Need for paediatric studies of off-label medicines
Off-label use of these drugs in children is an accepted practice considered superior to the alternative of withholding needed medications.
According to Bettina Nygaard Nielsen, Ph.D. Clinical Pharmacist and a part of the Paediatric Research Team at the Department of Anaesthesiology, Juliane Marie Centre, Rigshospitalet, University of Copenhagen, not much has changed since the publication of the American study and Europe is in a similar situation. There is still much to do to determine efficacy and safety of drugs that lack labelling for children who is a vulnerable group of patients.
Unmet medical need for effective and safe drugs for children
“Despite the fact, that the European legislation gives an opportunity to extend the IPR protection of a drug if a company conducts paediatric trials with the drug - in anaesthesiology we do not see a paediatric interest from the pharmaceutical industry (see BOX: Paediatric Investigation Plan). The majority of drugs we use in paediatric anaesthesiology and treatment of pain are well-known drugs without IPR protection. This makes it a huge challenge to develop new formulations of medicine for children,“ says Bettina Nygaard Nielsen and continues: “Today we base off-label treatment on clinical experience and scientific evidence of varying degree and often treatment effect varies from patient to patient. There is a continued unmet need for effective, safe and age-appropriate formulations of off-patent drugs for children, and it is a shared responsibility between academia, the pharmaceutical industry and authorities that we can offer children safe and effective treatment.”
The Paediatric Research Team from the Department of Anaesthesiology, The Juliane Marie Centre, Rigshospitalet, has recently published a large randomized, placebo-controlled paediatric trial in the Lancet Child & Adolescent Health with the participation of three Danish hospitals and almost 400 children, aged 1-5 years. Data management was carried out by Copenhagen Trial Unit and the clinical trial was monitored by the GCP Units at Copenhagen University Hospital and Odense University Hospital. All the children were scheduled for elective surgery for instance hernia, orchiopexy and tonsillectomy. The trial aimed to determine the preventive effect of clonidine at postoperative agitation. Clonidine is an old off-patent drug approved for indications such as prevention of menopausal flushes, migraine and treatment of high blood pressure, but is used off-label for a number of indications for example as adjuvant therapy for sedation at paediatric intensive care units, for treatment of acute pain and postoperative agitation.
Yearlong off-label use of clonidine
“Postoperative agitation, a condition where the child after anaesthesia and surgery is waking up being agitated and thrashing around – like a child waking up in the middle of a nightmare - is a frequent and stressful condition for a child, parents and health care professionals. Clonidine has been used off-label as a trial and error approach for years to treat agitation after the anaesthesia and surgery in paediatric patients. There is currently no standard of care for treatment or prevention of postoperative agitation in children. Our intention was to determine whether a single dose of clonidine administered during surgery could prevent postoperative agitation and pain with and acceptable safety profile in a population of paediatric surgical patients. We wanted to measure the effect on agitation and pain in the recovery room and follow-up on adverse events for up to 30 days. Furthermore, some of the children had blood sampling done to investigate how clonidine is distributed and excreted from the body and any age-related differences,” says Bettina Nygaard Nielsen. The results of the trial are encouraging – clonidine may safely reduce the risk of postoperative agitation with more than 40%. Also postoperative pain, nausea, and vomiting were reduced in the clonidine treatment group; however, the effect only reached statistical significance in boys, since few girls participated in the trial because of the type of surgery.
Paediatric studies are different but not necessarily difficult and untimely
“It is not necessarily difficult to conduct paediatric studies compared to adult studies – but paediatric studies are different. First of all: Children cannot give informed consent themselves and their understanding of participation in a trial varies with age,“ explains Bettina Nygaard Nielsen. “When you plan a paediatric study, you have to focus on minimizing risks and maximizing benefits. Basically, data collection should focus on what you need to know more than what is nice to know. In addition, there may be differences in how you measure effect between age groups, pain is a good example; children do not express pain in the same manner as adults, and pain expression varies among different age groups because of developmental differences. One more thing I would like to emphasize is how important it is to know your patient population when you plan a clinical trial, a good clinical understanding of the patient population will allow you to design a successful study. In paediatric anaesthesia we have a high patient flow compared to general paediatrics, which allow large randomised-controlled trials to be conducted in a timely manner.”
Bettina Nygaard Nielsen and the Paediatric Research Team managed to conduct the clinical trial in a timely way. “We managed to recruit 379 participating children in only 11 months, and we are very thankful for the support from all the parents who gave consent for their children to participate and the parents also appreciated in follow-up calls from the clinic the day after surgery,” she says.
No genuine interest in funding paediatric trials
“In my opinion the market for paediatric labelled drugs has too little attention. There is no genuine interest in funding paediatric clinical trials. This is a big shame,” says Bettina Nygaard Nielsen. “We will continue to focus on paediatric clinical studies to improve the treatment of children. For example we want to determine better administration systems of for instance sedating and pain-relieving drugs, like replacing injections with a nasal spray for treatment of acute pain in children” Bettina Nygaard Nielsen ends.
In 2008, the European Medicines Agency (EMA) made a regulatory requirement for new not yet approved drugs. An application for marketing approval shall contain either results of all studies performed in compliance with a paediatric investigation plan (PIP) or a waiver or deferral granted by EMA. In 2009, EMA issued a requirement regarding approved patent protected drugs. Any application for new indications, a new pharmaceutical forms or new routs of administration shall include results of all studies performed in compliance with PIP approved by EMA and a waiver or deferral granted by EMA. From 2007 approved out-of-patent drugs may receive a paediatric-use marketing authorisation (PUMA) provided the necessary data in accordance with a PIP. Such an authorization paves the way for an extended data and marketing protection.