to purchase it .

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

**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 more****14 day regimens**

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

**Notes:**
In summary, in answering my first question,  you can look across these diverse types of data, and see that even in the prescription setting, it is clear that there is a range of use of PPIs which undoubtedly reflects the range of symptoms with only about 20 to 25 % of the use being chronic.  So most people don’t use omeprazole chronically.

Note to NLZ:
47-Rx
54 – Rx and MD
15 – FHB not return 3 mos. But > 14 days
12 – FHB did return and didn’t go to doc or take Rx
128/649 = 19%

## 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??**
**Do consumers with FHB go to their physicians? Will OTC omeprazole change that?**
**What benefits and risks might result from use without physician involvement?**

**Considerations of OTC Chronic Use of Omeprazole Without Physician Involvement**

**Notes:**

So, returning to the consideration of  chronic use without physician involvement, we need to ask – will these people who may use omeprazole chronically see a physician?
The literature and our Actual Use study show that they will.

To begin it is helpful to review what we know about how often people with HB talk with their physician about their condition.

## Do Consumers With FHB Go toTheir Physicians?

**Oliveria Study Design**

**Do Consumers With FHB Go to****Their Physicians?**

**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**

**Notes:**
 In a very comprehensive study published by Oliveria who was at Cornell University at the time, more than 2000 people with HB were surveyed.  The study was designed to capture people’s understanding of HB, assess how they managed their symptoms, and how often they consulted with their physician. 

## Do Consumers With FHB Go toTheir Physicians? 

**Oliveria Study Results**

**Do Consumers With FHB Go to****Their Physicians? **

**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**

**Notes:**

More than 90% of these people were taking therapy – with 75% taking OTC medications.  

In regard to physician involvement, what the researchers found was logical:  The more frequent and severe peoples’ symptoms, the more likely they were to see their doctors.  In fact, people with the most frequent heartburn were 4 times more likely to see their physician than those who had heartburn less than twice a week, with 78% of the people with FHB having discussed their HB with their physician.

This is reassuring data and is typical of what is found in the literature in general.  But relative to our discussion today is whether Omeprazole’s availability in the OTC market will change this consumer behavior.  

The recent move of H2RAs to OTC status in the mid 1990s provides a historical perspective on this question.

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

**OTC H****2****RA’s Effect on Physician Visits**

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

**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**

**Notes:**

Let’s look at three studies that specifically examined what happened to physician visits when the H2RAs became available over the  counter.

This is a relevant comparison because even though the H2RAs were switched at half the prescription dose,  the introduction of H2RAs into into a world that only had OTC antacids was a meaningful therapeutic jump. 

For perspective, a study by Simon and colleagues published in the American Journal of Therapeutics in 1995, stated that 70% of the subjects who obtained only some degree relief using antacids, claimed that they experienced complete relief of symptomatic episodes of HB using H2RA in the OTC dose.  Yet as you will see there was no negative consequence relative to physician visits for HB.

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

**Fallon Community Healthcare System****Pre & Post OTC H****2****RA**

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

**0.67**

**0.72**

**GERD-related clinic visits/yr (mean)**

_**7/95-7/96**_

_**7/94-7/95**_

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

**Notes:**

Here are the data from the Andrade study of 2000 patients in the Fallon Community Healthcare system who had a GERD-related diagnosis and were receiving a prescription medication in 1994.  The yearly number of clinic visits in those patients with a GERD-related diagnosis was unchanged comparing before and after the switch with an average of just under one visit/year for these people.

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

**Minneapolis Cross-Sectional Survey:****Physician Visits in Past Year**

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

**23.5**

**22.0**

**Dyspepsia**

**21.9**

**23.6**

**Heartburn**

**1997**
**(n=1238)**
**%**

**1993**
**(n=1141)**
**%**

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

**Notes:**
Shaw published a study which was a cross sectional survey of adults in Minneapolis in 1993 (pre-switch) and again in 1997 (after the switches).  Within this general population, the percent of people who went to the physician with complaints of dyspepsia or heartburn did not change when H2RAs became available.  

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

**MEDSTAT Marketscan Data Base****1995-1998**

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

**2.12**

**2.00**

**2.04**

**0.16**

**0.18**

**0.16**

**0.14**

**UGI****Endoscopy****(% of pop)**

**1998**

**1997**

**1996**

**1995**

**2.09**

**Visits/UGI****Dx Code (mean)**

**Notes:**
Finally, we conducted a study examining the MEDSTAT Marketscan database of administrative claims that covers million of lives. Looking at the  people who had continuous coverage during the period before and after the switch of H2RAs, the percent of people undergoing endoscopy was not changed and the mean number of visits for acid-related diseases was constant with a mean of 2 visits/year.

So from these three studies we found that there was no evidence that potent acid reducing drugs kept people from seeking physician care.

So the question for today is...would OME be different.  For that we can look at our Actual Use Trial.  What was the behavior of these participants who had OME available to them without a prescription?

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

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

**Rate of physician consultation for heartburn doubled during the study**
**20% contacted a doctor for the first time about their heartburn during****the study **
**53% of people taking more than****14 doses, talked to their physician during or just after the study**

**Actual Use Trial Results**

**Notes:**
When we looked at physician contact in the study during the period of our trial, we found that on average, that the monthly rate of physician visits actually rose during the trial. The rate of physician contact per month was twice that what is was in the year prior.
This was in part due to the encouraging behavior of two important groups of individuals.
1) We were pleased to see that 20% of the potentially hard-to-reach group, those who had never before seen a doctor for their heartburn opted to consult a physician about their heartburn for the first time. 
2) And importantly, over 50% of those individuals who took more than one 14 day regimen were in contact with their physician during the study or had an appointment already scheduled when we spoke with them at the 3 month follow-up.

We were very encouraged by this behavior and believe this increased physician contact was driven, in part, by the label and package insert.

(Notes for Nora – not to be delivered)
48% in 12 mos.  26% in 3 mos.  Rate went from 4 to 8contacts/mo.
265 had never talked to a doctor, 54 went the first time. 85% of the subjects who took more than 14 doses had either consulted their physician during the study about their heartburn or had done so in the past year.  (NOTE 14/34 or 41% actually during the study)

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

**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 H****2****RA’s were available OTC**
**The Actual Use Trial suggests that physician visits will not decrease and may increase****with OTC omeprazole**

**Notes:**
So, from the published literature and the results of our Actual Use Study we see a consistent picture.

--The majority of people with frequent heartburn see their doctor for their symptoms. 
--People also continued to see their physicians after the H2RA’s became available over the counter.  
The label we have proposed for OTC Omeprazole encourages people to go to their doctor and  we believe that’s an important point, because in our Actual Use trial we saw the rate of physician visits actually increase.  Consequently, physician visits should not decrease and could in fact increase when OME is available OTC.

## 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?**
**Do consumers with FHB go to their physicians? Will OTC omeprazole****change that?**
**What benefits and risks might result from use without physician involvement?**

**Considerations of OTC Chronic Use of Omeprazole Without Physician Involvement**

**Notes:**

While the data we just reviewed is reassuring, in that most people who choose to use OME will not do so chronically and those who do use it chronically are the people who are most likely to seek physician involvement.  What about those who will use the product on a more chronic basis and chose not to discuss their HB with a physician.  What are the risks and benefits for these consumers?

## Considerations of OTC Chronic Use of Omeprazole Without Physician Involvement

**Considerations of OTC Chronic Use of Omeprazole Without Physician Involvement**

**The label is clear - see physician if FHB returns**
**OTC omeprazole a better option than current OTC therapies**

**Benefit to User**

**Notes:**
While, our position is very clear and the label advocates physician involvement, for those individuals who will not seek physician involvement, omeprazole is a better option for FHB than current OTC therapies and as Dr Levine discussed the risks are minimal . 

In considering this population who might choose to use the drug chronically without physician intervention,  the majority of these people will have non-erosive disease – for these individuals, symptoms will be well-managed with little chance of adverse consequences.  However, it is clear that the some of these people could have some degree of erosive disease.  Consequently, it is important to examine the potential benefit for this population. 
Studies published in the literature have clearly shown that PPI’s provide better healing of mucosal injury compared to other therapies. 
Let’s look at some of that data, relative to esophageal healing 

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

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

**Notes:**
This graph is from a Meta analysis published by Chiba.  This analysis compiled the results of studies monitoring the time course of  healing of grade II-IV erosive esophagitis comparing Ppi to H2RA.  
The top line with the greatest effect is Ppi, the middle is H2RA and the lower line is placebo.  There are 2 points I want to emphasize from this data: the PPIs healed a similar percentage of patients at 2 weeks compared to H2RAs healing at 12 weeks and that the majority of healing occurs by the 2nd week of dosing with a PPI. People who are not healed at two weeks experience only a modest benefit from an additional two weeks of therapy.

This data clearly shows that for those few people who have erosive esophagitis and who choose not to see their physician, a 14 day regimen of omeprazole is going to be a much better option for them compared to any other medication they would take OTC. 

## Considerations of OTC Chronic Use of Omeprazole Without Physician Involvement

**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**

**Notes:**
So in summary, we believe the data in the literature, our analysis of large databases,  and our Actual Use Trial support that...

The majority of consumers will not use the product chronically
Those consumers who may choose to use the product on a more frequent basis will be in contact with their physician and  
Considering what we heard from Dr. Peura and Dr. Levine, the potential for risk with chronic dosing is minimal
while the known 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**

**Notes:**
I would like to summarize what you have heard here today.
You have heard that Omeprazole will fill a critical gap in the OTC options for those people who suffer from frequent heartburn and who currently have no OTC therapy to prevent their symptoms.  Omeprazole is ideally suited to meet the needs of these people for effective prevention of heartburn symptoms for 24 hours.
From Dr. Peura, you heard that OTC omeprazole fits into current medical practice and will be a safe and effective medication  over-the-counter.

We have identified the right target population for OTC omeprazole, as requested by the last advisory committee.  This target population is those people with frequent heartburn.  This is the population that will benefit most from omeprazole and it is the target population in our pivotal clinical studies.

We have shown you that the proposed label provides clear instructions for use.  The Actual Use study demonstrated that this label is understood by consumers and that they appropriately self selected and used the product. The study also demonstrated that consumers who had a recurrence of heartburn symptoms responded appropriately.  

This label is congruent with our proposed use of omeprazole. It brings the right  target population and  the right indication for OTC omeprazole together with clear use instructions and a set of clear directions for physician involvement when appropriate.

You heard that OTC omeprazole should be labeled for a 14 day regimen of therapy.  Our efficacy trials and actual use studied showed that people received maximum benefit within 14 days and understood and complied with this label.  14 days is a conservative application of clinical guidelines.  It also represents an appropriate period of OTC use, after which a person should contact a doctor if symptoms continue or return.

You also heard that 14 days provides healing to most of that fraction of the target population who may have erosive esophagitis. For all of these reasons the OTC label should not specify a longer treatment regimen.

You have heard that some people may use OTC omeprazole on an ongoing basis, without seeing their doctor. Some of these individuals may have GERD or erosive esophagitis. They will be receiving a more beneficial therapy than any medication that is available today over the counter, and that any potential risks will be outweighed by these known benefits.

## Conclusion

**Omeprazole can be safely and effectively used OTC**

**Notes:**
In conclusion, omeprazole can be safely and effectively used OTC.

## Slide 81