Royal Decree 1015/2009 regulates the availability of drugs in special situations in Spain.1 It establishes rules for compassionate use of drugs undergoing clinical trials, drugs authorised in other countries but not in Spain and drugs used under conditions other than those established in the summary of product characteristics (SmPC). In regard to the latter, the decree specifies that such use would be exceptional and limited to situations where there is no authorised drug that could be used as an alternative in a given patient, adhering to established restrictions regarding the prescription and/or dispensation of the drug and the treatment protocols of the health care facility. The physician in charge must document an appropriate justification of the need for the drug in the health record and inform the patient of its potential benefits and risks, obtaining consent as required by Law 41/2002 of 14 November. According to this law, “Consent will generally be verbal. However, it will be obtained in writing in the following cases: surgical intervention, invasive diagnostic and therapeutic procedures and, in general, for any use of procedures that involve risks or disadvantages known to have a deleterious effect on the health of the patient.”2

The term exceptional implies an exception to the rule, but not infrequent use. The information offered in the SmPC of paediatric drugs is often insufficient, incomplete and outdated.3 Current regulations do not address some of the situations commonly experienced in clinical practice. For instance:

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  If authorised drugs are available as an alternative but the scientific evidence shows that an unauthorised treatment is more effective or efficient, which one should be used?

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  What are the potential risks of using a drug under conditions other than those authorised in the SmPC? Are they known to have a predictable negative impact on the health of the patient? Does verbal consent from the parents or legal guardians suffice?

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  Are paediatricians aware of when they are prescribing a drug outside the conditions established in the SmPC or that is not approved in Spain?

In this document, the Committee on Medicines (CM) of the Asociación Española de Pediatría (Spanish Association of Paediatrics, AEP) seeks to clarify these and other concerns and propose potential solutions to improve the availability of data on drugs used in the paediatric population.

The results of previous studies are widely heterogeneous as a result of differences in methodology, classification criteria and sources.4 Most authors apply the criteria proposed by Turner et al.,5 who defined off-label (OL) as drugs that are used outside the terms of their product licence that apply to indication, age, dose, or route of administration, and unlicensed (UL) as drugs not yet licensed, specifically contraindicated in children, used in a modified formulation or for which there is no data on its use in the paediatric age group.

The main barrier to the inclusion of indications for paediatric use in the SmPC is the lack of specific clinical trials in the paediatric population. This is due to6:

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  Difficulties in designing paediatric trials.

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  The complex and particular ethical issues involved in research in children.

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  The time required to complete the follow-up required in trials in children, which is longer compared to adult trials.

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  The protracted drug authorization processes.

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  Cost of performing the trials.

The proportion of drugs that lack specific indications for use in paediatrics is large (50%–90%). Approximately 150 million inhabitants in the European Union are aged less than 18 years. Given these circumstances, the unauthorised use of drugs is simply necessary.6 A review published in 2018 found that more than 80% of paediatric patients received OL drugs and more than 70% received UL drugs.7

Paediatricians have the duty to manage children as well as possible, which invariably involves the unauthorised use of drugs. Paediatricians are forced to seek accurate and updated information on the drug from other sources,8 as the intended use is not included in the SmPC. This problem is addressed by examining clinical trials with variable levels of evidence, clinical guidelines, expert consensus documents, books and specific databases such as Cochrane, Lexicomp or Harriet Lane.8 Preferably, databases belonging to the specific country will be consulted. One example in the case of Spain, would be Pediamécum.9

Most studies agree that the highest proportion of OL prescriptions are found in the field of neonatology.4,10,11 Sucasas Alonso et al.10 found a proportion of OL prescription of 22.5%, while Arocas Casañ et al.11 found a proportion of 41.4%. When it comes to the type of drug based on the Anatomical Therapeutic Chemical (ATC) classification of active substances, the highest proportion of OL prescriptions corresponds to antiinfective drugs,4,11 although Sucasas Alonso et al.10 found a higher proportion of drugs acting on the alimentary tract and metabolism. Off-label prescription was more frequent in surgical patients, very preterm infants and patients with a length of stay greater than 1 week, corresponding to the most vulnerable population.10

In paediatric intensive care units (PICUs), exposure to unauthorised drugs is also frequent. Blanco-Reina et al.4 reported a proportion of OL prescription of 52%, mainly due to doses (79%) or indications (13.5%) outside those specified in the SmPC. When it came to the type of drug, antiinfective drugs were once again the group most frequently prescribed under these conditions (80.2%), followed by drugs acting on the nervous system (63%), which can be attributed to the need for sedation and analgesia characteristic of the PICU. García-López et al.6 found 53.9% of prescriptions were OL, most frequently on account of the indication (55.7%), followed by age (31.2%). The analysis by age group showed that the use of drugs under conditions not approved in the SmPC decreased with age (63% in patients aged <2 years vs 45.2% in patients aged 13 years and older). In this instance, the most frequent group was drugs acting on the cardiovascular system, followed by drugs acting on the nervous system.

Few studies on the subject have focused on the primary care setting. Another study conducted by Blanco-Reina et al.12 found a proportion of OL prescription of 27.4%, most frequently due to age (60%) and of drugs acting on the respiratory system (63%). In regard to the latter, Suarez-Castañón13 reported that 85% of cold medicines were prescribed under conditions outside the SmPC, most frequently corresponding to cough medicines, with the most frequent reason for classification as unauthorised being age, especially in children aged less than 2 years, followed by indication.

When it comes to UL prescription, the frequency in Spain, which ranges between 5% and 8%, is lower compared to other developed countries, with frequencies ranging between 10% and 15%.4,10–12 Most of these prescriptions in Spain are classified as UL due to the preparation of the drug, for instance through compounding. Thus, the percentage of UL prescriptions may be influenced by the pharmaceutical practices in each country and the availability of specific formulations for the paediatric population.

Lastly, a large study conducted in the United States to analyse the use of OL drugs in children aged less than 18 years found that OL prescription was mainly associated with young age, long lengths of stay and severe disease.14

The CM-AEP already posed this question to paediatricians that were members of the AEP or any of its subsidiary speciality and regional societies between July 2012 and March 2013. Six hundred and seventy-three paediatricians participated in a survey conducted by means of an online questionnaire.3

Of all respondents, 71.5% reported knowing what OL meant. Also, 61% were aware of prescribing drugs outside the conditions established in the SmPC, and 47% knew that this needed to be documented in the health record. However, barely half informed the parents of it, and only 22% documented it in the health record.

That is, based on these findings, 4 out of 10 paediatricians in Spain did not know when they were prescribing a drug under unauthorised conditions and only 2 out of 10 adhered to current regulations. It became evident that Spanish paediatricians needed to change. In addition, the CM-AEP considers the ongoing effort to develop consensus documents and clinical practice guidelines to increase the information regarding the efficacy and safety of OL drug prescription in children a priority with the goal of including these uses in the conditions authorised under the SmPC.

In 2013, the Pediamécum of the AEP featured up to 384 uses outside the conditions established in the SmPC in its 634-drug database. Many consensus documents and clinical practice guidelines have been published since. In 2020, the number of active substances registered in Pediamécum9 was 672, and the number of documented OL uses had increased to 411.

This document includes 2 tables on active substances commonly used in paediatrics. We analysed substances with known uses outside the SmPC that are either documented (Table 1) or not documented (Table 2) in the Pediamécum database at the time of the last update of the corresponding drug datasheet.

The use of medicines under unauthorised conditions is appropriate and, as research in children shows, often necessary. In many instances there is no authorised drug for a given treatment goal, or those available are less appropriate for a given patient. Therefore, OL drug prescription is legal and is in the scope of lex artis ad hoc. In other words, it is a good medical practice based on up-to-date scientific evidence and diagnosis and treatment protocols. Nevertheless, such use is outside the conditions guaranteed by drug regulatory authorities and, should a claim be made, the pharmaceutical company would not be liable.3,15

Paediatricians must be aware that the goal is for the treatment to benefit the patient and should convey this to the parents. This is why it is important to justify OL prescription based on current evidence and clinical practice, document the justification in the health records and obtain consent, at least verbally, from the parents or legal guardians.3 It is also important that paediatricians are informed and made aware of the need to notify as a suspected adverse drug reaction any unexpected adverse event following use of a drug under unauthorised conditions. Malpractice and its potential legal ramifications could result from not performing these actions, but never from the mere OL or OL prescription of a drug.3,15

The use of pharmaceuticals under unauthorised conditions may lead to the development of adverse effects not previously described or ineffective treatment. Thus, this practice is not always safe.16,17 However, as noted above, it is the ethical duty of paediatricians to keep their knowledge of the evidence up to date in order to offer patients the best possible treatment.

The pharmacokinetics and pharmacodynamics of drugs are different in children compared to adults and vary based on age, body weight and developmental stage. These differences entail the need of prescribing different doses (based on age or body weight) to achieve the expected effectiveness. In the case of OL prescription in children, this may need to be done by extrapolating data obtained in other age groups, which may lead to differences in the effectiveness or safety of the drug.18

However, and despite efforts made in recent years to increase and improve the development of drugs for use in children,19 there are still many situations in which the paediatrician has to resort to OL or UL prescription to offer patients the best possible treatment.4,10–12 Therefore, it is essential that paediatricians not only keep in mind the legal conditions for OL drug prescription, but also the do no harm principle, weighing the benefits and risks at the time of prescription, during treatment and in the subsequent follow-up, actively reporting adverse events associated with the use of drugs under these conditions and including parents and, should age allow, the patients in the decision-making process.

While in many situations the OL prescription of drugs in paediatrics is supported in scientific and clinical evidence that provides some assurance about their use, there are also situations in which the available data are much scarcer. This is particularly common in the prescription of recently marketed drugs, high-risk drugs, used in the most vulnerable subsets of the paediatric population or through routes of administration that carry a higher risk of adverse reactions. All of them are situations requiring careful evaluation and follow-up of pharmaceutical treatment.

Another aspect to consider is that the use of drugs not meant for paediatric patients may result in the administration of excipients that are not appropriate for certain age groups, especially newborn infants, or patients with underlying disease or intolerance.20–22 To determine their presence, it may be useful to consult databases that provide this information, such as the Safety and Toxicity of Excipients for Paediatrics (STEP),23 or to consult directly with the pharmacist.

Considering all of the above, the answer seems evident. Children are a vulnerable population that must be protected. There is no better way to do this than to promote high-quality research in the paediatric field so that appropriate drugs are available with fitting formulations and tested in the paediatric population.

In 2007, Europe developed specific regulations to protect the health of children. This gave rise to paediatric investigation plans, research and development programmes intended to guarantee the generation of the necessary data to establish the conditions under which a drug may be authorised for use in the paediatric population.24 Ten years later, the results of this strategy were evaluated.25 Although there was a significant increase in research in the paediatric field and new indications for use were authorised, the impact was not as expected, and there is still considerable room for improvement. This should translate to a reduce use of drugs under OL conditions, but, to put an example, the data on the use of pharmaceuticals outside the conditions established in the SmPC registered in Pediamécum in Spain show no such reduction.9 To increase the efficiency of regulatory measures and the development of more drugs specifically intended for the paediatric population, the European Medicines Agency (EMA) published an action plan in 2018 to identify the medical needs of the paediatric population and to increase transparency in everything related to drugs used in children, among other objetives.26

Clinical trials in children are necessary, but also complicated. This type of research must be promoted zealously, establishing collaborative networks focused on research in children, such as the Red Española de Ensayos Clínicos en Pediatría27 (RECLIP), which leads paediatric clinical trials in Spain. New clinical trial designs must be developed to include the adolescent population from the outset. The administration should explicitly promote these initiatives by offering real support to these networks so that they do not depend exclusively on clinical trials funded by the pharmaceutical industry. Many drugs that are of little interest to the industry due to their low market price or the target population being too small could be investigated in independent clinical trials if there was adequate support of paediatric research.

It is also important to undertake studies of a different kind, multicentre studies focused on different diseases of childhood, which are often rare and require a concerted effort to get significant results in a population that is smaller compared to adult diseases. Networking in different paediatric specialities is a strongpoint of paediatrics that is developing significantly in Spain and allows the collection of data that could not be obtained otherwise, producing evidence on treatment with drugs outside authorised conditions.28 There are numerous examples of networks on specific subjects in Spain, as evinced in some recent publications.29 In short, research in the paediatric population must be pursued to gain knowledge on the drugs appropriate for use in this age group, combining every possible resource, whether public or private.

We must also emphasise the need to report potential adverse effects through the national pharmacological surveillance network. In 2018, the EMA published a guideline on good pharmacovigilance practices with a chapter devoted to the paediatric population. The guideline explicitly established that the use of medicines under unauthorised conditions can expose paediatric patients to an increased risk of adverse effects and medication errors.30 The notification of adverse events to the national pharmacological surveillance network is an excellent tool to contribute to the available information on the use of drugs in uncertain scenarios.

On the other hand, it is essential that the knowledge of paediatricians as to what constitutes use of a drug outside the authorised conditions, the current legislation on the subject and how to do it safely improves. Initiatives such as those advanced by the Asociación Española de Pediatría and its flagship journal, Anales de Pediatría, to educate and inform paediatricians, are among the many tools that can improve this knowledge. Paediatrics manuals and handbooks, and Pediamécum9 as an example of such sources, must always note whether there is evidence supporting the OL use of a drug in the paediatric population and provide the prescriber all the available information. Specific training of paediatricians through educational platforms such as Continuum31 can also offer valuable knowledge on this subject to all prescribers. Making a difficult subject such as this one appealing is also an important challenge. The health of children deserves this effort.

The authors have no conflicts of interest to declare.