Pediatric Clinical Trials: The Need for Regulation (Part 1)

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1 WRITTEN BY CONTACT INFORMATION Dr. Martine Dehlinger-Kremer Vice President, Global Medical and Regulatory Affairs, SynteractHCR SynteractHCR 5909 Sea Otter Place, Carlsbad, CA SynteractHCR.com Pediatric Clinical Trials: The Need for Regulation (Part 1) A little history Despite the fact that some labeling for children did exist since 1979, more than 80 percent of listed medications labels lacked prescribing information for children because most of them were being used off label. Why? Because percent of medicines being used for children were not tested and evaluated in children. Even in hospitals, at least one third of hospitalized children and 90 percent of neonates in ICU were receiving off-label prescriptions. Needless to say, this was not a good situation due to the risks posed for ineffective under-dosing, or worse, adverse effects from overdosing. It was exceptionally hard to determine formulations for pediatric populations and this resulted in delayed access to innovative medicines for children. But how could this problem be solved? There had been a limited number of clinical trials for children and a limited number of participants even in those trials. There was no suitable trial methodology and no real infrastructure for pediatric trials, in part due to a lack of funding for this research. All of the regulatory bodies knew this situation had to change. Objectives for pediatric research established Both the EU and the US had the same goals: to improve the health of children through high quality, ethical research that would increase the availability of authorized medicines for children and increase information on these medicines, without unnecessary studies being conducted on children and without delaying authorization for adults. Over time, several different rules and regulations have been in effect, with the Pediatric Regulation of 2006 in the EU and the FDASIA of 2012 in the US, which made BPCA and PREA permanent, having the greatest significance.

2 History of Pediatric Regulations in the US and EU US 1979 Product Labels Include Pediatric Use Section 1997 FDAMA Pediatric Exclusivity; Written Request 2003 Pediatric Research Equity Act (PREA); Replaced the Pediatric Rule 2010 Biologics Price Competition & Innovation Act (BPC); pediatric exclusivity for Biologics 1994 Pediatric Use Labeling Rule 2002 Best Pharmaceuticals for Children Act (BPCA); Replaced FDAMA 2007 FDAAA; Reauthorization of BPCA and PREA 2012 FDASIA; BPCA & PREA Now Permanent EU 2006 Pediatric Regulation Adopted 2007 Entry into Force for Regulation; Establishment of Pediatric Committee (PDCO) Collaboration becomes the key to improvement Since 2007 when the EMA and FDA agreed upon collaboration and common principles of interaction, a great deal of progress has been made. A monthly teleconference to discuss product specific pediatric drug development and general scientific, regulatory and safety issues has been held. Japan PMDA and Health Canada joined, initially as observers in 2009 and 2010, respectively, and both are now active participants. Documents are exchanged through a secure link, Eudralink. This communication does not mean that pediatric development programs will have exactly the same protocols or ask the same question or even arrive at the same regulatory decisions. However, the objectives of the exchanges are valid to avoid exposing children to unnecessary trials and to enhance the science while decreasing the risk to children. Where are we now 10 years after the EU Pediatric Regulation Pediatric development has now become part of drug development. The proportion of clinical trials including children under 18 has increased to approximately 11.5 percent with about trials per year in the EU. In the US, in 1999, 20% of new medicines relevant to pediatrics had pediatric information, by 2008, it was 41 percent. In the EU, by the end of 2011, a pediatric indication was included in the marketing authorization application of 70 percent of all new medicinal products. 2

3 A new guideline on the application of PIPs was published by the Commission in September 2014 helping to create improvements and to streamline paper work. Only one PIP is now required for drugs that have applicability in more than one condition. New trial methodologies are also available, with modeling and simulation allowed as well as extrapolation. Extrapolation of data is available in a reflection paper. Between January 2007 and December 2016, a total of 273 new medicines and 43 additional pharmaceutical forms appropriate for use in children were authorized in the EU, and 950 PIPs were agreed to by the EMA. In addition, 486 waivers of the development of a medicine in one or more medical conditions were allowed. Marketing Authorization Applications (MAAs) showed that the Pediatric Regulation, with its legal requirement to promote the development of children s medicines, had closed the gap to include new medicines with potential pediatric usage. More information is available than ever before with changes in the summary of product characteristics and package leaflets. On 27 October 2016, the EMA presented the 10 Year report of the Pediatric Regulation to the European Commission. As per the report, the Pediatric Regulation has had a very positive impact on pediatric drug development: More medicines for children as well as better and more information for prescribers and patients Better pediatric research and development More regulatory support for pediatric matters, and Pediatrics have become an integral part of medicine development. Transparency is enhanced. For the first time ever, results of pediatric studies are publicly available. The EU Clinical Trials Register currently displays 31,359 clinical trials with a EudraCT protocol, of which 5,041 are clinical trials conducted with subjects less than 18 years old. The register also displays information on 18,700 older pediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006). Perhaps most important, there have been no delays in authorizations of medicines for adults due to the implementation of the Pediatric Regulation. 3

4 What comes next? A second report, mandated by the Pediatric Regulation in Article 50(3), is expected before the end of This second report will provide a more in-depth analysis of the experience with the Regulation, both with regard to public health goals and with regard to the economic rewards provided. The report will be informed by several projects and data sources, currently assembled by the Commission with the support of external partners. This includes data collected by the European Medicines Agency (EMA) together with its Pediatric Committee (PDCO) regarding the key health related outputs. Additionally, a study has been commissioned analyzing the economic impact of the Regulation. In order to prepare its 10 years report, the Commission issued a consultation paper to support the drafting. The comments to the consultation paper can be reviewed at this link: It is important to note that PSP and PIP are mandated unless waivered or deferred, although there are a few exceptions to this. Waiver means that the pediatric studies are not needed. Deferral means that the pediatric studies can be deferred to the post-marketing stage in adults. If not waived or deferred the regulations are these: In EU: a pediatric investigation plan (PIP) and compliance with that pediatric investigation plan is required for marketing authorization application for all new medicinal products, with a few exceptions, as well as for modifications such as e.g., new indication, new route of administration. In case the applicant is not compliant with the pediatric plan the marketing authorization application will not be validated and not reviewed. Exceptions in the EU include: Generics, biosimilars and well established use products Medicinal products such as homeopathic and traditional Herbal medicinal products In the US a pediatric study plan (PSP) is required for new drugs, new indications, new dosage form, new route administration. The PSP must be submitted 60 days after the end of the Phase II meeting with the FDA, and if no meeting with FDA is held, then, at the latest, 210 days prior to NDA submission. The PSP is to be included in the NDA/BLA. The FDA cautions that an applicant should not submit a marketing application or supplement until agreement has been reached on the PSP. This, of course, could include a deferral request or waiver of the requirements. But, nonetheless, FDA maintains that the PSP must be addressed ahead of any NDA (original or supplements) filing if the filing falls under PREA. While progress has definitely been made, there is still work to do. Come back for Part 2 of this article next month! 4

5 Bio for Dr. Martine Dehlinger-Kremer Vice President, Global Medical and Regulatory Affairs at SynteractHCR Dr. Martine Dehlinger-Kremer has 30 years of experience in the clinical research industry, including more than 27 years of progressively higher levels of Regulatory and Medical Affairs leadership responsibility. She has contributed to the global development of numerous products, including orphan drugs and biosimilars. She has participated in more than 100 New Drug Applications (NDAs) and Marketing Authorization Applications (MAAs) globally and in numerous clinical studies across all phases. Dr. Dehlinger-Kremer has served as Chair of the Pediatric Working Group of EUCROF since 2008 and has influenced the standards, protocols and number of trials conducted for drugs being administered to children. Dr. Dehlinger-Kremer is chair of the EFGCP Children Medicines Working Party and is also a member of Working Parties of Enpr-EMA, the European Network of Pediatric Research at the European Medicines Agency. Dr. Dehlinger-Kremer is also the President of EUCROF, the European CRO Federation, which represents approximately 400 CROs. In addition, she is a Board member of EFGCP, the European Forum for GCP. In August 2015, she was named one of PharmaVOICE 100 s Most Inspiring People in Life Sciences as an industry leader recognized for impact, experience and advocacy in clinical research. Dr. Dehlinger-Kremer holds a Doctorate in Sciences from the University of J.W. Goethe in Frankfurt, a general academic studies degree in neurophysiology from the Louis Pasteur University in Strasbourg, France, and a Master of Science from the University Moulin de la House in, France. 5

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