Pediatric Studies

Question 1

First documented study in pediatric population

Answer 1

Edward Jenner’s smallpox vaccination on a 8 year old in 1796

Question 2

When did systematic pediatric research begin

Answer 2

18th century

Question 3

In the 19th centry what ids were used in trails

Answer 3

children in hospitals and orphanages

Question 4

What led to the passage of the Federal food DRUG AND Cosmetic Act

Answer 4

1937 Elixer of Sulfanilamide tragedy

Question 5

What established the need for efficacy in drug development

Answer 5

1962 Kefauver-Harris Amendments

Question 6

Who coined the term Therapeutic orphans and what does it describe

Answer 6

In 1963 Dr. Harry Shirkey coined the term “therapeutic orphans” to describe children’s exclusion from drug development.

Question 7

When did the Amercian Academy of pediatrics and FDA begin developing guidelines for evaluating drugs in children

Answer 7

the 1970s

Question 8

When did the FDA created a “Pediatric Use” subsection in drug labels.

Answer 8

in 1979

Question 9

In 1994 the FDA Final Rule allowed what

Answer 9

Pediatric Labeling allowed labeling of drugs for pediatric use based on extrapolation from adult studies, with additional pediatric-specific studies.

Question 10

When were incentive for conducting pediatric drug development studies introduced

Answer 10

IN 1997 the FDA Modernization Act

Question 11

when was Best Pharmaceuticals for Children Act (BPCA) was enacted, providing additional incentives for pediatric studies

Answer 11

In 2002

Question 12

when was the Pediatric Research Equity Act (PREA) mandated the study of drugs in pediatric populations for certain indications.

Answer 12

in 2003

Question 13

When were the BPCA and PREA Made permanent

Answer 13

2012

Question 14

What significantly expanded pediatric clinical trial requirements in oncology through the Research to Accelerate Cures and Equity (RACE) for Children Act. T

Answer 14

The FDA Reauthorization Act (FDARA) of 2017

The legislation amended the Pediatric Research Equity Act (PREA) to require pediatric studies for new cancer drugs with molecular targets relevant to pediatric cancers.

Question 15

Key changes introduced by the RACE for Children Act include:

Answer 15

The FDA can now require pediatric studies for new drugs and biologics intended to treat adult cancers if the molecular target is relevant to pediatric cancer growth or progression.

The Act extended pediatric study requirements to drugs treating rare cancers, which were previously exempt.

Question 16

Pediatric studies must yield for oncology

Answer 16

clinically meaningful data on dosing, safety, and preliminary efficacy to inform potential pediatric labeling.

Question 17

The RACE Act provisions went into effect on

Answer 17

on August 18, 2020, three years after the law’s enactment.

These changes aim to stimulate the development of targeted therapies for pediatric cancers and address the historical lack of pediatric labeling for many cancer drugs.

Question 18

Pediatric trials are more likely to be

Answer 18

open-label, while adult trials are more often randomized controlled trials.

Pediatric trais tend to have smaller sample size and enrollment numbers

Question 19

For atopic dermatitis what is used to measure outcomes for adults adn children

Answer 19

the Eczema Area and Severity Index (EASI) is used in adult trials, while the Scoring Atopic Dermatitis (SCORAD) is more prevalent in pediatric trials.

Question 20

What must pediatric trails account for

Answer 20

different age groups and developmental stages, requiring appropriate dosing, assessments, and outcome measures.

Question 21

The FDA emphasizes identifying the appropriate pediatric population, which can be divided into

Answer 21

neonates, infants, children, and adolescents.

Question 22

The FDA recognizes four distinct pediatric populations

Answer 22

Neonates: birth to 27 days
Infants: 28 days to 23 months
Children: 2 to 11 years
Adolescents: 12 to less than 17 years

Question 23

The Pediatric Research Equity Act (PREA) requires

Answer 23

companies to assess safety and effectiveness of new drugs and biologics in pediatric patients (mandatory), while the Best Pharmaceuticals for Children Act (BPCA) provides financial incentives for pediatric studies (voluntary).

Question 24

To compensate for additional expenses, conducting pediatric trials may result in extended

Answer 24

market exclusivity rights or additional years of commercial exclusivity for orphan medications.

Question 25

PREA allows for

Answer 25

for full or partial waivers of pediatric assessments under specific circumstances, such as when the disease doesn't exist in children or when studies are impossible or highly impracticable.

Question 26

Approvals for pediatric trails

Answer 26

Pediatric trials often have a longer approval process than adult trials for several reasons: Children's bodies undergo significant developmental changes, affecting how they metabolize drugs. Trials must account for these differences across various age groups, which adds complexity and time to the process. Children are considered a vulnerable population, requiring additional safeguards and careful risk-benefit evaluations. This leads to more stringent ethical review processes.

Question 27

Pediatric trials typically occur only

Answer 27

after a drug has been tested in adults, animals, and laboratory settings. This sequential approach inherently extends the timeline for pediatric approvals.

Question 28

What add layers of complexity to the approval process.

Answer 28

Specific pediatric regulations, such as the Pediatric Research Equity Act (PREA) and Best Pharmaceuticals for Children Act (BPCA),

Question 29

Accelerating Approval Process

Answer 29

Leverage FDA programs such as Fast Track, Breakthrough Therapy, Accelerated Approval, and Priority Review. These programs are designed to expedite the development and review of drugs that meet serious conditions and fill unmet medical needs, allowing for faster access to potentially beneficial treatments for children. Early engagement with the FDA in the drug development process to discuss pediatric study requirements and expectations. This includes submitting an iPSP to outline the proposed pediatric studies, which can help clarify regulatory pathways and expectations. Participate in forums like the Pediatric Strategy Forums, which facilitate communications among stakeholders (academia, industry, regulators, patient advocates) to prioritize pediatric drug development and share information that can inform clinical trial designs. Implementing adaptive trial designs that allow for modifications based on interim results. This flexibility can lead to more efficient trials and quicker decision-making regarding treatment efficacy and safety. Utilizing surrogate endpoints that can predict clinical benefit without waiting for long-term outcomes. This approach can significantly reduce the time required for approval. Begin developing age-appropriate formulations early in the process to avoid delays related to formulation challenges later on. Ensuring that formulations are suitable for children can facilitate smoother trial conduct. Work with patient advocacy groups to raise awareness about the importance of pediatric trials, which can help improve recruitment efforts and support from families. Utilize waivers and deferrals when necessary, but aim to minimize their use by planning pediatric studies effectively from the outset. Simplify and the informed consent process for families while ensuring ethical standards are met, which can help improve enrollment rates.

Question 30

Ethical Considerations

Answer 30

Aim to protect children while advancing pediatric health, a balance between the need for research and protection of a vulnerable population. The trial should benefit the child or pediatric population, with risks reasonable in relation to potential benefits. Children should not be exploited for the benefit of the general population, and inclusion/exclusion criteria should be based on valid scientific questions. Parental or guardian consent is required, along with the child's assent when appropriate (typically for children over 7 years old). Transparency and public access to information from pediatric studies is crucial for ethical conduct. Risk-benefit assessment must be conducted with careful evaluation of whether a trial is in a child's best interest, with additional safeguards to protect children throughout the study. Study designs must minimize risks and burden for child participants while maintaining scientific validity.

Question 31

IRB for pediatric trials

Answer 31

All pediatric trials must be reviewed and approved by institutional review boards, which may require additional safeguards, especially regarding children's safety and well-being. IRBs ensure compliance with PREA and BPCA. All pediatric trials must be reviewed and approved by institutional review boards, which may require additional safeguards, especially regarding children's safety and well-being. IRBs ensure compliance with PREA and BPCA. IRBs may require longer-term review of pediatric trials, particularly for assessing long-term safety. Evaluate the risk-benefit ratio, ensuring that the potential benefits justify the risks. For studies with more than minimal risk but potential direct benefits, the IRB conducts a thorough risk-benefit assessment.

Question 32

IRBs classify pediatric studies into different risk categories, each with specific requirements:

Answer 32

Minimal risk Minor increase over minimal risk Greater than minimal risk with prospect of direct benefit Greater than minimal risk with no prospect of direct benefit

Question 33

IRBs reviewing pediatric trials must include

Answer 33

members with pediatric expertise who understand the medical, psychological, ethical, and social needs of child research participants.

Question 34

Pediatric Study Plans (PSP)

Answer 34

Development plans which ensure that necessary data are obtained through clinical trials in pediatric populations. Required regulatory documents in the US. Typically submitted early in the drug development process, ideally during the initial stages of clinical development. Serves as a roadmap to identify and plan pediatric studies, ensuring increased effectiveness and safety in the pediatric population.

Question 35

Under PREA requirements the FDA requires iPSP submission for drugs with: (Pediatric Study Plan)

Answer 35

New active ingredients New indications New dosage forms New dosing regimens New routes of administration

Question 36

Exceptions from PREA Requirements

Answer 36

1. Orphan drug designation are exempt from PREA requirements. 2. The FDA may grant full or partial waivers if: Studies are impossible or highly impracticable Evidence suggests the drug would be ineffective or unsafe in pediatric patients The drug doesn't represent a meaningful therapeutic benefit over existing therapies and is unlikely to be used in a substantial number of pediatric patients Attempts to produce a pediatric formulation have failed

Question 37

The FDA may defer pediatric studies if:

Answer 37

The drug is ready for adult approval before pediatric studies are complete. Additional safety or effectiveness data need to be collected before conducting pediatric studies. There is another appropriate reason for deferral such as scientific issues with study design or endpoints.

Question 38

PSP Components

Answer 38

Plans for pediatric-specific formulations Timeline for conducting pediatric studies Requests for deferrals or waivers (if applicable) Safety considerations for pediatric clinical trials to reflecAn initial PSP is required for sponsors planning to submit a marketing application for a NDA or BLA, except for drugs granted orphan designation for the proposed indication. The iPSP can be amended as necessary throughout the development process t new information or changes in the study design.

Question 39

If an iPSP is deemed incomplete,

Answer 39

, the sponsor has 30 days to correct the deficiencies and submit a complete iPSP.

Question 40

the FDA may issue a PREA Non-Compliance letter to an applicant who fails to submit a required pediatric assessment or report within the required timeframe under what section of the regulations

Answer 40

Under section 505B(d)(1) of the FD&C Act,

Question 41

Applicants are required to annually report the progress of all PREA postmarket requirements as part of the requirements under

Answer 41

PREA requires that the results of all required pediatric studies be included in the product label, whether the data is negative, positive, or inconclusive.

Question 42

After receiving FDA approval, studies conducted under BPCA or PREA undergo a safety evaluation specifically focused on children by the

Answer 42

Pediatric Advisory Committee (PAC) within eighteen months.

Question 43

The FDA requires sponsors to develop and test age-appropriate formulations if one is not already available. Formulations must be:

Answer 43

Easy to swallow Palatable Stable Possible to be dosed accurately in small volumes Including safe excipients

Question 44

BPCA: \ Nature of STUDY scope OF STUDY Indication Expansion FDA's Authority

Answer 44

Sudies are voluntary Can include both approved and unapproved uses ("off-label") Can be used to expand indications for drug use, including orphan indications FDA issues a Written Request for pediatric studies

Question 45

PREA Nature of STUDY scope OF STUDY Indication Expansion FDA's Authority

Answer 45

PREA: Studies are mandatory Limited to approved or pending indications ("on-label") Cannot be used to expand indications beyond those in the NDA submission FDA requires pediatric assessments for drugs and biologics

Question 46

Primary regulatory mechanism under BPCA for obtaining data for pediatric drug approvals and product labeling, addresses:

Answer 46

Type and objective of studies to be performed Indications to be studied Number of patients to be studied Age groups for the studies Study endpoints Timing of assessments Entry criteria

Question 47

Australia

Answer 47

There is a growing recognition of the need for more pediatric clinical trials and a national approach to improve access to novel therapies for Australian children. While Australia has made some progress in pediatric drug development, it still faces challenges due to its small market size and limited influence on global pharmaceutical development. Australian regulatory framework for pediatric drug development is less comprehensive compared to the US, and some key aspects to consider: Therapeutic Goods Administration (TGA) regulates the licensing and labeling of medicines in Australia. Therapeutics must generally be entered on the Australian Register of Therapeutic Goods (ARTG) prior to import, export, supply, or advertising. Australia has established a Pediatric Medicines Advisory Group to provide guidance on pediatric drug development.

Question 48

Challenges

Answer 48

Safety concerns as children are not simply "small adults," and their developing bodies may react differently to medications. Different pharmacokinetics (PK) and pharmacodynamics (PD) as age and developmental stage significantly influence how drugs are absorbed, distributed, metabolized, and excreted in children. Creating age-appropriate dosage forms that are easy to administer and palatable is crucial. Ethical considerations with balancing the need for pediatric research with the protection of vulnerable subjects.

Question 49

Informed Consent Challenges

Answer 49

Parents must understand complex medical information about the trial's purpose, risks, benefits, and alternatives. The consent process is often lengthy and cumbersome, negatively impacting enrollment. Consent from both parents and children may be required, especially for higher-risk studies. Children and parents have varying literacy levels. Parents may be influenced by emotional stress or anxiety about their child's condition. Recruiting children for clinical trials presents challenges that can hinder participation and affect the overall success of the research. Parents often have significant apprehensions about the safety of clinical trials and the potential risks involved for their children. This hesitation can lead to reluctance in enrolling their children in studies. The involvement of children in research raises ethical issues, particularly regarding informed consent and the capacity of children to understand the implications of participation. Researchers must review these complexities carefully, which can complicate recruitment efforts.

Question 50

Recruitment Challenges

Answer 50

Practical issues such as transportation difficulties, time constraints, and financial costs associated with participation can deter families from enrolling their children in trials. These logistical challenges are particularly pronounced in rural areas where access to trial sites may be limited35. There is often a general lack of understanding about clinical trials among parents and caregivers, which can lead to mistrust of the research process. This lack of awareness can result in misconceptions about the purpose and safety of trials. The informed consent process for pediatric trials is more complicated than for adults, requiring both parental consent and child assent depending on age. This complexity can prolong recruitment timelines and deter participation. Certain ethnic and socioeconomic groups may be underrepresented in pediatric trials due to cultural mistrust or barriers to access, which can limit the generalizability of trial results. Families may perceive participation as burdensome due to frequent visits, assessments, or procedures involved in clinical trials, leading to reluctance to enroll. Many studies rely on a single recruitment method, which may not be effective. Using multiple strategies like community engagement and social networks has been shown to enhance recruitment rates but is not always implemented.

Question 51

Decentralized clinical trials (DCTs)

Answer 51

DCTs allow for remote participation, minimizing the need for families to travel to clinical sites. This is beneficial for pediatric patients who may have limited mobility or live far from study sites. Home health visits and telehealth consultations can facilitate participation without the burden of travel. Can occur at convenient times, such as during school hours, allowing children to receive assessments without missing significant time from school. Decentralized elements can lead to higher retention rates in pediatric trials by lowering the barriers to participation. Families are more likely to remain engaged when trial processes are convenient and less disruptive to their daily activities. The use of digital tools and wearables also allows for continuous monitoring and data collection without frequent site visits, which can enhance participant adherence. DCTs utilize digital platforms for data collection, which improves the accuracy and reliability of patient-reported outcomes. Electronic consent systems and mobile applications enable real-time data entry, reducing the likelihood of errors associated with traditional paper-based methods.

Question 52

Takeaways

Answer 52

Pediatric clinical trials play a vital role in advancing children's health, but they require careful consideration of ethical implications, safety measures, and age-specific factors to ensure their well-being. Pediatric trials help create age-appropriate dosages, formulations, and interventions and contribute to understanding how children's bodies respond to medications differently from adults. For children with severe conditions or those not responding to standard therapies, clinical trials can offer new treatment options, addressing unmet needs.