navigating research in pediatric populations

fully accredited since 2006

Navigating Research in Pediatric Populations

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Accredited

• Fully Accredited by the Association for Accreditation of Human Research Protection Programs (AAHRPP) through 2014

• Fully compliant with FDA and OHRP requirements

International capabilities

• Boards available for the review of US and Canadian Studies

Strong Framework

• Approx. 200 employees – one of the largest IRBs in the US

Certified IRB Professionals (CIP)

• 60% of Affiliated IRB members, 40% of Regulatory staff and 20% of study management & study support positions

About Quorum Review IRB

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• 13 Board meetings each week

• 24-hour site turnaround, 36-hour amendment review,

and same day site changes

• One time CV and audit documentation submission

• Support available 8am-8pm ET

• Dedicated Study Manager

The Quorum Advantage

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• Secure portal with Smart Forms, status reports, and

approval documents

• Customized Phase I and Post-Marketing processes

• Flexible, customized process for AMCs

• 100% Quality Control on all documents

The Quorum Advantage

8

Regulatory Attorney

Mitchell Parrish, JD, CIP

IRB Experience • Joined Quorum Review IRB in January 2010

• Regulatory Counsel with WIRB prior to Quorum

• Former Regulatory Advisor to the National Cancer Institute Central IRB

• CIP certified

Legal Background • Juris Doctor from the University of Oregon School of Law

• Member of the Washington State and American Bar Associations

• Member of the Health and Corporate Law Sections of the WSBA

About the Presenter

9

Importance of Research in Pediatric Populations 11

Regulatory Landscape 21

Research Permitted in Pediatric Populations 24

Recruiting Pediatric Populations 32

Consenting Pediatric Populations 40

Conducting Research in Pediatric Populations 64

Key Take Aways 74

Webinar Overview Description of Topic Page

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Importance of Research in

Pediatric Populations

Importance of Research in Pediatric Populations

The evolving view of children in research has changed from protecting children from research to protecting children through research

12

Old View Protect children from research

• Result = Children not subjected to the potential harm from research

• End Result = A limited number of medical products evaluated for use in children

New View Protect children through research

• Result = Children subjected to potential harm, but such harm is mitigated by ensuring ethically and scientifically sound research that includes additional protections

• End Result = The development of medical products appropriately evaluated for use in children


13

Without medical products approved for children, certain harms may occur:

Denial of a potential treatment

o Physicians refusing to use a drug or device approved for adults “off label”

The wrong dose

o Dose too high (harmful) (Ex. Use of the Antibiotic Chloramphenicol in the 1950s)

o Dose too low (ineffective)


Supporting the New View Why it’s necessary to develop medical products evaluated for children

14

Children are not small adults. Simply adjusting a drug’s dose or

modifying a device according to a child’s weight is not always

sufficient or appropriate due to additional considerations:

o dynamics of growth

o maturation of organs

o changes in metabolism throughout infancy and childhood

o changes in body proportion

o other developmental changes that affect how drugs are

metabolized



15

Drugs may behave in a qualitatively different manner based on

age. There may also be quantitative differences including:

o dose-response relationships

o pharmacokinetic parameters

o magnitude of effect

o risk of an adverse event

o other variables that require defining based on the study population

Basing conclusions on the effects observed in adults is not always

useful, or feasible, because responses in pediatric patients may be

different from those reported in adults



16

• Potential harms

• Children are not small adults

• Products behave qualitatively and quantitatively based on age

Therefore, medicinal products should be studied in children who

are representative of the range of patients likely to receive the

product once it’s marketed



17

• Ibuprofen: Studies in infants established safe and effective dosing information for children ages 6 months to 2 years

• Zantac (ranitidine): Studies in infants established accurate dosing information for safer and more effective use of the drug to manage gastroesophageal reflux in seriously ill infants

• Claritin (loratadine) syrup: Treats allergies and hives. Studies established that patients ages 2 to 5 require a lower dose compared to older children and adolescents


Examples of demonstrated SUCCESS in conducting research in children: Changing Drug Labels

FDA Web Article, Drug Research in Children

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• Pepcid (famotidine) tablets, capsules, and oral solution:

Studies revealed patients up to 3 months require a lower dose

to treat gastroesophageal reflux disease because their ability to

get rid of drug is less than that of older children and adults

• Midazolam hydrochloride syrup and injection: Used as a

sedative. Studies showed a higher risk of serious and life-

threatening adverse events for children with congenital heart

disease and pulmonary hypertension and identified the need to

begin therapy with doses at the lower end of the dosing range to

prevent respiratory problems in pediatric populations


FDA Web Article, Drug Research in Children

Examples of demonstrated SUCCESS in conducting research in children: Changing Drug Labels

19

• While products specifically evaluated in children will

help protect children, there are undoubtedly still

risks from participating in research

• To mitigate these risks, all parties (sponsor, CROs,

investigators, research staff, IRB) must ensure

research is ethically and scientifically sound


Supporting the New View Ethically and Scientifically Sound Research

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Regulatory Landscape

FDA 21 CFR 50 (Protection of Human Subjects)

• Subpart D – Additional Safeguards for Children in Clinical Investigations

21 CFR 56 (Institutional Review Boards)

FDASIA (FDA Safety and Innovation Act, title V)

FDAAA (FDA Amendments Act of 2007, Pediatric Tracking Requirements)

PREA (Pediatric Research Equity Act of 2007)

BPCA (Best Pharmaceuticals for Children Act of 2007)

DHHS 45 CFR 46 (Protection of Human Subjects)

• Subpart D – Additional Protections for Children Involved as Subjects in Research

Regulatory Landscape United States

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• Tri-Council Policy Statement (TCPS 2) (Ethical Conduct for Research Involving Humans)

• ICH-E11 (Clinical Investigation of Medicinal Products in the Pediatric Population)

• Health Canada Addendum to the ICH-E11

Regulatory Landscape Canada

23

Research Permitted in Pediatric Populations

IRBs may only APPROVE research in children that falls into one of

the following four categories:

1. Research not involving greater than minimal risk (21 CFR 50.51/ 45 CFR 46.404 )

o Permission of parent/guardian and assent of participant

2. Research involving greater than minimal risk but presenting the

prospect of direct benefit to individual participants (21 CFR 50.52/ 45 CFR 46.405 )

o Risk is justified by the anticipated benefit to participant

o Risk to benefit is at least as favorable to participant as available

alternatives

o Permission of parent/guardian and assent of participant

Definition of Minimal Risk = the probability and magnitude of harm or discomfort anticipated in

the research are not greater in and of themselves than those ordinarily encountered in daily life

or during the performance of routine physical or psychological examinations or tests


25

3. Research involving greater than minimal risk and no prospect of

direct benefit to individual subject, but likely to yield generalizable

knowledge about the subjects’ disorder or condition (21 CFR 50.53/ 45 CFR 46.406 )

o The risk represents a minor increase over minimal risk

o Study presents experiences that are similar to actual non-research medical,

dental, psychological, social, or educational situations

o Study is likely to yield generalizable knowledge about the participant’s

disorder or condition that is vital to understanding or ameliorating the

disorder or condition

o Permission of both parents/guardians and assent of participant

Note: To enroll a “ward” research must be 1) related to child’s status as a ward or

conducted in setting where majority of children are not wards (schools, hospitals)

and 2) each ward must have an advocate


26

4. Research not otherwise approvable that presents an opportunity to

understand, prevent, or alleviate a serious problem affecting the

health or welfare of children (21 CFR 50.54/45 CFR 46.407)


IRB may not approve unless

27

IRB finds and documents that study will further the understanding,

prevention, or alleviation of a serious problem affecting children

The DHHS Secretary or FDA Commissioner in consultation with a

panel of experts and following opportunity for public review and

comment, determines:

o the study presents an opportunity to further the understanding,

prevention, or alleviation of a serious problem affecting children

o the study will occur with sound ethical principles, and

o There are adequate provisions for obtaining both

parents/guardians permission and participant assent

Note: To enroll a “ward” research must be 1) related to child’s status as a ward or

conducted in setting where majority of children are not wards (schools, hospitals)

and 2) each ward must have an advocate


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Testing Our Knowledge

A survey study is being conducted to record statistics on illicit drug use in

middle school and high school students. As part of the research, students

are asked to complete a series of questions regarding their drug use, if

any, and are asked to sign and date the questionnaire.

Assuming the study is likely to yield generalizable knowledge about

underage drug use and addiction, which regulatory category

applies?

29


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A. 21 CFR 50.51/45 CFR 46.404 \ Research not involving greater than minimal risk

B. 21 CFR 50.52/45 CFR 46.405 \ Research involving greater than minimal risk but

presenting the prospect of direct benefit to individual participants

C. 21 CFR 50.53/ 45 CFR 46.406 \ Research involving greater than minimal risk

and no prospect of direct benefit to individual subject, but likely to yield

generalizable knowledge about the subjects’ disorder or condition

D. 21 CFR 50.54/45 CFR 46.407 \ Research not otherwise approvable that

presents an opportunity to understand, prevent, or alleviate a serious problem

affecting the health or welfare of children


Answer:

31

C. 21 CFR 50.53/ 45 CFR 46.406 \ Research involving greater than

minimal risk and no prospect of direct benefit to individual subject,

but likely to yield generalizable knowledge about the subjects’

disorder or condition

Recruiting Pediatric Populations

Recruiting activities are the beginning of

the informed consent process


Recruiting Study Subjects – Information Sheet:

Guidance for Institutional Review Boards and Clinical Investigators Most applicable guidance in knowing what to consider when advertising to or recruiting children

33

Based on FDA guidance, the IRB needs

to review advertising and recruitment to

ensure advertisements to children:

• Are not unduly coercive

• Do not promise or imply a favorable outcome or other

benefits beyond what is contained in the protocol

• Do not communicate that the study product is safe or

effective for the purposes under investigation


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• Do not make claims that the study product is known to be equivalent or superior to any other study product

• Do not include language indicating that regulatory authorities, such as the FDA and IRB, have approved the research

• Do not cause therapeutic misconception (e.g. modify the word “treatment” or “medicine” with a word that does not imply a benefit)


35

• Do not promise or imply free medical treatment when the

intent is only to say subjects will not be charged for

participation in the investigation

• Do not emphasize payment

• Provide information limited to that which subjects need to

determine their eligibility and interest

• Do not include statements that are generally misleading


36

Recruiting Pediatric Populations Testing Our Knowledge

A proposed radio advertisement to be played on the local #1 hit music station reads:

Do you suffer from Asthma? Asthma is a chronic disease of the airways that makes

breathing difficult. ABC Health Clinics is conducting a research study to test the

safety and effectiveness of an investigational drug that will cure asthma. If you are

16-22 years old, have asthma, and want $300 to help buy those next concert tickets,

then call 1-800-123-4567 to see if you qualify for the study.

What information in the advertisement would the IRB find most problematic?

37

What information in the advertisement would the IRB find most

problematic?


A. “that will cure asthma”

B. “want $300 to help buy those next concert tickets”

C. “test the safety and effectiveness of an investigational

drug”

D. A and B

E. A, B and C

38


Answer:

D. A and B

39

Consenting Pediatric Populations

To enroll a child into research there must be

permission AND assent


41

Note: There is a significant difference between having the authority to consent on behalf of a child for medical care versus enrollment in research


LAR

Parent

Guardian

a child’s biological

or adoptive parent

individual who is

authorized under

applicable state or

local law to consent

on behalf of a child

individual or judicial or other body

authorized under applicable law to

consent on behalf of a child

Who Can Give Permission?

42

Permission Definition: The agreement of

parent(s) or guardian to the

participation of their child or ward in

research [21 CFR 50.3(r)/ 45 CFR 46.402(c)]

In other words: A parent must

provide their consent consistent

with the consent regulations

Therefore, for a child to participate

in research the parent must

generally sign a consent form on

behalf of their child and that

consent form must contain all

applicable consent elements

• Explanation of the research

• Any benefits

• Confidentiality

• Contact information

• Foreseeable risks & discomforts

• Alternative Procedures

• Compensation and Treatment for injuries

• Voluntary participation and no loss of benefits

• Additional elements found at 21 CFR 50.25(b)/ 45 CFR 46.116(b) (e.g. costs)


43

Permission


One or both Parents/Guardians

1. Research not involving greater than minimal risk

(21 CFR 50.51/ 45 CFR 46.404 )

• One parent/guardian

2. Research involving greater than minimal risk but presenting the

prospect of direct benefit to individual participants

(21 CFR 50.52/ 45 CFR 46.405 )

• One parent/guardian

44

Permission


One or both Parents/Guardians

3. Research involving greater than minimal risk and no

prospect of direct benefit to individual subject, but likely to

yield generalizable knowledge about the subjects’ disorder

or condition (21 CFR 50.53/ 45 CFR 46.406 )

• Both parents/guardians

4. Research not otherwise approvable that presents an

opportunity to understand, prevent, or alleviate a serious

problem affecting the health or welfare of children (21 CFR

50.54/45 CFR 46.407)

• Both parents/guardians

45

If Permission of both Parents/Guardians is required then . . .

both parents/guardians must give their permission

unless one is deceased, unknown, incompetent, or

not reasonably available, or when only one has legal

responsibility for the care and custody of the child


46

Consenting Pediatric Populations Testing Our Knowledge

An IRB is reviewing a Phase III study involving an investigational drug for juvenile diabetes. The drug has some potential significant side effects.

47


Is permission of one or both parents required?

Testing Our Knowledge An IRB is reviewing a Phase III study involving an investigational drug for juvenile diabetes. The drug has some potential significant side effects.

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A. One, since the research does not involve greater than minimal risk

B. One, since the research involves greater than minimal risk but presents

the prospect of direct benefit

C. Two, since the research involves greater than minimal risk but presents

the prospect of direct benefit

D. Two, since the IRB determined that while the research presents the

prospect of direct benefit, the drug has potential significant side effects

49


Answer:

D. Two, since the IRB determined that while the research

presents the prospect of direct benefit, the drug has potential

significant side effects

50

Minor

a person who, under local law, is under the

age of majority. The age of majority is the age

at which the individual is considered an adult.

Generally, minors cannot consent to

participate in research

Child

defined by federal regulations as a person

who has not attained the legal age for consent

to treatments or procedures involved in

research under local law

Ward

a minor who is has a guardian appointed by a

court or governmental agency; in other words,

a minor who is under the temporary custody

or care of the local jurisdiction in which they

reside (e.g. a foster child)

Emancipated Minor

a person who is recognized to have the full

legal rights of an adult under local law even

though he/she is a minor. Minors can become

emancipated through certain actions, such as

marriage, enlistment in the military or living

independently. Emancipation may require a

court order. Emancipated minors may be able

to consent to research depending on local law

Mature Minor

a person who, under local law, may consent

to certain health care treatment or procedures

(such as drug or substance abuse or sexually

transmitted diseases) even though he/she is a

minor. Mature minors may be able to consent

to research depending on local law

Consenting Pediatric Populations Who Must Assent?

51


Minor

Mature Minor

(consent)

Emancipated

Minor (consent)

Child

(assent)

Ward

(assent)

52


States that are not “18” – see map

AL

19 MS

21

NE

19

PA

21

Puerto Rico

21

53


Provinces and Territories in Canada that are not “18” – see map

BC

19

NB

19

NL

19

NT

19

NS

19

NU

19

YT

19

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Definition:

A child’s affirmative agreement to participate in research

(mere failure to object may not be construed as consent) [21 CFR 50.3/45CFR46.402]


55

Assent

To determine whether Assent is required,

how to administer assent, and how to

document assent the IRB must consider

• age

• maturity

• psychological state


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Assent

Waiver of Assent. Requirement for

Waiver 21 CFR 50.55(c)/45 CFR 46.408(a)

1. The capability of some or all of the

children is so limited that they

cannot reasonably be consulted

or

2. the study presents the prospect of

direct benefit that is important to

the health or well-being of the

children and is available only in

the context of research (ex. pediatric

oncology trials)


57

Assent requirements

Based on age

below7

Option 1: Assent form

for ages 7-18 with

reading levels at lowest

age

• participant signs

assent (or assent is

documented in

participant’s chart)


58

Based on age Between

7 and 18

Reminder! • Different ages of majority

• Whenever a participant turns the age of

majority during a study that participant

must be consented with the consent form

Assent requirements

Option 2: Assent Form

for ages 7-11 and 12-18

with reading levels at

the lowest age

• participant signs assent

(or assent is documented

in participant’s chart)


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7 and 18





Assent requirements


7 and 18

Option 3: Assent form

7-15; or assent forms 7-

11 and 12-15; and

consent/assent form for

participants 16-18 • means the consent form is

written at a level in which a 16

year old could understand and

means that the participant will

provide their written assent on

the actual consent form after

their parent/guardian’s consent

signature


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Assent requirements

The IRB can always waive assent altogether for all

participants if the following criteria are satisfied:

• The clinical investigation involves no more than minimal

risk to the subjects;

• The waiver will not adversely affect the rights and welfare

of the subjects;

• The clinical investigation could not practicably be carried

out without the waiver; and

• Whenever appropriate, the subjects will be provided with

additional pertinent information after participation


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Waiving Assent no matter the age, maturity, or psychological state

45 CFR 46.408(a)

Conducting Research in Pediatric Populations

Must the child be provided with the assent form for participants 7-

11 years old and provide her assent in order to remain in the trial?

An IRB reviewing a non-Hodgkin’s lymphoma oncology clinical trial (with

the potential for direct benefit) waived the requirement for assent for those

participants under the age of seven. A six-year-old child with non-

Hodgkin’s lymphoma is enrolled in the trial. After three months in the trial,

the child has her seventh birthday.

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Must the child be provided with the assent form for participants 7-

11 years old and provide her assent in order to remain in the trial?

An IRB reviewing a non-Hodgkin’s lymphoma oncology clinical trial (with

the potential for direct benefit) waived the requirement for assent for those

participants under the age of seven. A six-year-old child with non-

Hodgkin’s lymphoma is enrolled in the trial. After three months in the trial,

the child has her seventh birthday.

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NO

In order to approve Pediatric research that is permitted under the regulations an IRB must ensure . . .

• risks to participants are minimized

• risk to benefit ratio is acceptable

• selection of participants is equitable

• informed consent and assent will be sought and documented

• adequate safety monitoring is in place

• adequate privacy protections are in place

• additional safeguards are in place to protect the rights and welfare of participants


21 CFR 56.111 and 45 CFR 46.111

65










21 CFR 56.111 and 45 CFR 46.111

66










21 CFR 56.111 and 45 CFR 46.111

67

Minimizing Risks To Participants To help understand what it means to minimize risks to children evaluate risks from the perspective of a child:

• Medical facilities are scary and cause distress Conduct the research in a child friendly atmosphere to reduce distress ex. play equipment, furniture, age appropriate food, activities

• Medical procedures hurt Use procedures to reduce pain ex. topical anesthesia to place IV catheters, indwelling catheters rather than repeated venipunctures for blood sampling

• More procedures equal more distress and more pain Be efficient to reduce distress and pain

ex. if possible, conduct interventions at the same time clinically indicated interventions are scheduled; utilize staff that is experienced working with children to ensure they are skilled and quick at administering procedures, such as blood draws

68


Minimizing Risks To Participants To help understand what it means to minimize risks to children, evaluate the protocol and consent process specifically for children

• Minimize risks to children by tailoring the consent process to children Design the consent and assent process to ensure comprehension, appropriate parental/guardian involvement, and privacy issues

• Ex. Assent forms written at the appropriate reading level

• Ex. Inclusion of graphs, charts, or visuals incorporated into the assent discussion

• Ex. Separate discussions with children and their parents as necessary

• Minimize risks to children by scientifically evaluating risks Design protocols to protect against adverse outcomes that generally only affect minors

• Ex. impairments of cognitive growth or skeletal development

• Ex. reduce the overall amount of blood required for the study by using sensitive assays, pediatric-enabled laboratories, and population pharmacokinetic approaches

69


The IRB determines an

appropriate blood draw volume

taking into account the following

Blood Draw Volumes in Children

• Type of research in which the child is enrolled

• Severity of the child’s condition

• Hemoglobin levels

• Frequency of blood draws

• Collection procedure

• Age of population

• Protocol justification for the volume


70

Ex. Various Children’s Hospitals throughout

the United States follow these

recommendations:

Maximum Allowable Blood Draw Volumes

(Clinical + Research)

Maximum of 2.5% of total blood volume in one

blood draw and a maximum of 5.0% of total

blood volume in a 30 day period.

www.seattlechildrens.org/pdf/blood-volume-chart.pdf


Is the potential blood collection volume acceptable?

A study in children involves several blood draws over the course of 30

days. The target total amount of blood drawn within that time is 5% of a

participant’s blood volume. The protocol for the study notes that a blood

draw may have to be repeated in the event that a child’s blood sample is

contaminated in the laboratory.

71



Is the potential blood collection volume acceptable?

A study in children involves several blood draws over the course of 30

days. The target total amount of blood drawn within that time is 5% of a

participant’s blood volume. The protocol for the study notes that a blood

draw may have to be repeated in the event that a child’s blood sample is

contaminated in the laboratory.

72


NO

• Require that each Investigator has

the appropriate training and

expertise in pediatric populations

(i.e. use a pediatrician, pediatric

oncologist, pediatric cardiologist,

etc.)

• More frequent DSMB meetings

• Omit any discussion of

compensation from the assent

discussion

• Develop documents to periodically

check a child’s willingness to

continue in the research (remember,

assent is an active and ongoing

process!)

73


Additional Safeguards

First, one additional safeguard is

ensuring the protocol fits into one of

the categories of research in children.

Remember, the IRB cannot approve

the research unless it fits into one of

the four applicable regulatory

categories

Second, other examples include:

Key Take Aways

• Research in children is important and know how to protect the rights, safety, and welfare of these young participants

• The key regulatory documents are 21 CFR 50, Subpart D; 45 CFR 46, Subpart D; and in Canada ICH-E11

• The IRB can only approve research in children that falls into one of four categories and these categories also tell us whether the consent of one or both parents/guardians is required

• Tailor advertisements appropriately to children when they are your audience

• Permission and assent are required in order to enroll children into research and understand how to obtain and document both

• Always ensure the research minimizes risks to children and includes additional safeguards

Key Take Aways

75

Additional Questions

• You may submit questions during our webinar

survey, or

• You may email your questions to:

[email protected]

• We will do our best to follow-up individually or

answer your questions in the Q&A we post on

our website

76

Webinar Follow-Up

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and Q&A will be posted on our website

• We will email you a link to view these

items as they become available

• We value your opinion – please take our

SURVEY and provide us with feedback

77

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78

Thank You for Attending!

79

fully accredited since 2006

Navigating Research in Pediatric Populations

navigating research in pediatric populations

Health & Medicine

research result

research potential harm

evolving view of children

pediatric populations40

pediatric populations64

quorum review irbaccredited

regulatory staff

use end result