Better Medicines For Children Research Articles

Dosage Forms Suitability in Pediatrics: Acceptability of Antibiotics in a German Hospital.

Although drug acceptability can have a significant impact on patient adherence in pediatric therapy, data are limited, even for common therapeutic areas. We present the second part of an acceptability study conducted at the University Children's Hospital Düsseldorf, Germany. The study investigated the acceptability of most commonly used antibiotics in a pediatric hospital setting. The researchers used the acceptability reference framework to score the acceptability of five antibiotics based on 150 real-life observer reports of medicine intake. Four antibiotics assessed in this study were formulated as preparations for injection (ampicillin, ampicillin/sulbactam, ceftriaxone, and gentamicin) and one as a powder for oral liquid suspension (co-amoxiclav). All the antibiotics formulated as preparations for injection were rated negatively due to high rates of negative reactions (80%), the use of restraint (51%), the use of extra devices (99%), and long preparation and administration times (100%). The antibiotic formulated as a powder was significantly more well accepted. The study concluded that there is a lack of appropriate formulations for antibiotics for use in children. These findings are important in improving knowledge on acceptability drivers and might help in formulating and prescribing better medicines for children. The study highlights the need for healthcare professionals to have knowledge about the acceptability of different products to select the best-adapted product for each patient.

Dosage Forms Suitability in Pediatrics: Acceptability of Analgesics and Antipyretics in a German Hospital.

Although medicine acceptability is likely to have a significant impact on the patient’s adherence in pediatrics and therefore on therapy success, there is still little data even for common therapeutic areas. For analgesics/antipyretics, healthcare professionals face a wide variety of products and need knowledge to select the best adapted product for each patient. We investigated acceptability of those products most used at the University Children’s Hospital Düsseldorf, Germany. Based on 180 real-life observer reports of medicine intake, we used the acceptability reference framework to score acceptability of six distinct medicines. Both ibuprofen and paracetamol tablets, mainly used in adolescents, were positively accepted. This was not the case for the solution for injection of metamizole sodium. Regarding syrups, mainly used in children under 6 years of age, ibuprofen flavored with strawberry and provided with an oral syringe was positively accepted, while paracetamol flavored with orange and provided with a measuring cup was not. Suppository appeared to be an alternative to oral liquids in infants and toddlers with palatability and administration issues. Differences appeared to be driven by dosage forms and formulations. These findings improve knowledge on acceptability drivers and might help formulating and prescribing better medicines for children.

European Paediatric Formulation Initiative (EuPFI)-Formulating Ideas for Better Medicines for Children.

The European Paediatric Formulation Initiative (EuPFI), founded in 2007, aims to promote and facilitate the preparation of better and safe medicines for children through linking research and information dissemination. It brings together the capabilities of the industry, academics, hospitals, and regulators within a common platform in order to scope the solid understanding of the major issues, which will underpin the progress towards the future of paediatric medicines we want.The EuPFI was formed in parallel to the adoption of regulations within the EU and USA and has served as a community that drives research and dissemination through publications and the organisation of annual conferences. The membership and reach of this group have grown since its inception in 2007 and continue to develop and evolve to meet the continuing needs and ambitions of research into and development of age appropriate medicines. Five diverse workstreams (age-appropriate medicines, Biopharmaceutics, Administration Devices, Excipients and Taste Assessment & Taste Masking (TATM)) direct specific workpackages on behalf of the EuPFI. Furthermore, EuPFI interacts with multiple diverse professional groups across the globe to ensure efficient working in the area of paediatric medicines. Strong commitment and active involvement of all EuPFI stakeholders have proved to be vital to effectively address knowledge gaps related to paediatric medicines, discuss potential areas for further research and identify issues that need more attention and analysis in the future.

'Better medicines for children' within the Integrated Management of Childhood Illness framework: a qualitative inquiry in Uganda.

BackgroundThe Integrated Management of Childhood Illnesses is the main approach for treating children in more than 100 low income countries worldwide. In 2007, the World Health Assembly urged countries to integrate ‘better medicines for children’ into their essential medicines lists and treatment guidelines. WHO regularly provides generic algorithms for IMCI and publishes the Model Essential Medicines List with child-friendly medicines based on new evidence for member countries to adopt. However, the status of ‘better medicines for children’ within the Integrated Management of Childhood Illnesses approach in Uganda has not been studied.MethodsQualitative interviews were conducted with: two officials from the ministry of health; two district health officials and, 22 health workers from public health facilities. Interview transcripts were manually analyzed for manifest and latent content.ResultsChild-appropriate dosage formulations were not included in the package for the Integrated Management of Childhood Illnesses and ministry officials attributed this to resource constraints and lack of initial guidance from the World Health Organization. Underfunding reportedly undercut efforts to: orient health workers; do support supervision and update treatment guidelines to reflect ‘better medicines for children’. Health workers reported difficulties in administering tablets and capsules to under-five children and that’s why they preferred liquid oral dosage formulations, suppositories and injections.ConclusionsThe IMCI strategy in Uganda was not revised to reflect child-appropriate dosage formulations – a missed opportunity for improving the quality of management of childhood illnesses. Funding was an obstacle to the integration of child-appropriate dosage formulations. Ministry of health should prioritize funding for the Integrated Management of Childhood Illnesses and revising the Essential Medicines and Health Supplies List of Uganda, the Uganda Clinical Guidelines and, the Treatment Charts for the Integrated Management of Childhood Illnesses to reflect child-appropriate dosage formulations.

The contributions of the European Medicines Agency and its pediatric committee to the fight against childhood leukemia.

BackgroundAlthough the diagnosis of childhood leukemia is no longer a death sentence, too many patients still die, more with acute myeloid leukemia than with acute lymphoblastic leukemia. The European Union pediatric legislation was introduced to improve pharmaceutical treatment of children, but some question whether the European Medicines Agency (EMA) approach is helping children with leukemia. Some have even suggested that the decisions of EMA pediatric committee (PDCO) are counterproductive. This study was designed to investigate the impact of PDCO-issued pediatric investigation plans (PIPs) for leukemia drugs.MethodsAll PIPs listed under “oncology” were downloaded from the EMA website. Non-leukemia decisions including misclassifications, waivers (no PIP), and solid tumors were discarded. The leukemia decisions were analyzed, compared to pediatric leukemia trials in the database http://www.clinicaltrials.gov, and discussed in the light of current literature.ResultsThe PDCO leukemia decisions demand clinical trials in pediatric leukemia for all new adult drugs without prioritization. However, because leukemia in children is different and much rarer than in adults, these decisions have resulted in proposed studies that are scientifically and ethically questionable. They are also unnecessary, since once promising new compounds are approved for adults, more appropriate, prioritized pediatric leukemia trials are initiated worldwide without PDCO involvement.ConclusionEMA/PDCO leukemia PIPs do little to advance the treatment of childhood leukemia. The unintended negative effects of the flawed EMA/PDCO’s standardized requesting of non-prioritized testing of every new adult leukemia drug in children with relapsed or refractory disease expose these children to questionable trials, and could undermine public trust in pediatric clinical research. Institutions, investigators, and ethics committees/institutional review boards need to be skeptical of trials triggered by PDCO. New, better ways to facilitate drug development for pediatric leukemia are needed.

Explaining the slow transition of child-appropriate dosage formulations from the global to national level in the context of Uganda: a qualitative study.

BackgroundIn 2007, the Sixtieth World Health Assembly (WHA) passed a resolution entitled “Better medicines for children” and subsequently the World Health Organization (WHO) recommended the inclusion of child-appropriate dosage formulations in the essential medicines lists of member countries. However, child-appropriate dosage formulations are not highlighted in the Essential Medicines and Health Supplies List of Uganda (EMHSLU) 2012 and they are still limited in availability in public health facilities. Several stakeholders influenced the status of child-appropriate dosage formulations in the EMHSLU 2012.ObjectiveTo explore stakeholders’ views about the relevance of the globally recommended child-appropriate dosage formulations in the context of Uganda.MethodsThe findings derive from thirty three in-depth interviews with stakeholder representatives and the results of a follow up validation meeting where preliminary findings were shared with stakeholders. Policy analysis and policy transfer theories were used to guide a deductive analysis for manifest and latent content.ResultsAccording to stakeholders, the transition to the globally recommended child-appropriate dosage formulations has been slow in Uganda due to a number of factors. These factors include resource constraints at the global and national levels, lack of Ministry of Health (MOH) formal commitment to the adoption of the child-appropriate dosage formulations policy and a lack of consensus between those who advocated for the availability of liquid oral dosage formulations for easy administration and effectiveness and those who were more convinced by economic arguments and preferred the procurement of solid oral dosage formulations intended for adults.ConclusionsThe global policy for child-appropriate dosage formulations still remains to be implemented in Uganda and other low income countries. This has been due to lack of resources that hindered formal transfer of the policy from the global to the local level. To achieve this transfer there is a need for resource mobilisation at both the international and local levels, together with the revitalisation of UMTAC to enable it to take on a leadership role of the coalitions supporting child-appropriate dosage formulations.

A New Ethical Challenge for Institutional Review Boards (IRBs)/Ethics Committees (ECs) in the Assessment of Pediatric Clinical Trials.

Both the US and EU have introduced pediatric pharmaceutical legislation to facilitate clinical trials in children and development of better medicines for children. The first concerns were published in 2014 that the European Medicines Agency (EMA)’s Pediatric Committee (PDCO) may be over-enthusiastic and has compelled questionable pediatric clinical trials from pharmaceutical companies. Numerous clinical trials are mandated in rare conditions for which not enough patients exist for even one trial. Furthermore, where these trials are mandated in adolescent patients, the legal age limit of the 18th birthday is confused with a medical age limit and can result in separate clinical trials in adolescent patients that neither make medical nor scientific sense nor will ever recruit enough patients for a meaningful outcome. To confirm our concerns we searched the registry clinicaltrials.gov and found examples for PDCO-triggered unethical trials. We conclude that such trials should not be accepted by institutional review boards (IRBs)/ethics committees (ECs) and that clinical trials resulting from negotiations with EMA’s PDCO need extra careful scrutiny by IRBs/ECs in order to prevent unethical studies and damage to pediatric research and unnecessary risks to pediatric patients.

Essential medicines for children

Millions of children die every year before they reach the age of 5 years, of conditions largely treatable with existing medicines. The WHO Model List of Essential Medicines was launched...

Pediatric drug formulations: a review of challenges and progress.

Children differ from adults in many aspects of pharmacotherapy, including capabilities for drug administration, medicine-related toxicity, and taste preferences. It is essential that pediatric medicines are formulated to best suit a child's age, size, physiologic condition, and treatment requirements. To ensure adequate treatment of all children, different routes of administration, dosage forms, and strengths may be required. Many existing formulations are not suitable for children, which often leads to off-label and unlicensed use of adult medicines. New regulations, additional funding opportunities, and innovative collaborative research initiatives have resulted in some recent progress in the development of pediatric formulations. These advances include a paradigm shift toward oral solid formulations and a focus on novel preparations, including flexible, dispersible, and multiparticulate oral solid dosage forms. Such developments have enabled greater dose flexibility, easier administration, and better acceptance of drug formulations in children. However, new pediatric formulations address only a small part of all therapeutic needs in children; moreover, they are not always available. Five key issues need to be addressed to stimulate the further development of better medicines for children: (1) the continued prioritization of unmet formulation needs, particularly drug delivery in neonates and treatment gaps in pediatric cancers and childhood diseases in developing countries; (2) a better use of existing data to facilitate pediatric formulation development; (3) innovative technologies in adults that can be used to develop new pediatric formulations; (4) clinical feedback and practice-based evidence on the impact of novel formulations; and (5) improved access to new pediatric formulations.

Progress review of the European Paediatric Regulatory Framework after six years of implementation

The EU regulation (EU 1901/2006 Paediatric Regulation) that entered into force in 2007 has changed the field of medicinal drug development for children in the EU. Five years after its implementation a large number changes due to this regulation have been incorporated by Pharmaceutical Industry considering the development of new candidate drug. This report is a review of changes already implemented and the aspects of paediatric drug development, which still needs to be addressed in future working in the fields to provide better medicines for children.

The Vision of Better Medicines for Children and the Role of Regulatory Authorities

The Vision of Better Medicines for Children and the Role of Regulatory Authorities

‘Formulating better medicines for children’ – Setting the pace for the future

‘Formulating better medicines for children’ – Setting the pace for the future

Reflection: medicines for children—science alone is not enough

Access to medicines filling children's therapeutic needs is a long-standing global problem. The problem has been recognised and initiatives for correction were adopted in the USA in the late 1990s, and in the European Union in the first decade of this century. Paediatric medicines are particularly problematic in middle- and low-income countries, where most of the children of the world live. A paediatric medicines initiative involving the WHO in parallel with the US and EU initiatives was seen as important by the global paediatric and paediatric clinical pharmacology community, but the WHO was resistant to getting involved. Advocacy, networking, cooperation, persistence, hard work and some luck were needed to get the "Better medicines for children" resolution 60.20 adopted by the World Health Assembly in May 2007. Science has been a key enabler of the developments leading to and following the adoption of the paediatric initiatives, but as the example of the WHO shows, science alone was not enough to make the change.

Is the European Pediatric Medicine Regulation Working for Children and Adolescents with Cancer?

The European Pediatric Medicine Regulation was launched in 2007 to provide better medicines for children. Five years later, the number of new anticancer drugs in early development in the pediatric population remains low, and most children with cancer are still largely denied access to innovative drugs in Europe, as compared with the United States. We analyzed individual pediatric investigation plan (PIP) and waiver decisions for oncology drugs and all oncology drugs that have been approved for marketing authorization since 2007 in Europe. Among the 45 approved PIPs, 33% concern leukemias and lymphomas, 29% solid tumors, 13% brain tumors, and 20% a drug for supportive care. No specific PIP exists for life-threatening diseases such as high-risk neuroblastoma, whereas there are several PIPs in extremely rare malignancies in children and adolescents such as gastrointestinal stromal tumor, melanoma, thyroid cancer, and chronic myeloid leukemia. This paradoxical situation is due to approval of a PIP being driven by the adult indication. Twenty-six of 28 authorized new oncology drugs have a potentially relevant mechanism of action for pediatric malignancies, but 50% have been waived because the adult condition does not occur in children. The most striking example is crizotinib. Implementation of the pediatric regulation should no longer be driven by the adult indication but should be guided instead by the biology of pediatric tumors and the mechanism of action of a drug. This change will be achievable through voluntary PIPs submitted by Pharma or revocation of the oncology class waiver list.

Conference Report: Formulating Better Medicines for Children: 4th European Paediatric Formulation Initiative Conference

The fourth annual European Paediatric Formulation Initiative (EuPFI) conference on Formulating Better Medicines for Children was held on 19-20 September 2012 at the Institute of Molecular Genetics Congress Centre, Prague, Czech Republic. The 2-day conference concentrated on the latest advances, challenges and opportunities for developing medicinal products and administration devices for pediatric use, both from European and US perspectives. It was aimed specifically at providing exposure to emerging practical applications, and for illustrating remedies utilized by pediatric drug-development teams to overcome hurdles faced in developing medicines for pediatric patients. The conference format included plenary talks, focus sessions on each of the EuPFI work streams (extemporaneous preparations, excipients, pediatric administration devices, taste masking and taste assessment, age-appropriate formulations), case studies, soapbox sessions and a parallel poster display. This conference report summarizes the keynote lectures and also gives a flavor of other presentations and posters from the conference.

Drug Development

Drug Development

Better medicines for children: challenges and unmet needs

Better medicines for children: challenges and unmet needs This review deals with the use of medicinal products in children. Many medicinal products administered routinely to paediatric patients have been either not licensed for use in children (unlicensed use) or have been prescribed outside the terms of their product license (off-label prescribing). A lot of surveys have been conducted in the context of identifying the extent of off-label used drugs in children documenting high rates (45-60 %) of such use. Recognising and meeting challenges as development of suitable formulations for very young children and realization of clinical trials involving children present important steps in the enhancement of the present situation. To improve the health of children in Europe, the Regulation (EC) No 1901/2006 addressing the pharmaceutical industry, research teams and member states proposing important incentives and obligations was assigned. Paediatric Investigation Plan and Paediatric Use Marketing Authorisation present the key measures of the EU regulation on medicinal products for paediatric patients.

European Paediatric Formulation Initiative's (EuPFI) 2nd conference commentary—Formulating better medicines for children

European Paediatric Formulation Initiative's (EuPFI) 2nd conference commentary—Formulating better medicines for children

Dried Blood Spots, Pharmacokinetic Studies and Better Medicines for Children

Determining circulating drug concentrations in children is an ongoing obstacle to the development of age-appropriate dosing regimens. The requirement for small blood sample volumes in children compared with adults is a significant barrier to obtaining age-specific pharmacokinetic-pharmacodynamic data for this population and hence optimizing the efficacy and safety profile of medicines used by this group. This article discusses the potential for dried blood spot sampling to offer a solution to this issue.

Pediatric Pharmacy Advocacy Group International Pediatric Pharmacy and Pharmacology Symposium, 24–26 April 2009; Orlando, Florida, USA†

This milestone meeting, expertly organized by Mr David Knoppert (Scientist, Children’s Health Research Institute, Department of Pharmacy, St Joseph’s Hospital, London, ON, Canada), was the first international symposium on paediatric clinical pharmacy andpharmacology.Over 220paediatric pharmacists and clinical pharmacologists, representing more than 20 countries and all continents, were welcomed by Dr Stuart MacLeod (Department of Paediatrics, University of British Columbia, and Child & Family Research Institute, Vancouver, BC, Canada) representing the International Alliance for Better Medicines for Children (IABMC). Plenary sessions, lectures, round table discussions and workshops were given/led by an international contingent of experts. The content reflected the interdisciplinary nature of paediatric therapeutics, covering, in addition to clinical pharmacy and pharmacology, drug policy, drug safety, pharmacogenomics, drug regulation, international health, pharmacy education and pharmaceutical formulation science. The themes of the symposium were outreach, translational research and clinical practice. Within this framework, presenters and attendees examined how paediatric pharmacy and pharmacology, through international collaboration, can contribute to optimal drug therapy for the world’s children. The need for multidisciplinary networks through enhanced communication and collaboration was evident throughout the meeting; practitioners, educators and researchers from industry, government and pharmacy organizations emphasised this. Representatives included Dr Agnes Saint Raymond (European Medicines Agency [EMEA]), Ms Sara Arenas (European Society of Clinical Pharmacy [ESCP]),Dr David Hoff (American College of Clinical Pharmacy’s [ACCP] Practice and Research Network [PRN]), Dr John van den Anker (European Society for Developmental Perinatal & Paediatric Pharmacology [ESDPPP]), Dr Michael Christensen (Pediatric Pharmacy AdvocacyGroup [PPAG]),DrGeorge Giacoia (National Institutes of Health [NIH]), Dr Suzanne Hill (WHO), Dr Sharon Conroy (Neonatal and Paediatric Pharmacists Group [NPPG]) and Dr Klaus Rose (Roche). They identified specific areas to target, including (i) enhancing undergraduate and graduate training in paediatric pharmacy; (ii) developing a system for data integration and information sharing across countries; (iii) focusing on collaborative research and capacity building of researchers/ clinicians; (iv) increasing the quality of paediatric drug clinical trials in all age groups (including neonates and pregnant women) and increasing the number of multicentre trials to maximize the use of a limited pool of patients; (v) advocacy of paediatric medication issues through government and nongovernment non-profit entities and the pharmaceutical industry; (vi) focusing on formulations, unlicensed use of medications, reference sources and prescription monitoring; (vii) identifying the players (product, supply, research, use, policy, pharmacoepidemiology) and including representatives inmultidisciplinary teams; and (viii) offering knowledge to developing countries and encouraging trained paediatric clinicians to reach out to the remote and underserved. There are both many challenges and opportunities. There is a lot of enthusiasm within the sector but the workload is huge, and paediatric pharmacists and pharmacologists are underrepresented. We need to learn from past mistakes, maximize