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GAPP Report Summary

Project ID: 602962
Funded under: FP7-HEALTH
Country: Italy

Periodic Report Summary 2 - GAPP (GAbapentin in Paediatric Pain)

Project Context and Objectives:
Neuropathic pain in children is considered rare, although in the most recent years the prevalence seems increasing particularly in the context of serious medical conditions. Suffering from pain can limit a child’s ability to attend school, socialize with peers, and participate in physical activity. In fact, health care providers and school personnel often recommend that children not attend school or participate in other activities while they are attempting to manage their pain. Ironically, this can exacerbate the child’s pain. The quality of life for children with chronic pain has been compared to that of young people with cancer and other chronic diseases (Gold JI. 2009).
In this environment, it is of great concern that very few drugs are approved for the paediatric population. Most of the currently used medications for the treatment of paediatric pain lack formal approval in children and are largely used off-label. In addition, because of the lack of a stringent regulation on the need of paediatric data at the time of the marketing authorisation, to date analgesic drugs used in children’s pain have a very variegated authorization status across Europe and their availability is rather limited. The further lack of evidence-based data to support any effective treatment of neuropathic chronic pain in children was underlined in the “WHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses” (2012) where the need of conducting appropriately randomised controlled trials with the drugs currently used off-label is considered a priority.
Gabapentin has shown efficacy in a wide variety of pain syndromes, especially neuropathic and mixed pain. In adults it is indicated for the treatment of peripheral neuropathic pain such as painful DNP and PHN. However, evidence of efficacy to treat neuropathic pain is lacking in paediatric patients where only anecdotal and case series reporting the efficacy of gabapentin in treating chronic pain with a neuropathic component are available (Butkovic D et al. 2006; Rusy LM et al. 2001; McGraw T and Stacey BR. 1998).
For the above mentioned reasons gabapentin was included also in the PDCO Priority list.
The GAPP (GAbapentin in Paediatric Pain) project aims to increase the availability of paediatric medicines, by developing a full clinical strategy on gabapentin tested in a condition, chronic pain, where the therapeutic need in children is very high and well recognised.
The development plan to be implemented in the project was approved by the PDCO (EMEA-001310-PIP01-12) which endorsed the overall objectives re-stating the concept that: ”...there is a significant therapeutic need in the management of pain in children, not only in the availability of child appropriate formulations but also in generating efficacy and safety data in pharmacological agents of different classes”.
The agreed specifications provide a comprehensive drug development package which includes:
• a liquid oral gabapentin formulation to be developed for the needs of the entire paediatric population (>3 months to <18 years of age);
• the tackling of the uncovered therapeutic need in ‘neuropathic’ or ‘mixed’ chronic pain where morphine and other opioids show scarce efficacy, by conducting two controlled, parallel-arm efficacy-safety clinical trials in patients aged from 3 months to less than 18 years with moderate and severe pain (GABA-1 e GABA-2 respectively);
• the implementation of innovative approaches such as extrapolation and modelling for the collection of informative data also in of the smallest age subsets (<3 years of age);
• the completion of a toxicokinetic study for the investigation of the potential effects of gabapentin on the CNS development;
• the development of a market and HTA analysis aimed to clarify the sustainability under an economic and industry point of view of the development of a new liquid formulation. A HTA report will integrate this analysis in a social, medical and ethic perspective.
The GAPP Consortium is composed by an international, scientifically experienced paediatric network committed to conduct the trials adopting sound ethical and quality standards and make the results available for a PUMA application expanding the number of drugs suitable for children.
The GAPP Project actively collaborates with the TEDDY Network, to which most of the GAPP Beneficiaries adhere. TEDDY is an independent, multidisciplinary, multinational Network, composed by partners from EU and non-EU countries with the aim to perform and support paediatric clinical trials, which is strongly engaged in favouring awareness on the topics of paediatric research, to identify unmet medical needs in paediatrics and to spread information on the rational use of paediatric medicines.

Project Results:
The second reporting period (M19-M36) was critical for the development and implementation of the GABA-1 and GABA-2 clinical studies.
During the first reporting period (M1-M18) the GAPP Consortium identified some specific issues with the implementation of key quality and clinical measures as set in the PIP that had already been approved by the PDCO at the EMA. The heterogeneity of paediatric pain management across the different European and non-European clinical sites and the paucity of any data (and treatment) for paediatric neuropathic pain revealed that some clinical key elements discussed and agreed with the PDCO were rather empirical and of difficult implementation in the clinical practice. The issues were addressed through a thorough review of literature carried out by the specific Working Groups established in the context of WP2 and by the DSMC. The suggestions for improvement deriving from this exercise were implemented in the first revision of the GABA-1 and the GABA-2 protocols. However, such changes to the protocols implied misalignment to the key binding elements of the quality and clinical measure as previously defined in the PIP, which was agreed with the EMA’s PDCO on 23/03/2013 (PDCO decision 001310-PIP01-12). Consequently, after consultation with the PDCO, two separate PIP modifications were deemed necessary: one related to the request for modification of the clinical measures dated 10/07/2015 (PDCO decision 001310-PIP01-12-M01) and the subsequent one on the quality measures dated 30/10/2015 (PDCO decision 001310-PIP01-12-M02).
Furthermore, it was proposed to incorporate two voluntary exploratory studies on pharmacogenetics and metabolomics: additional exploratory objectives were added to the core study to collect information on the metabolomic profile following drug treatments and to explore genetic polymorphisms and their impact on pharmacokinetics (PK) and pharmacodynamics (PD). The aim of these two studies is to collect information on the molecular mechanisms leading to neuropathic pain and the response to the treatment.
The PDCO acknowledged the challenges posed by the proposed development plan in an almost undiscovered area with high unmet medical needs but with very little evidence-based medical information and, after repeated consultation, an agreement was reached with the regulatory agency on the final development plan.
The quality measure modification in the PIP implied that the developed gabapentin paediatric liquid formulation had to be modified, changing the levels of one of the excipients. This led to a delay of several months in the delivery of the first IMP clinical batches.
It was only after the approval received from the PDCO that the two Study Protocols and Statistical Analysis Plans for both GABA-1 and GABA-2 as well as the IMPD for gabapentin could be further elaborated and finalized.
In parallel, the following documentation adjunctive to the protocol was developed for the GABA-1 clinical trial and the same is close to be completed for the GABA-2 clinical trial: Case Report Form; Patient diary; Patients information leaflets and informed consent forms.
The last part of this reporting period was especially focused on the coordination and management of all activities aimed at obtaining the approval of the clinical trials in each recruitment site. All the concerned Ethics Committees and Competent Authorities of each recruiting site were contacted in order to collect information on specific regulatory requirements for the Clinical Trial Application. A master application package (compliant to EU Directive 2001/20/EC) was prepared to serve as a template. It was complemented by specific locally required documents for the review of the studies by CAs and Institutional Review Boards (IRBs)/ECs.
At present, the GABA-1 study was submitted in France, the Netherlands, Italy and Germany, and the first CAs (the Netherlands and Italy) and/or ECs (France and Italy) favourable opinions were received. The GABA-2 study submission will start by M39, capitalising on the experience acquired during the GABA-1 submission.
In view of the implementation of the GABA-1 study, the clinical trial infrastructure was defined and organised in the context of WP4 and sets the bases for the initiation of the studies and enrolment of the first patients which is expected for 4Q2016 (Drug management, Electronic Data Capture, Monitoring, Pharmacovigilance). Furthermore, a Data Safety Monitoring Committee (DSMC) in charge for both studies was established to overlook on patients’ safety throughout the trials. A request for Amendment was submitted to the European Commission in August 2016.

Potential Impact:
Many false myths still remain and may be responsible for the inadequate pain management of many children in palliative care. Especially infants and very young children often do not receive sufficient analgesia, because their discomfort is different from that of adults.
To date opioids, non-steroidal anti-inflammatory drugs (NSAIDs), antidepressant and anticonvulsant are used as pharmacological agents to treat pain also in children. However, no single class of drugs has been found to be effective in all types of pain syndromes, probably because of the different underlying aetiologies. Indeed, non-steroidal anti-inflammatory drugs and opioid medications may be the standard therapy for mild to severe non-neuropathic pain, but opioids have demonstrated to be less efficacious for neuropathic pain syndromes.
The lack of evidence-based data to support any effective treatment of chronic pain with the neuropathic component in children has also been underlined in the “WHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses” (2012) where the need of conducting appropriately randomised controlled trials with the drugs currently used off-label is considered a priority. Moreover, it is now beginning to be accepted that ethical concerns that too many vulnerable children will be recruited into clinical trials must be balanced against limiting the number of off-label prescribing and obtaining age-appropriate information on paediatric use (Davies EH et al., 2010).
Gabapentin has shown efficacy in a wide variety of pain syndromes, and its use is of particular interest in the reduction of chronic pain affecting children with chronic mixed pain for which morphine is often used as standard therapy. Indeed children in severe pain quite often need strong pain medication, i.e., morphine or other strong opioids. As in adult, gabapentin could represent not only a valuable alternative to morphine but also a mean to reduce morphine requirement and addiction risk (Keskinbora K et al., 2007; Gilron I et al., 2005).
The availability of gabapentin for the treatment of paediatric chronic pain can make a difference because of its relative freedom from serious adverse effects, its lack of interactions with other drugs and its lack of potential for causing drug dependence. Currently a children-friendly oral formulation is lacking and extemporaneous preparations are being prepared in clinical practice and causing potential under-or over-dosing errors.
The GAPP project provides the opportunity to progress beyond the present situation by generating:
• results of randomised, comparative studies to demonstrate that gabapentin is safe and efficacious in the treatment of children affected by chronic pain with a neuropathic component both as monotherapy and as adjuvant therapy;
• clear dosage indication for each paediatric age;
• availability of a new oral formulation, tailored for children, thus reducing the risk of administration errors and involuntary adverse reactions.
An additional value of this project is the use of innovative approaches such as modelling and simulation for data extrapolation from older to younger children (GABA-3), which will allow the reduction of the number of children to be enrolled in experimental clinical trials. The TEDDY Network has supported the set up of the research partnership proposing the GAPP Project and the introduction of this innovative approach, and will be further involved in the studies management as well as in the exploitation of results.
In conclusion, the development plan proposed in the GAPP project is expected to cover the existing therapeutic gap and to provide reliable data in support the registration of gabapentin in the treatment of chronic pain in paediatrics, a patient population where the need of treatment for this indication is particularly high. In addition, by proposing innovative study designs, the project will contribute to advance the search for new methodologies in small patients population for whom the conventional efficacy-safety study designs may not always be feasible.
All information generated within the GAPP project are available to patients, via the project portal (found at

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