Off‑label prescribing rampant in paediatrics as clinical trials for children lag behind

Ensuring the safety and effectiveness of medicines for children is a healthcare priority. However, the reality is that many drugs still lack adapted paediatric formulations and an evidence base. On International Children’s Day, GxP News prepared a review of the problems associated with clinical trials in paediatrics.

The desire to shield children from “medical experiments” – i.e., from participating in clinical trials – has inevitably led to paediatrics being largely cut off from reliable data on drug efficacy and safety. In recent years, public attitudes towards research involving children have begun to shift, but the process remains slow.

According to WHO data, as of 2010, around 75% of childhood diseases lacked specialised drug supplies. According to the European Medicines Agency, which issued the first guidance on drug safety for children in 2005, more than 50% of drugs used in paediatric practice were either unlicensed or prescribed off‑label.

As of 2025, the WHO Model List contains more than 520 drugs, including 374 for children. Yet despite the large number of medicines registered worldwide – including in Russia – for paediatric use, only a small fraction have proven efficacy and safety, and some turn out to be simply ineffective. This is primarily because controlled clinical trials in children are not conducted in most areas of paediatrics.

Deputy Health Minister Sergei Glagolev told a meeting of the Expert Council on Healthcare in 2020 that off‑label prescribing accounts for 20% of all prescriptions and more than 70% in paediatrics. One report stated that in the European Union, off‑label prescribing in hospital paediatrics ranges from 13% to 69%, and in outpatient settings from 2% to 100%.

“In paediatrics, the problems of lacking clinical trials for the child population and off‑label drug use are most acute. Paediatricians are in an extremely vulnerable position, acting at their own risk,” said Vasily Denisov, a paediatrician at the Fantasy children’s clinic.

Off‑label prescriptions are most often given to the most complex and vulnerable patients: newborns (especially premature infants with extremely low birth weight), infants with congenital malformations (e.g., heart defects), and patients in haematology, oncology and immunology units. This also includes children needing organ transplants, cystic fibrosis patients and those with other orphan diseases. In these groups, doctors most often have to use drugs that are formally not approved for their age.

Paediatricians always stress: children are not “small adults”. Paediatric specialists divide the child population into five subgroups: preterm and term newborns (0‑27 days), infants/toddlers (28 days – 2 years), young children (2‑11 years) and adolescents (11‑16/18 years). Adult drug formulations and dosages are clearly not suitable for adolescents and are completely unsuitable for infants and young children. Beyond differences in height and weight, these groups differ in physiology and metabolism. Ideally, medicines for them should be designed based on the body’s anatomical and physiological characteristics. Moreover, the child’s body has incomplete development or even absence of several enzyme systems that play a key role in drug biotransformation.

“Off‑label drug use carries certain difficulties, including the challenge of finding an effective dose. Not only does child metabolism differ from adult metabolism, it also varies within specific paediatric groups – and that is without considering the condition of organs and systems directly or indirectly affected by the underlying disease,” said paediatrician Vasily Denisov.

Clearly, a huge problem for both doctors and parents is the need to split tablets, open and divide capsules themselves to obtain the required dosage.

“At one time, I worked with newborn infants with severe congenital defects. We had to split tablet‑form drugs – absolutely not intended for newborns – into eight pieces. It was an utterly routine daily practice,” Denisov recalls.

Apart from being complicated and inconvenient, the process increases other risks: therapy may be insufficiently effective, and side effects may become more frequent. Young children are especially vulnerable: not only is the medicine often unpalatable, but it is also unclear how much of the drug in an unapproved formulation reaches the child’s bloodstream and what effect the excipients will have.

How to motivate manufacturers

Developing drugs for children, and even more so conducting clinical trials, involves a whole range of problems – but above all, it is commercially risky for manufacturers. The 2010 “Report to WHO concerning international guidelines for paediatric medicines” lists the following reasons:

– Large sales volumes cannot be expected from paediatric drugs.

– The appropriate dosage for a given drug in children is often unknown or unproven.

– Recommended doses differ across age groups, so the drug must accommodate multiple dosing regimens, increasing development costs – and the emergence of new evidence can make the drug less competitive.

– Liquid formulations used in paediatrics are less stable than solid ones, giving them shorter shelf lives, which also has commercial consequences.

– The instability of liquid drugs calls into question the very feasibility of developing such products, even though they are preferred for children.

In another document, “Promoting Safety of Medicines for Children”, the WHO recommends that member states work to improve the scientific basis of clinical trials involving children and develop national databases containing up‑to‑date information on drug efficacy and safety.

To date, there is still no unified global approach to this issue. However, several countries have managed to “incentivise” pharmaceutical companies to conduct organised clinical trials involving children.

US regulators offer manufacturers a number of incentives. For example, the Pediatric Exclusivity mechanism provides an additional six months of patent protection for conducting clinical trials of drugs on the Paediatric Priority List.

In Europe, since July 2008, clinical trials have become mandatory when registering any new drug or new indication. If a drug is approved by the regulator for paediatric use, the manufacturer also receives an additional six months of “paediatric exclusivity”.

“At Roche, paediatric studies have become an integral part of the comprehensive development programme for innovative molecules. Studies are initiated whenever a disease is relevant to childhood. If a drug is intended for both adults and children, paediatric trials are usually approved only after safety data from adult patients are available. The process goes ‘from older to younger’: first the 12‑18 age group, and only after safety is confirmed – younger age categories,” said Yulia Nikiforova, head of clinical research at Roche Russia.

Roche also has successful research experience in Russia, for example in orphan diseases such as spinal muscular atrophy, where the use of an innovative drug began precisely with the paediatric population.

The Russian framework

Under Russian law, Article 43 of Federal Law No. 61‑FZ of 12 April 2010 “On Circulation of Medicines” states: “A clinical trial involving children is possible only if it is necessary to improve children’s health or to prevent infectious diseases in childhood, or if the purpose of the trial is to obtain data on the best dosage of a drug for treating children… such a trial must be preceded by a clinical trial in adult citizens.”

In 2014, an amendment was adopted allowing foreign research results for orphan drugs to be recognised. In 2021, the Russian Health Ministry considered an initiative that would allow the registration of paediatric indications based on foreign clinical trials, as well as on systematic experience of use in federal medical organisations and published literature – for drugs that had been used long‑term but lacked official paediatric indications. Instead, amendments were made to Law No. 323‑FZ allowing drugs included in clinical guidelines or medical care standards to be prescribed for indications not listed in the package insert. The list is established by the government and mainly concerns onco‑haematology drugs.

In 2009, the Union of Paediatricians of Russia developed the National Paediatric Formulary of Medicines, which included drugs with proven efficacy and safety in children based on evidence‑based medicine. However, the formulary is only advisory and not mandatory for medical organisations.

Only a combination of clinical trials in the paediatric population with a functioning pharmacovigilance system in the country can guarantee a full understanding of a drug’s safety profile in children. With international companies scaling back clinical trials, transitioning to EAEU legislation has become relevant. However, the EAEU Pharmacopoeia is still under development, so issues of paediatric clinical trials will only be discussed over the next few years.

Moreover, according to Ravil Khamitov, vice president for research and development at Generium, a major problem could be the shortage of paediatricians in Russia and EAEU countries who are sufficiently qualified for clinical trials and have relevant experience.

“This is directly linked to the small number of trials being conducted. Even when the country had up to 800 clinical trials at any one time, only about 10% of them were paediatric. As a result, no cohort of investigator physicians has been formed; they have not gained relevant experience. No experience – no approval from the Russian Health Ministry,” he said.

Russian company Nanoled has experience in clinical trials involving children as part of its HPV vaccine development. The results obtained allowed the company to extend the indications for use in children aged 9‑17.

As Maya Benashvili, director of preclinical and clinical research at Nanoled, told GxP News, the current regulatory system allows trials involving children to be conducted in accordance with international standards and with a high level of participant safety.

“It is also important to note that Russia has developed a quality infrastructure for conducting paediatric research, and the expertise of research centres allows such projects to be carried out at a high level,” Benashvili said.

She also stressed that paediatric clinical trials require close work with parents and compliance with informed consent procedures.

Yulia Nikiforova from Roche confirms this: “The informed consent process in paediatrics is much more complex. Consent is signed by both parents (legal guardians), and from a certain age, by the child as well. We prepare different document forms adapted to the patient’s age so that participation in the trial is as informed and transparent as possible for the family.”

Maya Benashvili noted that in some cases, trials require longer preparation and follow‑up, and the cost of such projects is generally higher compared with adult clinical trials. In her view, the current approach enshrined in Law 61‑FZ strikes the necessary balance between advancing clinical trials and protecting underage participants.

“At the same time, it would be useful to clarify certain practical scenarios related to paediatric trials – for example, cases where a drug is intended for use only in the paediatric population in Russia, while the international development programme simultaneously includes adult trials. Such clarifications could increase the predictability of regulatory procedures for developers without lowering research safety requirements,” Benashvili said.

Alexander Bykov, director of healthcare economics at R‑Pharm, agreed that developing paediatric drugs is costly for pharmaceutical companies, partly due to stricter requirements for such medicines.

“Therefore, the main task is to make their development economically viable. A package of support measures could help, such as priority inclusion of such drugs on formularies, guaranteed procurement volumes and special pricing approaches,” he said.

Bykov also noted that a separate task is to define the specific needs: which INNs, dosages and formulations are truly necessary for the healthcare system.

Biocad also conducts paediatric clinical trials. Specifically, an ongoing trial of its original drug netakimab in children with moderate‑to‑severe plaque psoriasis is covering 155 patients aged 6‑17. The company has already filed for registration of the drug for paediatric use.

“In our view, the current regulation of paediatric clinical trials already provides a high level of protection for underage patients and accounts for the specifics of paediatric research. At the same time, as innovative therapy develops, it is important to continue improving expert and ethical support mechanisms and to create conditions for clinical trials in socially significant and rare diseases. This will broaden access for underage patients to modern therapies,” said Yulia Linkova, deputy general director for clinical development and research at Biocad.

The state regulatory model for paediatric medicines requires not only a balanced, evidence‑based approach but also measures to stimulate pharmaceutical development. According to Ravil Khamitov of Generium, several legislative changes are possible to protect children’s rights and accelerate the development of safe paediatric drugs. These include requiring pharmaceutical companies to develop paediatric investigation plans (similar to US and EU practice) at early stages of drug development, even before completing adult trials. A legislative requirement to submit such a plan to the Russian Health Ministry for evaluation would incentivise companies to study drug effects in children, not just in adults.

As an additional support measure, Khamitov suggests introducing legislative preferences for manufacturers that conduct paediatric trials – for example, extending drug patent terms or providing tax breaks to offset the high costs of paediatric clinical trials, especially those conducted abroad.

Another important step, according to Khamitov, is to support non‑profit and academic research: “Reduce administrative and financial barriers to clinical trials initiated by medical and scientific centres (academic trials). Create a state funding fund to study the effectiveness of already registered ‘adult’ drugs that are widely used off‑label in paediatric oncology and orphan diseases.”

Personalised medicines

Abroad, compounding pharmacies make a significant contribution to drug supply for paediatric patients, because due to limited demand, pharmaceutical companies see no point in mass‑producing paediatric dosages. As a result, the US and EU countries are seeing a trend towards a growing number of pharmacies offering dosage forms prepared on a doctor’s prescription for a specific patient.

In Russia, a law on the revival of compounding pharmacies came into force in September 2023. High hopes were placed on it to meet the need for individual drug dosages – especially small children’s dosages – and to develop the individual and small‑batch manufacture of drugs needed in paediatric practice. However, over the past years, pharmacy compounding procedures have not become widespread. This is still hampered by an imperfect regulatory framework, a large number of legal gaps and quality control issues for compounded drugs.

According to Alexander Bykov of R‑Pharm, on a national scale, compounding pharmacies could provide small‑batch production of drugs for patient groups whose needs are too small for full‑scale industrial production.

“Compounding must be based on full‑fledged pharmaceutical development: selection of composition, technology, packaging, quality control methods, justification of stability, shelf life and storage conditions. In essence, the scientific and technological base should be comparable to industrial development, even if the scale is that of a pharmacy,” he said.

Pharmacies can become an important tool for solving the problem of missing paediatric dosages, the expert believes. At the same time, however, they cannot and should not be seen as a complete replacement for industrially manufactured drugs, Bykov said.