# Presentation: 136981

## Pediatric Obesity: Issues Facing the Center for Devices and Radiological Health

**Ron Yustein, M.D.**
**Clinical Deputy Director**
**Office of Device Evaluation**
**Center for Devices and Radiological Health**
**November 16, 2005**
**This presentation may contain images which may be copyrighted**

## Goals 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

**Goals 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**

## CDRH’s Meeting Goals

**Provide 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.**** **

## 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**.

## The “Epidemic”

## Current Treatment Options

- Diet
- Exercise

**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??

**? ? ? ? ? ?**

**Notes:**
Now I’ll discuss the continuum of treatment options.

The vast majority of patients with low back pain are successfully managed nonoperatively.  

A wide variety of nonoperative treatments are available including physical therapy, medications, and injections.  

But there is really no set treatment protocol.

## 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
-       RYGB

**DEVICES ???**

- Less Effective??

-  More Effective??

**Notes:**
Now I’ll discuss the continuum of treatment options.

The vast majority of patients with low back pain are successfully managed nonoperatively.  

A wide variety of nonoperative treatments are available including physical therapy, medications, and injections.  

But there is really no set treatment protocol.

## 
CDRH/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.

**CDRH/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.**

## Device Evidence

**Valid 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

##            Definitions I

|  |   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**

## 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%**

## 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.**

## 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.

**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.**

## Supporting Data (78 adult subjects at 3 sites)

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

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

**Supporting Data (78 **_***adult***_** subjects at 3 sites)**
_**Effectiveness data**_** **
**Mean implant time****	****	****7.5 months**
**At 4 months (n=50)****	****	****Mean 34 lb. loss**
**At 6 months (n=41)****	****	****Mean 40 lb. loss**
**At 10 months (n=4)****	****	****Mean 76 lb. loss**
_**Safety data**_
**Deflation w/pyloric obstruction****	****1**
**Deflation w/SBO****	****	****	****	****1**
**Gastric ulcer****	****	****	****	****1**

## Post-marketing experience
>100 MDRs in first 2 years
79 surgeries to remove deflated balloon from small bowel.
1988	Marketing Discontinued

1992	PMA Voluntarily Withdrawn

**Post-marketing experience**
**>100 MDRs in first 2 years**
**79 surgeries to remove deflated balloon from small bowel.**
**1988****	****Marketing Discontinued**
**1992****	****PMA Voluntarily Withdrawn**

## 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.

**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

## Supporting 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

**Supporting 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**

_**Safety**_
**N/V****	****	****	****51%**
**GERD****	****	****	****34%**
**Abd. Pain****	****	****27%**
**Band Slippage ****	****24%**
**Stoma Obstruction****	****14%**
**Esophageal Dil****	****10%**
**Dysphagia  ****	**** ****	**** 9%**
**Erosion  ****	**** ****	**** 1%**
**Revision Surgeries****	**** 9%**

## Post-marketing Experience
Port/Tubing Leak
New Port + Advisory on Technique (2002)

U.S. Clinical Experience
Replacing VBG as restrictive procedure?
Results approaching European experience
1 year: 40-50% EWL
2 year: 40-60% EWL
Decreased adverse events

**Post-marketing Experience**
**Port/Tubing Leak**
**New Port + Advisory on Technique (2002)**
**U.S. Clinical Experience**
**Replacing VBG as restrictive procedure?**
**Results approaching European experience**
**1 year: 40-50% EWL**
**2 year: 40-60% EWL**
**Decreased adverse events**

## Other Approaches per Literature

**Gastric Space-Occupying Devices**
**Newer Balloons**
**Stimulators**
**Gastric electrical stimulation**

## The Study of Obesity Devices in Adults

## 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.

**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.**

## 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.

**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.**

## Pivotal Study Design

FDA encourages randomized, sham-controlled studies when possible: 
Surgically implanted devices with on/off modes
Endoscopically implanted devices

	Active Group 		 Control Group*
     Active device  		  Sham Procedure
					   Inactive Device
Diet/Behavior/Exercise      Diet/Behavioral/Exercise

**Pivotal Study Design**
**FDA encourages randomized, sham-controlled studies when possible: **
**Surgically implanted devices with on/off modes**
**Endoscopically 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**

## Typical Study Issues

**“****Problem” with Sham Control Studies**

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

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

## Typical Study Issues

**Other Possible Designs:****	****	****	**
**Control with approved product (Lap-BAND).**
**Superiority study**
**Non-inferiority study with pre-specified delta.**
**Control with surgery (RYGB).**
**Non-inferiority study?**
**Control with Optimal Medical Care (OMC)**
**Diet**
**Behavior**
**Exercise**
**Pharmacological agents**
**Patient as own control**

## Duration/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

**Duration/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**

## Endpoints
Effectiveness
Primary 
%EWL 

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

**Endpoints**
_**Effectiveness**_
**Primary **
**%EWL **
**Secondary **
**Absolute Wt ****Δ**
**Δ**** in BMI**
**QoL Assessments**
**Δ**** in Comorbidities**
**Δ**** hip/waist circum **

_**Safety**_
**Procedure or surgery related adverse events**
**Device related adverse events**

## Concurrent Treatments
Diet
Calorie restriction (-500 Cal/day) or ad-lib

Behavioral Modification and Therapy
Group or Individual Therapy

Exercise or Physical Activity

No weight loss medications or herbals.

**Concurrent Treatments**
**Diet**
**Calorie restriction (-500 Cal/day) or ad-lib**
**Behavioral Modification and Therapy**
**Group or Individual Therapy**
**Exercise or Physical Activity**
**No weight loss medications or herbals.**

## Issues for Discussion:What We Will Ask You? 

## 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. 

**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.**

## 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

**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**

## 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.**

## What 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?

**What 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?**

## What 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.

**What 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