Pediatric Obesity: Issues Facing the

Center for Devices and Radiological Health

Ron Yustein, M.D.Clinical Deputy Director

Office of Device EvaluationCenter for Devices and Radiological Health

November 16, 2005This presentation may contain images which may be copyrighted

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OutlineGoals for This Meeting

The “Epidemic”

Role of CDRH and ODE

Background of Approved Devices

Typical Features of Adult Trials

Questions to be Addressed by Panel

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CDRH’s Meeting GoalsProvide an open forum for discussion between FDA, the clinical community, and the public on a vital public health issue.

Discuss the epidemiology of obesity in the U.S. pediatric population.

Discuss current treatment options for obesity in the pediatric population.

Discuss issues related to designing and performing trials for devices to treat obesity in the pediatric population and provide recommendations for such to FDA.

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CDRH’s Meeting Goals

Although prevention of obesity is certainly a key issue when addressing this “epidemic”, CDRH would like this meeting to focus on the treatment of the condition after it presents.

Keep the differences between drugs and devices as well as the differences in regulations of the two in mind and recognize that devices pose their own unique issues.

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The “Epidemic”

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Current Treatment Options

DietExercise

Diet/exercise and pharmacological therapy are less invasive than surgery, but are also probably generally less effective.

Less Invasive

More Invasive

Meds Surgery

RYGB

Less Effective??

More Effective??

? ? ? ? ? ?

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Filling the Void with Devices?

Diet

Exercise

Endoscopically or surgically implanted devices may fill a niche and offer treatment options which are intermediate in effectiveness and risk.

Less Invasive

More Invasive

Meds Surgery

RYGBDEVICES ???

Less Effective??

More Effective??

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Role of CDRH and ODECDRH/ODE: Promote & Protect the Public Health by Ensuring the Safety and Effectiveness of Medical Devices. Assess pre-clinical & clinical data.

Regulation/oversight of investigative trials.

Approve devices for marketing which are

reasonably safe and effective.

Keep or remove unsafe or ineffective devices

from the market.

Monitor devices after marketing.

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Device EvidenceValid Scientific Evidence per Device Regulations:

Well-Controlled Studies

Partially Controlled Studies

Objective Trials without Matched Controls

Case Histories

Significant Human Experience

Some Background:

Devices and Obesity

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Adults

BMI

Children

BMI-for-Age

Normal 18.5-24.9 5th- 84th Percentile

At Risk for Overweight 85th - 95th Percentile

Overweight 25-29.9 >95th Percentile

Obese 30-34.9

Obese – Severe 35-39.9

Obese – Extreme 40-49.9

Obese – Super 50-59.9

Obese – Super, Super > 60

BMI > 40 may also be referred to as “Morbid Obesity”

Definitions I

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Definitions II

% Excess Weight Loss (%EWL) Amount of weight lost as a fraction (%) of the

amount by which the person was over “ideal” weight (for height and frame) at baseline.

% EWL = [Wt Lost] / [Baseline Wt – Ideal Wt]

Example:Baseline Weight = 300 #

Ideal Weight for Height and Frame = 180#

Excess Weight = 120#

Patient Loses 40# at 12 months

% EWL = 40/120 = 33%

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Background

Only 2 devices have ever been approved by FDA specifically for the treatment of obesity – both for adults. Garren-Edwards Bubble

Inamed Lap-BAND

However, these may only be the tip of the

iceberg.

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Garren-Edwards Gastric Bubble

PMA Approved September 17, 1985

Indications for Use: Temporary aid to diet

and behavior modification in people who are at least 20% over their ideal weight.

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Garren-Edwards Bubble – Part II

Supporting Data (78 adult subjects at 3 sites)

Effectiveness data Mean implant time 7.5 monthsAt 4 months (n=50) Mean 34 lb. lossAt 6 months (n=41) Mean 40 lb. lossAt 10 months (n=4) Mean 76 lb. loss

Safety dataDeflation w/pyloric obstruction 1Deflation w/SBO 1Gastric ulcer 1

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Garren-Edwards Bubble – Part III

Post-marketing experience >100 MDRs in first 2 years 79 surgeries to remove deflated balloon

from small bowel.

1988Marketing Discontinued

1992PMA Voluntarily Withdrawn

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Inamed’s Lap-BAND Adjustable Gastric Band

Approved June, 2001

Indications for Use: For weight reduction for

severely obese patients 18 and over with BMI > 40 or BMI > 35 with > 1 severe comorbid condition, or those who are > 100 lbs over estimated ideal weight.

Inamed Website

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Lap-BAND – Part IISupporting Data (Pre-Market)299 adult patients (as own control) x 3 years

Effectiveness

% EWL Δ Wt Δ BMI

1 Year 34.5% 52# 8.5

2 Years 37.8% 59# 10.5

3 Years 36.2% 53# 9.0

SafetyN/V

51%

GERD34%

Abd. Pain 27%

Band Slippage 24%

Stoma Obstruction 14%

Esophageal Dil 10%

Dysphagia 9%

Erosion 1%

Revision Surgeries 9%

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Lap-BAND – Part IIIPost-marketing Experience Port/Tubing Leak

New Port + Advisory on Technique (2002)

U.S. Clinical ExperienceReplacing VBG as restrictive procedure?

Results approaching European experience 1 year: 40-50% EWL 2 year: 40-60% EWL Decreased adverse events

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Other Approaches per Literature

Gastric Space-Occupying Devices Newer Balloons

Stimulators Gastric electrical stimulation

The Study of Obesity Devices in Adults

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Typical Study Issues

Patient Eligibility Age 18 and over

BMI

> 40 or

> 35 with at least one co-morbidity

Lower-risk devices may be studied in patients with BMI > 30 with at least one co-morbidity

Minimum duration of disease (3-5 years).

Failure to respond to conservative treatments.

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Typical Study Issues

Patient Eligibility Exclusion of (poorly controlled) diabetics.

Exclusion of patients with bulimia, etc.

Certain baseline characteristics that may

identify subjects most likely to respond prior

to treatment.

Normal swallowing and GI motility.

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Typical Study IssuesPivotal Study Design FDA encourages randomized, sham-controlled

studies when possible: Surgically implanted devices with on/off modesEndoscopically implanted devices

Active Group Control Group* Active device Sham Procedure

Inactive Device

Diet/Behavior/Exercise Diet/Behavioral/Exercise

*Activated or offered device after pre-determined amount of time

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Typical Study Issues“Problem” with Sham Control Studies

Ethics of keeping patients Ethics of keeping patients without effective treatment without effective treatment for prolonged period of for prolonged period of time (1 year or more)time (1 year or more)

Fact that device may not Fact that device may not reach maximum or reach maximum or meaningful effectiveness meaningful effectiveness in shorter time period. in shorter time period.

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Typical Study Issues

Other Possible Designs: Control with approved product (Lap-BAND).

Superiority studyNon-inferiority study with pre-specified delta.

Control with surgery (RYGB).Non-inferiority study?

Control with Optimal Medical Care (OMC)DietBehaviorExercisePharmacological agents

Patient as own control

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Typical Study IssuesDuration/1° Endpoint Assessment > 1 year for permanent implant.

3 - 6 months for temporary implants depending on design and intended use.

Anticipate requesting continued evaluation postmarket for 2-5 years for long-term implants in adults.

Long-term safety

Maintenance of weight loss

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Typical Study IssuesEndpoints Effectiveness

Primary %EWL

Secondary Absolute Wt Δ Δ in BMI QoL Assessments Δ in Comorbidities Δ hip/waist circum

SafetyProcedure or surgery related adverse events

Device related adverse events

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Typical Study Issues

Concurrent Treatments Diet

Calorie restriction (-500 Cal/day) or ad-lib

Behavioral Modification and TherapyGroup or Individual Therapy

Exercise or Physical Activity

No weight loss medications or herbals.

Issues for Discussion:

What We Will Ask

You?

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Issues for Obesity Device Trials

Please keep in mind that, unlike most drugs, devices come in different forms:

Permanent unremovable (for-life) implant

Permanent but removable (long-term) implant

Temporary removable implant

External devices (non-implants)

Anatomy altering devices

Anatomy preserving devices

Please consider this when discussing each question as you may have different recommendations for different device types.

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Question # 1

What are appropriate patient populations to include in these trials? Age Weight/BMI Developmental Milestones Medical Co-morbidities Failure of prior conservative therapies Psychological assessments Specific exclusion criteria Assent/Consent issues

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Question # 2

What are appropriate endpoints for studying devices to treat obesity in the pediatric population?

Appropriate primary and secondary effectiveness endpoints.

Appropriate safety endpoints.

Appropriate duration for assessment of primary endpoints.

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Question # 3What are appropriate study designs for these trials? Role of RCT.

Role of Sham Controls.

Other appropriate study designs and controls.

Minimizing confounding factors.

Appropriate duration of pre-market study.

Role of DMC or DSMBs?

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Question # 4What long-term safety and effectiveness issues may be important and how should they best be addressed? Effect on future growth and development. Effect on future comorbidities. Maintenance of weight loss. Role of post-approval studies (PAS) to

collect this information. Registries.

Thank You