Development Of Paediatric Medicines Research Articles

DEVELOPMENT AND ESTABLISHMENT OF A QUALITY-FRAMEWORK FOR THE LENA PROJECT

BackgroundThe LENA (Labeling of Enalapril from Neonates up to Adolescents) project has been initiated to improve the healthcare of children with heart failure by an enalapril orodispersible mini-tablet. The LENA consortium combines academic clinical research centers, SMEs (small and medium-sized enterprises) and a patient/parent advocacy organization. The objective of the project requires to comply with respective GxP regulations like Good Manufacturing Practice (GMP), Good Clinical (Laboratory) Practice (GCP/“GCLP”1) and Good Vigilance Practice (GVP). The project team is comprised of sub-teams experienced in paediatric clinical practice, medicines development, clinical research and project management, but not all team members work in an appropriate quality framework. Aim: To establish a well-documented, efficient quality system applying a new approach for ensuring quality in all trial aspects by combining existing organization-related quality system elements of the project partners with newly developed SOPs and overarching, integrating trial-specific elements to ensure a reliable quality environment for the LENA Phase I clinical trial.MethodsBased on the network-structure of the project organization, a strategy based on a team approach with joint responsibilities for the quality conduct of the project was pursuit, forming a QM Team consisting of the project leader, the leaders for pharmaceutical and clinical development and an external quality expert. The team compiled a quality manual and an organizational chart displaying the sub-teams and their responsibilities. Another responsibility of the team is the integration of existing SOPs and Work Instructions as well as the creation of procedures at the project level and furthermore the verification of appropriate qualification of all staff involved in the project through CVs, job descriptions and training records.ResultsFor the Phase I study, a thorough analysis of all existing relevant SOPs and Work Instructions, forms and other quality elements was performed, uncovered trial-related processes were identified and a work plan was established to fill the gaps with the smallest possible number of newly developed organization-related SOPs/Work Instructions and by preparing trial-specific process manuals. Demonstration of the trial team members was ensured by completing documentation concerning CVs, job description and training records. Among the sub-teams, the GCLP environment of the bioanalytical laboratory was started from scratch and could adequately support the LENA Phase I study by “GCLP” quality work and sample logistics.ConclusionThe consortiums approach enabled the preparation of a comprehensive, reliable GxP compliant quality system within a short timeframe and with the limited resources of a publicly funded project.1 “GCLP” is used as acronym for a quality system established in compliance with “Reflection paper for laboratories that perform the analysis or evaluation of clinical trial samples” (EMA/INS/GCP/532137/2010; 28 February 2012)The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA).

Enhanced Paediatric Pharmacovigilance at the European Medicines Agency: A Novel Query Applied to Adverse Drug Reaction Reports.

Databases of suspected adverse drug reactions (ADRs) are a cornerstone of pharmacovigilance. With increasing numbers of reports, additional statistical approaches are needed to better use the data. The present study was aimed at elucidating the European Medicines Agency's (EMA) use of a novel 'paediatric' query to analyse the data in its ADR database 'EudraVigilance'. The proportional reporting ratio (PRR) is a measure of disproportionality for which the underlying principle is that a drug-event pair of interest is reported more often than expected relative to an independence model. The EMA's paediatric query, based on PRRs, was applied to the data in EudraVigilance to investigate the extent to which the known association between enalapril and renal toxicity was reflected in reported ADRs comparing children with adults and with adjustment for the effect of multiplicity. The comparison of PRRs for children (14.91, 95% confidence interval [CI] 13.05-17.04) versus adults (2.66, 95% CI 2.52-2.82) confirmed a higher risk of renal ADRs with enalapril when used in children compared with all other medicines and compared with adults. The EMA's paediatric query can be used to highlight an imbalance for a drug-event pair among ADRs for a medicine when used in children and as compared with adults. Applying the query in practice can help the EMA to decide on whether stand-alone paediatric medicine development is warranted, and which, if any, further studies are necessary. Ongoing evaluation of the query is contributing to the development of new methods and guidance.

History of pediatric critical care medicine.

OBJECTIVES: to review and cite important individuals and events in the development of pediatric critical care medicine (PCCM). DATA SOURCES: A MEDLINE search was performed looking for citations of the history of PCCM. This yielded 85 citations of which 46 were obtained. Thirty nine of the 85 were rejected as inappropriate either by title (e.g., pediatric emergency medicine) or because they were in a foreign language only. After review of the 46, 21 were included in this review and the others rejected as inappropriate. Textbooks of PCCM were reviewed for chapters on the history of PCCM and four were included. Forty-eight personal communications were made to individuals and four to organizations to elicit and verify information. One speech is referenced and from these sources, a total of 37 additional textbooks, monographs and chapters and 47 journal manuscripts and reference sites were found and included. SELECTION AND EXTRACTION: Materials pertinent to the specific disciplines, individuals and events in the development of CCM(Critical care medicine) and PCCM were included in this review. CONCLUSIONS: PCCM owes a great debt to the expertise in anesthesiology, neonatology, pediatric cardiology, pediatric general and cardiovascular surgery and nursing for its evolution. The modern PCCM unit and service is more the result of the need to treat and organize care for critically ill and injured patients than to any developments in technology.

The development of pediatric anesthesiology and critical care medicine at the Cincinnati Children's Hospital: an interview with Dr. Theodore Striker

Dr. Theodore W. 'Ted' Striker (1936-), Professor of Anesthesiology and Pediatrics at the University of Cincinnati, has played a pioneering role in the development of pediatric anesthesiology in the United States. As a model educator, clinician, and administrator, he shaped the careers of hundreds of physicians-in-training and imbued them with his core values of honesty, integrity, and responsibility.

Orally disintegrating films and mini-tablets-innovative dosage forms of choice for pediatric use.

Oral drug delivery is a non-invasive and therefore a very convenient route of administration. Orally disintegrating dosage forms, like soluble films and (mini-)tablets, appear promising for use in the pediatric population. New guidance for the development of pediatric medicines has been published, which provides considerations on how pediatric products should be designed. However, most of the considerations leave a lot of room for interpretations. Bearing in mind the different aspects discussed in the latest guideline, the use of orally disintegrating films and tablets, in particular, small-sized tablets, is discussed and reflected upon by providing evidence from the scientific literature. The available dosage forms for children are various and examples of currently licensed products for use in the pediatric population were compiled. Aspects such as the appropriateness for pediatrics, the choice of excipients, the opportunities for modified drug release preparations or fixed-dose combinations, the acceptability and palatability, and also limitations were discussed with respect to the new dosage forms of orally disintegrating films and mini-tablets. This paper points out that innovation in pediatric medicines are planned and should be encouraged; however, supported by the regulatory guidance, only general considerations are provided. Nevertheless, the guideline summarizes multiple points to consider during the development of medicines for pediatric use. Considering the scientific evidence and the regulatory guidance, orally disintegrating dosage forms, like soluble films and (mini-)tablets, offer an innovative solution for pediatric drug delivery.

PReS13-SPK-1576: Unmeet needs in JIA treatment

Conducting clinical trials in paediatric rheumatology has been difficult in the past mainly because of the lack of funding for academic studies and the lack of interest by pharmaceutical companies for the small and non-rewarding paediatric market. The situation changed dramatically few years ago with the introduction of the Best Pharmaceuticals for Children Act in USA and of a specific legislation for paediatric medicines development (Paediatric Regulation) in the European Union (EU). The main reasons for success are: the availability of two large international non-for-profit networks working in close collaboration, such as the Pediatric Rheumatology Collaborative Study Group (PRCSG at http://www.prcsg.org), covering North America, and the Paediatric Rheumatology International Trials Organisation (PRINTO at http://www.printo.it), covering more than 50 countries worldwide; the availability of validated measures to evaluate response to therapy, now called JIA American College of Rheumatology (ACR) criteria, accepted by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA); last but not least the advent of the biologic therapies (anti TNF, Anti IL 1 and 6, anti CTL4Ig) which have revolutionized juvenile idiopathic arthritis (JIA) treatment. Some problems however remain still to be solved: There is a need to harmonise all the regulatory aspects related to drugs that are used in the treatment of paediatric rheumatic diseases and in particular in JIA; the issue of me too drugs; the issue of proper pK studies; the ethics of drugs provision and of trial implementation; the implementation of proper pharmacovigilance systems. This presentation will review the reasons for success and the problems that still remains to be solved for conducting trials in JIA.

Sleep Disorders in Children

During the past 25 years, development of Pediatric and Adolescent Sleep Medicine (PASM) has become an imperative child health care discipline. During the past decade, the American Academy of Sleep Medicine (AASM) prepared a modern path for certification in competency in the practice of Sleep Medicine by the American Board of Medical Specialties (ABMS) by applying for recognition of sleep medicine training programs by the Accreditation Council for Graduate Medical Education (ACGME) and pursuing ABMS approval of the certification process.1 In addition, the American Board of Pediatrics (ABPeds) joined together with the American Board of Family Medicine (ABFM), American Board of Otolaryngology (ABOto), the American Board of Psychiatry and Neurology (ABPN), and the American Board of Internal Medicine (ABIM). ABIM was designated as the administrative board. Accreditation requirements were established for post-graduate fellowship training in sleep medicine in 2004. ABMS approved sleep medicine certification in 2005. The first certification examination in Sleep Medicine was administered in 2007. Medical content areas often overlapped (for example, obstructive sleep apnea, hypersomnolence, sleep-related movement disorders), but only 2% of the examination focused on considerations and disorders unique to childhood.2 None-

Impact of the European paediatric legislation in paediatric rheumatology: past, present and future

Conducting clinical trials in paediatric rheumatology has been difficult mainly because of the lack of funding for academic studies and the lack of interest by pharmaceutical companies in the small...

The development of Pediatric Critical Care Medicine at The Children's Hospital of Philadelphia: an interview with Dr. John J. ‘Jack’ Downes

Dr. John J. 'Jack' Downes (1930-), the anesthesiologist-in-chief at The Children's Hospital of Philadelphia (1972-1996), has made numerous contributions to pediatric anesthesia and critical care medicine through a broad spectrum of research on chronic respiratory failure, status asthmaticus, postoperative risks of apnea in premature infants, and home-assisted mechanical ventilation. However, his defining moment was in January 1967, when The Children's Hospital of Philadelphia inaugurated its pediatric intensive care unit--the first of its kind in North America. During his tenure, he and his colleagues trained an entire generation of pediatric anesthesiologists and intensivists and set a standard of care and professionalism that continues to the present day. Based on an interview with Dr. Downes, this article reviews a career that advanced pediatric anesthesia and critical care medicine and describes the development of that first pediatric intensive care unit at The Children's Hospital of Philadelphia.

Enhancing Electronic Health Record Usability in Pediatric Patient Care: A Scenario-Based Approach

Usability of electronic health records (EHRs) is an important factor affecting patient safety and the EHR adoption rate for both adult and pediatric care providers. A panel of interdisciplinary experts (the authors) was convened by the National Institute of Standards and Technology to generate consensus recommendations to improve EHR usefulness, usability, and patient safety when supporting pediatric care, with a focus on critical user interactions. The panel members represented expertise in the disciplines of human factors engineering (HFE), usability, informatics, and pediatrics in ambulatory care and pediatric intensive care. An iterative, scenario-based approach was used to identify unique considerations in pediatric care and relevant human factors concepts. A draft of the recommendations were reviewed by invited experts in pediatric informatics, emergency medicine, neonatology, pediatrics, HFE, nursing, usability engineering, and software development and implementation. Recommendations for EHR developers, small-group pediatric medical practices, and children's hospitals were identified out of the original 54 recommendations, in terms of nine critical user interaction categories: patient identification, medications, alerts, growth chart, vaccinations, labs, newborn care, privacy, and radiology. Pediatric patient care has unique dimensions, with great complexity and high stakes for adverse events. The recommendations are anticipated to increase the rate of EHR adoption by pediatric care providers and improve patient safety for pediatric patients. The described methodology might be useful for accelerating adoption and increasing safety in a variety of clinical areas where the adoption of EHRs is lagging or usability issues are believed to reduce potential patient safety, efficiency, and quality benefits.

Mineral Waters, Electricity, and Hemlock: Devising Therapeutics for Children in Eighteenth-Century Institutions

The development of paediatric medicine as a formal field of medical specialisation is usually traced to the mid-nineteenth century at the earliest. While it is true that formal specialisation in children's medicine was not, on the whole, typical for eighteenth-century medical practitioners, many displayed a deep and lasting interest in the diseases of children, and were consequently eager to develop therapeutic practices which could be targeted at infants and children. This led to a variety of attempts at innovation, many of which benefitted from the co-operation of, and opportunities afforded by, institutions. By examining the efforts of several medical practitioners at the London Foundling Hospital and at the Dispensary for the Infant Poor, this article explores how eighteenth-century medical practitioners used their affiliations with institutions to address the problems of devising or adapting therapeutic practices and treatments for children. In tailoring medical practice to suit children and, more specifically, in using institutions to do so, medical practitioners were demonstrating that child patients required special consideration, that children's diseases could be managed medically and with the benefit of new approaches and methods, and that children's health, as a whole, was the province of medical practitioners.

Journey of KK Children's Hospital — Collective Memories

This paper presents the collective memories of many individuals who were closely associated with the growth and development of the Children's Hospital. It is based on the perspective of the authors' personal recollections and by no means the whole of this exciting story. The focus is on the development of paediatric medicine in KK Women's and Children's Hospital (KKH). Neonatology will be discussed in a separate paper.

WHO guideline development of paediatric medicines: Points to consider in pharmaceutical development

WHO guideline development of paediatric medicines: Points to consider in pharmaceutical development

The Challenge of Pediatric Hospital Medicine Research

The launch of Hospital Pediatrics as a full-fledged journal represents a major turning point in the development of pediatric hospital medicine as an academic field and demonstrates that we have a sufficient number of scientific inquiries to warrant an independent, peer-reviewed journal. However, there are persistent challenges for hospitalists who desire an academic career, including insufficient research training, dedicated research time, and academic mentorship and role models. An additional challenge, as well as opportunity, for those with an interest in pediatric hospital medicine research is the wide range of activities in the field, including quality improvement (QI), comparative effectiveness research, educational evaluation, health services research, and practice management. Although there is often overlap among these areas, they are rapidly evolving so that definitions and training needs are not always clear. The demand for high-quality research in all of these areas has never been greater. QI has taken a place at center stage, as we …

The status of paediatric medicines initiatives around the world—what has happened and what has not?

This review was conducted to examine the current status of paediatric medicines initiatives across the globe. The authors made a non-systematic descriptive review of current world situation. Two regions, the United States (US) and the European Union (EU), and the World Health Organization (WHO) have introduced strong paediatric initiatives to improve children's health through improving access to better paediatric medicines. The experience from the US initiative indicates that it is possible to stimulate development and study of paediatric medicines and provide important new information for improvement of paediatric therapy. The early results from the EU initiative are similarly encouraging. In Canada, Japan, Australia and other developed countries, specific paediatric medicines initiatives have been less extensive and weaker, with modest results. Disappointingly, current evidence suggests that results from clinical trials outside the US often do not benefit children in the country in which the trials were largely conducted. Pharmaceutical companies that have derived a financial benefit commensurate with the cost of doing the paediatric trials in one country do not seem to be making the results of these trials available to all countries if there is no financial incentive to the company. The WHO campaign 'make medicines child size' has produced substantive accomplishments in building improved foundations to improve mechanisms that will enhance children's access to critical medicines in resource-limited settings. However, practically all of this work has been performed using an amalgamation of short-term funding from a variety of sources as opposed to a sustained, programmatic commitment. Although much still needs to be done, it's clear that with concerted efforts and appropriate resources, change is possible but slow. Retaining and fostering public and political interest in paediatric medicines is challenging, but pivotal for success.

Three years of paediatric regulation in the European Union

To investigate whether the Paediatric Regulation has already succeeded in addressing the needs of the paediatric population both quantitatively with respect to paediatric development plans and trials, and qualitatively with respect to the content of the plans. The Paediatric Regulation No 1901/2006 entered into force in Europe on 26 January 2007, with the aim to improve the development of medicinal products, to address the lack of age-appropriate formulations and to provide information on efficacy, safety and dosing for the paediatric population. The Regulation requires applications for marketing authorisations to be accompanied by either a product-specific waiver or a paediatric investigation plan, to be agreed by the Paediatric Committee (PDCO) of the European Medicines Agency (EMA). A retrospective analysis of the applications for Paediatric Investigation Plans (PIPs) and Waivers submitted to the EMA, from 2007 until end of 2009, was performed. The content of scientific opinions adopted by the Paediatric Committee was compared to the proposals submitted by industry, and the paediatric clinical trials registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database were examined. An increasing paediatric medicine development can be expected following the adoption of this legal framework. The highest number of PIPs was in the fields of endocrinology (13.4%), oncology (11%) and infectious (10.8%) and cardiovascular diseases (7.1%), but most therapeutic areas now benefit from paediatric development. A large number of PIPs include measures for the development of age-appropriate formulations (23%), and most include studies on dosing, efficacy and safety to cover the respective paediatric subsets, including the mostly neglected neonates (26%). In many proposals (38%), however, the PDCO had to request major modifications to the proposed PIPs to ensure that the results will meet the needs, in particular by requesting better methodology. The proportion of paediatric trials as a percentage of all clinical trials has moderately increased (from 8.2 to 9.4% of all trials), and this may reflect the fact that paediatric trials are generally deferred (82%) until after adult development. This is the first analysis of the general impact of the Paediatric Regulation on the development of medicinal products in Europe. Three years after the implementation of the Paediatric Regulation, we were able to identify that the PIPs address the main gaps in knowledge on paediatric medicines. The key objective of the Paediatric Regulation, namely, the availability of medicines with age-appropriate information, is going to be achieved. It is clear also that modifications of the initial proposals as requested by the PDCO are necessary to ensure the quality of paediatric developments. The impact on the number of clinical trials performed remains modest at this point in time, and it will be of high interest to monitor this performance indicator, which will also inform us whether paediatric medicine research takes place in Europe or elsewhere.

Juvenile animal studies in the development of pediatric medicines: experience from European medicines and pediatric investigation plans

The need for early consideration of pediatric investigation plans (PIP) to support an indication in pediatric population has led to an increased focus on the relevance of nonclinical studies in juvenile animals (JAS). The usefulness of JAS is not yet established and a criterion for request is still a learning process. This article compares data from JAS in all medicines approved by European centralized procedure before Pediatric Regulation (1995-2005) and data from JAS in the nonclinical information on all approved PIP (2007-2009). Of the 226 substances licensed by centralized procedure in 10 years, 31.9% were considered for children and 31 JAS were described in 9.7%. Since 2007, of the 205 PIP decisions, 50 PIP (24.3%) have 87 JAS planned or requested. The mean number of JAS in each medicine or PIP, increased from 1.4 to 1.7 between the two periods and the juvenile rat remained as the prevalent species. Results demonstrate that JAS planned/performed in EU environment has significantly increased.

Juvenile animal studies for the development of paediatric medicines: a description and conclusions from a European medicines agency workshop on juvenile animal testing for nonclinical assessors

A workshop organised by the European Medicines Agency involved assessors and experts present in a Nonclinical Working Group evaluating juvenile animal studies for Paediatric Investigation Plans in collaboration with the Paediatric Committee and the Safety Working Party of the Committee for Human Medicinal Products. The objective of the workshop was to analyse which juvenile animal studies proposals were received and agreed by the Paediatric Committee, to check consistency and how to apply the existing European guideline on juvenile animal studies. A comparison of main organ system development in man vs. animal species was presented to guide the review and to support species selection and protocol design. An analysis of juvenile animal studies included in finalised PIP's was also presented. Out of 109 paediatric investigation plans finalised between November 2008 and March 2009, 43 included one or more juvenile animal studies. In most cases the preferred species was the rat; one species only was requested to be studied (20/22), but in a minority two species were required (2/22). When deciding on the characteristics of the juvenile animal studies, such as age of animals at study start, the age of the children targeted by the medicine was considered. It is expected that the increasing experience gained by Applicants and Regulators will allow further refining the criteria for these juvenile animal studies. Further research on this topic is highly encouraged in the European Regulatory framework.

Pediatric Anesthesiologists Contributions to the Development of Pediatric Critical Care Medicine: A historical interview with John J. Downes

Pediatric Anesthesiologists Contributions to the Development of Pediatric Critical Care Medicine: A historical interview with John J. Downes

Pediatric Anesthesiologists Contributions to the Development of Pediatric Critical Care Medicine: A historical interview with Mark C. Rogers and the history of pediatric intensive care medicine at Johns Hopkins Hospital

I visited Mark Rogers at his summer home on a private island on the Chesapeake just 30 minutes south of Baltimore last February for what is going to be a series of interviews about the history of pediatric anesthesia. Little did I know that my journey would take me through a glimpse of an era where pediatric critical care as we know it today did not exist. Imagine a time when spending 6 months in the operating room with pediatric patients meant that you were the most qualified pediatric anesthesiologist in the hospital. A period when radiology films were dipped by hand at midnight and a blood gas stat meant calling in an irate technician from home to run the test. This was a time well before the formal training that today’s pediatric anesthesiology and PICU fellows face. This was the 1960s! Many might know Mark Rogers for his leadership as the Chairman of the Department of Anesthesiology and Critical Care Medicine and the Director of the Pediatric Intensive Care Unit at Johns Hopkins in the 1980s. Perhaps, many own a copy of the Rogers’ Textbook of Pediatric Intensive Care, “the bible” of pediatric critical care textbooks because of its comprehensiveness. Some might know of his contributions in developing critical care medicine abroad in countries such as Thailand or his efforts at creating World Congresses of Pediatric Intensive Care meetings. Even Pediatric Anesthesiologists Contributions to the Development of Pediatric Critical Care Medicine: A historical interview with Mark C. Rogers and the history of pediatric intensive care medicine at Johns Hopkins Hospital