“Bayer takes up the specific medical, ethical and technical challenges associated with the development of medication suited to the needs of children.”
- Dr. Stefanie Breitenstein, Pediatrician and Clinical Expert, Bayer
Clinical trials with medicinal products for pediatric use are certainly one of the most sensitive areas in science – both from a medical and an ethical standpoint. Everyone involved in clinical trials with children holds a special responsibility. Medically speaking, children are not just “little adults”: the composition of their bodies and maturity of their organs not only differ from those of adults quantitatively, a number of diseases only occur in children or progress differently in children than in adults. From an ethical and legal standpoint, children also differ from adult study participants and need special protection because of their intellectual and emotional limitation to provide informed consent. Therefore, especially strict regulations and ethical standards have been developed for pediatric studies.
Studies on children for children
In order to help children, pediatricians often have no alternative but to prescribe medicines for their young patients that have only been tested on or approved for the treatment of adults, which also counts as off-label use. However, efficacy and safety of a medical therapy cannot just be extrapolated from practical experiences made with adults. Organs such as the liver, the kidneys and the gastrointestinal tract are not yet fully developed in children and therefore metabolize the active ingredients of medicine in a different way. Their bodies also differ in terms of muscle, fat and water composition from adults. Growth spurts and sexual maturation are also unique in childhood and adolescence.
For this reason, the safety, efficacy, and correct dosage of a medicine must be determined separately for each age group. However, not only the dosage of medicines, but also their form must be adapted to fit the young organism. Young children can simply not swallow tablets. For this reason, pediatric medicines must also be developed in a dosage form suitable for children, such as mini-tablets, oral liquids or infusions.
Guidelines for the development and authorization of pediatric medicines
For many years, only a few trials with children were conducted due to ethical concerns. This led to widespread “off-label” use of medication in children. To address this, the EU initiative “Better Medicines for Children” declared in 2002 that children and adolescents have the right to take part in medical progress. According to the initiative, children should not be protected from clinical trials, but rather be included in them.
To ensure the safety of pharmaceuticals in children, the EU requires that clinical trials are performed in children if applicable. Since 2006, a directive (EU 1901/2006/EG) has provided more regulatory clarity: pediatric investigational plans for clinical trials with children of all age groups must be submitted for any product for which marketing authorization is being applied for, provided that children are affected by the disease and will benefit from the new medicinal product. The ultimate goal is to ensure the efficacy, safety and tolerability of medicines used in pediatrics.
In Europe, the “Pediatric Committee” (PDCO) of the European Medicines Agency (EMA) is responsible for the processing of the pediatric investigational plans.
The International Conference on Harmonization (ICH) of technical requirements for registration of pharmaceuticals for human use has issued a guideline on clinical investigation of medicinal products in the pediatric population (E11).
A detailed Pediatric Investigation Plan (PIP) must be submitted to the PDCO by the pharmaceutical company. A PIP is a development plan aimed at ensuring that all necessary data are obtained through applicable preclinical studies and clinical studies in children. If the primary indication is treatment of a disease in adults, this will be described in the PIP as well. The pharmaceutical company and the PDCO will then discuss and in most cases agree upon a PIP.
In some cases, studies can be deferred until the data of the studies in adults are available. This ensures that research in children is done only when a positive benefit/risk ratio has been established for adults.
As some diseases do not affect children, a PIP is not required and it will be waived in such case.
Unique consent process for pediatric trial subjects and their parents
Children are counted as members of a vulnerable population at risk of exploitation and are afforded special protection in clinical research.
Consent in pediatric research involves a “consent dyad”— informed permission from both parents and age-appropriate information and consecutive assent from children.
The parents undergo a consent process, and then may grant informed permission for their child to participate. In parallel, a willingness to participate, or assent, is solicited from children following an age-appropriate information process.
One of the specific challenges of pediatric studies lies in the character of pediatric diseases itself. Fortunately, most children are healthy and serious diseases are rare or even very rare, like hemophilia A which occurs in 1-9 children per 100,000. However, this leads to less available patients for the studies.
Pediatric studies at Bayer: medicines for children
Bayer takes responsibility for young patients and is committed to researching and developing medicines for children and adolescents. To ensure optimal implementation in accordance with all existing guidelines, Bayer has set up a special Pediatric Advisory Group. In this group, pediatric specialists from various disciplines work together to ensure that the extensive specifications can be met and internal processes are adapted to the requirements of developing pediatric medicines.
Bayer’s first pediatric investigational plans were approved in 2009 and related study programs began a year later.
Pediatric studies at Bayer: medicines for children
All completed and ongoing clinical trials of Bayer with children (birth – 17 years) are publicly accessible at www.clinicaltrials.gov
Excerpt of Bayer trials with pediatric subjects:
|Condition||Intra-abdominal infections||Venous Thrombosis||Hemophilia A|
|Study Purpose(s)||Safety of treatment with Moxifloxacin in a pediatric population||Safety of treatment with Rivaroxaban in children and how long it stays in the body||Safety and efficacy of treatment with BAY81-8973 for prophylaxis and breakthrough bleeds in children with severe hemophilia A.|
|Eligible Ages for Study||3 months to 18 years||Ages 6 to 18||up to 12 years|
|Study Phase||Phase III||Phase II||Phase III|
|Study Locations||United States, South America, Europe, and others||United States, Australia, Europe, and others||United States, South America, Europe, and others|
|Estimated Primary Completion Date||April 2015||September 2015||December 2016|
|Link to Study Details||Click here||Click here||Click here|