# Presentation: 657320

## Orlistat OTC

**Joint Endocrinologic and Metabolic Drugs – Nonprescription Drugs Advisory Committee Meeting**

## Orlistat for Over-the-Counter Use

**Orlistat for ****Over-the-Counter Use**

**John Dent, PhD****GlaxoSmithKline**

## Unmet Need – American Health CrisisOTC Target Population

**64% overweight****1**
**$100 billion annual healthcare cost****2**
**34% trying to lose weight****3 **

- 1.	National Center for Health Statistics (CDC), National Health and Nutrition Examination Survey.
- 2.	U.S. Food and Drug Administration Working Group on Obesity. “Counting Calories.”3.	Mintel Weight Loss U.S. Report, April 2005.

## Orlistat Promotes Gradual, Sensible Weight Loss

**Not a “magic pill”**
**Targets people committed to losing weight**
**Different from any other weight loss drug**
**Works best with low-fat diet**
**Consistent with NIH recommendations**

## Orlistat Development History

**April 1983****	****Molecule synthesized**
**Early 1998****	****Launched in New Zealand ****	****and Argentina**
**Sept. 1998****	****Launched in EU**
**April 1999****	****Approved in United States**
**June 2001****	****Roche begins OTC ****	****development**
**April 2003****	****Roche conducts AUT**
**July 2004****	****GSK licenses rights to ****	****OTC orlistat****	**

## Orlistat Has Extensive Clinical & Post-Marketing History

**More than 100 clinical studies**
**30,000 clinical trial patients**
**Data in up to 4 years of treatment**
**22 million people used orlistat **
**Available in more than 145 countries**

## Label: OTC Orlistat

**Target User: Overweight adults **
**Dose: 60 mg**
**Directions: 1-2 capsules 3X a day****with meals containing fat**
**Indication: Weight loss**
**Duration: Up to 6 months**

## Consumer Understanding of Overweight 

**Overweight defined as BMI between 25-29.9**
**Obesity defined as BMI ********30**
**Consumers can’t calculate BMI**
**Clinically obese consider themselves overweight **

## “The OTC population can include a wide range of BMIs ranging from slightly overweight to obese.”

- FDA Minutes, Pre-NDA Meeting December 8, 2004

## Orlistat Development Program

**Iterative process informed label development**
**Warning statements improved**
**Key communications stayed the same**

## More Than a Pill... a Program

**In-pack educational materials**
**Tailored, Web-based support program**

## GSK Success with Behavioral Therapies

**1996 nicotine replacement therapy (NRT) switch**
**Support program proven to enhance quit rates**
**Successful program to manage potential risks **

## Agenda

**Public Health Rationale****	****Caroline Apovian, MD****	***Assoc. Professor of Medicine/Pediatrics**	**Boston University School of Medicine*
**Safety & Efficacy****	****Vidhu Bansal, PharmD**** ****	***Director of Medical Affairs**	**GlaxoSmithKline*
**Consumer Behavior****	****Saul Shiffman, PhD****	***Professor of Health Psychology**	**University of Pittsburgh*
**Consumer Education****	****Steve Burton****	***Vice-President of Weight Control**	**GlaxoSmithKline*
**Summary & Commitments****	****John Dent, PhD****	***Sr. Vice-President CHRD**	**GlaxoSmithKline*

## Expert Consultants

**Joel S. Bennett, MD ****(Hematology)**
*Physician and Professor of Medicine*
*Division of Hematology-Oncology, University of Pennsylvania Hospital*
**Gary D. Foster, PhD ****(Weight Loss)**
*Clinical Director of the Weight and Eating Disorders Program*
*University of Pennsylvania School of Medicine*
**Marsha D. Marcus, PhD ****(Eating Disorders)**
*Chief of Eating Disorders and Behavioral Medicine*
*Western Psychiatric Institute & Clinic, University of Pittsburgh Medical Center*
**Ron Shapiro, MD ****(Transplant)**
*Professor of Surgery, Director, Kidney, Pancreas, Islet Transplantation*
*Thomas E. Starzl Transplantation Institute,University of Pittsburgh School of Medicine*
**Holly R. Wyatt, MD ****(Obesity/Metabolism)**
*National Program Director for the Centers for Obesity Research and Education**Denver, Colorado*

## The Public Health Need forFDA-Approved Weight Loss Tools

** ****Caroline Apovian, MD**
**Associate Professor of Medicine & Pediatrics, ****Boston University School of Medicine**
**Director, Center for Nutrition & Weight Management, ****Boston Medical Center**
**Co-Principal, New England Centers for Obesity Research & Education**
**Vice Chair, Massachusetts Medical Society Committee on Nutrition**

**The Public Health Need for****FDA-Approved Weight Loss Tools**

## Prevalence of Overweight and Obesity Among US Adults, Age 20-74 Years

**JO Hill, HR Wyatt, GW Reed, JC Peters, Obesity and the****Environment: Where do we go from here? *****Science***** 299:853-855 (2003).**

## Risk of Developing Obesity Higher Than Previously Thought

**Data are for people free of obesity at baseline.**
**Vasan RS et al. *****Ann Intern Med*****. 2005;143:473-80.**

**10**

**20**

**30**

**0**

**Years**

**Adjusted cumulative incidence, % obesity**

**0**

**10**

**20**

**30**

**40**

**Men**

**10**

**20**

**30**

**0**

**Years**

**0**

**10**

**20**

**30**

**40**

**Women**

**Age 40-44 y**

**Age 50-54 y**

## Low Levels of Overweight AssociatedWith Negative Health Consequences

- Low Levels of Overweight AssociatedWith Negative Health Consequences

**Women**

**Men**

**Body Mass Index (kg/m****2****)**

**Body Mass Index (kg/m****2****)**

**Relative Risk**

**Relative Risk**

**Willett WC, et al.***** N Engl J Med. *****1999;341:427– 434.**

## Even Small Weight Losses Have Positive Impact on Risk Factors

**HbA1c**

**HDL cholesterol**

**Blood pressure**

**Triglycerides**

**Total cholesterol**

** ****5%-10% ****Weight Loss**

**~****5% ****Weight Loss**

**1. Wing RR et al. *****Arch Intern Med*****. 1987;147:1749-1753.**
**2. Mertens IL, Van Gaal LF. *****Obes Res*****. 2000;8:270-278.**
**3. Blackburn G. *****Obes Res*****. 1995;3(Suppl 2):211S-216S.**
**4. Ditschunheit HH et al. *****Eur J Clin Nutr*****. 2002;56:264-270.**

**1**

**2**

**3**

**3**

**--**

**1**

**2**

**3**

**3**

**4**

## Every 1 kg of Weight Loss Can Provide Improvements in Risk Factors

|  | Change per kilogram of weight loss |  |
| --- | --- | --- |
|  | Mean |  |
| Measure | % change |  |
| Cholesterol1 | -0.99 | -2.28 mg/dL |
| LDL cholesterol1 | -0.68 | -0.91 mg/dL |
| Triglycerides1 | -1.93 | -1.54 mg/dL |
| HDL cholesterol1 | 0.15 | 0.07 mg/dL |
| Systolic blood pressure*2 | -0.49 | -0.68 mm Hg |
| Diastolic blood pressure†2 | -0.38 | -0.34 mm Hg |

*** Baseline systolic blood pressure = 140 mm Hg.****† Baseline diastolic blood pressure = 90 mm Hg.**

**1. Dattilo AM, Kris-Etherton PM. *****AM J Clin Nutr.***** 1992;56:320-8.**
**2. MacMahon SW, Cutler J, Brittain E, Higgins M. *****Eur Heart J.***** 1987;8:57-70.**

## Modest Weight Loss ImprovesQuality of Life Co-Morbidities

**Sleep apnea****1**
**Osteoarthritis****2**
**GERD****3**
**Back pain****4**
**Infertility****5**
**Urinary incontinence****5,6**

**1. ****Grassi G, Facchini A, Trevano FQ et al. *****Hypertension***** 2005;46:321-5.**
**2. Focht BC, Rejeski WJ, Ambrosius WT, Katula JA, Messier SP. *****Arthritis Rheum*****. 2005;53:659-65.**
**3. Hampel H, Abraham NS, El Serag HB. *****Ann Intern Med*****. 2005;143:199-211.**
**4. Liuke M, Solovieva S, Lamminen A et al. *****Int J Obes (Lond)***** 2005;29:903-8.**
**5. Villareal DT, Apovian CM, Kushner RF, Klein S. *****Obes Res*****. 2005;13:1849-63.**
**6. Dwyer PL, Lee ET, Hay DM. *****Br J Obstet Gynaecol*****. 1988;95:91-6.**

## Even Small Amounts ofWeight Can Be Difficult to Lose 

**Staying motivated is a challenge**
**Frustration can lead to giving up**
**Result can be further weight gain, obesity ****and co-morbidities**

## Most Overweight People Don’t See Physicians For Weight Management

**People may be embarrassed to discuss overweight with doctor**
**Weight management often not covered****by insurance**
**Many people can’t afford doctor visits**
**In general, doctors not accustomed to counseling patients on weight management **

## U.S. Consumers Spend $1 Billion/YearOn Weight Control Drugs and Supplements 

**Source: Ipsos-Insight PharmTrends Report, 2004**

**$1 Billion Spent Annually**

**Herbal & ****Dietary****Supplements**
**(DSHEA products)**

**Rx Weight****Control**

**10%**

**90%**

## The Lure of Unproven“Weight Loss” Supplements

- The Lure of Unproven“Weight Loss” Supplements

## Summary and Conclusion

**Overweight / obesity a growing epidemic**
**Modest weight loss provides important benefits**
**People rely on unproven non-prescription products**
**We need a wide variety of FDA-approved prescription and OTC weight loss tools **

## Safety and Efficacy Orlistat 60-120 mg 

**Vidhu Bansal, PharmD****Director, Medical Affairs ****GlaxoSmithKline **

## Agenda

**Overview**
**Efficacy**
**Mechanism of action**
**Efficacy of 120 mg dose**
**Efficacy of 60 mg dose**
**Improvements in risk factors**
**Safety**
**Tolerability**
**Abuse/misuse**
**Drug interactions**
**Conclusions**

## 60 mg Dose Meets Weight Loss Criterion

**Orlistat 120 mg Rx dose FDA-approved in ****1999 based on weight loss criterion**
**Significantly greater proportion of subjects on ****60 mg treatment achieved a 5% weight loss after one year, compared to placebo**
**60 mg also meets this criterion at both****6 months and 1 year**

## Orlistat: A Unique Mechanism of Action

- Orlistat: A Unique Mechanism of Action

******Monoglycerides**

**Small intestine wall**

******Fatty acids**

## Orlistat Mechanism of ActionProvides Unique Benefits 

**Non-systemic acting**
**Non-CNS acting**
**Non-addictive**
**No negative impact on cardiovascular system**
**Minimally absorbed**
**No residual effect**

## Orlistat Dose-Response Curve

**% fecal fat excretion**

**Orlistat dose (mg) tid**

**30**

**120**

**240**

**400**

**60**

**60**

**50**

**40**

**30**

**20**
**10**
**0**

**Zhi J et al. *****Clin Pharmacol Ther***** 1994; 56: 82–85.**

## 60 mg Ideal Starting Dose for OTCStudy BM14150 – Dose Ranging Study

**6 month randomized, double-blind, placebo-controlled, multi-center, confirmatory dose ranging study **
**Weight Loss Results:**** **
**Orlistat 60 mg is minimum effective dose**

| Dose tid | N | Placebo-Subtracted Weight Loss (kg) SE | P-value Active vs. Placebo |
| --- | --- | --- | --- |
| 30 mg | 122 | - 0.95  0.59 | p=0.106 |
| 60 mg | 123 | - 1.86  0.59  | p=0.002 |
| 120 mg | 120 | - 2.55  0.60  | p<0.001 |

## Orlistat 60 mg Controlled Clinical Studies

| Study # | Location | NITT | Duration | BMI | Dose |
| --- | --- | --- | --- | --- | --- |
| BM14149 | Europe | 716 | 2 years | 28-43 | Plc, 60, 120 mg |
| NM14161 | U.S. | 635 | 2 years | 30-43 | Plc, 60, 120 mg |
| NM17247 | U.S. | 378 | 4 months | 25-28 | Plc, 60 mg |
|  | Total | 1,729 |  | 25-43 | Plc, 60, 120 mg |

## Low Level of Interventionin Controlled Studies

| Study # | Dietary Instructions and Intervention | Behavioral Modification | Exercise |
| --- | --- | --- | --- |
| BM14149 | Counseling by dietitians 1X/month for first year |  None | Subjects advised to exercise |
| NM14161 | AHA adapted diet sheets | Subjects were offered 4 videos for viewing on their own  | No formal  counseling; subjects encouraged to walk more |
| NM17247 | Self-instructional materials  | Self-instructional materials | Reading materials on exercise  |

## Low Level of Interventionin Controlled Studies

| Study # | Dietary Instructions and Intervention | Behavioral Modification | Exercise |
| --- | --- | --- | --- |
| BM14149 | Counseling by dietitians 1X/month for first year |  None | Subjects advised to exercise |
| NM14161 | AHA adapted diet sheets | Subjects were offered 4 videos for viewing on their own  | No formal  counseling; subjects encouraged to walk more |
| NM17247 | Self-instructional materials  | Self-instructional materials | Reading materials on exercise  |

## Low Level of Interventionin Controlled Studies

| Study # | Dietary Instructions and Intervention | Behavioral Modification | Exercise |
| --- | --- | --- | --- |
| BM14149 | Counseling by dietitians 1X/month for first year |  None | Subjects advised to exercise |
| NM14161 | AHA adapted diet sheets | Subjects were offered 4 videos for viewing on their own  | No formal  counseling; subjects encouraged to walk more |
| NM17247 | Self-instructional materials  | Self-instructional materials | Reading materials on exercise  |

## Design of Two Well-Controlled StudiesStudies NM14161 and BM14149

- Design of Two Well-Controlled StudiesStudies NM14161 and BM14149

**Placebo **

**Single-blind dietary **
**lead-in period **

**Double-blind randomized ****treatment period**

**- 4 weeks**

**0**

**52 weeks**

**Orlistat 120 mg tid **

**Orlistat 60 mg tid **

**Placebo**

**Hypocaloric Diet**

## Orlistat + Diet Significantly More Weight Loss Than Placebo + Diet (BM14149)

- Orlistat + Diet Significantly More Weight Loss Than Placebo + Diet (BM14149)

**-10**

**-9**

**-8**

**-7**

**-6**

**-5**

**-4**

**-3**

**-2**

**-1**

**0**

**0**

**4**

**8**

**12**

**16**

**20**

**24**

**28**

**32**

**36**

**40**

**44**

**48**

**52**

**% change from baseline**

- Placebo

**Treatment week**

**Significant relative weight change from baseline at 6 months for 60 mg vs. placebo ****and 120 mg vs. placebo, P<0.001 - ITT population, observed data; mean +/-- SE**

## Orlistat + Diet Significantly More Weight Loss Than Placebo + Diet (NM14161)

- Orlistat + Diet Significantly More Weight Loss Than Placebo + Diet (NM14161)

- Placebo

- 60 mg tid

- 120 mg tid

**-10**

**-9**

**-8**

**-7**

**-6**

**-5**

**-4**

**-3**

**-2**

**-1**

**0**

**% change from baseline**

**0**

**4**

**8**

**12**

**16**

**20**

**24**

**28**

**32**

**36**

**40**

**44**

**48**

**52**

**Treatment week**

**Significant relative weight change from baseline at 6 months for 60 mg vs. placebo ****and 120 mg vs. placebo, P<0.001 - ITT population, observed data; mean +/-- SE**

## Orlistat 60 mg is Effective at 6 Months (BM14149)

| Treatment | N | Weightloss SE(kg) | Orlistat effect SE (kg) | Responderrate (%) |
| --- | --- | --- | --- | --- |
| Placebo | 204 | 3.1  0.34 | – | 30.9 |
| 60 mg tid | 216 | 5.3  0.33 | 2.2*  0.46 | 54.6* |
| 120 mg tid | 221 | 5.6  0.33 | 2.5*  0.45 | 54.8* |

*******	****Significant difference with respect to placebo (P<0.05)**
**	****responder: ********5% weight loss from baseline to month 6**

**ITT, observed**

## Orlistat 60 mg is Effectiveat 6 Months (NM14161) 

*******	****Significant difference with respect to placebo (P<0.05)**
**	****responder: ********5% weight loss from baseline to month 6**

| Treatment | N | Weightloss SE (kg) | Orlistat effect SE (kg) | Responderrate (%) |
| --- | --- | --- | --- | --- |
| Placebo | 173 | 1.1  0.35 | – | 21.3 |
| 60 mg tid | 182 | 3.8  0.34 | 2.7*  0.48 | 37.7* |
| 120 mg tid | 178 | 4.6  0.34 | 3.5*  0.48 | 42.8* |

**ITT, observed**

## Design of Lower BMI (25-28 BMI) Study(NM17247)

**Placebo, N=195**

**Orlistat 60 mg tid, N=196**

**Double-blind randomized ****treatment period**

**0**

**16 weeks**

**Hypocaloric Diet**

## Weight Loss Consistent With Pivotal Studies (NM17247)

**-8**

**-7**

**-6**

**-5**

**-4**

**-3**

**-2**

**-1**

**0**

**0**

**4**

**8**

**12**

**16**

**Treatment week**

**Relative change ****from baseline (%) **

- Placebo

*******	****Significant relative weight change from baseline at 16 weeks for 60 mg vs. placebo,**
**	****ITT population, observed data; mean +/-- SE**

*****

**P=0.002**

## Orlistat 60 mg Improves Risk Factors at 4 Months in Overweight

*** Significance from baseline at 4 months for 60 mg vs. placebo, p<0.05****ITT population, observed data**

**Total-C**

**LDL-C**

**Systolic BP**

**Diastolic BP**

*****

*****

*****

*****

**-6**

**-5**

**-4**

**-3**

**-2**

**-1**

**0**

**1**

**% change from randomization**

**Placebo**

**60 mg tid**

## 60 mg and 120 mg Doses Achieve Criteria for Responder Analysis at 6 Months in Overweight and Obese Populations

| BMI | Treatment | N | Responderrate (%) |
| --- | --- | --- | --- |
| 26.7- 29.9 | Placebo | 28/83 | 33.7 |
|  | 60 mg tid | 43/70 | 61.4* |
|  | 120 mg tid | 46/78 | 59.0* |
| 30 | Placebo | 108/488 | 22.1 |
|  | 60 mg tid | 188/505 | 37.2* |
|  | 120 mg tid | 218/493 | 44.2* |

**ITT, LOCF. Studies included: NM14161, BM14149, NM14150 **

*******	****Significant difference with respect to placebo (P<0.05)****	****Responder: ********5% weight loss from baseline to month 6**

## Orlistat Shows Significant and Consistent Weight Loss Across All Studies 

**Placebo**

**60 mg tid**

**120 mg tid**

**-10**

**-8**

**-6**

**-4**

**-2**

**0**

**0**

**4**

**8**

**12**

**16**

**20**

**24**

**Pooled BM14149 and NM14161**

**% change from baseline**

**Study Week**

**-10**

**-8**

**-6**

**-4**

**-2**

**0**

**0**

**4**

**8**

**12**

**16**

**20**

**24**

**NM17247**

**% change from baseline**

**Study Week**

**ITT population, observed data; mean +/-- SE**

## Orlistat Has Well Established Safety Profile

**Extensive clinical trial data and ****post-marketing experience**
**Overall good tolerability**
**Low withdrawal rates**
**Few drug interactions**
**Minimal impact on fat soluble vitamins**

## GI Side Effects Predictable and Manageable

|  | 6 Months |  |  |
| --- | --- | --- | --- |
|  | Placebo | 60 mg tid | 120 mg tid |
| Adverse event | N=634 | N=623 | N=632 |
| Fecal urgency | 7.9% | 18.8% | 23.4% |
| Oily spotting | 1.1% | 17.7% | 21.7% |
| Flatus with discharge | 1.9% | 17.3% | 19.9% |
| Fatty/Oily stool | 2.7% | 17.2% | 21.7% |
| Oily evacuation | 0.6% | 11.6% | 13.4% |
| Increased defecation | 2.7% | 7.1% | 8.2% |
| Fecal incontinence | 0.8% | 4.7% | 7.8% |

*** Significantly different 60 mg compared 120 mg (p<0.05)**

*****

*****

*****

*****

## Orlistat 60 mg vs. 120 mg 

**Advantages of 60 mg vs. 120 mg:**
**Fewer GI events with 60 mg dose**
**Significantly lower chance of GI events in ****first four weeks of treatment  **
**One third fewer GI events within first week **
**Lower withdrawal rate due to GI events **
**60 mg dose provides flexibility to potentially enhance compliance  **

## Low Withdrawal Rates at 6 Months

**0**

**5**

**10**

**15**

**20**

**25**

**Placebo**

**60 mg tid**

**120 mg tid**

**% of subjects**

**19.7%**

**10.4%**

**10.8%**

**1.4%**

**1.8%**

**2.0%**

**0.8%**

**3.2%**

**5.4%**

## Orlistat Has Low Potential for Misuse

**No abuse liability **
**Not centrally acting**
**No subjective effect**
**Low misuse potential**
**4 published cases of misuse reported worldwide **
**No published reports of misuse by anorexics/teens**
**No dose dependent effect**

## Rate of 2 Consecutive Below-NormalVitamin Levels in 6 Months of Treatment  

*******	****Significant difference between 60-mg and 120-mg doses; Fisher’s Exact Test  at p<0.05**
**	****This analysis includes all U.S. Studies (NM14336, NM14161, and NM14185) conducted by ****	****Roche of orlistat 60 and 120 mg that did not require routine vitamin supplementation **

|  | Placebo (%) | 60 mg tid (%) | 120 mg tid (%) |
| --- | --- | --- | --- |
| Vitamin A | 3/580 (0.5) | 1/203 (0.5) | 15/962 (1.6) |
| Vitamin D | 13/558 (2.3) | 2/209 (1.0)* | 50/954 (5.2) |
| Vitamin E | 2/565 (0.4) | 7/196 (3.6) | 29/944 (3.1) |
| Beta-carotene | 2/576 (0.3) | 3/207 (1.4) | 40/977 (4.1) |

## Orlistat Has LowPotential for Drug Interactions

**Warnings**
**Do not use **
**if you are taking cyclosporine (a drug given after organ transplant)**
- if you have been diagnosed with problems absorbing food
- if you are allergic to any of the ingredients in orlistat capsules
- if you are not overweight

- Orlistat Has LowPotential for Drug Interactions

## Orlistat Has LowPotential for Drug Interactions

**Ask a doctor or pharmacist before use if you are**** **
- taking medicine for diabetes.  Your medication dose may need to be adjusted during weight loss.
- taking warfarin (blood thinning medicine)
- taking other weight loss drugs

- Orlistat Has LowPotential for Drug Interactions

## Summary

**Orlistat 60 mg, 1-2 capsules tid:**
**Orlistat plus diet always significantly better than placebo and diet alone**
**Safety and tolerability suitable for OTC**

## Consumer Understanding and Use in OTC Setting

**Saul Shiffman, PhD**
**Research Professor of Health Psychology and Pharmaceutical Sciences**
**University of Pittsburgh**

## Key Consumer Behavior Questionsfor Appropriate OTC Use

**Can people recognize the condition?**
**Do people understand the label?**
**Do people self-select appropriately? **
**Do people use the product correctly?**
**Can people use the product safely?**
**Are people satisfied with the product?**

## Summary: Key Consumer Behavior Questions for Appropriate OTC Use

**People recognize overweight**
**People understand the orlistat label**
**Self-selection for orlistat was initially poor**
**Label changes improved self-selection**
**Potential risk will be managed through programs**
**People used orlistat correctly, according to label**
**People used orlistat safely**
**People lost weight and were satisfied**

## Behavioral ResearchProgram for OTC Orlistat

| Study | Timing | Objective |
| --- | --- | --- |
| Label Comp #1 | 2002 | Comprehension |
| Label Comp #2 | 2002 | ComprehensionSelf-selection |
| Actual Use Trial (AUT) | 2003 | Self-selectionUsage |
| Label Comp #3 | 2004 | ComprehensionSelf-selection |
| Label Comp #4 | 2005 | Comprehension |
| Cyclosporine self-selection | 2005 | Self-selection |
| Warfarin self-selection | 2005 | Self-selection |
| Teen self-selection  | 2005 | Self-selection |
| Weight survey  | 2005 | Self-recognition |

## Behavioral ResearchProgram for OTC Orlistat

| Study | Timing | Objective |
| --- | --- | --- |
| Label Comp #1 | 2002 | Comprehension |
| Label Comp #2 | 2002 | ComprehensionSelf-selection |
| Actual Use Trial (AUT) | 2003 | Self-selectionUsage |
| Label Comp #3 | 2004 | ComprehensionSelf-selection |
| Label Comp #4 | 2005 | Comprehension |
| Cyclosporine self-selection | 2005 | Self-selection |
| Warfarin self-selection | 2005 | Self-selection |
| Teen self-selection  | 2005 | Self-selection |
| Weight survey  | 2005 | Self-recognition |

## Behavioral ResearchProgram for OTC Orlistat

| Study | Timing | Objective |
| --- | --- | --- |
| Actual Use Trial (AUT) | 2003 |  |
|  |  |  |
|  |  |  |
|  |  |  |
|  |  |  |
|  |  |  |

**Self-selection in special populations**

**Focused self-selection studies:****	****- Cyclosporine users****	****- Warfarin users****	****- Teens**

**2005**

**Self-selection****Usage**

**Label Comp #4**

**2005**

**Comprehension**

**Weight survey**

**2005**

**Self-recognition**

## Key Consumer Behavior Questionsfor Appropriate OTC Use

**Can people recognize the condition?**
**Do people understand the label?**
**Do people self-select appropriately? **
**Do people use the product correctly?**
**Can people use the product safely?**
**Are people satisfied with the product?**

## Self-Recognition: People Can Judge if They are Overweight

**US random-digit dial survey, N=1,629 adults**
**Roper Survey Center, University of Connecticut **
**Compare self-classified weight status vs. BMI **
**Self-classified “overweight”**
**BMI based on self-reported height, weight**
**88% of consumers who consider themselves overweight have BMI ********25**
**11% BMI 20-25**
**1% BMI <20**

## Key Consumer Behavior Questionsfor Appropriate OTC Use

**Can people recognize the condition?**
**Do people understand the label?**
**Do people self-select appropriately? **
**Do people use the product correctly?**
**Can people use the product safely?**
**Are people satisfied with the product?**

## Label Comprehension Study 4: Design

**13 facilities, geographically dispersed  **
**Presented with label**
**Presented with hypothetical usage scenarios, asked “okay” or “not okay to use?” **
**Responses coded as correct, acceptable, incorrect**
**Study Population  **
**304 general population (from mall intercept)**
**160 low literacy (from research databases)**
**18 years or older, English speaking, interested in weight loss**
**65% female, 62% White, 30% African-American, ****9% Hispanic**

## Label Comprehension Study 4: Objective

**Assess consumers’ ability to understand key labeling communications on proposed label**
**Indication – Use **
**Target population**
**Dosing directions**
**Warnings – *****Do Not Use***** and *****Ask A Doctor***

## Consumers Understand LabelIndication & Directions – LC#4

|  | General PopulationN=304 | Low LiteracyN=160 |
| --- | --- | --- |
| Indication & population |  | 	 |
| 	Used to lose weight | 100% | 100% |
| 	Not OK to use if not overweight | 79% | 78% |
| Directions for use |  |  |
| 	Recommended dosage | 95% | 91% |
| 	Maximum daily dose (6) | 86% | 67% |
| 	When to increase dose | 89% | 80% |
| 	Stop at  6 months | 78% | 74% |
| Diet & vitamins |  |  |
|     Need to change diet | 96% | 93% |
|     How to control GI effects | 86% | 69% |
|     Take vitamin daily | 93% | 88% |
|     Take vitamin 2 hrs from orlistat | 79% | 66% |

## Consumers Understand Label Warnings – LC#4

|  | General PopulationN=304 | Low LiteracyN=160 |
| --- | --- | --- |
| Do not use |  |  |
| 	Using cyclosporine | 96% | 90% |
| 	Under 18 years | 98% | 98% |
| 	Problems absorbing food | 92% | 89% |
| 	Allergic to ingredients | 99% | 97% |
| 	Breast feeding | 96% | 93% |
| Ask a doctor (or pharmacist) if... |  |  |
| 	Taking warfarin	 | 94% | 93% |
| 	Had kidney stones | 97% | 97% |
| 	Had gallbladder problems | 99% | 97% |
| 	Taking medicine for diabetes | 97% | 96% |
| 	Taking other weight loss drug | 98% | 98% |

## Key Consumer Behavior Questionsfor Appropriate OTC Use

**Can people recognize the condition?**
**Do people understand the label?**
**Do people self-select appropriately? **
**Do people use the product correctly?**
**Can people use the product safely?**
**Are people satisfied with the product?**

## Actual Use Trial Design:Self-selection Phase 

**18 community pharmacies, geographically dispersed **
**Recruited by in-pharmacy and newspaper****ads for weight loss**
**Reviewed label, asked if appropriate**
**Completed medical history**
**Asked to purchase**
**Evaluate by labeled conditions**
**Inclusion: Age ********18**

## Actual Use Trial Sample

**79% female **
**Mean age: 45 years**
**Race:**
**79% Caucasian**
**6% African American**
**8% Hispanic**
**6% Other**

## Actual Use Trial Subject Disposition

**681 evaluable**
**543 said “appropriate”  **

## Warnings on Actual Use Trial Label and Current Proposed Label

| Warnings on Actual Use Trial Label |  |  |
| --- | --- | --- |
| Actual Use Trial label only | 	Current proposed label |  |
| 	More than 30 lbs to lose | 	Allergic to ingredients |  |
| 	High blood pressure | 	Medicine for diabetes |  |
| 	High cholesterol/triglycerides | 	Other weight loss drugs |  |
| 	On a doctor recommended diet | 	Gallbladder problems |  |
|  | 	Problems absorbing food |  |
|  | 	Warfarin  |  |
|  | 	Cyclosporine |  |

## Self-selection Results Among People with Exclusions

**Percent of people who have label conditions who make correct selection decisions**
**23% Actual Use Trial label**
**29% current proposed label **

## Self-selection Results AmongAll People Current Proposed Label 

| Exclusions & Self-Selection Status
N=681 |
| --- |
| 	No label exclusion, correct	560	82% |
| 	Exclusion, correct selection	 35	  5% |
| 	Exclusion, incorrect selection	86	13% |

## Percent Incorrect SelectorsCurrent Proposed Label

| Percent Who Incorrectly Selected Orlistat
13%
Total N=681 |
| --- |
| 		n	% |
| Allergic to ingredients	0	0 |
| Other weight loss drugs	29	4.3 |
| Gallbladder problems	15	2.2 |
| Problems absorbing food	10	1.5 |
| Medicine for diabetes	30	4.4 |
| Warfarin	7	1.0 |
| Cyclosporine	1	0.3 |

## Revised Cyclosporine Warning

**Actual Use Trial Label**

**Proposed Label**

## Cyclosporine Self-selection Study 

**Cyclosporine self-selection study**
**Recruited transplant patients from national consumer research panel**
**46 cyclosporine users interested in ****losing weight**
**89% appropriately selected not to use**
**Cyclosporine education/prevention program**

## Revised Warfarin Warning

**Actual Use Trial Label**

**Proposed Label**

## Warfarin Self-selection Study 

**Warfarin self-selection study**
**Recruited warfarin users from clinical databases**
**54 warfarin interested in losing weight**
**72% appropriately selected not to use**
**Warfarin education/prevention program**

## Teens and Those Not Overweight

**Teens**
**Not overweight**

## Teen Recruitment

**Teen self-selection study **
**Teens (14-17) interested in weight loss**
**Recruitment in 8 cities via flyers for weight loss **
**Locations frequented by teens: teen-oriented mall stores (e.g., Abercrombie, Hollister, Claire’s), video arcades, high schools, etc.**
**Recruited 147 teens**

## Teen Self-selection

**147 ad respondents (14-17) shown package **
**59% appropriately selected not to use**
**87% not interested in purchase **
**Of 13% interested in purchase:**
**67% overweight or at risk for overweight; ********85****th**** percentile BMI**
**33% normal weight; 85****th**** percentile BMI**
**4% of those who responded to ads**
**0% underweight**

## “What Led You To Make That Decision?”Teens Who Incorrectly Selected Orlistat

**“****I want to lose just a small amount of weight and this seems to be a sensible way to do it.”**
**“****It’s because it’s for people who know you can’t just take a pill you have to diet as well.” **
**“****The box says the program helps you and teaches you to eat healthy foods in moderation. That’s good for losing or maintaining weight which is what I need for my life.”**
**“****The label said that you have to follow a well balanced diet while using this product and I feel that I would be able to do that.”**

## BMI Distribution of Orlistat Self-Selectors in Actual Use Trial

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

******18.5**

******18.5-22**

******22-25**

******25-30**

******30-35**

******35**

**Baseline BMI (kg/m****2****) **

**% of subjects (N=543)**

**Under**

**Normal**

**Over**

**Obese**

## Key Consumer Behavior Questionsfor Appropriate OTC Use

**Can people recognize the condition?**
**Do people understand the label?**
**Do people self-select appropriately?**** **
**Do people use the product correctly?**
**Can people use the product safely?**
**Are people satisfied with the product?**

## Actual Use Trial Design: Usage Phase

**3 month open label **
**Required product purchase**
**Exclusions: Absolute ‘Do Not Use’ conditions, pregnancy, under 18, prior use of orlistat**
**543 said “appropriate”   ****494 included****262 purchased****237 used and assessed**

## Actual Use Trial Design:Usage Phase Procedures

**Dispensing **
**Orlistat + behavioral materials**
**No instruction/counseling**
**Data collection by phone **
**Days 14, 30, 60, 90**
**Usage patterns**
**AEs**
**Weight loss**
**Satisfaction**
**Duration of use**
**Median 77.5 days**
**46% still using at 90 days**

## Consumers Took Orlistat 2-3 Times a Day

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**0**

**1**

**2**

**3**

**4+**

**Occasions per day**

**% of subjects**

**Day 14 (N=217)**

**Day 90 (N=148)**

**95% took orlistat with meals**

## Consumers Took 1-2 Capsules per Occasion

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**0**

**1**

**2**

**3+**

**Capsules per occasion**

**% of subjects**

**Day 14 (N=217)**

**Day 90 (N=148)**

## Consumers FollowedLabel Recommendations

**74% took multivitamin during study**
**87% followed a diet **
**74% followed a low fat diet **
**90% “successful” following diet**
**51% exercised more**
**79% used weight loss materials**
**80% rated materials as useful**

## Key Consumer Behavior Questionsfor Appropriate OTC Use

**Can people recognize the condition?**
**Do people understand the label?**
**Do people self-select appropriately? **
**Do people use the product correctly?**
**Can people use the product safely?**
**Are people satisfied with the product?**

## Consumers Use Orlistat Safelyand Tolerate Side Effects

**Safety population = 284**
**SAEs**
**4 unrelated, resolved**
**Urinary tract infection (2), syncope, pregnancy with miscarriage**
**2 possibly related, resolved without consequence**
**Esophageal spasm**
**Abdominal pain**
**15% discontinued due to AEs**
**72% had AE**
**50% had defecation pattern changes****	**

## Users Managed Orlistat-specific GI Effects

## Key Consumer Behavior Questionsfor Appropriate OTC Use

**Can people recognize the condition?**
**Do people understand the label?**
**Do people self-select appropriately? **
**Do people use the product correctly?**
**Can people use the product safely?**
**Are people satisfied with the product?**

## Users Are Satisfied with Orlistat

**Interviewed Day 30 (N=219)**
**74% reported losing weight**
**5 lbs. median self-reported weight loss **
**83% satisfied or very satisfied with orlistat**
**Interviewed Day 90 (N=148)**
**91% reported losing weight**
**10 lbs. median self-reported weight loss **
**81% satisfied or very satisfied with orlistat**

## Summary: Key Consumer Behavior Questions for Appropriate OTC Use

**People recognize overweight**
**People understand the orlistat label**
**Self-selection was initially poor in AUT**
**Label changes improved self-selection**
**Potential risk will be managed through programs**
**People used orlistat correctly, according to label**
**People used orlistat safely**
**People lost weight and were satisfied**

## Orlistat’s Consumer Education and Behavioral Support Program

**Steve Burton****Vice-President of Weight Control****GlaxoSmithKline**

## OTC Orlistat – Need for Candid Communications

**GSK is committed to a program that helps people adopt a healthy eating plan**
**Set realistic expectations – gradual****weight loss**
**Promote low-fat diet to manage ****treatment effects**
**Encourage other lifestyle changes, ****e.g., exercise**

## OTC Orlistat: More Than a Pill...It’s a Program

## Behavioral Support with Purchase

## Additional Behavioral Support Online

**Weight Loss**
**with Orlistat **

**Maintenance**
**without Orlistat**

**First 6 months**

**Second 6 months**

**Online Support for 1 Year**

**+**

## Additional Behavioral Support Online

**Weight Loss**
**with Orlistat **

**Maintenance**
**without Orlistat**

**First 6 months**

**Second 6 months**

**Online Support for 1 Year**

**Customized Weight Loss Plan**
**Weekly Monitoring**

**Customized Exercise Plan**
**Monthly Follow-Up**

**Exercise**

**Diet Reminder**

**Multivitamin Use**

**Weight**

## Engaging the Healthcare Professional

**Help HCP become ****more engaged **
**Physicians**
**Pharmacists**
**Nurses**
**Dietitians**
**Provide tools and resources to HCPs**
**Counseling kits**
**Patient leaflets**
**Continuing education**
**HCP website**

## GSK’s Commitments in Smoking Control

**Surveillance programs in place up to 6 years after the switch to OTC status**
**Surveillance to detect signals of misuse/abuse**
**Quarterly reports and extra measures deemed unnecessary after 6 years**
**Continue to monitor/report as like other OTCs**

## Summary

**Promote healthy behavior change and be candid about what to expect from orlistat**
**Education and behavioral support to help sustain lifestyle changes **
**A new treatment option that can improve the health and well-being of overweight adults**

## Summary and Proposed CommitmentsOrlistat OTC

- Summary and Proposed CommitmentsOrlistat OTC

**John Dent, PhD**
**GlaxoSmithKline**

## Cyclosporine and Warfarin Safety Nets

**Enhanced warnings on label**
**Targeted educational outreach to pharmacists**
**Orlistat warning stickers on warfarin****and cyclosporine bottles **
**Educational materials at patient discharge **

## Responsible Marketingto Committed Adults

**Marketing orlistat as a program, not a pill**
**Ensuring consumers understand importance of behavior change**
**Advertising through age-appropriate media**

## Orlistat Unlike Any Other Weight Loss Drug

**Non-systemic**
**Minimally absorbed**
**Not CNS-acting**
**No negative effects on cardiovascular system**
**Not addictive**
**Not an appetite suppressant**
**Not a stimulant**

## Orlistat Summary

**Reduces absorption of fat calories**
**Clinically proven, safe and effective **
**Provides effective weight loss **
**Consumers use safely and are satisfied **
**Benefit outweighs potential risk**

## Conclusion

**Orlistat 60 mg is an appropriate **
**OTC weight loss aid**

## Backups Shown

## Mean Percent Change from Baseline Body Weight, LOCF – ITT Population, XENDOS

**Change in weight (kg)*******

**26**

**156**

**208**

**0**

**-12**

**0**

**-10**

**-6**

**-2**

**-4**

**-8**

**Week**

**52**

**78**

**104**

**130**

**182**

**-4.1 kg**

**-6.9 kg**

**p<0.001**

**Placebo + lifestyle**

***Mean ± SEM**

**JH-25**

## Effect of Orlistat on Fat-soluble Vitamin Levels

**Vitamin D 25-hydroxy**

**Vitamin D 1, 25-dihydroxy**

**0**

**20**

**40**

**60**

**80**

**100**

**120**

**140**

**BL**

**6**

**12**

**18**

**24**

**30**

**36**

**40**

**48**

**Months**

**120 mg tid **

**nmol/L**

**0**

**40**

**80**

**120**

**160**

**200**

**BL**

**6**

**12**

**18**

**24**

**30**

**36**

**40**

**48**

**Months**

**pmol/L**

**JH-6  **

## Vitamin D Metabolism

|  | N | 25-OHD(ng/ml) | 1,25 (OH)2D(pg/ml) | PTH(pg/ml) |
| --- | --- | --- | --- | --- |
| Obese | 12 | 8 | 37 | 518 |
| Non-obese | 14 | 20 | 29 | 243 |
| P-value |  | <0.001 | <0.01 | <0.001 |

**From Bell, et al. JCI, 76, 1985.**

**JH-44**

## Effect of Orlistat on Fat-soluble Vitamin Levels

**0**

**0.5**

**1.0**

**1.5**

**2.0**

**2.5**

**3.0**

**3.5**

**4.0**

**BL**

**6**

**12**

**18**

**24**

**30**

**36**

**40**

**48**

**μ****mol/L**

**Months**

**Vitamin A**

**120 mg tid **

**JH-7  **

## Labels for BMI Research 

- Labels for BMI Research

**AT-286 **

## Results of BMI Research –Target Population

**Across all 4 BMI labels, <45% consumers correctly reported BMI****1**

**1**** For those respondents whose BMI was included in the chart.**

**AT-287 **

## XENDOS Study: Marked Laboratory Abnormalities in Bone Markers

| Parameter |  | Year 1 |  |  | Year 2 |  |  | Year 3 |  |  | Year 4 |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  |  | N | n | % | N | n | % | N | n | % | N | n | % |
| Calcium Low | PlaceboOrlistat | 16551649 | 32 | (0.2)(0.1) | 12681477 | 02 | (0.0)(0.1) | 9921291 | 00 | (0.0)(0.0) | 636958 | 01 | (0.0)(0.1) |
| Parathyroid hormone High | PlaceboOrlistat | 16551649 | 62 | (0.4)(0.1) | 12681477 | 107 | (0.8)(0.5) | 9921291 | 1321 | (1.3)(1.6) | 636958 | 1519 | (2.4)(2.0) |
| Osteocalcin High | PlaceboOrlistat | 16551649 | 10 | (0.1)(0.0) | 12681477 | 11 | (0.1)(0.1) | 9921291 | 12 | (0.1)(0.2) | 636958 | 10 | (0.2)(0.0) |
| Urine N-T High | PlaceboOrlistat | 16551649 | 37 | (0.2)(0.4) | 12681477 | 55 | (0.4)(0.3) | 9921291 | 20 | (0.2)(0.0) | 636958 | 34 | (0.5)(0.4) |

**JH-25 **

## XENDOS Study: Bone Mineral Density (g/cm2)

|  |  | N | Mean | SD | Median |
| --- | --- | --- | --- | --- | --- |
| Placebo | Day 1 | 77 | 1.24 | 0.07 | 1.24 |
|  | Year 1 | 54 | 1.25 | 0.07 | 1.24 |
|  | Year 2 | 55 | 1.26 | 0.07 | 1.26 |
|  | Year 3 | 55 | 1.26 | 0.07 | 1.26 |
|  | Year 4 | 55 | 1.26 | 0.07 | 1.25 |
| Orlistat | Day 1 | 72 | 1.25 | 0.07 | 1.24 |
|  | Year 1 | 65 | 1.24 | 0.08 | 1.24 |
|  | Year 2 | 65 | 1.26 | 0.07 | 1.26 |
|  | Year 3 | 65 | 1.26 | 0.07 | 1.25 |
|  | Year 4 | 65 | 1.26 | 0.07 | 1.25 |

**JH-27  **

## Serum 25-OH Vitamin D Levels in Post-menopausal Women Not Receiving Estrogen Replacement Therapy  

|  | Placebo(n=29) | 120 mg
(n=59) | p-value |
| --- | --- | --- | --- |
| Baseline serum 25-OH vitamin D ± SD (nmol/L) | 52.5 ± 26.5 | 52.6 ± 20.4 |  |
| 2-year change from baseline ± SD (nmol/L) | -5.5 ± 14.1  | -8.6 ± 24.1 | NS |
| Incidence of 2 consecutive low serum 25-OH vitamin D values (%) | 14.3% | 8.7% | NS |

**JH-43  **

## Intermittent vs. Continuous Weight Loss Therapy Provide Comparable Efficacy

**Wirth A, Krause J. Long-term weight loss with sibutramine: a randomized controlled trial. *****Jama*****. 2001;286:1331-1339.**

**-10**

**-9**

**-8**

**-7**

**-6**

**-5**

**-4**

**-3**

**-2**

**-1**

**0**

**0**

**4**

**8**

**12**

**16**

**20**

**24**

**28**

**32**

**36**

**40**

**44**

**48**

**Randomized Treatment**

**Change in Body Weight (kg)**

**Run-in**

**Week**

**Placebo (n=201)**

**Intermittent Sibutramine Therapy (n=395)**

**Continuous Sibutramine Therapy (n=405)**

**All Patients (n=1001)**

**PH-43  **

## Orlistat Shows Significant and Consistent Weight Loss Across All Studies 

**-10**

**-8**

**-6**

**-4**

**-2**

**0**

**0**

**4**

**8**

**12**

**16**

**20**

**24**

**-10**

**-8**

**-6**

**-4**

**-2**

**0**

**0**

**4**

**8**

**12**

**16**

**20**

**24**

**Pooled BM14149 and NM14161**

**NM17247**

**% Change From Baseline**

**% Change From Baseline**

**Study Week**

**Study Week**

**ITT population, observed data; mean ± SE.**

**EF-20   **

## 3% Weight Loss at 4 Months is Predictive of 5% Weight Loss at 6 Months – NM14161, BM14149

**76.3% of subjects who lost ********3% of their body weight at 4 months also lost ********5% of their body weight at 6 months **
**These data confirm that weight loss of ********3% at months is a strong predictor of achieving a weight loss of ********5% at 6 months **

**EF-23   **

## Relative Weight Change at 4 Months Predicts Relative Weight Change at 6 Months for Orlistat 60 mg tid

- N = 385
- Radj2 = 0.81
- ITT Population, observed data
- Studies: BM14149, NM14161

**EF-24   **

## Prevalence of Exclusions on Actual Use Trial Label & Current Proposed Label

*Prevalence* of Exclusions on Actual Use Trial Label & Current Proposed Label

| Actual Use Trial Label
N=681
68% |  |  |
| --- | --- | --- |
| Actual Use Trial label only
50% | Current Proposed Label
18% |  |
|                                                               n          % |                                                             n           % |  |
| More than 30 lbs to lose	        346	    51 | Allergic to ingredients		        0           0 |  |
| High blood pressure		        166	    24 | Other weight loss drugs	       33          5 |  |
| High cholesterol/triglycerides	        147       22 | Gallbladder problems		       25          4 |  |
| On a doctor recommended diet	         48	     7 | Problems absorbing food	       12          2 |  |
|  | Medicine for diabetes		       46          7 |  |
|  | Warfarin 		                         14         2 |  |
|  | Cyclosporine	                          2         <1 |  |

## Detailed Description of Level of Intervention in Controlled Studies

| Study # | Written diary guidance | Interactions with dietitians | Diet diary provided | Review of diet diary with patient | Informational material on exercise |
| --- | --- | --- | --- | --- | --- |
| BM14149 |  |  |  |  |  |
| NM14161 |  |  |  |  |  |
| NM17247 |  |  |  |  |  |
| AUT and OTC Material |  |  |  |  |  |

**EF-41   **

## Low Cyclosporine Level – Medical OutcomePost-marketing Experience from Roche WW Safety Database

**29,333 Total Cases in Roche WW Database Through 11/05**

**44 reports with cyclosporine as co-suspect or concomitant **

**38 Low ****cyclosporine levels**

**2 Documented change****in graft status**

**35 No change****in graft status**

**1 Not in transplant patient ****(Nephrotic Syndrome)**

**NH-3     **

## Few Marketed Drugs with Log P 6.5

| Drug | Log P |
| --- | --- |
| Astemizole | 6.4 |
| Atovaquone | 6.4 |
| Isotretinoin | 7.9 |
| Phytonadione | 11 |
| Terfenadine | 7.7 |
| Halofantrine | 8.5 |
| Amiodarone | 8.9 |
| Probucol | 10.9 |
| Cyclosporine | 14.4 |

**JB-24     **

## Quick Start

## Treatment Effects

## Variations from Typical Dosing Patterns – Users Group

**Were there times when you took fewer/more capsules at a time?**
**Were there periods when you did not use the medicine?**

|  | Users Group (N=237) |  |  |  |
| --- | --- | --- | --- | --- |
|  | Day 14 Interview(N=217)% | Day 30 Interview(N=219)% | Day 60 Interview(N=197)% | Day 90 Interview(N=148)% |
| < Average | 50.7 | 57.1 | 51.8 | 50.0 |
| > Average | 24.4 | 26.9 | 30.5 | 28.4 |
| Times not used | 46.5 | 53 | 68.5 | 67.6 |
| Missing | 1 | 2 | 2 | 3 |

**AT-128   **