Orlistat OTC, 60 mg capsules GlaxoSmithKline GSK Consumer Healthcare New Drug Application 21887 Actu

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Orlistat OTC, 60 mg capsulesGlaxoSmithKline
(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
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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

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Actual Use Issues and Objectives forOrlistat 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?

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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.

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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?

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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

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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

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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.

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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

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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.

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Actual Use Study Results
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Disposition of Subjects
703 Screened subjects
Eligible for analysis?
22 subjects protocol violation
At one pharmacy site, subjects were given
information at enrollment that potentially biased
the self-selection process.
681 Eligible subjects
Do you think this medicine is appropriate for
you to use?
52 No 86 Dont know
543 answer YES

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

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Disposition of Subjects(cont.)
681 Eligible subjects
261 No 66 Dont know 15 missing
Would you like to purchase the medicine today?
339 Want to purchase
Subject met inclusion/ exclusion criteria?
49 did not meet criteria
28 did not purchase
262 Purchasers
Subject used orlistat and completed an interview?
7 did not use 18 no interview
All 22 subjects excluded for protocol violations
purchased orlistat, 21 used it.
237 Evaluable users
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Who enrolled? Who used orlistat?
The AUS study population
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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 Dont Know), but I need to check with my
  doctor first.

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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
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Self-selection
681 Eligible subjects
216 No labeled exclusions
465 Labeled exclusion
7 Self-selected incorrectly
209 Self-selected correctly
107 Self-selected correctly
358 Self-selected incorrectly

• Correct self-selection 107 209 316
• 46.4 of all eligible subjects made a correct
  self-selection decision

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AUS self-selection decisions Do Not Use
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AUS self-selection decisions
Ask before use warnings

• 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

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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.

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Baseline BMI and perceptions of body weight
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Correct use decisions

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

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Typical subject use behaviors (N 237)
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Multivitamin (MVI) use among orlistat users (N
237) during the AUS
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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

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Use of educational materials
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Self-Reported Dietary Behavior
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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.

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Body weight lost
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Measured weight loss and baseline BMI(Pharmacy
visit Days 61 90)
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Actual Use Study Adverse Events (AEs)
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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.

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Common GI Adverse events

• 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)

• 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)

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Actual Use Study Answers and Conclusions
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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.

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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.

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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.

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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.