WHITE PAPER

AuthorsScott Daigle, PhDSenior Principal Medical WriterPRA Health Sciences

Brenda Sanchez, MS, RACDirector, Regulatory Strategy PRA Health Sciences

Pediatric Product Development Plans

White Paper | Pediatric Product Development Plans

Children are not Small AdultsIn 1973, a survey of approximately 2000 approved drugs

revealed that 78% of USFDA-approved drugs lacked labeling

information for use in pediatric patients.6 Administering

medication to children in such cases amounts to treating

patients without a standard of care for guidance. There was

a lack of data, which caused the lack of instruction. Since

then, in efforts to close the gap on data and labeling

information between adult and pediatric patients,

legislation in the US, Europe, and elsewhere has tried to push

and pull drug developers to perform research in pediatrics.

From the 1990’s the US and EU have created our current

regulatory environment. It employs rewards and requirements

for drug developers to research drugs in the pediatric population.

But what is the problem and what is the scale? Without

complete labeling for pediatric patients, off-label use of an

approved medication is a possibility. In 2012, Kemland et al

estimated that between 46% and 64% of children in primary

care in the US receive off-label medications. Off-label use

increases with the intensity of care. Also, approximately

67% of children in a hospital receive off-label medication

and approximately 90% of children in neonatal or pediatric

intensive care receive off-label medication.7 Administering

medicine to children is not simply a matter of adjusting

the adult dose for weight. Children are not simply small

adults. Besides height and weight, children have important

differences in metabolism, metabolizing pathways, physiology,

hormones, and diets from adults. For example, some common

metabolizing enzymes, such as CYP1A2, reach adult-level

activities by the age of 3 months in a child8 while others, such

as CES2, take 2 years.9 Most metabolizing pathways continue

to mature through age 6. Research and labeling information

must account for the developing maturity. Consequently, as

a result of the differences in maturity, metabolism, size, diet,

and physiology, in both clinical studies and in the healthcare

systems, there remains a lack of information about how to

monitor for safety or efficacy when treating children with

drugs. Understanding the differences between adult and

pediatric patients requires study and development.

However, drug developers have not invested as earnestly in

development of pediatric treatments as with adults. Clinical

research is expensive, requiring deep expertise and focus

from developmental teams within pharmaceutical companies.

Trials in pediatrics frequently require additional monitoring,

Executive Summary Development of the Pediatric Study Plan (PSP) for the United States Food and Drug Administration (USFDA) and the Paediatric

Investigation Plan (PIP) for the European Medicines Agency (EMA) must be an integral part of the overall clinical development

plan. Development of these plans should begin 1 to 2 years in advance of the anticipated start of the adult Phase 3 program. The

Pediatric Research Equity Act (PREA, 2003, 2007)1, 2 gives the USFDA the legal authority to mandate that drug developers conduct

studies in children, unless the USFDA grants a specific waiver. The PIP laws from the European Parliament from 20073, 4 empower

the EMA to require that drug developers conduct studies in children to support the authorization for medicines for children in the

European Union (EU). The Better Pharmaceuticals for Children Act (BPCA)2 within the USFDA Modernization Act of 19975 in the

United States (US) awards drug developers an additional 6 months of market exclusivity, if the Sponsor conducts pediatric research

as requested by the USFDA.

Children with diseases need safe and effective treatments, but it is widely acknowledged that drug development has historically focused on treatments for adults. This produces a significant deficit in well-studied drugs for pediatrics.

White Paper | Pediatric Product Development Plans

independent Data Monitoring Boards, and pediatric clinical

supplies, increasing complexity, resource allocations, and

costs. Most importantly, the ethical considerations in a

pediatric trial are different. Children are still developing.

Long-term risks to bone, muscle, cognitive, and sexual

development are significant concerns when administering

a medication to a child, especially in a research environment

when there are so many unknowns. Children cannot provide

their own consent; they require a decision from parents. The

net result of these factors: pediatric research has been avoided

whenever possible.

Children with diseases need safe and effective treatments,

just like adults. But, it is widely acknowledged that drug

development has historically focused on safe and effective

treatments for adults. This produces a significant deficit in

well-studied drugs for pediatrics. For example, according

to CenterWatch, in each year from 2015 through 2017,

the USFDA approved 70 to 100 new drugs or new indications

for treatment for adults, compared with 3 to 10 approvals for

drugs to treat pediatric patients.

Globally, the United Nations estimates for the year 2019

indicate that pediatrics (0 to 17 years) comprise about 30%

of the population.10 In the US and across Europe, pediatrics

represent 22% and 19%, respectively, of the population.

However, the pediatric population represents less than

10% of the global market sales for the same year. Although

population and sales may not track together perfectly, the

proportions would expect to be similar; the market potential

would seem to be there.

Regulations and IncentivesResearch is necessary to understand the risks and provide

guidance to physicians treating pediatric patients with

products primarily studied in adults. Clinical trials in pediatric

patients are necessary.

Since the 1990s, the governments of major markets in the

US and the EU have provided a system of incentives and

requirements to encourage drug developers to conduct more

research in children and close the information gap between

the adult and pediatric administration of drugs. The Better

Pharmaceuticals for Children Act (BPCA)2 within the USFDA

Modernization Act of 19975 in the US awards drug developers

an additional 6 months of market exclusivity if they conduct

pediatric research as requested by the USFDA. The additional

6 months of exclusive sales (adults and pediatrics) for a drug

can be a significant financial benefit. The PREA1, 2 gave the

USFDA the legal authority to mandate that drug developers

conduct studies in children unless the USFDA grants a specific

waiver. Similarly, in the EU, the PIP requirements from 20073, 4

follow a similar pattern, empowering the EMA to require that

drug developers conduct studies in children to support the

authorization for medicines for children in the EU.

The regulatory goal of providing labeling information specific

to pediatric patients is being achieved: from 1998 through

2018 the USFDA approved 770 labeling changes (representing

620 unique drugs) for pediatric patients.11 During that same 20

year period, the USFDA received 453 requests for approved

drugs12 and granted additional exclusivity for 242 drugs.13

Drug makers must have a plan for conducting research in pediatric subjects and must implement it early in the overall drug development program.

Development of the PSP and PIP must be an integral part of the overall clinical development plan. Development of these plans should begin 1 to 2 years in advance of the anticipated start of the adult Phase 3 program.

White Paper | Pediatric Product Development Plans

Process and TimingThe results of these legislations in the US and EU is strategically

simple: the drug maker must have a plan for conducting

research in pediatric subjects and must have it early in the

overall drug development program.

The US requires the Sponsor to submit an initial PSP to the

relevant drug’s Investigative New Drug (IND) no later than

60 days after the date of the End-of-Phase 2 (EOP2) meeting.14

The USFDA provides advice to the Sponsor, and together the

USFDA and Sponsor reach an agreement for the initial PSP.

Similarly, the EMA requires that the applicant submit an initial

PIP to its Pediatric Committee (PDCO) around when Phase 2

clinical studies in adults are initiated and no later than when

Phase 3 clinical studies are initiated. The PDCO, represented

by a rapporteur, and an independent peer reviewer, provide

feedback to the applicant. The PDCO makes a recommendation

to the EMA, who approves or rejects the PIP. For each of the

regulatory agencies, a pediatric product development plan

should be in place before initiating Phase 3 clinical trials

in adults.

The details of the regulations and processes, of course, are

different, but the outcome is the same: an agreement for a

pediatric development plan that the drug maker is obligated

to complete.

There is a philosophical difference between the USFDA and

EMA. In the initial PSP, the USFDA expects the Sponsor to

provide a minimal outline of the pediatric development plan,

consistent with the understanding of the disease state in

pediatrics and the stage of the product development. As

clinical and nonclinical studies complete, data are collected

and analyzed. As the whole drug development program

evolves, the USFDA expects the Sponsor to add to the PSP

with evermore detailed information. In contrast, the EMA

requires a full and complete PIP at the outset. However, the

PIP can be amended if necessary.

In practice, the PSP and PIP are reviewed, updated, and revised

as the drug program evolves. Each revision to a PSP requires

a new agreement with the USFDA; similarly, each revision to a

PIP requires a new PDCO review and recommendation to the

EMA, who may approve or reject the revised PIP.

Building a Pediatric Development ProgramThe PSP and PIP are organized differently, but include the

same information for the most part in varying degrees of

specificity: summary of the disease, proposed indication and

condition, ages to be studied or excluded, incidence rates

(especially in the region governed by each agency), description

of the drug, summary of the planned nonclinical, modeling, and

clinical studies in the drug program, with particular emphasis

on studies expected to provide decisive pharmacokinetic,

dosing, safety, and efficacy results supporting the pediatric

trials. The Sponsor/applicant must provide a plan for the

pediatric formulation and presentation. This part of the plan must

describe whether the adult formulation and presentation will be

used or if a pediatric-specific formulation and presentation will

be developed. The formulation and presentation plan must cover

the materials to be used in the pediatric clinical trials, as well as

the product that is expected to be marketed, assuming the

whole development program has positive results and yields

a marketable product. Perhaps most importantly, the PSP and

PIP must provide a schedule of when the planned studies and

formulation/presentations milestones start and finish so that

the dependencies are obvious.

Development of the initial PSP and PIP must be an integral

part of the overall clinical development plan and should begin

1 to 2 years in advance of the anticipated start of the adult

Phase 3 program. The PSP and PIP processes are complex,

with multiple dependencies that require particular expertise

and coordination.

White Paper | Pediatric Product Development Plans

Citations

1 Pediatric Research Equity Act (PREA) of 2003 (Public Law 108–155—DEC. 3, 2003).

2 Food and Drug Administration Amendments Act of 2007 (FDAAA), Title IV Public Law 110-85—Sept. 27, 2007).

3 Regulation (ec) no 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal

products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive

2001/83/EC and Regulation (EC) No 726/2004.

4 Regulation (EC) No 1902/2006 of the European Parliament and of the Council of 20 December 2006 amending

Regulation 1901/2006 on medicinal products for pediatric use.

5 Food And Drug Administration Modernization Act of 1997 Public Law 105–115—NOV. 21, 1997.

6 Wilson JT. Pragmatic assessment of medicines available for young children and pregnant or breast-feeding women.

Basic and therapeutic aspects of perinatal pharmacology. In: Morselli PL, Garattini S, Sereni F, editors. Basic and

therapeutic aspects of perinatal pharmacology. New York, NY: Raven Press, pp. 411-21.

7 Kimland E, Odlind V. Off-label drug use in pediatric patients. Clin Pharmacol Ther 2012;91:796-801.

8 Tateishi T, Asoh M, Yamaguchi A, et al. Developmental changes in urinary elimination of theophylline and its

metabolites in pediatric patients. Pediatr Res 1999;45(1):66-70.

9 Pearce RE, Gaedigk R, Twist GP, et al. Developmental expression of CYP2B6: a comprehensive analysis of mRNA

expression, protein content and bupropion hydroxylase activity and the impact of genetic variation. Drug

Metab Dispos 2016;44(7):948-58.

10 United Nations DoEaSA, Population Division World population prospects of the United Nations, Department of

Economic and Social Affairs, Population Division. 2019. Accessed 05 May 2020.

11 USFDA. Food and Drug Administration. New pediatric labeling information database. 2019. Accessed June 30, 2019.

12 USFDA. Food and Drug Administration. Written requests issued: approved active moieties to which FDA has issued a

written request for pediatric studies under section 505A of the Federal Food, Drug, and Cosmetic Act. 2019. Accessed

July 10, 2019.

13 USFDA. Food and Drug Administration. Pediatric exclusivity granted: drugs to which FDA has granted pediatric

exclusivity for pediatric studies under section 505A of the Federal Food, Drug, and Cosmetic Act.. 2019.

Accessed May 29, 2019.

14 Under the Food and Drug Administration Safety and Innovation Act (FDASIA) Public Law 112-144–July 9, 2012;

(21 USC 355c(a) and (e)).

PRA Health Sciences conducts comprehensive Phase I-IV biopharmaceutical drug development. To learn more about our solutions, please visit us at prahs.com or email us at prahealthsciences@prahs.com.

White Paper | Pediatric Product Development Plans

Contact Information

For further information, or to discuss PRA’s services and Pediatric Product Development Plans, please contact your PRA account manager or the PRA employees listed below:

JUN

E 2020

Scott Daigle, PhD

Senior Principal Medical Writer

PRA Health Sciences

995 Research Park Blvd, Suite 300,

Charlottesville, Virgina 22911, USA

Phone: +1 434 951 3426

DaigleScott@prahs.com

Brenda Sanchez, MS, RAC

Director, Regulatory Strategy

PRA Health Sciences

4130 ParkLake Avenue, Suite 400

Raleigh, North Carolina 27612 USA

Phone: +1 919 788 3257

SanchezBrenda@prahs.com

World Headquarters

4130 ParkLake Avenue, Suite 400

Raleigh, North Carolina 27612 USA

Phone: +1 (919) 786 8200

Fax: +1 (919) 786 8201

www.prahs.com