WHITE PAPER
Global Pediatric Drug Development Collaboration:
Part Two
Authors
Dr. Martine Dehlinger-Kremer Vice President of Scientific Affairs, Pediatric Subject Matter Expert Center for Pediatric Clinical DevelopmentPRA Health Sciences Jo Dewhurst, BSc (Hons), LLB DipPediatric Strategy Liaison, Center for Pediatric Clinical DevelopmentPRA Health Sciences Melissa Hansen, MSN, APRN, CNP-PediatricsPediatric Strategy Liaison, Center for Pediatric Clinical DevelopmentPRA Health Sciences Jacqui Whiteway, PhDSenior Pediatric Strategy Liaison, Center for Pediatric Clinical DevelopmentPRA Health Sciences
Pediatric Legislations in the US and the EU – Similarities and Differences The need for drug development programs specifically for
pediatric patients is an issue that authorities in the US have
been working on since the 1990s. In 2003, US authorities
made it mandatory for new products to have a pediatric
drug development plan. In the US, two laws govern pediatric
development: Best Pharmaceutical for Children Act (BPCA)1
and Pediatric Research Equity Act (PREA).2 PREA requires
companies to determine safety and efficacy of new drugs and
biological agents in pediatrics unless a waiver is granted or
the product is exempt from PREA. An initial Pediatric Study
Plan (iPSP) must be submitted to the FDA for medicines falling
under PREA. This means that, with exemption of waivers or
deferrals, marketing applications for new products need
to contain pediatric data as well. In 2006, the EU followed
suit, closely guided by the US model. In 2006, Regulation
1901/20063 as amended (Pediatric Regulation) was enacted
and came into force on January 26, 2007. The Pediatric
Regulation introduced a single system of pediatric obligations
and incentives to facilitate the evaluation of newly authorized
drugs protected by a Supplementary Protection Certificate.
For new products, the pediatric investigation plan (PIP)
applications are required to be submitted to the EMA no later
than upon completion of adult human pharmacokinetic studies.
An overview of pediatric legislations in the US and EU,
including similarities and differences, is depicted in Table 1.
White Paper | Global Pediatric Drug Development Collaboration: Part Two
IntroductionThe pediatric population who needs treatment represents a small population when compared to the adult population, hence the
importance of global drug developments. As pediatric legislations are not global, collaboration to achieve agency alignment is
a way to global drug development. Pediatric development is driven by US and EU legislations. These legislations have both similarities
and differences that must be overcome for global drug development. Several tools and processes have been implemented to
facilitate agencies collaboration in view of supporting global pediatric drug development.
In Part One of this white paper series, we outlined the unique challenges that face pediatric drug development and shared some
effective examples of industry collaboration. You can read Part One here. In Part Two, we discuss some of the different pediatric
legislations in place, as well as steps that global agencies are taking to better facilitate pediatric drug development. We share examples
of effective collaboration that have helped shape the current drug development paradigm, and call for continued harmonization
and innovation of pediatric science and research to ensure children get the medicines they need faster.
DescriptionEU US
PIP PUMA PREA BPCA
Applicable regulationRegulation (EC) No 1901/2006 and as amended 1902/2006
Regulation (EC) No 1901/2006 and as amended 1902/2006
PREA and FDASIA 2012 BPCA and FDASIA 2012
Scope Mandatory Optional Mandatory Optional
Applicable product classifications
Drugs, biologics (including orphan products): new products, new indications, or pharmaceutical forms that qualify for or are protected by a supplementary protection certificate (SPC)
• Already authorized• No longer covered by SPC
or patent that qualifies for a SPC
• Products indicated exclusively for use in the pediatric population
Drugs, biologics and biosimilars involving new active ingredient, indication, dosage form, dosing regimen, or route of administration
Drugs, biologics (including biosimilars, orphan products, and off-patent products)
Exemptions
• Genetics• Hybrids• Traditional herbal products• Biosimilars• Well-established use• “Class waiver” products
Not applicable, optional scope
• Orphan designated products*
• Generics• Dietary (including herbal)
supplements
Dietary (including herbal) supplements
Grounds for waiver (partial or full waivers)
• Likely to be ineffective or unsafe
• Condition only occurs in adults or a pediatric subset
• Does not represent significant therapeutic ben-efit over existing treatments for pediatrics
Not applicable
• Evidence strongly suggests product would be ineffective or unsafe
• Necessary studies impossible or highly impossible
• Does not represent significant therapeutic benefit over existing therapies for pediatrics and not likely to be used in a substantial number of pediatric patients
• Not possible to develop an age-appropriate pediatric formulation
Not applicable
Scope
• Derived from adult indication within the same condition
• One PIP may cover more than one condition/ indication
Condition/indication exclusive to pediatric use
• Only required for indication that will be under review
• One iPSP for each indication
Related to the entire moiety. The FDA may request studies for a different indication including an indication not approved in adults
Table 1: Regulatory requirements for PIP, PUMA, PREA, and BPCA
* The FDA Reauthorization Act of 2017 (PL-115-52 August 18, 2017) provides the FDA with new authority to require a pediatric investigation into an adult cancer drug if that drug is directed at a molecular target that is relevant to a pediatric cancer. Federal Food, Drug, and Cosmetic Act (as amended through P.L. 115-92, enacted 12 December 2017) Section 21 USC 321(g)(1). Office of the Legislative Counsel website (Available at: https://bit.ly/1k73myS)
White Paper | Global Pediatric Drug Development Collaboration: Part Two
DescriptionEU US
PIP PUMA PREA BPCA
TimingEnd of Phase 1 (adult pharmacokinetic data)
End of Phase 1 (adult pharmacokinetic data)
• Within 60 days of End of phase 2 (EOP2) meeting
• If no EOP2, at least 210 days prior to planned NDA/BLA filing
• Determination of exclusivity is based on completed reports for all studies listed in the written request (WRI)
• The FDA has up to six months to review reports to make a final determination
• The FDA’s decision on exclusivity determination should be made no later than nine months before the patient or exclusivity expiration or pediatric exclusivity will not be granted
Instrument PIP PIP iPSP
• Proposed pediatric study request (PPSR) issued by the sponsor to the FDA
• WR issued by the FDA
Key rewards and incentives
• Six month extension to supplementary protection certificate
• For orphan products an additional two years of market exclusivity
• Free pediatric scientific advice
• Automated access to centralized procedure
• Eight years data + two years of market protection
• Partial exemption from submission fees and post-authorization fees for one year
None
• Additional six months of exclusivity to an existing patent on the entire moiety
• Priority review status for pediatric applications/supplements
Table 1: Regulatory requirements for PIP, PUMA, PREA, and BPCA
The FDA’s two pediatric regulatory pillars, BPCA and PREA,
work together to accomplish the goal of obtaining adequate
efficacy and safety data for labeling. However, long periods
remain between adult approval and pediatric data and
labeling with nine years still being the norm.4 The needs of
pediatric-specific diseases are stark, especially in respect
of neonates and premature infants as well as for cancer and
genetic diseases.
Progress is being made gradually. We have seen the imple-
mentation of pediatric extrapolation, adoption of innovative
clinical trial designs, exploration and acceptance of Real
World Evidence, the set-up of clinical trial networks, and global
alignment activities led by regulators.
White Paper | Global Pediatric Drug Development Collaboration: Part Two
Global Agency Collaboration — Tools and Processes
FDA and EMA Parallel Scientific Advice
The parallel scientific advice program provides a mechanism
for FDA reviewers and EMA assessors to concurrently exchange
with sponsors their views on scientific issues during the
development phase of a new product. The interactions aim
to provide a deeper understanding of the bases of regulatory
decisions, optimize the development program, and avoid
unnecessary testing replication or unnecessary diverse
testing methodologies.
For pediatric developments, going through an EMA–FDA
parallel scientific advice procedure before finally drafting and
submitting the iPSP and PIP will facilitate global alignment of
the pediatric development program. This may be of particular
benefit to pediatric plans for medicines that are first in class or
present an innovative approach.
Pediatric scientific advice agreed upon by the Scientific Advice
Working Party (SAWP) and endorsed by the Committee for
Human Medicinal Products (CHMP), is considered as important
in the Pediatric Committee (PDCO) PIP assessment. There is
a close collaboration between the SAWP and the PDCO, the
latter being involved in pediatric scientific advice, including
the parallel scientific advice with the FDA.
Pediatric Cluster Meetings
The pediatric cluster meetings were established in 2007,
shortly after the first PDCO meeting took place. The cluster
meetings are monthly teleconferences held between the FDA
and EMA, together with Health Canada, Pharmaceutical and
Medical Device Agency (PMDA) (Japan), and Therapeutic
Goods Agency (TGA) (Australia). The objective of the cluster
is to support global development plans for pediatrics by
exchanging information on products and general issues. More
than one approach may be possible but unnecessary studies
are to be avoided. The aim is to seek a harmonized approach
to the fullest extent possible and, whenever possible, consensus
on their requirements for the individual pediatric plans.
Between August 2007 and March 2019, information has been
exchanged on 517 products, with 172 discussions on general
topics.5 Frequently discussed product issues include scope of
pediatric product development, waiver, quality, non-clinical,
adult and pediatric study results, indication, safety, trial design,
sample size, dose, endpoints, study population, extrapolation,
timelines, and long-term follow-up. General discussions
include endpoints, extrapolation, meetings/workshops, joint
publications, and regulatory action.
Between 2014 and 2017, convergence on approaches have
been achieved for 73% of the issues discussed. From 1997
to 2017, over 650 products in the US have been labeled with
additional information gathered from pediatric trials. Since
the implementation of the regulation in the EU, 238 new
medicines for use in children and 39 new pharmaceutical
forms appropriate for children were authorized between
2007 and 2015.6
The EMA and EU Commission also plan to enhance cluster
meetings on topics and therapeutic areas requiring greater
exchange of information.
In terms of product-specific discussions, between 2007 and
2016, 425 products were discussed. The majority of these
products were in oncology (see Figure 1), showing the
importance of oncology in the pediatric field and the need
for global development plans.
White Paper | Global Pediatric Drug Development Collaboration: Part Two
Oncology
Gastroenterology/Inborn Errors
Endocrine/Metabolic
Anti-Virals
Cardio/Renal
CBER
Neurology
Special pathogens/Transplant/Opthlamology
Anti-infectives
Pulmonary/Rheumatology
Anesthesia/Analgesia
Dermatology
Psychology
Hematology
Reproductive/Urology/Bone
0 10 20 30 40 50 60 70 80 90 100
92
55
50
46
36
28
20
18
17
16
14
12
9
8
4
Figure 1: Pediatric Cluster Product Discussions (2007-2016)7
Figure 2: Type of clinical trial issues discussed during the pediatric cluster meetings (2007-2016)
Pediatric Cluster Products Discussed by Division (2007–2016)
n=425
Number of Product Discussions
When reviewing the type of clinical trial issues discussed
during the cluster meetings for the period from 2007 to 2016,
the scope of pediatric development is the most important
subject followed by safety, trial design, and regulatory aspects.
Work
shop/M
eeting
Form
ulatio
n
Timing
Age Gro
up
Extrapolat
ion
Non-clinica
l
Dosing
Waive
rs (in
cludes F
ull
and Parti
al Waive
rs
Primary
Endpoint
Study P
opulatio
n
Types o
f Clin
ical T
rial
Regulatory
/
Regulatory
Acti
on
Trial D
esign
Safety
Scope o
f Pediat
ric
Develo
pment
Types of Clinical Trial Issues Discussed
Num
ber
of D
iscu
ssio
ns
250
200
150
100
50
0
27 29 3148
65 70 76 81 87 90 95 101 103
159
218
White Paper | Global Pediatric Drug Development Collaboration: Part Two
There are a few issues faced at the pediatric clusters. Individ-
ual divisions have varying levels of pediatric expertise and
international experience which have their importance as the
pediatric cluster aims to avoid the fragmentation of pediatric
development activities. The pediatric cluster is also responsible
for ensuring that the appropriate pediatric and other subject
matter experts are in attendance and providing additional
coordination with the Pediatric Review Committee (PeRC) and
other divisions.
These clusters are important because there are different laws
in different regions: PREA requires certain thing to be studied,
BPCA provides incentives for doing more, and the EU pediatric
legislation requires earlier commitment to pediatric plans.
Anticipating together, with the FDA and EMA, is essential to
avoid missed opportunities and learnings.
The pediatric cluster shows efficiency in resolving differences.
One example is in respect to the patient population for an
oncology product designed to treat a specific type of medullo-
blastoma. The sponsor proposed to the EMA newly diagnosed
and relapsed/refractory patients with medulloblastoma and
to the FDA relapsed/refractory patients with medulloblastoma
only. As an outcome of the common discussion, the FDA re-
quested the sponsor to study both patient populations.
The collaboration between the agencies is also successful in
resolving discrepancies in respect to timing of the pediatric
trials. For a drug to be used as add-on to insulin to treat Type
1 Diabetes Mellitus (T1DM), the initial position of the EMA was
that pediatric trials would start after efficacy and safety data
were available in adults with T1DM as the drug was an add-
on drug and the first in its class to be studied in children with
T1DM. The FDA position was that it would be sufficient to have
interim adult data in T1DM and pediatric PK/PD T2DM data
in patients who received this product. The FDA based their
position on the fact that there was a significant unmet need,
i.e., many children and adolescents with T1DM did not achieve
their glycemic targets on insulin alone. Following discussion in
the cluster meeting, the EMA understood the rationale of the
FDA and aligned with it on an earlier timing of the pediatric
program in order to address the significant unmet need.
These examples demonstrate how important a global pediatric
approach is to successfully develop much needed medicines
for children. Such a global approach can be realized through
ongoing harmonization of the science, which will make pediatric
product development easier and faster. Key contributors
to this are the pediatric cluster teleconferences, but also
initiatives such as joint working groups, workshops and expert
meetings for extended discussions, joint publications, and the
development of global pediatric trial networks and consortia.
The European Medicines Agency and European Commission
(DG Health and Food Safety) action plan on pediatrics published
in October 2018 includes a strengthening of cooperation of
decision makers. The plan foresees an enhanced integration
of EMA/FDA pediatric cluster activities to ensure knowledge
and information exchange between PDCO and the pediatric
regulatory cluster. This will also increase transparency with
regard to EMA/FDA pediatric cluster discussions to better
inform sponsors about pediatric cluster discussions and to
increase transparency for all relevant stakeholders regarding
outcomes of non-product related interactions. A deadline for
completion of the latter is June 2020. A progress report for
the action plan on pediatrics is to be published in July 2020.8
Common Commentary
A new tool, the “common commentary,” was launched in
2012 to inform sponsors of issues discussed for some
products at the pediatric cluster, showing a commitment to
a more collaborative approach with industry.
The common commentary serves to inform sponsors in writing
of products discussed where the FDA and EMA have come to
an agreement on the proposal at the pediatric cluster meeting.
The document is non-binding and is not regulatory advice.
The common commentaries pertain to pediatric development
plans that have been submitted to both the FDA and EMA, are
under review by both agencies, and have been discussed at
the cluster.
Between 2012 and 2015, 25 issues were considered. Oncology
(n=10) and gastroenterology (n=9) were the therapeutic areas
most often discussed, with the remaining therapeutic
areas being cardiology (n=2), and one each for neurology,
dermatology, inborn errors, and antimicrobial.
In addition, the two agencies have collaborated in publishing
manuscripts and editorials pertaining to development of
products for the treatment of pediatric ulcerative colitis,
Crohn’s disease, and type 2 diabetes mellitus.
White Paper | Global Pediatric Drug Development Collaboration: Part Two
Common Commentary – Impact on Pediatric Cancer Drug Development
With respect to oncology, joint efforts and common commen-
taries directly influenced the decisions on pediatric cancer
drug development plans. Between 2012 and 2016, 46
scientific discussions of 26 distinct oncology products were
held.9 Those discussions focused on toxicity, non-clinical data
versus adult patient experience and suggested monitoring
plans, eligible patient populations, planned indication,
and study design. Common commentaries were issued for
eight oncology products (see Table 2 below). All sponsors
expressed appreciation for the common commentaries.
Global collaborative studies were recommended in many cases.
All common commentaries directly influenced decisions PIPs,
PSPs, and Written Requests (WR). Initial common commentaries
resulted in parallel scientific advice in some cases. As of
today, two of the drugs have a pediatric labeling approved
and others have ongoing pediatric trials in view of approval
for the pediatric population.
Following the implementation of the Research to Accelerate
Cures and Equity (RACE) for Children Act, an increase in the
development of drugs for pediatric cancers is expected. For
those developments, collaboration for the investigation of new
agents will be key due to the small subpopulation of children
with low incidence cancers. Duplication and competing trials
must be avoided.
Product Sponsor Date Discussion Topics
Sonidegib Novartis 2012 Toxicity, eligibility, indication, in vitro diagnostic assay, unmet clinical need
Volasertib Boehringer Ingelheim 2013 Eligibility, indication, trial design, unmet clinical need
Nivolumab BMS 2013Toxicity, eligibility (age-related concerns), indication, dosing plans, combination therapy plans, trial design, potential for partial extrapolation
Blinatumomab Amgen 2013 Toxicity, eligibility, indication, trial design, dosing optimization
Evofosfamide Threshold 2013Relevance to pediatric cancer, clinical pharmacology, trial design, potential for partial extrapolation
Inotuzumab Pfizer Not sent Toxicity, eligibility, indication, trial design
Oncology Matrix Proposal Roche/Genentech 2015 Eligibility, indication, trial design
Dabrafenib Novartis 2016Toxicity, eligibility (age-related concerns), indication, dosing plans, combination therapy plans, trial design, in vitro diagnostic assay
Table 2: Examples of FDA EMA Common Commentaries 2012-201610
White Paper | Global Pediatric Drug Development Collaboration: Part Two
Common Commentary – Impact COVID-19 Pandemic
A unique and successful example of collaboration between
agencies is the global approach for the development of an
initial Pediatric Study Plan (iPSP) and Pediatric Investigation
Plan (PIP) for the prevention and treatment of COVID-19. Due
to the global public health crisis resulting from the coronavirus
disease 2019 (COVID-19) pandemic, the FDA and EMA are
providing procedural assistance to sponsors and applicants
who anticipate submission of pediatric product development
plans for new drugs and biological products for the treatment
or prevention of COVID-19.
On June 2, 2020, the FDA and EMA published a common
commentary to streamline administrative processes and
facilitate efficient submission of an iPSP and PIP. This common
commentary11 addresses only the submission of an iPSP
and PIP for a drug or biological product for treatment or
prevention of COVID-19. This is an excellent example of
how greater alignment can be achieved.
There are many similarities between FDA’s iPSP template and
EMA’s PIP template, as depicted in the diagram below. However,
due to the differences in legislations, a single template would
not serve the regulatory needs of both agencies.
Given the need to generate clinical trial data to inform safe
and effective use of products to treat and prevent COVID-19 in
pediatric patients, the FDA and EMA agree to and encourage
early submission of an iPSP and PIP (no difference in timelines).
Furthermore, the FDA and EMA would meet as needed to
exchange information to facilitate the product development
for the pediatric population. This is an encouraging example
that shows the flexibility of the agencies and what can be
achieved through close collaboration.
White Paper | Global Pediatric Drug Development Collaboration: Part Two
Table 3: Comparison of specific PSP and PIP template structures 12
PSP Template
Initial Pediatric Study Plan Template
1. Overview of the Disease in the Pediatric Population
2. Overview of the Drug or Biological Product
3. Overview of Planned Extrapolation of Effectiveness to Specific Pediatric Populations
4. Planned Request for Drug-Specific Waiver(s)
5. Plan to Request Deferral of Pediatric Studies
6. Tabular Summary of Planned Nonclinical and Clinical Studies
7. Age Appropriate Formulation Development
8. Nonclinical Studies
9. Clinical Data to Support Design and/or Initiation of Studies in Pediatric Patients
10. Planned Pediatric Clinical Studies10.1 A Brief Outline of Any Proposed Pharmacokinetic Studies10.2 A Brief Outline of Any Proposed Clinical Effectiveness and Safety Studies
11. Timeline of the Pediatric Development Plan
12. Agreements for Pediatric Studies with Other Regulatory Authorities
PIP Template
Part B Overall Development of the Medicinal ProductB.1.1 Similarities and differences of the disease/condition between populationsB.1.2 Pharmacological rationale and explanationB.2 Current methods of diagnosis, prevention, or treatment in pediatric populationB.3 Significant therapeutic benefit/fulfillment of therapeutic needs
Part C Applications for Product-specific WaiversC.1 Overview of waiver request(s)C.2 Justifications for a product-specific waiverC.2.1 Applications based on likely lack of efficacy or safetyC.2.2 Applications based on the disease or condition not occurring in the specified pediatric subset(s)C.2.3 Applications based on lack of significant therapeutic benefit
Part D Proposed Pediatric Investigation PlanD.1.1 Pediatric investigation plan indicationD.1.2 Selected pediatric subset(s)D.1.3 Information on the existing quality, non-clinical, and clinical dataD.2 Pediatric Formulation DevelopmentD.2.1 General strategyD.2.2 Summary of all planned and/or ongoing measures in the pharmaceutical developmentD.3 Non-clinical StudiesD.3.1 General StrategyD.3.2 Summary of all planned and/or ongoing non-clinical studiesD.4 Pediatric Clinical StudiesD.4.1 General StrategyD.4.2 Pediatric pharmacokinetic/pharmacodynamic studiesD.4.3 Clinical efficacy and safety studiesD.4.4 Summary of all planned and/or ongoing clinical studiesD.4.5 Details of the planned and/or ongoing pediatric clinical studiesD.5 Other Studies — Modeling and Simulation/ExtrapolationD.5.1 Modeling and simulation studiesD.5.2 Extrapolation studies
Part E Request for DeferralsE.1 Timelines
White Paper | Global Pediatric Drug Development Collaboration: Part Two
Ongoing Progress to Intensify Collaboration for Pediatric Drug Development
Relevant Molecular Targets in Pediatric Cancers
In March 2018, the EMA and European Commission held a
workshop with patients, academia, healthcare professionals,
industry, and FDA representatives to discuss how to better
apply the Pediatric Regulation to boost development of
medicines for children. One of the 21 actions following the
March 2018 meeting was to establish a framework for collabo-
ration with EMA/PDCO and the FDA’s Oncology Center of
Excellence to assess relevant molecular targets in pediatric
cancers by December 2019. The progress report of the pediatric
action plan will be published in July 2020. For the time being,
the EMA reviews pediatric oncology programs with the FDA
on a monthly basis via the pediatric cluster. Furthermore, both
the EMA and FDA have been represented in the ACCELERATE
steering committee since 2019 and are actively engaged in the
organization of pediatric strategy forums addressing needs in
children with malignancies.
The relevant molecular targets in pediatric cancers is not
envisioned to restrict authority or flexibility. The molecular
target list13 is a great example of international collaboration.
It was constructed by the Oncology Center of Excellence
(OCE) with the National Cancer Institute (NCI) and input from
international content experts in an open public meeting on
April 20, 2018 at the FDA. The target list is continuously
reviewed by means of semi-annual public workshops, with
the possibility of on-going recommendations for additions
and deletions through internal and external advice panels.
Enhance the Integration of EMA/FDA Pediatric Cluster Activities
Another of the 21 actions from the pediatric action items list
which resulted from the March 2018 stakeholder meeting
was to enhance the integration of EMA/FDA pediatric cluster
activities to ensure knowledge and information exchange
between PDCO/EMA and the pediatric regulatory cluster.
The deadline for final outcome is June 2020. A report is to
be published in July 2020.
Further Collaboration and Alignment NeededOne of the greatest challenges facing pediatric drug develop-
ment is the fact that children are generally healthy and therefore
pediatric patients are limited. Current pediatric legislations in
the US and EU do not present a possibility of prioritization of
disease based on unmet medical need or a data-driven process
that can equitably identify and prioritize drugs for clinical trials.
As a result, concerns regarding execution of the pediatric
trials that are part of agreed pediatric development plans have
been noted.14
In 2013, the EMA held a workshop in response to the pediatric
studies that were required under the Pediatric Regulation for
several new drugs for type 2 diabetes mellitus. At that time,16
PIPs (with a total of 31 studies) had been agreed upon across
the class of glucagon-like peptide-1 analogues, dipeptidyl
peptidase 4 inhibitors, and sodium-glucose co-transporter 2
inhibitors, of which none had been able to successfully progress.
ICH E11 (R1)
The FDA and EMA, along with other global regulatory authorities
and industry representatives, participated in the addendum
R1 of the International Council for Harmonization (ICH) E11
guideline, “Clinical Investigation of Medicinal Products in the
Pediatric Population.” The addendum aims to advance pediatric
research with clear, compatible guidance specific to global
product development of pediatric medicines. Addendum
R1 provides clarification and current regulatory perspectives in
pediatric drug development among others on commonality of
scientific approaches for pediatric drug development programs.
ICH E11A Pediatric Extrapolation
This new ICH Guideline is proposed for harmonization of
methodologies and strategies to incorporate pediatric
extrapolation into overall drug development plans. This will
improve the speed of access to new drugs for pediatric
patients while limiting the number of children required for
enrollment in clinical trials.
White Paper | Global Pediatric Drug Development Collaboration: Part Two
There is a need for a rational, collaborative, and data-driven
approach to identifying and prioritizing drugs for studies
that are within the scope of legislative requirements. Drug
development should be driven through science. There is also
a need for choosing and prioritizing the potentially best drugs
to move forward. Working together with regulators, sponsors,
patient advocates, and academic experts across company
portfolios will help better inform and facilitate prioritization
of developments.
EU and FDA regulators should continue to discuss coordinated
approaches to minimize unnecessary pediatric trials and to
optimize trial design, safety, and conduct so that the limited
pediatric populations available are enrolled only in ethically
implemented, scientifically important trials. Innovative
approaches to data generation, the creation of international
databases to facilitate data sharing, and the use of preexisting
data through innovative analytical strategies could be part of
the solution.
Conclusion Collaboration is essential for successful global pediatric drug
development. To ensure adequate availability of drugs for
children, the following aspects will be important:
• Regulatory collaboration to seek alignment
• Engagement with other stakeholders beside regulators
• Education on regulatory science and procedures
• Continued and collaborative discovery of efficient pathways
to ensure safe and effective medicines are developed
• Strategic and creative approach
• Emboldened approaches to public health
Discussions with the FDA and EMA could be facilitated to
shape pediatric development programs, resulting in optimal
development plans. One could envisage piloting an interaction
with the FDA and EMA on pediatric development programs to
further support global alignment, including:
• Use the pediatric cluster teleconferences as platform
• The output as non-binding common commentary provides
recommendations for streamlined PIP/PSP/PPSP addressing
children’s needs and regulatory requirements
• Option for trilateral discussions with the applicant and both
agencies at the same time
The agencies systematically collaborate using all of their
experience to support pediatric assessment. Discussion
of initial pediatric development plans and a coordinated
international scientific review is key for the efficient evaluation
of new agents and will be an essential success factor for
developing new agents to treat children with the drugs
they need.
Ongoing harmonization of pediatric science and research is
important to make pediatric product development easier and
faster in order for children to get the medicines they deserve.
White Paper | Global Pediatric Drug Development Collaboration: Part Two
1. US Congress. Best Pharmaceuticals for Children Act Amending Section 505A of the Federal Food, Drug & Cosmetic Act
(Public Law 107-109). 2002.
2. US Congress. Pediatric Research Equity Act amending Section 505B of the Federal Food, Drug & Cosmetic Act
(Public Law 108- 155). 2003.
3. European Parliament and the Council of the European Union. Regulation (EC) No. 1901/2006 on medicinal products
for pediatric use. 2006.
4. : Yao. L. (2017). Current state of pediatric drug development.
Available at https://www.fda.gov/media/107592/download.
5. US Food & Drug Administration. International Collaboration/Pediatric Cluster. 2020.
Available at https://www.fda.gov/science-research/pediatrics/international-collaboration-pediatric-cluster.
6. European Medicines Agency. 10-year Report to the European Commission. 15 August 2017. EMA/231225/2015.
Available at https://ec.europa.eu/health/sites/health/files/files/paediatrics/docs/paediatrics_10_years_ema_techni-
cal_report.pdf.
7. Kweder, S. (2017). Better together: Harmonizing pediatric drug development. Paediatric Conference, European
Commission and TOPRA Available at https://www.topra.org/topra/topra_member/pdfs/10_Sandra_Kweder.pdf.
8. Written communication from EMA dated 15 June 2020.
9. Reaman, G., Herold, R., Norga, K., et al. (2016). Impact of the Food and Drug Administration (FDA)-European
Medicines Agency (EMA) Common Commentary (CC) on Paediatric Cancer Drug Development. Ped.Blood Cancer,
63, S212.
10. Poster for the 48th Congress of the International Society of Paediatric Oncology, October 19-22, 2016 in Dublin,
Ireland, G. Reaman et al.
11. US Food & Drug Administration, European Medicines Agency. FDA/EMA Common Commentary on Submitting
an initial Pediatric Study Plan (iPSP) and Paediatric Investigation Plan (PIP) for the Prevention and Treatment of
COVID-19. 2 June 2020. Available at https://www.ema.europa.eu/en/documents/other/fda/ema-common-commen-
tary-submitting-initial-pediatric-study-plan-ipsp-paediatric-investigation-plan-pip_en.pdf.
12. The iPSP template is included in FDA’s draft guidance for industry, Pediatric Study Plans: Content of and Process
for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans, which when finalized will
represent FDA’s current thinking on the topic. Available at https://www.ema.europa.eu/en/documents/tem-
plate-form/template-scientific-document-part-b-f_en.doc.
13. Candidate Pediatric Molecular Target List. Available at https://www.fda.gov/media/120331/download.
14. Karres J., Pratt V., Guettier J.M., et al. (2014). Joining forces: a call for greater collaboration to study new medicines
in children and adolescents with type 2 diabetes. Diabetes Care, 37:2665–2667.
References
White Paper | Global Pediatric Drug Development Collaboration: Part Two
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 [email protected].
Contact Information
For further information, or to discuss any aspect of PRA’s services offered in the field of pediatric clinical development, please contact your Business Development Manager, or PRA’s Center for Pediatric Clinical Development below:
Center for Pediatric Clinical Development
https://prahs.com/centers/the-center-for-pediatric-clinical-development
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
JULY 2020
White Paper | Global Pediatric Drug Development Collaboration: Part Two