Paediatric drug treatment relies on the use of both unlicensed (medicines which have not been licensed for human use) and off label drugs (licensed drugs prescribed without their marketing authorisation). Off label prescribing, which is more common than unlicensed drug use, often occurs because of a lack of appropriate clinical trials data and licensed alternatives. At least one third of children admitted to hospital and 90% of children in neonatal units are prescribed off label medicines,^1–,⁴ which recent evidence suggests may be associated with an increased level of adverse drug reactions, and possible treatment failure.^5–,⁸ Although in the United Kingdom, prescribing a medicine off label is not illegal,⁹ there is concern over the extent and possible effects of such prescribing in this vulnerable population. In the USA these problems have been tackled by the introduction of the 1997 FDA Modernisation Act (FDAMA), the 1998 “Pediatric Rule”, the 2002 Best Pharmaceuticals for Children Act (BPCA), and the 2003 Pediatric Research Equity Act (PREA). These Acts not only ensure appropriate reward for pharmaceutical companies willing to undertake paediatric studies, but also that the appropriate legislative framework and funding is available to ensure the assessment of drugs for paediatric use.^10,11 In the European Union there has been a slower paced development of guidelines to encourage the pharmaceutical industry to perform appropriate clinical studies in children but as yet no legislative framework,^12,13 although an additional period of market exclusivity for companies that undertake appropriate studies is proposed.¹⁴

As we have previously investigated the attitudes and experiences of general practitioners to off label prescribing in the community, where it is frequently initiated by a hospital based paediatrician, we sought to assess the attitudes and experiences of the latter to off label prescribing and to paediatric clinical trials.

METHODS

A 25 item questionnaire comprising 24 questions with a combination of tick box responses or 5–6 point scale questions, three of which also allowed written comment, and one free text question were sent to all 259 hospital based consultant paediatricians and paediatric specialist registrars in Scotland during 2003–2004 (appendix A). In addition to the acquisition of baseline demographic data, questions focused on knowledge of and reasons for off label prescribing, actual and potential concerns about off label medicines, communication with parents, guardians, and GPs, and attitudes towards the need for and the performance of clinical studies in children. The joint Grampian ethics committee approved the study.

RESULTS

The responses to the questionnaire are detailed in table 1⇓.

DISCUSSION

The majority of hospital paediatricians were familiar with the concept of off label prescribing and knowingly prescribed medicines in this manner, citing as the most common reasons prescribing for a younger age, at a higher dose, or for a different indication than recommended—findings consistent with the results of previous studies of off label prescribing in the United Kingdom.^2–4,16

Although only about half the respondents believed that the use of off label medicines disadvantaged their patients, a larger number expressed concerns about safety and efficacy issues, reporting high levels of treatment failure and ADRs. These responses clearly highlight current deficiencies in paediatric practice and the need for more extensive efficacy, outcome, and safety data. Neonatologists were the least concerned, which is surprising considering their high usage of off label or unlicensed drugs.^3,17,18 While these responses could reflect a greater experience and confidence with off label prescribing, they may also reflect the difficulties in identifying ADRs in sick neonates.

Unexpectedly only a third of respondents thought that specific paediatric formulations were required, highlighting an unawareness of the current situation where pharmacists overcome the lack of paediatric formulations by supplying extemporaneous preparations, imported medicines, or unlicensed special products.

In contrast to veterinary practice, where informed consent is strongly advised,¹⁹ only about a third of paediatricians sought parental consent, or informed parents or the child’s GP that an off label medicine was being prescribed. These issues have been partially addressed by a recent policy statement by the Royal College of Paediatrics and Child Health, which states that it is not necessary to take additional steps beyond those normally taken in obtaining consent, although recognising the need for communication with parents and other professionals when the continuing care of a child prescribed an unlicensed or off label drug is handed over to others.²⁰

Despite concerns over the safety and efficacy of off label medicines, only half the respondents believed that medicines should undergo trials in children, citing as the reasons for this less than enthusiastic attitude “that there was already a significant level of empirical knowledge available”, and possible ethical issues regarding informed consent. These attitudes are at variance with those expressed by Scottish GPs,²¹ who, while less concerned about the safety issues (15% v 70% of hospital paediatricians), were more convinced of the need for appropriate clinical trials (79% v 54%). The ethical concerns surrounding informed consent also need to be reconciled with the current unsatisfactory situation in which the use of off label drug treatment is associated with levels of treatment failure and ADRs that would be unacceptable in adults.^5–,⁸ Consideration of this ambivalent attitude may become an important issue when legislative actions to promote clinical trials in children are taken, although the establishment of the UK Medicines for Children Research Network should help to allay some of the concerns and apparent lack of enthusiasm.

APPENDIX

QUESTIONNAIRE: “OFF LABEL” MEDICINES IN CHILDREN

1. Are you a consultant or SPR in paediatrics?

Consultant □ SPR □

2. How long have you been working as a paediatrician?

0–4 years □ 5–10 years □ more than 10 years □

3. What is your current main speciality?

Neonatology □ Community □ Intensive Care □ General □ Other □

4. Which age groups do you see the most?

Please score 1–5, with 5 the most frequent and 1 the least.

0–11 months □ 1–2 years □ 3–6 years □

7–11 years □ 12–16 years □

5. How familiar are you with the concept of ‘off-label’ prescribing of medicines?

Very familiar □ Reasonably familiar □ Unfamiliar □

6. Do you knowingly prescribe medicines off-label?

Yes □ No □

7. Please indicate which of the following is the most important and which is the least important cause for off-label prescribing. Please score 1–6, with 6 the most important and 1 the least.

Use of lower than recommended dose □

Use of higher than recommended dose □

Use at a younger age than recommended □

Use via a different route of administration □

Use of a different formulation □

Use of a different indication □

8. Do you believe that off-label prescribing may disadvantage children?

Yes □ No □

If yes, please give reasons.

9. Do you have concerns about the efficacy of off-label medicines?

Yes □ No □

10. Do you have concerns about the safety of off-label medicines?

Yes □ No □

11. Have any of your patients, to your knowledge, ever experienced an adverse drug reaction following the use of an off-label medicine?

Yes □ No □

12. Have you ever experienced treatment failure due to the use of an off-label medicine?

Yes □ No □

13. What are your most common medical reasons for prescribing off-label medicines? (e.g., pharyngitis/ tonsillitis, ear ache, parental pressure)

14. Do you request informed consent from a parent or guardian before prescribing an off-label medicine?

Yes □ No □

15. Do you inform the GP that you have recommended an off-label medicine when you discharge a child from hospital or clinic?

Yes □ No □

16. Do you routinely inform parents that you are prescribing an off-label medicine for their child?

Yes □ No □

17. What sources of prescribing information do you use?

British National Formulary (BNF)

Medicines for Children (by Royal College of Paediatrics and Child Health)

Colleagues’ experience

All of the above

Others

16. Is it important to develop more paediatric formulations?

Yes □ No □ Don’t know □

17. Should all new medicines be trialled in children prior to use?

Yes □ No □ Don’t know □

18. Should the UK government provide an incentive to stimulate pharmaceutical companies to perform clinical trials in children?

Yes □ No □ Don’t know □

19. Should all current medicines which have not been studied in children undergo trialling in a paediatric population?

Yes □ No □ Don’t know □

If yes, please give reasons.

If no, do you believe that medicines in common paediatric use could continue to be used safely without detailed clinical trials? Please give reasons and the class of medicines.

20. Would you like to be actively involved in clinical trials?

Yes □ No □ No opinion □

21. Would you like to recruit subjects for clinical trials from your patients?

Yes □ No □ No opinion □

22. Would you allow your own child to participate in a clinical trial?

Yes □ No □ No opinion □

23. Do you believe that clinical trials in children involve ethical issues?

Yes □ No □ No opinion □

Please give reasons.

THANK YOU VERY MUCH FOR COMPLETING THIS QUESTIONNAIRE

If you would like to be identified and receive a copy of the results, please write your name and address here:

Name:

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