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Pediatric trials in the US and EU: some drug companies still missing deadline

This article was originally published in SRA

Executive Summary

Despite the existence of legislation in the US and the EU mandating the carrying out of pediatric trials of new medicines, a small but not insignificant number of sponsors are failing to carry out such trials in a timely manner. Peter Charlish looks at the extent of the problem.

Legislation is in place on both sides of the Atlantic to ensure that clinical trials of new medicines are carried out in pediatric as well as adult subjects.

While this requirement may be relaxed in certain circumstances, such as in the case of products whose use in children would be inappropriate (potential treatments for Alzheimer's disease, for example), the general approach nowadays is that if a product could be used in children it must first be tested in children. However, in a number of cases, sponsors are failing to carry out these trials.



Although there had been earlier attempts to encourage the testing of pharmaceutical products in children, the effective regulation of pediatric trials in the US can be traced back to the Food and Drug Administration Modernization Act1 of 1997, which first established an incentive for companies to conduct pediatric studies. In return for carrying out studies to evaluate the safety and efficacy of individual products in pediatric patients, manufacturers were entitled to claim an extension of six months in the product's market exclusivity. This was achieved by extending a product's patent protection or by delaying the subsequent approval of generic versions of the product, or of a closely related product.

Until 1998, carrying out pediatric studies under FDAMA was purely voluntary. In that year, however, the Food and Drug Administration issued its Pediatric Rule2, which mandated the evaluation of safety and effectiveness of products in pediatric patients if they were expected to be used in a substantial number of children. However, the rule was struck down by a US district court in 2002 on the grounds that it exceeded the FDA's authority3.

In the meantime, however, the Best Pharmaceuticals for Children Act4 had come into effect in January 2002. BPCA extended the incentives available under FDAMA by offering an opportunity for sponsors to obtain an additional six months of patent exclusivity for on-patent drugs tested for pediatric use in response to a "written request" from the FDA. Subsequently, in 2003, the Pediatric Research Equity Act5 was passed giving the FDA clear authority to require (not just request) a pediatric assessment for certain indications when a new drug application is filed for a new active ingredient, or for a new indication, dosage form, dosing regimen or route of administration for an existing product.

Significantly, PREA permitted the FDA to defer or waive the requirement for pediatric studies, either in response to a request from the manufacturer or on its own initiative. Situations in which a deferral could be granted include those where waiting for the outcome of pediatric studies would delay the availability of a product to adult patients, or where concerns about the safety of the product in children necessitate further review of the adult data before granting permission for pediatric studies. A waiver for pediatric studies could be granted where pediatric studies were extremely difficult or impossible to perform (perhaps because the patient population was too small), where the product was never likely to be used in a significant number of children, where there was evidence that the product would be unsafe or ineffective in children, or where a drug formulation appropriate for use in children could not be made.

PREA and BPCA were reauthorized and updated by the Food and Drug Administration Amendments Act6 of 2007. Amendments relating to PREA were designed to improve FDA and applicant accountability for agreed pediatric assessments, including deferred assessments. Although the original PREA permitted pediatric assessments to be deferred "until a specified date after approval," the FDAAA amendments imposed the requirement that they can only be deferred if there is "a timeline for the completion of such studies." In addition, FDAAA required applicants to update the FDA annually on the status of deferred pediatric assessments. The FDA retained the power to waive PREA pediatric assessments for various reasons, including if "the applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary for that age group have failed." At the same time, however, FDAAA imposed the additional requirement that if the FDA waives the PREA obligation on this basis, the applicant must provide the FDA with full supporting documentation, and the applicant's submission will then be made publicly available on the FDA website. A further requirement was that the FDA set up an internal committee with pediatric expertise to carry out certain activities under PREA and BPCA.


In the EU meanwhile, rules governing the development of medicinal products to meet specific therapeutic needs of the pediatric population (defined as that part of the population aged between birth and 18 years) were laid down in Regulation (EC) No 1901/20067 and Regulation (EC) No 1902/20068 (jointly known as the Paediatric Regulation), which came into force on 26 January 2007. The Paediatric Regulation requires all marketing authorization applications to include the results of studies carried out under an agreed paediatric investigation plan (PIP), unless the EMA has granted a waiver or deferral. Waivers may be granted if the product is deemed likely to be ineffective or unsafe in pediatric patients, if the target disease occurs only in the adult population, or if the product does not represent a significant therapeutic benefit over existing treatments for pediatric patients. Deferrals may be granted where it is appropriate to conduct studies in adults before the pediatric population or when pediatric studies will take longer to conduct than studies in adults.

In the case of products that are protected under a supplementary protection certificate or by a patent that qualifies for the granting of a supplementary protection certificate, the Paediatric Regulation applies to applications for new indications, new pharmaceutical forms and new routes of administration.

The Paediatric Regulation also mandated the setting up of a Paediatric Committee (PDCO) within the European Medicines Agency, comprising representatives of the agency's Committee for Medicinal Products for Human Use, the EU member states, health professionals and patients' groups. The role of the PDCO is to assess the design of PIPs, to give its opinion of applications for waivers or deferrals, and to give its opinion on the data generated under a PIP.

Non-compliance letters

According to the FDA website9, a total of 469 pediatric studies pursuant to FDAAA were completed between 27 September 2007 and 18 November 2013 (see interactive table below).

However, in a small number of cases, pediatric assessments required under PREA are not completed in time, or at all. Section 505B(d)(1) of the Food and Drug Administration Safety and Innovation Act of 201210 requires the FDA to send a PREA non-compliance letter to sponsors who have:

  • failed to submit their pediatric assessments required under PREA by the final due date;
  • failed to seek or obtain a deferral or deferral extension; or
  • failed to request approval for a required pediatric formulation.

The non-compliance letter requires the sponsor to respond in writing within 45 calendar days; the response may include a request for a deferral extension if applicable.

Section 505B(d)(1) also states that the non-compliance letter and the sponsor's written response shall be made publicly available on the FDA website 60 calendar days after issuance (with redactions for any trade secrets and confidential commercial information). The product that is the subject of a non-compliance letter may be considered to be misbranded solely because of that failure, and subject to appropriate enforcement action, although such action would not include withdrawal of the product's approval.

In cases where a sponsor requests a deferral extension, the FDA does not post a PREA non-compliance letter until it has determined whether to grant or deny the request. If a sponsor has requested a waiver, the FDA does not post a non-compliance letter or sponsor's response until it has determined whether the letter was issued in error: if a sponsor's waiver request has been granted, the non-compliance letter and sponsor's response are not posted.

As of the end of February 2014, a total of 12 non-compliance letters had been issued, as shown in Table 2.

Table 2. Non-compliance letters under 505B(d)(1) of the Federal Food, Drug, and Cosmetic Act



Date of non-compliance letter

Purdue Pharma

Palladone (hydromorphone hydrochloride extended release) capsules

10 April 2013


Renvela (sevelamer carbonate) tablets

11 April 2013


Renvela (sevelamer carbonate) for oral suspension

11 April 2013


Hectorol (doxercalciferol) capsules

12 April 2013

Amedra Pharmaceuticals

Twinject/Adrenaclick (epinephrine injection, USP 1:1000) 0.15 mg and 0.3 mg

13 May 2013

The Medicines Company

Cleviprex (clevidipine) intravenous emulsion 0.5 mg/mL

14 May 2013

Salix Pharmaceuticals

Apriso (mesalamine) capsules

10 June 2013

Sunovion Pharmaceuticals

Xopenex (levalbuterol HCl) Inhalation Solution

13 June 2013


Protonix I.V. (pantoprazole sodium) for injection

14 June 2013


Protonix I.V. (pantoprazole sodium) for injection

14 June 2013

Nautilus Neurosciences

Cambia (diclofenac potassium) for oral solution

3 July 2013

Tris Pharma

Nexiclon (clonidine) extended-release oral suspension

3 October 2013

Individual sponsors' responses

As well as providing links to the FDA's non-compliance letters, the FDA website provides links to the individual sponsors' responses. Most of the letters reiterate the companies' full commitment to pediatric studies. The most common reasons given for failure to submit a pediatric assessment relate to the development of an appropriate protocol; other reasons given include manufacturing issues and issues pertaining to generic competition.

For example, in Genzyme's response to PREA non-compliance letters relating to its urological product Renvela, dated 24 May 2013, the company noted that it had been in correspondence with the FDA about pediatric study design since 200611. Over the intervening period, Genzyme submitted eight revisions of its pediatric study design based on feedback from the FDA. In particular, an advice letter dated 17 February 2011 contained further recommendations on the study design, while still requiring the final clinical study report by 31 December 2011. Agreement was finally reached over a protocol submitted on 16 November 2011, and in May 2012 the first patient consented for the study. As of May 2013 there had been 40 patients randomized in the US, and clinical sites in Europe were preparing for start-up. Currently, the registry and results database has details of a safety and efficacy study of sevelamer carbonate in hyperphosphatemic pediatric patients with chronic kidney disease which began in May 2012 and is estimated to be completed by November 201512.

Salix Pharmaceuticals, in its response to a non-compliance letter about Apriso (mesalamine) capsules, simply states that "unfortunately, it has taken longer than expected to develop an appropriate study design, pediatric-feasible formulation, and dosing regimen for mesalamine granules in pediatric patients", and requests a deferral extension for the pediatric study13.

In Nautilus Neurobiosciences' heavily redacted response to an FDA PREA non-compliance letter in respect of Cambia (diclofenac 50 mg powder for oral solution)14, the company discusses the significance of the phrase "due diligence" in the wording of the Federal Food, Drug, and Cosmetic Act's requirement that a sponsor must submit "evidence that the studies are being conducted or will be conducted with due diligence and at the earliest possible time" in order to support a deferral or deferral extension. The company concludes that "due diligence" implies a certain level of reasonableness and in this context notes that it had to devote a significant part of its limited financial resources to fighting the threat of generic competition to the product. Under these circumstances "it was reasonable to postpone the Pediatric Development Program as we could not know whether we would have the resources to fund the Pediatric Development Program or indeed, complete the pediatric clinical study that had been started".

EU annual report

In the EU, a rather different procedure is adopted for highlighting companies that have failed to comply with the Paediatric Regulation. Article 50(1) of the regulation states that, at least once a year, the European Commission must publish a list of the companies and the products that have benefited from any of the rewards and incentives contained within the regulation "and the companies that have failed to comply with any of the obligations in this Regulation" [emphasis added]. The most recent report, published in April 2013, covers the calendar year 201215. Unlike in previous years, the report contains information on deferred studies, with evidence that some reports of these studies are not submitted; an overview of the completion of pediatric plans; and a new register to record deadlines of the placing on the market.

Article 16 of the Paediatric Regulation requires pharmaceutical companies to submit applications for a PIP and/or a waiver no later than when pharmacokinetic studies are completed in adults – usually around the end of Phase I. Late submissions of PIP/waiver applications are included in the annual report if there has been a delay of greater than six months. Table 3 shows non-justified late submissions of applications for PIPs or waivers in 2012.

Table 3. Non-justified late submissions of applications for PIPs or waivers in the EU in 2012



Delay (months)

Paediatic Investigation Plan

GE Healthcare



Mpex London

levofloxacin hemihydrate


Novartis Europharm



Glaxo Group

migalastat hydrochloride


Roche Products



Gilead Sciences International



GlaxoSmithKline Trading Service

N-[3-[3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-D]pyrimidin-1(2H)-yl]phenyl]acetamide, dimethylsulfoxide solvate


GlaxoSmithKline Trading Service

N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, methanesulfonate salt


Takeda Global Research & Development Centre (Europe)

lurasidone hydrochloride


Navidea Biopharmaceuticals

dextran, 3 [(2-aminoethyl)thio]propyl 17-carboxy-10,13,16-tris(carboxymethyl)-8-oxo-4-thia-7,10,13,16-tetraazaheptadec-1-yl 3-[[2-[[1-imino-2-(D-mannopyranosylthio)ethyl] amino]ethyl]thio]propyl ether


Bayer Pharma






UCB Pharma



Celgene Europe



Baxter Innovations

vonicog alfa (recombinant human von Willebrand Factor)



ALX-0081, anti-von Willebrand Factor Nanobody



tofacitinib (as tofacitinib citrate)


Full waiver

Merck Sharp & Dohme (Europe)

atorvastatin calcium/ezetimibe


Galderma R&D



Endocyte Europe

folic acid


Endocyte Europe



Takeda Pharma

azilsartan medoxomil/chlortalidone


Merck Sharp & Dohme (Europe)



AB Science

masitinib mesylate



deoxycholic acid


Menarini Ricerche

tramadol hydrochloride/dexketoprofen (as trometamol)


Source: European Medicines Agency report to European Commission, April 2013, Annex 7

For the same period, PIPs not completed by the agreed date (scheduled for completion by 30 June 2012) are listed in Table 4.

Table 4. PIPs not completed by the 30 June 2012 agreed date



Alcon Pharma

Cilodex (dexamethasone/ciprofloxacin HCl)

Abbott Laboratories


Aventis Pharma

Taxotere (docetaxel)

Nova Laboratories

Mercaptopurine monohydrate

NV Organon


Ichthyolgesellschaft Cordes, Hermanni

Ichthoseptal N (sodium bituminosulphonate/clindamycin phosphate)

Orphan Europe

Cystadrops (cysteamine HCl)

Leo Pharma

Picato (hydrocortisone/calcipotriol hydrate

DBV Technologies

Diallertest (skimmed cow's milk powder)

GlaxoSmithKline Biologicals

Arepanrix (split influenza virus, inactivated)

Sanofi Pasteur

Humenza (pandemic influenza vaccine, H1N1)

Sanofi Pasteur

Panenza (pandemic influenza vaccine, H1N1)

Baxter World Trade


Novartis Europharm

Afinitor, Votubia (everolimus)



GlaxoSmithKline Biologicals

Pandemrix (split influenza virus, inactivated)

Fresenius Kabi Deutschland

Neoven (amino acid solution)

Oblaya & Mhuguet

Glucose monohydrate


Titanium dioxide/bisoctrizole

Bayer HealthCare

Thrombin alfa

Baxter Innovations

HyQvia 100 (human normal immunoglobulin)

Merck Sharp & Dohme

Formoterol fumarate/mometasone furoate

Roche Registration

Tamiflu (oseltamivir phosphate)

Source: European Medicines Agency report to European Commission, April 2013, Annex 9

As well as publishing the names of companies that have failed to comply with the Paediatric Regulation, the commission has the power to impose financial penalties for infringements of the regulation (and for other aspects of pharmaceutical legislation). The relevant infringements are set out in subparagraphs 24 to 28 of Article 1 of Regulation (EU) 488/201216. However, to date, no procedure of infringement has started on matters relevant to the Paediatric Regulation17.

Because the organs involved with drug metabolism and excretion, such as the liver or the kidneys, are less well developed in children than in adults, the dosage of a medicine appropriate for a child cannot be calculated by simply amending the adult dose to compensate for the difference in physical size. Studies designed to determine the appropriate dosage in each age group are therefore essential. Equally important are studies designed to identify the optimum presentation of a medicine for use in children.

Legislation in the past 20 years has gone a considerable way to ensuring that such studies are performed, although clearly a small number of companies have experienced difficulties in meeting their obligations in this respect. What will the next 20 years bring? It is hard to be specific, but the appropriate use of medicines in infants and children, not to mention other vulnerable groups such as the elderly, will undoubtedly continue to improve.


  1. An Act To amend the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act to improve the regulation of food, drugs, devices, and biological products, and for other purposes, accessed 27 February 2014,
  2. Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients, Federal Register, 2 December 1998, 63, 231, 66631-66672

3.US judge throws out paediatric rule, Scrip World Pharmaceutical News, 30 October 2002

4.An Act to amend the Federal Food, Drug, and Cosmetic Act to improve the safety and efficacy of pharmaceuticals for children. accessed 27 February 2014

5.An Act To amend the Federal Food, Drug, and Cosmetic Act to authorize the Food and Drug Administration to require certain research into drugs used in pediatric patients. accessed 27 February 2014

6.An Act To amend the Federal Food, Drug, and Cosmetic Act to revise and extend the user-fee programs for prescription drugs and for medical devices, to enhance the postmarket authorities of the Food and Drug Administration with respect to the safety of drugs, and for other purposes. accessed 27 February 2014

7.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, Official Journal of the European Union, 27 December 2006, L 378/1-19

8.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 paediatric use, Official Journal of the European Union, 27 December 2006, L 378/20-21

9.US Food and Drug Administration - Breakdown of FDAAA Completed Pediatric Studies, accessed 27 February 2014,

10.An Act To amend the Federal Food, Drug, and Cosmetic Act to revise and extend the user-fee programs for prescription drugs and medical devices, to establish userfee programs for generic drugs and biosimilars, and for other purposes, accessed 28 February 2014,

11.Letter from Melanie Govignon, Principal Associate, Regulatory Affairs at Genzyme to Norman Stockbridge, Director of the Division of Cardiovascular and Renal Products at CDER, dated 24 May 2013, accessed 3 March 2014

12.An Efficacy and Safety Study of Sevelamer Carbonate in Hyperphosphatemic Pediatric Patients With Chronic Kidney Disease, NCT01574326, accessed 3 March 2014,

13.Letter from Benjamin M Burgin, Associate Director, Regulatory Affairs at Salix Pharmaceuticals to Donna Griebel, Director of the Division of Gastroenterology and Inborn Errors Products at CDER, 25 July 2013, accessed 3 March 2014

14.Letter from William R Maichle, CEO of Nautilus Neurosciences to Eric Bastings, Director of the Division of Neurology Products at CDER, 14 August 2013,, accessed 3 March 2014

15.European Medicines Agency, Report to the European Commission on companies and products that have benefited from any of the rewards and incentives in the Paediatric Regulation and on the companies that have failed to comply with any of the obligations in this Regulation, 30 April 2013,

16.Commission Regulation (EU) No 488/2012 of 8 June 2012 amending Regulation (EC) No 658/2007 concerning financial penalties for infringement of certain obligations in connection with marketing authorisations granted under Regulation (EC) No 726/2004 of the European Parliament and of the Council, Official Journal of the European Union, 9 June 2012, L 150/68-70

17.Personal communication, European Medicines Agency, 4 February 2014

Dr Peter Charlish is a principal analyst for Informa Business Information, the publisher of Scrip Regulatory Affairs. If you're a subscriber and would like more details on this article and/or a related subject, use our free Ask the Analyst service.




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