Eu Regulations for Clinical Studies in Pediatric Patients

7/25/2019 Eu Regulations for Clinical Studies in Pediatric Patients

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EU Regulations for Clinical Studies in Pediatric Patients

By Raj Kishore, PhD and Edward Tabor, MD

In 2006, the European Council (EC) and theEuropean Parliament adopted a regulationthat created major changes in the way clinicalstudies in pediatric patients would be plannedand conducted in the EU.1For many years,clinical evaluations of drugs and biologics wereconducted primarily in adults because it wassimpler and raised fewer ethical concerns thanconducting studies in children. Nevertheless,

following regulatory approval for use in adults,these products were often prescribed for chil-dren despite the lack of clinical trials in thispopulation. Physicians often used an empiricallyselected lower dose based on the weight of thechild. In some cases, this could have resulted inexposure to unsafe or ineffective doses becausechildren may metabolize a drug or biologic dif-ferently than do adults.

In September 2004, based on the success ofpediatric drug laws in the US,2,3the EC adopteda proposal to develop regulations for pediat-ric investigations for the EU. The EC passedPediatric Regulation (EC) No 1901/2006 in

2006, later amended by Regulation (EC) No.1902/2006,4to require clinical studies for pediat-ric drug development in the EU. The regulationtook effect on 26 January 2007.

Major Provisions of the European

Pediatric Regulation

The European Pediatric Regulationand itsamendment require that manufacturers sub-mit a Pediatric Investigation Plan (PIP) for allnew products and line extensions (new indica-tion, new formulation, new dosage form, etc.)for existing products. The PIP must outline

studies to be performed or state the reasonswhy a waiver or deferral should be grantedand should be submitted early during prod-uct development, in time for studies to beconductedbefore marketing authorizationapplications are submitted.5 However, it hasbeen recommended that a PIP be submittedwhen pharmacokinetic studies have been com-pleted, effectively at the end of Phase 1 studies inmost cases. In addition to providing the designfor each study, the PIP must provide timelinesfor the studies.

The regulation also specifies that PIPs muststate which pediatric age groups will be studied;a waiver or deferral for age groups not intendedfor studies should be requested as part of thePIP. The Marketing Authorisation Application(MAA) must cover all subsets of the paediat-ric population,6and thus must contain datafor use in each of the different pediatric agegroups unless waived or deferred. However,the Pediatric Regulationdoes not define the dif-ferent age groups; it only defines the pediatric

population as that part of the populationaged between birth and 18 years.7Pediatric agegroups are defined in ICH Guidance E11, ClinicalInvestigation of Medicinal Products in the PediatricPopulation,8as:

preterm newborn infants term newborn infants (0 to 27 days) infants and toddlers (28 days to 23

months) children (2 to 11 years) adolescents (12 to 16-18 years, depend-

ing upon the geographic region)

Manufacturers must submit a PIP to the

Paediatric Committee9(PDCO), an expert com-mittee of the European Medicines Agency

(EMA), created by the Pediatric Regulation toreview PIPs, waivers and deferrals of pediatricstudies. EMA has 30 days in which to vali-date the PIP for PDCO, and PDCO must issuea report within the following 60 days. Onceapproved by PDCO, the PIP is binding on themanufacturer unless it is formally revised due tothe availability of new information. Because thePIP is usually submitted very early in the courseof clinical development of the product, amend-ments are often necessary. PDCO also reviewsall PIP amendments, and all of its decisions are

posted on a public website.10

Other Provisions of the European

Pediatric Regulation

Waivers from the requirement for pediatric stud-ies in any of the age groups can be granted whenthe product is likely to be ineffective or unsafein part or all of the pediatric population, ifthe disease does not occur in pediatric patientsor if the product is not a significant advanceover existing treatments for children.11Waiverscan be given in one or more age groups or for

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one or more indications. The pediatric studyrequirement does not apply to generics or simi-lar biological medicinal products and medicinalproducts authorised through the well establishedmedicinal use procedure, nor to homeopathicmedicinal products and traditional herbal medic-inal products authorised through the simplifiedregistration procedures.12

Deferrals of pediatric studies can be granted

when the information available about theproduct suggests that it would be advisable toconduct the studies at a later date. Deferrals canalso be issued to delay pediatric studies untilpreliminary data on adults suggest it would besafe to proceed in children, until an age-appro-priate formulation is available or merely to avoidundue delay in making the product available foradult patients.

The regulation provides incentives for doingstudies in pediatric patients. If a product hasbeen granted a supplementary protection cer-tificate, i.e., a certificate providing additionalyears of exclusive marketing in the form of an

extension of patent protection (as a result of thepresent application or an earlier application foruse in adults), a six-month extension of the sup-plementary protection certificate can be given asa reward for the expense of conducting studiesin pediatric patients, even if the study results donot support a pediatric indication. However, thestudy results, if negative, must be added to thelabeling regardless of the approved indication.In order to encourage pediatric studies for prod-ucts that already have orphan designation foruse in adults, the regulation provides for a totalof 12 years of marketing exclusivity (exclusivityextension of two years) for doing pediatric stud-

ies for an orphan indication rather than the 10years provided in the EU for orphan indicationsapproved de novo.13 The six-month extension ofthe supplementary protection certificate cannotbe added to market exclusivity given becauseit is a pediatric orphan drug or to another typeof extension of exclusivity obtained for havingprovided significant clinical benefit in compari-son with existing therapies.14(In the EU, a drugor biologic is eligible for orphan designationif it is intended for the diagnosis, prevention,or treatment of a life-threatening or chronicallydebilitating condition affecting no more than fivein 10,000 persons in the European Union.15)

For products already on the market for usein adults that are not covered by a patent or asupplementary protection certificate, the regula-tion created a special application mechanism,the Paediatric Use Marketing Authorisation(PUMA). A PUMA may contain data from newclinical studies, data from pediatric studies inthe literature or data from studies in dossiers ofother approved products. This mechanism wasintended to provide an incentive for small and

mid-size companies to develop products for usein children. The regulation permits the use of theEU Centralised Procedure for applications withstudies conducted under a PIP (whether MAAsor PUMAs).16The regulation also cross-referencesan earlier regulation to provide 10 years of mar-ket protection as a reward for conducting clinicaltrials in pediatric patients for products approvedunder a PUMA.17

The regulation established a system ofoptional, free scientific advice from EMA forstudies in pediatric patients. It also created apublic database to list pediatric studies with thegoal of preventing unnecessary duplication ofstudies and of alerting regulators and research-ers to areas where developing pediatric productswould be desirable. The results of all ongoing,discontinued and prematurely terminated clini-cal trials in pediatric patients must be reported tothis database.

A marketing application based on studiesunder a PIP must include a plan for long-termfollow-up18 of adverse events and of efficacy

in pediatric patients. Where there are specialconcerns, a risk management plan or a plan forpostmarket studies must be submitted.

Comparison of Requirements for

Studies in Pediatric Patients in the

EU and the US

There are many similarities but also some sig-nificant differences between pediatric studyrequirements in the EU and the US, as shown inTable 1.

References:

1. Regulation (EC) No 1901/2006 of the European Parliamentand 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. EuropeanUnion website. http://eur-lex.europa.eu/LexUriServ/site/en/consleg/2006/R/02006R1901-20070126-en.pdf.Accessed 12 October 2010.

2. Best Pharmaceuticals for Children Act of 2002 (PublicLaw No: 107-109). 4 January 2002. US Food andDrug Administration website. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM049874.pdf. Accessed12 October 2010. (Amended by the Food and DrugAdministration Amendments Act of 2007. 27 September2007. US Food and Drug Administration web-site. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/

UCM049870.pdf. Accessed 12 October 2010.)3. Pediatric Research Equity Act of 2003 (Public Law No: 108-155). 3 December 2003. US Food and Drug Administrationwebsite. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM077853.pdf. Accessed 12 October 2010. (Amendedby the Food and Drug Administration Amendments Actof 2007. 27 September 2007. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM049870.pdf. Accessed 12October 2010.)

4. Amending Regulation (EC) No 1902/2006 onMedicinal Products for Paediatric Use. European Union


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website. http://eur-lex.europa.eu/LexUriServ/site/en/consleg/2006/R/02006R1901-20070126-en.pdf.

5. Regulation (EC) No 1901/2006, op.cit. Preamble,Paragraph 10.

6. Regulation (EC) No 1901-2006, op.cit. Article 7, Paragraph2.

7. Regulation (EC) No 1901-2006, op.cit. Article 2, Paragraph1.

8. ICH Harmonised Tripartite Guideline:Clinical Investigationof Medicinal Products in the Paediatric Population E11.International Conference on Harmonisation website.http://www.ich.org/LOB/media/MEDIA487.pdf.

Accessed 12 October 2010.9. Paediatric Committee (PDCO). European Medicines

Agency website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_con-tent_000265.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac0580028e9d&jsenabled=true. Accessed 12October 2010.

10. European Medicines Agency public website for postingof decisions on PIPs. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/pip_search.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d129&jsenabled=true. Accessed 12 October 2010.

11. Regulation (EC) No 1901/2006, op.cit., Article 11,Paragraph 1.

12. Regulation (EC) No 1901/2006, op.cit., Preamble,Paragraph 11.

13. Regulation (EC) No 1901/2006, op.cit.Article 37, Paragraph 1.14. Regulation (EC) No 1901/2006, op.cit.Article 36,

Paragraphs 45.15. Orphan drugs and rare diseases at a glance. European

Medicines Agency website. http://www.ema.europa.eu/pdfs/human/comp/29007207en.pdf. Accessed 27 October2010.

16. Regulation (EC) No 1901/2006, op.cit., Preamble,Paragraph 21.

17. Apparently stipulated by the fact that Article 38 Paragraph

1 of Regulation (EC) No 1901/2006 cross-references theearlier Regulation (EC) No 726/2004 of the EuropeanParliament and of the Council of 31 March 2004 layingdown Community procedures for the authorisation andsupervision of medicinal products for human and veteri-nary use and establishing a European Medicines Agency.European Commission website. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2004:136:0001:0033:EN:PDF. (See Article 14, paragraph 11). Accessed 12 October2010. The fact of this PUMA exclusivity is clearly stated onthe EMA website (viz. http://www.ema.europa.eu/htms/human/paediatrics/pumas.htm. Accessed 12 October2010.

18. Regulation (EC) No 1901/2006, op.cit. Preamble,Paragraph 24.

Table 1. Comparison of EU and US Requirements for Pediatric Drug Development

EU Pediatric Drug Development US Pediatric Drug Development

Covered under a regulation, (EC) No. 1901/2006

(amended by 1902/2006) covering all aspects of

pediatric drug development in one document.

Covered by two separate but complementary laws,

Pediatric Research Equity Act (PREA) requiring pediatric

studies, and Best Pharmaceuticals for Children Act

(BPCA) providing additional marketing exclusivity.

Pediatric population defined as between birth

and 18 years, interpreted as ending after age 17

Subpopulation age groups defined in ICH guidance.

Pediatric population defined as birth to 16 years in FDA

guidance.

Subpopulation age groups defined in prior FDA guidance

and in ICH guidance.

PIP recommended for submission before start of Phase

2 and must be approved before submission of MAA. It

can be amended.

Pediatric development plan must be submitted with or

before submission of the New Drug Application.

All PIPs are reviewed by PDCO. All pediatric development plans are reviewed by the

review division for the disease area being studied. All

Pediatric Study Requests issued by FDA, as well as

deferrals and waivers for pediatric studies, must be

approved by an internal but central FDA Pediatric Review

Committee (PeRC).

Free scientific advice available for pediatric studies. All scientific advice provided by FDA is free.

Criteria for waiver: 1) ineffective or unsafe in part of

pediatric population; 2) disease does not occur in

pediatric patients; or 3) product is not a significant

advance over existing treatments for children.

Criteria for waiver: 1) pediatric studies impossible or

highly impractical (e.g. number of pediatric patients

very small or geographically dispersed); 2) ineffective or

unsafe in part of pediatric population; 3) unlikely to beused in a substantial number of pediatric patients; or 4)

age-appropriate formulation cant be made.

Exemptions from Pediatric Regulation: 1) generic drugs;

2) homeopathic medicines; 3) traditional herbal

medicines.

Exemptions from PREA requirements: 1) orphan

products; 2) generic drugs.

Provides six months of additional marketing exclusivity

for products for which pediatric information has been

added to labeling based on studies.Two years of

additional marketing exclusivity are provided for orphan

products for pediatric patients (in addition to the 10

years for orphan products for adults).

Provides six months of additional marketing exclusivity

if studies in pediatric patients are completed in

accordance with a written Pediatric Study Request

issued by FDA, but only as an extension of other

granted exclusivity. Results of all pediatric studies must

be included in product labeling.

Ten-year exclusivity is available for off-patent drugs

developed for pediatric patients; does not need to be an

extension of other exclusivity.

No exclusivity is available for developing off-patent drugs

per se.


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AuthorsRaj Kishore, PhD,is senior director of regulatory affairs atQuintiles. He has more than 20 years of regulatory experienceat FDAs Center for Drug Evaluation and Research and in thepharmaceutical industry. He can be reached at [email protected]. Edward Tabor, MD,is vice president and globalhead of regulatory strategy at Quintiles. He was formerly anFDA division director in both the Center for Drug Evaluationand Research and the Center for Biologics Evaluation andResearch. He can be reached at [email protected].

2010 by the Regulatory Affairs Professionals Society (RAPS).Reprinted from the November 2010 issue of Regulatory Focuswith the permission of RAPS.

Eu Regulations for Clinical Studies in Pediatric Patients

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