Strategies to facilitate adolescent access to medicines: Improving regulatory guidance.

BACKGROUND: Historically, pediatric medicines are developed after adult trials are completed, even when identical drug targets and disease similarities exist across the populations. This has resulted in significant delays in the authorization of medicines for adolescent use, limiting access to beneficial drugs. This study sought to understand how adolescent inclusion in adult trials is positioned in regulatory guidance documents as they set critical expectations for trial design and regulatory decision-making. METHODS: This study utilized a qualitative analysis approach. Guidance documents were identified via Food and Drug Administration and European Medicines Agency websites. Utilizing a blinded adjudication process, the documents were classified as permissive, exclusionary, or silent regarding recommendations about adolescent inclusion in adult clinical trials. A post hoc analysis of similarities and differences between the Food and Drug Administration and European Medicines Agency guidance documents was conducted to assess the possible role of regional pediatric research laws on age-inclusive trial methodologies as well as emergent themes by therapeutic area. RESULTS: In total, 96 Food and Drug Administration (1977 to 2019) and 106 European Medicines Agency (1987 to 2019) guidance documents were identified for analysis. The guidance contained explicit or implicit recommendations supporting adolescent inclusion in adult trials in 32% of Food and Drug Administration and 15% of European Medicines Agency documents, while 14% and 21%, respectively, were found to be exclusionary. A large number of guidance documents were silent regarding the applicability of adolescent-inclusive trial designs (53% and 64%, Food and Drug Administration and European Medicines Agency, respectively). Analysis by therapeutic area revealed the most permissive of adolescent inclusion in Food and Drug Administration guidance for infectious diseases and conditions requiring blood products in European Medicines Agency guidance. A more holistic approach to age-inclusive trial design was identified in disease guidance published by the Food and Drug Administration Oncology Center of Excellence. DISCUSSION: There are many influences on the development and/or revision of regulatory guidance documents. Substantial scientific knowledge and regulatory precedence for the inclusion of adolescents within adult trials are available to inform research approaches. Our study has identified important opportunities for the enhancement of guidance. For example, contextualization of developmental factors influencing adolescent disease progression provides insights into the role of adolescent inclusion. If addressed, guidance documents can facilitate broader acceptance of age-inclusive trial methodologies and accelerate adolescent access to medicines.

Recommendations by the European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA) Working Group on preparedness of clinical trials about paediatric medicines process.

Conduct of clinical trials in babies, children and young people is often hindered by issues that could have been foreseen before the trial opened; that is, some clinical trials are often underprepared. In order to identify a good approach to trial preparedness, the European Network of Paediatric Research at the European Medicines Agency formed a working group. The Working Group included representation from regulators, industry, academics, paediatric clinical research networks and parents.The Working Group consulted widely about how to prepare for paediatric clinical trials. The Group's detailed recommendations have been published (https://www.ema.europa.eu/en/documents/other/preparedness-medicines-clinical-trials-paediatrics-recommendations-enpr-ema-working-group-trial_en.pdf).This paper is a summary of the key recommendations including the following: start early, preferably in parallel to designing the medicine's development plan and individual protocols; identify the rationale and clinical need; listen to the perspectives of children and families, and of patient advocacy groups; identify how many people will be eligible for the trial; identify the resources needed, such as clinical facilities (including play therapy) and out-of-pocket expenditure by participants and their families; use all available data to estimate what is possible; present information about preparedness in a structured way; deploy proportionate resources to support the preparation of trials.A well-prepared, well-designed trial is likely to require fewer changes during its course, be run in a shorter time frame and achieve expected objectives.

Quality considerations of paediatric investigation plans for monoclonal antibodies: A regulatory perspective from the MHRA.

Since the advent of the EU Paediatric Regulation in 2007, 78 of the 1688 Paediatric Investigation Plans (PIPs) have been for monoclonal antibodies (Mabs). Of these, 22 have been assessed by the MHRA. The purpose of this mini-review is to aid those researching and developing this class of drugs to better understand regulatory concerns leading to improved medicinal products for children. Three principal quality issues were identified for PIPs under Article 7 and 8: i) the level of anti-aggregation stabilisers, ii) acceptability and tolerability of administration (i.e. multiple injections, infusion time and volume), and iii) the need to develop new presentational forms (e.g. pre-filled syringe). Overall, two types of concerns were ascertained - those which are potentially avoidable (e.g. through development of new presentational forms) and others which require the evolution of new technologies in the sector (e.g. production of concentrated, stabilised preparations).

Foot and ankle injuries during the Athens 2004 Olympic Games.

BACKGROUND: Major, rare and complex incidents can occur at any mass-gathering sporting event and team medical staff should be appropriately prepared for these. One such event, the Athens Olympic Games in 2004, presented a significant sporting and medical challenge. This study concerns an epidemiological analysis of foot and ankle injuries during the Games. METHODS: An observational, epidemiological survey was used to analyse injuries in all sport tournaments (men's and women's) over the period of the Games. RESULTS: A total of 624 injuries (525 soft tissue injuries and 99 bony injuries) were reported. The most frequent diagnoses were contusions, sprains, fractures, dislocations and lacerations. Significantly more injuries in male (58%) versus female athletes (42%) were recorded. The incidence, diagnosis and cause of injuries differed substantially between the team sports. CONCLUSION: Our experience from the Athens Olympic Games will inform the development of public health surveillance systems for future Olympic Games, as well as other similar mass events.

Spatial frame correction of anterior growth arrest of the proximal tibia: report of three cases.

We report three cases of anterior growth arrest of the tibia in adolescent boys. Two of the three cases had a clear history of trauma and although there was a history of trauma in the third case, the patient also had human leukocyte antigen-B27 negative enthesitis that had not previously affected the knee. In all cases, a slowly deteriorating hyperextension of the knee developed that in the two posttraumatic cases was initially misinterpreted as a posterior cruciate ligament injury. Radiographs demonstrated an abnormal relationship between the tibial plateau and the long axis of the tibia on the lateral view--anatomical posterior proximal tibial angle. All patients were successfully treated by the Taylor spatial frame with correction of the anatomical posterior proximal tibial angle to normal, equalization of the legs and correction of any concomitant coronal deformity. Hyperextension of the knee developing after an injury in adolescents should raise the suspicion of anterior growth arrest prompting careful analysis of the lateral radiograph.

Simultaneous bilateral tibial tubercle avulsion fracture in an adolescent: a case report and review of the literature.

Avulsion fractures of the tibial tubercle are uncommon. Bilateral tibial tubercle avulsion fractures are extremely rare. In this article, we describe Watson-Jones type III simultaneous bilateral tibial tubercle avulsion fractures in a 17-year-old boy who fell on the ground while taking off in high jump in sport. An open anatomic reduction and internal fixation was performed. We report here on the successful surgical treatment of a simultaneous bilateral fracture of the tibial tuberosity in an adolescent. These types of fractures involve a growth plate, extend through the articular surface and appear to do well with open reduction and secure internal fixation despite their bilateral nature, with recovery and functional outcome comparable to results from unilateral tibial tubercle avulsion fractures.

Dissociation of bipolar hemiarthroplasty of the hip after dislocation. A report of five different cases and review of literature.

Little information is available about the rare but serious disadvantage of dissociation of modular components during dislocation or after close reduction in the bipolar hemiarthroplasty of the hip. In most cases, simple dislocation after primary bipolar hemiarthroplasty can safely be reduced by close methods. Dissociation leads almost always to reoperation and possible revision of the prosthesis. To avoid this complication, strict adherence to the surgical technique during the initial procedure and extra precaution during close reduction are recommended, in order to provide enhanced security over component disassembly. In the five cases presented in this study, dissociation is reported at different circumstances, along with the different methods of treatment required in each patient.