Studying Devices in the Pediatric

Population

Points to consider, future challenges

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Judith U. Cope, MD, MPH

Office of Pediatric Therapeutics

OC, FDA

Disclaimer

• This presentation represents the professional opinion of the speaker and is not an official document, guidance or policy of the U.S. Government, the Department of Health and Human Services, or the Food and Drug Administration, nor should any official endorsement be inferred

• The purpose of today's workshop is to facilitate information gathering. Our goal is not to request or achieve a consensus

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gathering. Our goal is not to request or achieve a consensus on any of the topics presented during discussion

• This meeting is not intended to promote any medical products as safe or effective. Any discussion mentioning specific devices is solely intended to illustrate a point or to be used to facilitate the intended information gathering.

• %o conflicts to declare

Outline- Children, Devices, Study Design

Age considerations

• CDRH definition of children

• Age group of study population

Pediatric population – 8 areas to consider

C-H-I-L-D-R-E-N mnemonic

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C-H-I-L-D-R-E-N mnemonic

Congenital, Healthy kids, Infections, Lifestyle, Development, Reproductive/endocrine, Exposures and Neoplasia

*Backup slides for general design issues pre- and post-market studies

Children and Devices

Device intervention in growing children

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Device intervention in growing childrenmay predispose to complications thatmay influence the rest of their lives.

We need to be sure kids are appropriately included in studies of

safety and effectiveness of device use.

Class 1

Class 2

Exam gloveCrutches Tanning booth

Adult Devices used in the Pediatric Age Group

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Class 2

Class 3

HIV testing “Cup & gown”

Orthopedic

hardwareTampon Contact lens

Insulin pump

AGE

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How are children defined by the

FDA?

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CDRH definition birth through 21 years, 2003 Guidance-

“Premarket Assessment of Pediatric Medical Devices”

Pediatric population subgroups categories –

CDRH Guidance

Neonate birth to 1 month

Infant >1 month to 2 years

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Child 2 to 12 years

Adolescent 12 to 21 years

Age group of study population

• Who will use the device?

• What age-related differences should be

considered with the device?

• What age group should be selected for

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• What age group should be selected for

the study?

Example: clinical thermometers

Thermometers

1. Who will use the device?

2. Clinical accuracy will be most important for what

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2. Clinical accuracy will be most important for what

age group?

Answer: The first few months of life.

– When the immune system is not fully mature

– Fever alone may be the first sign of sepsis

– Management of fever/rule out sepsis includes hospitalization and intravenous antibiotics

What else do you need to keep

in mind for this very special

population?

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population?

Congenital

Healthy kids

Infection

Lifestyle

CC--HH--II--LL--DD--RR--EE--NN

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Lifestyle

Development

Reproductive

Exposures

Neoplasia

Congenital or birth defects

Definition: Developmental abnormalities noted at

birth, or weeks to years later

Terminology:

• Deformity

• Defect

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• Anomaly

• Dysplasia

• Malformation

It is important to understand that many device

interventions are used in treatment of congenital

defects and that the type of abnormality and any

associated risk factors may affect the outcome!

Deformity

in utero compression

Dysplasia

Incomplete growth or

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Incomplete growth or

arrested development

Malformation

An organ develops wrongly,

or there is excessive or

defective tissue.

Congenital anomaly

(single)

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Cleft lip – Different stages of repair

�

Syndrome or

Genetic disease

(multi-system)

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Example of Syndrome = Neural tube defect

Underlying cause of defects may affect

interpretation of long-term outcomes

Is it an isolated defect or associated with inherited disease or genetic syndrome?

Example: Down syndrome child with congenital heart defect repair or surgery for a craniovertebral junction instability and in follow-up the child develops leukemia.

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Internet resources:

PubMed:

www.ncbi.nlm.nih.gov/entrez/query.fcgi

Online Mendelian Inheritance in Man (OMIM):

www.ncbi.nlm.nih.gov/OMIM/searchomim.html

Healthy children/Health statistics

• Morbidity

• Mortality

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Morbidity: Pediatric discharge rates from short-stay

hospitals, by first-listed ICD-9 diagnosis; US, 2001

(rate per 10,000)1

Respiratory (bronchiolitis, asthma, pneumonia) 117.9

Injury/poisonings (fractures, poisoning) 39.2

Digestive (30% appendicitis) 36.7

Metabolic, nutrition (60% volume depletion) 31.8

Infectious (sepsis 2.7) 30.0

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Infectious (sepsis 2.7) 30.0

Congenital anomaly 23.9

Mental disturbance 23.1

Nervous system 14.5

Genitourinary 13.9

Total rate all

conditions

423/10,000

1National Hosp Discharge Survey Data: www.cdc.gov/nchs

Mortality: US Vital statistics: Leading

causes of childhood deaths, 1-14 years

cancer

accidents

cerebral palsy

pneumonia

meningitis

cancer

other

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meningitis

heart disease

suicide

homicide

HIV infection

congenital

anomaliesother

accidentscongenital

Infections and Infectious complications

Common Pediatric Infections

• ENT (ear, nose, throat)

• Respiratory

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• Respiratory

• CNS (meningitis, brain abscess)

• Genitourinary (UTI, STI)

• Immunodeficiency (e.g., HIV)

Cochlear implants

Infections

– Most cases of meningitis related to cochlear

implants were caused by

Streptococcal pneumonia

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• Streptococcal pneumonia

• H. influenza

• E. coli and others

– CDC and FDA recommendation that all people

with cochlear implants have pneumococcal

vaccination

Lifestyle• Active lifestyle: activity

• Independence/dependence

• Human factors-behavior, social skills, coordination, testing limits, curiosity

• Not fully independent

• Move different

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• Move different

• Think different

• Act different

• May not listen or comply

• Adolescent risk-taking and

independent behavior

Development and growth

•Height, weight

•Head circumference

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•Head circumference

•Sexual maturation rating (SMR) or Tanner stage

Growth velocity curve

Growth velocity (cm/year)

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15

20

Girls

0-3 yr

3-21 yr

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0

5

10

2 4 6 8 10 12 14 16 18 20

Age (years)

Girls

BoysHeight

(inches)

Development and growth

• Long-term implants need to “grow” with the child and

different engineering is required

• Certain children may have

– Altered growth states

– Fluid and electrolyte problems

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– Fluid and electrolyte problems

– Feeding problems

• Special populations with unique challenges

• Low birth weight (< 5 pounds)

• Genetic disorders and syndromes

• Neurological disorders

• Endocrine problems

Development: Psychological, cognitive & behavioral

Human factor considerations

What is expected at what age?

– Infant separation, toddler independence, school-age autonomy, adolescence identity & risk-taking

– Different developmental screening tests, according to stage/age with different sensitivity (in

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according to stage/age with different sensitivity (in detecting problems) & specificity in determining if a problem exists

Age-related responses to medical devices

Think of body and behavior not always by age

– Big or small for age, maturation rate

– Teenagers (definitely a disconnect)

– Handicap or chronic illness (e.g., ADHD)

Reproductive/endocrine

• Devices might interfere

with developing organs

• Thyroid, pituitary,

insulin, estrogen, and

testosterone hormones

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testosterone hormones

• Pubescent girls could

get pregnant and how

should the study

address those issues

Consider any

interference retards growth and development

Exposures

Examples:

– Short-term

• Latex

– Long-term

• Radiation

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• Radiation

– Repeated use

• Latex

• Di-2-ethylhexyl phthalate (DEHP)

(a plasticizer used in flexible

catheters, tubing and other devices)

Exposure concerns with device materials

Implant reactions

• Hip prostheses combinations of metal on nonmetal, polyethylene on metal, ceramic on metal

• Other e.g., plastic metal or carbon heart valve with fabric mesh rim

Repeated use problems

• Contact lenses, soft or rigid hydrophilic polymer

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• Contact lenses, soft or rigid hydrophilic polymer

Tissue reaction

• Contact dermatitis & hypersensitivity with gloves

• Hepatotoxicity & polyurethane breakdown products

Cancer outcomes

• Ionizing radiation (x-rays); implanted biomaterials devices (e.g., chromium, cobalt, human derived bone morphogenic proteins)

Neoplasia (cancer)

• Are the device biomaterials carcinogenic?

• Animal testing may be needed.

• If a study patient develops cancer, is there

a plausible hypothesis?

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a plausible hypothesis?

• Further information should be obtained

regarding the age of onset, family history,

latency, anatomic site, histopathology,

and other risk factors

In summaryN

Special considerations for CHILDREN

-Age of the target population

-8 important areas when studying

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C-H-I-L-D-R-E-N

Back up slidesClinical trial and study design

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Clinical trial and study design

What Clinical Trials Do Well? • Determine with some certainty that the device is

effective & the common serious adverse events may be identified

Limitations of Clinical Trials• Seldom more than a 1000 patients

Clinical Trials & Post-approval studies

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• Seldom more than a 1000 patients

• Patients with complicated medical conditions often excluded

• Certain age subgroups may be excluded

• Patients receiving concurrent treatments may often excluded

• Trials often last only weeks to months; identification of reactions due to long-term use or latent effects is difficult

Study Design ConsiderationsStudy design and postmarket evaluation

� Hypothesis

� Bench or animal testing

� Study cohort (age, specific subgroups)

� Primary & secondary endpoints

� Training

� Overall efficacy and safety

� Exposures

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� Exposures

Post-approval study

� Hypothesis driven

� What’s the control population

� What’s the plan for training / evaluation of training

� Is the long-term follow-up, long enough?

� Comorbidities & other devices used in intervention

� Preventing loss to follow-up