Description of funded projects
According to the CORDIS database and other EC sources , in the period of 2006–2012, five calls have been launched in the context of the FP7 programme with reference to topic 4.2-1 ‘to develop off-patent medicinal products for the paediatric population’. Under the framework of these calls, a total of 76 proposals have been submitted and 20 have been funded with a success rate of 26.3 %. This analysis describes the 20 projects, listed in Table 1, devoted to paediatric studies to support a PUMA. The total amount awarded to these projects is 98.6 million euros (see Table 1).
The 20 approved projects are investigating a total of 24 active substances, 8 of which (methotrexate, 6-mercaptopurine, ciprofloxacin, budesonide, doxorubicin, deferiprone, hydrocortisone and clonidine) have been granted a European Orphan Drug (OD) designation. In four cases (methotrexate, 6-mercaptopurine, hydrocortisone and deferiprone) the orphan conditions matches the Priority List indications (acute lymphoblastic leukaemia for the first two, adrenal insufficiency and sickle cell disease, respectively).
The substances are intended to treat a total of 22 paediatric indications in 10 therapeutic areas (Table 2). The most represented area is ‘infection’ accounting for four projects.
The 20 Research Consortia generated by the projects encompass 246 European and non-European institutions. The smallest Consortium includes four partners; the biggest one includes 18 participant members (Table 1). In addition, an average number of 6–8 investigational centres are included as third parties in each project. A total of 29 countries (22 European Member States and 7 non-European Member States) are involved with the UK, France, Italy and Germany being the most frequently represented, both in terms of number of participants and number of projects (Fig. 1). Four projects (HIP trial, DEEP, NEO-CIRC and GAPP) also include non-EU countries in their partnership. France and Italy together account for 50 % of coordinators (respectively, six and four) followed by UK and Germany (three projects each).
Most of the partners are universities and public-funded national research centres or institutions, 51 are private companies of which almost 40 are SMEs. Seven out of 20 project consortia (03K, DEEP, EPOC, TAIN, CloSed, GAPP and NEO-CIRC) include a patient association, while 9 out of 20 project consortia (NEuroSIS, EPOC, DEEP, NeoMero, PERS, LENA, GAPP, NeoVanc, CloSed) include a not-for-profit research organisation, as member or coordinator.
Paediatric studies that contribute to the development of medicines for children
New forms/formulations development
Eighty percent of the projects include studies to develop new age-appropriate formulations or dosage form: ten oral new formulations (six liquid, three tablets soluble or effervescent and one granule), seven new intravenous formulations and three intravenous dosage forms.
Subgroups of paediatric population involved in clinical trials
All paediatric subgroups are represented in the clinical trials (Fig. 2). In particular, 17 out of 29 paediatric clinical trials include preterm and/or term newborns. Projects NeoOpioid, NEuroSIS, NEMO, TINN and TINN2, HIP trial, NEO-CIRC and NeoVanc specifically address neonatal condition and for this reason patients to be enrolled in clinical trials are only preterm/term newborns.
Number and type of studies
A total of 71 studies are to be completed by the end of the 20 projects. They include studies in healthy adult volunteers (3), formulation development (20), clinical trials in children (29), non-interventional studies (6), in silico modelling (10) and non-clinical studies in animals (3).
Two out of three studies planned in healthy adult volunteers were PK, dose ranging and safety and one was a PK study. On a total of 29 paediatric trials, 16 were randomised controlled, eight on clinical pharmacology (PK/pharmacodynamics (PD)/dose finding), 9 non-randomised efficacy and/or safety and 12 were PK/PD/efficacy/safety. The estimated enrolment for all projects is 7,300 children. A pharmacogenetic sub-study is foreseen in 13 clinical trials (Table 3). Almost all trials are multicentre, involving 387 investigational sites, both in European and non-European countries. Thirteen of the paediatric trials are registered on the European Clinical Trials Database (EudraCT).
Start of the studies and patients’ enrolment
Enrolment of participants has been evaluated in 15 of 20 projects, corresponding to 23 clinical trials (5 projects, receiving approval less than a year before the survey, have been excluded from this analysis). At the time of this review (July 2014), a total of 1,400 paediatric patients (equal to 22.4 % of the estimated enrolment for all 15 projects) have been included in trials. This relates to five completed and eight ongoing trials. Ten additional trials have concluded the approval procedures and are in the process of opening.
Support for SMEs
The partnership includes 51 private companies of which 13 are pharmaceutical companies and at least 40 meet the definition of an SME according to the information available to us. The projects are mainly coordinated by universities or other public Institutions while companies and not-for-profit research organisations are involved as coordinators in two and four projects, respectively. There are a significant number of private–public partnerships which would not have happened in the absence of pump-priming funding.
Paediatric Investigation Plans
Fifteen approved PIPs referring to 14 projects are available, while two projects (TINN and LENA) have submitted a PIP application but not yet received an approved plan. As indicated in Fig. 3, no PIP has been completed so far, and the completion date of the paediatric developmental plan ranges from January 2015 to end of 2018. No deferrals are foreseen in the plans. During the PIP approval process, some changes in the projects have been performed on PDCO request. These changes have included new measures and patient populations, additional trials or studies, sample size revision, modified statistical plan, and, more frequently, additional or modified paediatric indications (Table 2). These changes were mainly prompted by valuable scientific or regulatory concerns and were accordingly integrated in the projects. However, the need to come back for approval to the EC also influenced the timing and the complexity of the projects performance. In addition, even if new measures were requested by the PDCO, no additional funds were made available by the funding authority.
Progress towards PUMAs
PUMA applications require a PIP to be agreed, completion of all measures according to the agreed plan and confirmation of compliance with the agreed PIP. According the timelines of the FP7 projects, all of these steps should be completed within 5 years. While some projects may need extension, all of the studies will be conducted in this short period. This is different from the approach taken by many commercially funded PIPs. According to the 5-year report on the impact of the Paediatric Regulation drafted in 2012 by the EMA-PDCO , the number of PIPs in which studies are deferred is very high with 44 % of the approved PIPs not progressing as planned .