# Presentation: 759019

## Orlistat OTC, 60 mg capsulesGlaxoSmithKline (GSK) Consumer Healthcare New Drug Application 21-887 Actual Use Study NM17285

- Joint Meeting of the Nonprescription Drugs Advisory Committee and Endocrinologic and Metabolic Advisory Committee
- Bethesda, Maryland
- January 23, 2006
- Karen B. Feibus, M.D.
- Medical Officer
- Division of Nonprescription Clinical Evaluation

**Center for Drug Evaluation and Research**** **

##  Important elements of an actual use study (AUS)

- Attempts to simulate OTC use of the product
- Few exclusion criteria
- Self selection:
- Do people correctly choose to use or not use the product based on the label (ideally tested previously in LC studies)?
- Compliance:
- Do people dose and use the product based on the label directions?
- Efficacy information often limited by open-label, uncontrolled design.
- Objectives are product dependent

## Actual Use Issues and Objectives forOrlistat OTC

- Who will use orlistat OTC?
- Do subjects correctly choose to use or not use orlistat OTC based on label warnings and indications?
- Do subjects dose orlistat correctly?
- Do subjects lose weight?
- Are there safety concerns?
- Do subjects take a multivitamin correctly while using orlistat?
- Do non overweight subjects choose to use orlistat?
- Are there unexpected adverse events with orlistat use in the OTC environment?

## Study Design

- 90 days
- 18 U.S. pharmacies, six geographical areas
- Certified weight scale in each pharmacy
- Recruitment:  in-store advertising; newspaper ads where recruitment slow.
- Advertising notified consumers of compensation
- Enrolled individuals ages 18 years and older
- Subjects able and available to complete telephone interviews
- Subjects with a “Do Not Use” condition could participate in self-selection but could not purchase orlistat.

## Self-selection process

- Consumer presented with orlistat package and told:
*Imagine you are in a store and this is a new over-the-counter medicine.  You can take as much time as you need to look at the packaging.  Let me know when you are finished.*
- Self-selection question asked when  consumer finished examining the package:
*Do you think this medication is appropriate for you to use?*

## Purchase Decision

*The cost of this medicine is $45 for a bottle of 90 capsules.  Would you like to purchase the medicine today?*
- Information collected:
- Reason why did or did not want to purchase orlistat
- Height, weight

## Treatment

- All purchasers initially received an OTC orlistat package containing:
- Up to 3 bottles (#90) orlistat, 60 mg
- Supplementary educational materials (behavioral and nutritional support)
- Orlistat User Guide:  “How to Lose Weight with Orlistat.”
- Personal food diary
- Pocket fat gram counter
- Fat gram wheel
- Portion size information card
- Orlistat Diet Success Planner:

## Data collection

**Scripted telephone interviews**
- At about 14, 30, 60, 90, and 104 days after enrollment
- Conducted by trained clinical interviewers
- Interview content:
- Started orlistat? Contact with healthcare provider?
- Use patterns:  dose, frequency, timing with food
- Multivitamin (MVI) use
- Diet and exercise
- Discomforts? Changes in health or other medicines?
- Weight loss?
- Use of label, educational materials, website
- Interviews with at least one question answered were included in analysis.

## Data collection

- Pharmacy visits
- Subjects could return to pharmacy as needed to purchase more orlistat (up to 3 bottles at a time)
- One pharmacy visit required after enrollment, time unspecified
- Information collected:
- Drug log form:  dates, amount of drug purchased
- Weight measured
- Adverse events recorded

## AUS Design:  Comments

- The Drug Facts label and supplementary educational materials used are similar to those submitted to the NDA; however,
- some elements of Drug Facts are different in content or location
- the actual educational materials submitted to the NDA were not tested.
- Objective weight measurements were not required at the end of the study.
- Subject diaries were not analyzed or collected.
- Some telephone interactions may have influenced subject orlistat use behaviors.
- No assessment of discontinuation of use.
- 90 day AUS.  Proposed duration of orlistat use:  6 months.

## Actual Use Study Results

**Actual Use Study Results**

## Disposition of Subjects

**703 **
- Screened subjects

**681**
- Eligible subjects

**543**
- answer “YES”

- Regardless of self-selection decision, all eligible subjects:
-   Take REALM test
-   Provide demographic and health history information

- 22 subjects
- protocol violation

- Eligible for analysis?

- “Do you think this medicine
- is appropriate for you to use?”

- 52 No
- 86 Don’t know

-  At one pharmacy site, subjects were given information at enrollment that potentially biased the self-selection process.

## Disposition of Subjects(cont.) 

**681 **
- Eligible subjects

**339**
- Want to purchase

**262***
- Purchasers

**261** No
**66** Don’t know
**15** missing

- Would you like to purchase
- the medicine today?

- Subject met inclusion/
- exclusion criteria?

-  **49** did not
- meet criteria

**237**
- Evaluable users

- Subject used orlistat and
- completed an interview?

**7 **did not use
**18** no interview

**28** did not
- purchase

-  All 22 subjects excluded for protocol violations purchased orlistat, 21 used it.

## Who enrolled? Who used orlistat?  		               The AUS study population

| Demographic | Eligible (N = 681) | Users (N = 237) |
| --- | --- | --- |
| Gender                                          Female                                                | 79.4% | 86% |
| Mean age (years) | 45.4 | 44.9 |
| Age range (years) | 18 – 85 | 18 – 75 |
| Mean BMI (kg/m2) | 33.1 ± 6.7 | 32.0 ± 5.8 |
| BMI range (kg/m2) | 20.9 – 62.6 | 21 - 53 |
| Ethnicity                                   Caucasian
                                                    Hispanic
                                      African American | 79.3%
8.1%
6.2% | 82%
6%
3% |
| Education beyond high school | 76.5% | 84.4% |
| REALM test score  
                           Low literate (score ≤ 60)
              Literate, > 8th grade (score > 60)               | 
8.1%
91.5% | 
4.2%
95.8% |

## Correct self-selection responses

- Subject meets a condition listed in Drug Facts Warnings under “Do Not Use”:
*No, this medicine is not appropriate for me to use.*
- Subject meets a condition listed in Drug Facts Warnings under “Ask a doctor before use” or “Ask a doctor or pharmacist before use”:
*No, this medicine is not appropriate for me to use.*
*Yes  (or Don’t Know), but I need to check with my doctor first.*

## Drug Facts Label Comparison

**Orlistat OTC Label**
- Allergy to ingredients
- Taking cyclosporine
- Diagnosed with problems absorbing food
- Not overweight
- Gallbladder problems
- Kidney stones
- Taking diabetes medicine
- Taking warfarin
- Taking other weight loss drugs

**Actual Use Study Label**
- Allergy to ingredients
- Taking cyclosporine
- Taking warfarin
- Taking prescription diabetes medicine
- Problems absorbing food
- Gallbladder problems
- More than 30 lbs to lose
- Given diet by doctor
- Diabetes
- High blood pressure
- High cholesterol/triglycerides
- Taking medicine for high blood pressure or high cholesterol/triglycerides
- Taking other weight loss medicine or supplement

**Do **
**Not **
**Use**

**Ask **
**Doctor**
**Before **
**Use**

**Ask **
**Doctor/**
**Pharm. **
**Before**
**Use**

## Self-selection

- Correct self-selection:  107 + 209 = 316
- 46.4% of all eligible subjects made a correct self-selection decision

**681 **
- Eligible subjects

**216 **
- No labeled exclusions

**465 **
- Labeled exclusion

**7  **
- Self-selected
- incorrectly

**209**
- Self-selected
- correctly

**358**
- Self-selected incorrectly**  **

**107  **
- Self-selected
- correctly

## AUS self-selection decisions: “Do Not Use” 

| AUS label exclusion | Subjects w/ exclusion | Correct self-selection decisions |  |
| --- | --- | --- | --- |
|  |  | Number | Percentage |
| Allergic to ingredients   | 0 | - | - |
| Taking cyclosporine  | 2 |  1  | 50 |
| Taking warfarin  | 14 | 7 | 50 |
| Taking diabetes medicine   | 46 | 16 | 35 |

## AUS self-selection decisions:                      “Ask before use” warnings

| AUS label exclusion | Subjects w/ exclusion | % correct self selection |
| --- | --- | --- |
| Problems absorbing food   | 12 | 17 |
| Gallbladder problems   | 25 | 40 |
| High blood pressure   | 166 | 44 |
| High cholesterol/triglycerides   | 147 | 46 |
| More than 30 lbs to lose   | 346 | 21 |
| Taking a weight loss medicine   | 33 | 12 |
| On doctor-recommended diet  | 48 | 54 |

- NDA label warnings not tested in actual use study:
- “Do not use” if you are not overweight
- “Ask before use” if you have kidney stones

##  Purchase decision

- Of 631 eligible subjects, 284 purchased orlistat.
- Cost was the primary reason that most subjects (60%) did not want to purchase.
- 17% of those uncertain about purchasing cited a need to speak with a healthcare provider first.

## Baseline BMI and perceptions of body weight

| Baseline BMI for orlistat users |  |
| --- | --- |
| BMI (kg/m2) | Users (N = 237) |
| 21 – 24.9 | 18  (8%) |
| 25 – 29.9 | 76  (32%) |
| ≥30 | 143 (60%) |

| Subject self perceptions of body weight |  |
| --- | --- |
| Subject responses | Users (N = 237) |
| Slightly/moderately underweight | 2% |
| Average for height and weight | 0 |
| Mildly/moderately overweight | 81% |
| Severely overweight | 17% |

## Correct use decisions:  

- % subjects making correct use decisions
- based on self-report at telephone interviews
- Contact with healthcare provider was not confirmed.

| AUS label exclusion | # subjects w/
condition | # purchasers
w/ exclusion | Appropriate use
Decision (%) |
| --- | --- | --- | --- |
| Problems absorbing food   | 12 | 1 | 0 |
| Gallbladder problems   | 25 | 7 | 29 |
| High blood pressure   | 166 | 54 | 39 |
| High cholesterol/triglycerides   | 147 | 49 | 43 |
| More than 30 lbs to lose   | 346 | 114 | 24 |
| Taking a weight loss medicine   | 33 | 10 | 50 |
| On diet recommended by doctor  | 48 | 12 | 25 |

## Typical subject use behaviors (N = 237)

| Parameter | % of subjects interviewed |  |  |  |
| --- | --- | --- | --- | --- |
|  | Day 14
(N = 217) | Day 30
(N = 219) | Day 60
(N = 197) | Day 90
(N = 148) |
| Average capsules per dose                  
0 – 2
more | 
99.1
0 | 
97.3
0.5 | 
98.5
0 | 
96.7
0.7 |
| Average doses per day
0 – 3
more | 
97.8
1.8 | 
96.9
1.8 | 
98.0
0.5 | 
97.3
0 |
| Average capsules per day
0 – 6
more | 
99.2
0 | 
98.1
0 | 
98.0
0 | 
96.6
0.7 |
| Taking orlistat with meals | 97 | 96 | 98 | 95 |
| Still using orlistat | 87 | 86 | 63 | 46 |

## Multivitamin (MVI) use among orlistat users  (N = 237) during the AUS

| Pattern of MVI 
use by subjects | Telephone interview |  |  |  |
| --- | --- | --- | --- | --- |
|  | Day 14
(N = 217) | Day 30
(N = 219) | Day 60
(N = 197) | Day 90
(N = 148) |
| Currently using MVI | 163 (75.1%) | 178 (81.3%) | 163 (82.7%) | 127 (85.8%) |
| Taking MVI daily or 
more than once daily | 156 (71.9%) | 173 (79.0%) | 158 (80.2%) | 120 (81.1%) |
| Taking MVI at least 2 hours before or after orlistat | 83 (38.2%) | 98 (44.7%) | 88 (44.7%) | 79 (53.4%) |

## Multivitamin Use:  Comments

- MVI directions in Drug Facts:
- AUS label:  *Other Information*
- NDA label:  *Directions*.
- LC study results:
- 73% correct:  How to time MVI correctly with orlistat.
- Factors potentially influencing compliance:
- Label comprehension
- Conflicting label directions for MVI use with food

## Use of educational materials

| Educational material | % subjects using material | % subjects who found material useful |
| --- | --- | --- |
| Fat Counter | 64 | 86 |
| Fat Wheel | 46 | 79 |
| Personal food diary | 42 | 80 |
| Orlistat user guide | 42 | 85 |
| Diet success planner | 31 | 77 |

## Self-Reported Dietary Behavior

| Dietary behavior | Interview data |  |  |  |
| --- | --- | --- | --- | --- |
|  | Day 14
(N = 217) | Day 30
(N = 219) | Day 60
(n = 197) | Day 90
(N = 148) |
| Following any kind of diet | 80% | 69% | 58% | 61% |
| Reduced calorie diet | 43% | 41% | 33% | 36% |
| Reduced fat diet | 78% | 76% | 70% | 66% |
| Somewhat or very successful staying on diet | 95% | 96% | 98% | 97% |

## Weight loss efficacy

- Weight loss was a secondary study endpoint
- Self-reported weights collected telephone interviews.
- Weight change was documented only for subjects who lost weight.
- Objective weight measurements collected at enrollment and return pharmacy visits.
- Only one return pharmacy visit was required at an unspecified time.

## % Body weight lost

| % body weight lost | Measured weight |
| --- | --- |
|  | Day 61 – 90
(N = 60) |
| > 0 – 5% | 75% |
| > 5% | 42% |
| > 10% | 5% |

## Measured weight loss and baseline BMI(Pharmacy visit Days 61 – 90)

| Baseline BMI
(kg/m2) | Number of subjects | Median weight loss (lbs) | Range of weight change (lbs) |
| --- | --- | --- | --- |
| < 25 | 6 | 1.5 | +3 to -7 |
| 25 – 29.9 | 28 | 4.5 | +6 to -19 |
| ≥ 30 | 72 | 6.5 | +8 to -52 |
| Total | 106 | 6.0 | +8 to -52 |

**Measured weight loss and baseline BMI****(Pharmacy visit Days 61 – 90)**

## Actual Use Study Adverse Events (AEs)

## Safety Population (N = 284)

- The safety population included at least 8 subjects (and as many as 26 subjects) who did not use orlistat.
- 2 severe AEs possibly related to study drug:
- One case of esophageal spasm
- One case of abdominal pain with chronic anemia.
- 43 subjects experienced 65 adverse events that led to premature study discontinuation
- 12 non-gastrointestinal adverse events
- 53 gastrointestinal adverse events typically associated with orlistat use.

## Common GI Adverse events

- Decreased defecation (4.9%)
- Soft stools (4.2%)
- Nausea (3.9%)
- Abdominal distension (3.5%)
- Abdominal pain, upper (3.5%)
- Dyspepsia (1.8%)
- Constipation (1.4%)
- Hemorrhoids (1.4%)
- Vomiting (1.1%)

- Abdominal pain (15.1%)
- Oily spotting (13.4%)
- Fecal urgency (12.7%)
- Flatulence (12.7%)
- Liquid stools (10.9%)
- Flatus with discharge (10.6%)
- Fecal incontinence (8.1%)
- Fatty/oily stool (7.0%)
- Oily evacuation (7.0%)
- Increased defecation (5.3%)

## Actual Use Study Answers and Conclusions

## Answers to our questions:

- Who will use orlistat OTC?
- 92% of orlistat users were overweight or obese.
- Compared to the American population, the study population under-represented consumers of low literacy and non-Caucasian ethnicity.
- This may or may not accurately reflect consumers likely to use orlistat OTC.

## Answers to our questions (cont.):

- Do subjects correctly choose to use or not use orlistat OTC based on label warnings and indications?
- 1 of 2 subjects taking cyclosporine and 7 of 14 subjects taking warfarin incorrectly self-selected.
- Overall, 46% of eligible subjects self-selected correctly.
- GSK conducted 3 self-selection studies focused on cyclosporine and warfarin users and teens.  Studies not submitted to FDA.

## Answers to our questions (cont.):

- Do subjects dose orlistat correctly?
- Yes.  Subjects dosed orlistat according to labeled directions throughout the study.
- Most subjects followed a diet plan.  As labeled, most used a low-fat and/or reduced-calorie diet.
- Do subjects lose weight using orlistat OTC?
- The data suggest that 75% of subjects lost some weight, and 40% lost more than 5% body weight.

## Answers to our questions (cont.):

- Are there safety concerns?
- Do subjects take a multivitamin correctly while using orlistat?
- 38 – 53% of users used a MVI according to label directions during the study.
- Do non overweight subjects choose to use orlistat?
- 7.6% of users had a normal baseline BMI.  No underweight individuals enrolled.
- Are there unexpected adverse events with orlistat use in the OTC environment?
- No.