Pediatric Product Development Plans

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WHITE PAPERPediatric ProductDevelopment PlansAuthorsScott Daigle, PhDSenior Principal Medical WriterPRA Health SciencesBrenda Sanchez, MS, RACDirector, Regulatory StrategyPRA Health Sciences

White Paper Pediatric Product Development PlansExecutive SummaryDevelopment of the Pediatric Study Plan (PSP) for the United States Food and Drug Administration (USFDA) and the PaediatricInvestigation Plan (PIP) for the European Medicines Agency (EMA) must be an integral part of the overall clinical developmentplan. Development of these plans should begin 1 to 2 years in advance of the anticipated start of the adult Phase 3 program. ThePediatric Research Equity Act (PREA, 2003, 2007)1, 2 gives the USFDA the legal authority to mandate that drug developers conductstudies in children, unless the USFDA grants a specific waiver. The PIP laws from the European Parliament from 20073, 4 empowerthe EMA to require that drug developers conduct studies in children to support the authorization for medicines for children in theEuropean Union (EU). The Better Pharmaceuticals for Children Act (BPCA)2 within the USFDA Modernization Act of 19975 in theUnited States (US) awards drug developers an additional 6 months of market exclusivity, if the Sponsor conducts pediatric researchas requested by the USFDA.Children are not Small Adultshormones, and diets from adults. For example, some commonIn 1973, a survey of approximately 2000 approved drugsactivities by the age of 3 months in a child8 while others, suchrevealed that 78% of USFDA-approved drugs lacked labelingas CES2, take 2 years.9 Most metabolizing pathways continueinformation for use in pediatric patients.6 Administeringto mature through age 6. Research and labeling informationmedication to children in such cases amounts to treatingmust account for the developing maturity. Consequently, aspatients without a standard of care for guidance. There wasa result of the differences in maturity, metabolism, size, diet,a lack of data, which caused the lack of instruction. Sinceand physiology, in both clinical studies and in the healthcarethen, in efforts to close the gap on data and labelingsystems, there remains a lack of information about how toinformation between adult and pediatric patients,monitor for safety or efficacy when treating children withlegislation in the US, Europe, and elsewhere has tried to pushdrugs. Understanding the differences between adult andand pull drug developers to perform research in pediatrics.pediatric patients requires study and development.From the 1990’s the US and EU have created our currentregulatory environment. It employs rewards and requirementsfor drug developers to research drugs in the pediatric population.metabolizing enzymes, such as CYP1A2, reach adult-levelHowever, drug developers have not invested as earnestly indevelopment of pediatric treatments as with adults. Clinicalresearch is expensive, requiring deep expertise and focusBut what is the problem and what is the scale? Withoutfrom developmental teams within pharmaceutical companies.complete labeling for pediatric patients, off-label use of anTrials in pediatrics frequently require additional monitoring,approved medication is a possibility. In 2012, Kemland et alestimated that between 46% and 64% of children in primarycare in the US receive off-label medications. Off-label useincreases with the intensity of care. Also, approximately67% of children in a hospital receive off-label medicationand approximately 90% of children in neonatal or pediatricintensive care receive off-label medication.7 Administeringmedicine to children is not simply a matter of adjustingthe adult dose for weight. Children are not simply smalladults. Besides height and weight, children have importantdifferences in metabolism, metabolizing pathways, physiology,Children with diseases need safe and effectivetreatments, but it is widely acknowledged thatdrug development has historically focused ontreatments for adults. This produces a significantdeficit in well-studied drugs for pediatrics.

White Paper Pediatric Product Development Plansindependent Data Monitoring Boards, and pediatric clinicalsupplies, increasing complexity, resource allocations, andcosts. Most importantly, the ethical considerations in apediatric trial are different. Children are still developing.Long-term risks to bone, muscle, cognitive, and sexualdevelopment are significant concerns when administeringa medication to a child, especially in a research environmentwhen there are so many unknowns. Children cannot provideDevelopment of the PSP and PIP must be anintegral part of the overall clinical developmentplan. Development of these plans should begin1 to 2 years in advance of the anticipated startof the adult Phase 3 program.their own consent; they require a decision from parents. Thenet result of these factors: pediatric research has been avoidedwhenever possible.Children with diseases need safe and effective treatments,just like adults. But, it is widely acknowledged that drugRegulations and Incentivesdevelopment has historically focused on safe and effectiveResearch is necessary to understand the risks and providetreatments for adults. This produces a significant deficit inguidance to physicians treating pediatric patients withwell-studied drugs for pediatrics. For example, accordingproducts primarily studied in adults. Clinical trials in pediatricto CenterWatch, in each year from 2015 through 2017,patients are necessary.the USFDA approved 70 to 100 new drugs or new indicationsfor treatment for adults, compared with 3 to 10 approvals fordrugs to treat pediatric patients.Since the 1990s, the governments of major markets in theUS and the EU have provided a system of incentives andrequirements to encourage drug developers to conduct moreGlobally, the United Nations estimates for the year 2019research in children and close the information gap betweenindicate that pediatrics (0 to 17 years) comprise about 30%the adult and pediatric administration of drugs. The Betterof the population. In the US and across Europe, pediatricsPharmaceuticals for Children Act (BPCA)2 within the USFDArepresent 22% and 19%, respectively, of the population.Modernization Act of 19975 in the US awards drug developersHowever, the pediatric population represents less thanan additional 6 months of market exclusivity if they conduct10% of the global market sales for the same year. Althoughpediatric research as requested by the USFDA. The additionalpopulation and sales may not track together perfectly, the6 months of exclusive sales (adults and pediatrics) for a drugproportions would expect to be similar; the market potentialcan be a significant financial benefit. The PREA1, 2 gave thewould seem to be there.USFDA the legal authority to mandate that drug developers10conduct studies in children unless the USFDA grants a specificwaiver. Similarly, in the EU, the PIP requirements from 20073, 4follow a similar pattern, empowering the EMA to require thatdrug developers conduct studies in children to support theDrug makers must have a plan for conductingresearch in pediatric subjects and must implementit early in the overall drug development program.authorization for medicines for children in the EU.The regulatory goal of providing labeling information specificto pediatric patients is being achieved: from 1998 through2018 the USFDA approved 770 labeling changes (representing620 unique drugs) for pediatric patients.11 During that same 20year period, the USFDA received 453 requests for approveddrugs12 and granted additional exclusivity for 242 drugs.13

White Paper Pediatric Product Development PlansProcess and TimingThe results of these legislations in the US and EU is strategicallysimple: the drug maker must have a plan for conductingresearch in pediatric subjects and must have it early in theoverall drug development program.Building a PediatricDevelopment ProgramThe PSP and PIP are organized differently, but include thesame information for the most part in varying degrees ofspecificity: summary of the disease, proposed indication andThe US requires the Sponsor to submit an initial PSP to thecondition, ages to be studied or excluded, incidence ratesrelevant drug’s Investigative New Drug (IND) no later than(especially in the region governed by each agency), description60 days after the date of the End-of-Phase 2 (EOP2) meeting.14of the drug, summary of the planned nonclinical, modeling, andThe USFDA provides advice to the Sponsor, and together theclinical studies in the drug program, with particular emphasisUSFDA and Sponsor reach an agreement for the initial PSP.on studies expected to provide decisive pharmacokinetic,Similarly, the EMA requires that the applicant submit an initialdosing, safety, and efficacy results supporting the pediatricPIP to its Pediatric Committee (PDCO) around when Phase 2trials. The Sponsor/applicant must provide a plan for theclinical studies in adults are initiated and no later than whenpediatric formulation and presentation. This part of the plan mustPhase 3 clinical studies are initiated. The PDCO, representeddescribe whether the adult formulation and presentation will beby a rapporteur, and an independent peer reviewer, provideused or if a pediatric-specific formulation and presentation willfeedback to the applicant. The PDCO makes a recommendationbe developed. The formulation and presentation plan must coverto the EMA, who approves or rejects the PIP. For each of thethe materials to be used in the pediatric clinical trials, as well asregulatory agencies, a pediatric product development planthe product that is expected to be marketed, assuming theshould be in place before initiating Phase 3 clinical trialswhole development program has positive results and yieldsin adults.a marketable product. Perhaps most importantly, the PSP andPIP must provide a schedule of when the planned studies andThe details of the regulations and processes, of course, areformulation/presentations milestones start and finish so thatdifferent, but the outcome is the same: an agreement for athe dependencies are obvious.pediatric development plan that the drug maker is obligatedto complete.Development of the initial PSP and PIP must be an integralpart of the overall clinical development plan and should beginThere is a philosophical difference between the USFDA and1 to 2 years in advance of the anticipated start of the adultEMA. In the initial PSP, the USFDA expects the Sponsor toPhase 3 program. The PSP and PIP processes are complex,provide a minimal outline of the pediatric development plan,with multiple dependencies that require particular expertiseconsistent with the understanding of the disease state inand coordination.pediatrics and the stage of the product development. Asclinical and nonclinical studies complete, data are collectedand analyzed. As the whole drug development programevolves, the USFDA expects the Sponsor to add to the PSPwith evermore detailed information. In contrast, the EMArequires a full and complete PIP at the outset. However, thePIP can be amended if necessary.In practice, the PSP and PIP are reviewed, updated, and revisedas the drug program evolves. Each revision to a PSP requiresa new agreement with the USFDA; similarly, each revision to aPIP requires a new PDCO review and recommendation to theEMA, who may approve or reject the revised PIP.

White Paper Pediatric Product Development PlansCitations1Pediatric Research Equity Act (PREA) of 2003 (Public Law 108–155—DEC. 3, 2003).2Food 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 medicinalproducts for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive2001/83/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 amendingRegulation 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 andtherapeutic aspects of perinatal pharmacology. New York, NY: Raven Press, pp. 411-21.7Kimland 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 itsmetabolites 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 mRNAexpression, protein content and bupropion hydroxylase activity and the impact of genetic variation. DrugMetab Dispos 2016;44(7):948-58.10 United Nations DoEaSA, Population Division World population prospects of the United Nations, Department ofEconomic 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 awritten request for pediatric studies under section 505A of the Federal Food, Drug, and Cosmetic Act. 2019. AccessedJuly 10, 2019.13 USFDA. Food and Drug Administration. Pediatric exclusivity granted: drugs to which FDA has granted pediatricexclusivity 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)).

White Paper Pediatric Product Development PlansContact InformationFor further information, or to discuss PRA’s services and Pediatric Product DevelopmentPlans, please contact your PRA account manager or the PRA employees listed below:Scott Daigle, PhDSenior Principal Medical WriterPRA Health Sciences995 Research Park Blvd, Suite 300,Charlottesville, Virgina 22911, USAPhone: 1 434 951 3426DaigleScott@prahs.comBrenda Sanchez, MS, RACDirector, Regulatory StrategyPRA Health Sciences4130 ParkLake Avenue, Suite 400Raleigh, North Carolina 27612 USAPhone: 1 919 788 3257SanchezBrenda@prahs.comWorld Headquarters4130 ParkLake Avenue, Suite 400Raleigh, North Carolina 27612 USAPhone: 1 (919) 786 8200Fax: 1 (919) 786 8201www.prahs.comJUNE 2020PRA Health Sciences conducts comprehensive Phase I-IV biopharmaceutical drugdevelopment. To learn more about our solutions, please visit us at prahs.com oremail us at prahealthsciences@prahs.com.

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

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