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Editorial www.jpgmonline.com

Unlicensed and Off-label Drug Use in Children

Bavdekar SB, Gogtay NJ

Journal of Postgraduate he purpose of licensing is to ensure that medicines are marketed only after having been
Medicine,
Seth GS Medical College
T examined for safety, efficacy, and quality.[1] When a drug is prescribed outside these param-
eters, this support is lacking. Despite this, unlicensed and off label drug use in children is wide­
& KEM Hospital, spread.[2-23] This is ironical to say the least, since the licensing process itself was introduced in the
Mumbai-400 012, India. US and European countries mainly as a response to drug-related tragedies [chloramphenicol-in­
duced gray baby syndrome, thalidomide-induced phocomelia and deaths following diethylene gly-
Correspondence:
col poisoning] that occurred in newborn babies, infants and children. Estimated to vary from 10-
Bavdekar SB
E-mail: 72% (Table 1), the magnitude of such use varies amongst others, according to the level of healthcare
drsbavdekar@vsnl.com available, subspecialty concerned and certain patient characteristics. The prevalence of off-label
and unlicensed drug use is higher in neonates and infants and in premature and low birth-weight
babies.[21] Topical preparations such as eye drops, ear drops and dermatological products also ac-
PubMed ID : 16388164 count for much of the off-label and unlicensed drug use,[3,21] as these are hardly ever subjected to
J Postgrad Med 2005;51:249-52 formal evaluation in children. Amongst the systemic drugs, bronchodilators, anti–migraine prepa­

rations, gastro-intestinal agents, anti-hypertensive agents, oral
hypoglycemic agents, anti-spasmodics, oxymetazoline,
ondansetron and amphotericin B, are commonly prescribed
off-label. [2,3,5,8,9.11,21,24]
Why is Unlicensed and Off-Label Drug Use Common?
Off label drug use refers to the use of drugs outside the condi-
tions of the product license in terms of dose, patient age, route
of administration, indication and contra- indication;[24] while
unlicensed use refers to using a drug in children when it has
not received market authorization for use in them. For several
years, children have been excluded from clinical trials carried
out during the process of market authorization; as the society
and law makers thought it prudent not to expose children to
molecules, whose safety and efficiency had not been estab­
lished. This resulted in drugs being marketed without pediatric
safety and efficacy data. Ironically, society’s desire to protect
children from clinical studies has resulted in a much larger
number of children getting exposed to the drugs when a clear
evidence of safety, efficacy or favorable risk-benefit ratio has
not been generated, when information about effective and safe
dosages are not available and when there is no active monitor­
ing for adverse events and that too, in an uncontrolled fash­
ion. Also, such exposure in clinical practice does not yield sig­
nificant generalizable data, as practitioners do not report off­
label or unlicensed drug use. It is not surprising that now the
fundamental dilemma of whether children are to be protected

Table 1: Summary of selected studies estimating the use of drugs beyond license
Investigators Clinical setting (Country) No of prescriptions Unlicensed or
(No. of patients) off-label drug use (%)
Turner, et al., 1996[12] 1 PICU (UK) 862(166) 31
Turner, et al., 1998[13] 2 pediatric Wards (UK) 2013 (609) 25
Conroy, et al., 1999[14] 1 NICU (UK) 455 (70) 64.6
Turner, et al., 1999[23] 5 pediatric wards 4455 (936) 48
Wilton, et al 1999[15] Community† NA (24337) 12.6
‘t Jong, et al., 2000[16] 4 pediatric wards 2139 (238) 66
Conroy, et al., 2000[11] 5 pediatric wards (five European countries) 2262 (624) 46
Gavrilov, et al., 2000[18] 1 pediatric ambulatory hospital ward* (Israel) 222 (132) 42
Chalumeau, et al., 2000[7] 77 pediatricians (France) 2522 (989) 33
McIntyre, et al., 2000[8] 1 pediatric ambulatory* (UK) 3347 (1175) 10.8
Craig, et al., 2001[19] 1 pediatric unit (Northern Ireland) 237 (74) 22.8
‘t Jong, et al., 2001[2] 1 pediatric ward+ 3 PICU (The Netherlands) 2139 (237) 66
Pandolfini, et al., 2002[6] 9 pediatric wards (Italy) 4625 (1461) 60
O’Donnell,et al., 2002[20] 1 NICU (Australia) 1442 (97) 58
‘t Jong, et al., 2002[3] Community† (The Netherlands) 17453 (6141) 28.9
Bucheler,et al., 2002[9] Records with health insurer† (Germany) 1.74 million 13.2
Carvalho, et al., 2003[5] PICU(Brazil) 747 (51) 54.2
Schirm, et al., 2003[21] Community† (The Netherlands) 66222 (18943) 37.2
Neubert, et al., 2004[22] Pediatric isolation ward (Germanay) 740 (178) 22.7

*retrospective studies; †: Presentation monitoring studies; NA: not available

J Postgrad Med December 2005 Vol 51 Issue 4 249 �

CMYK249
� Bavdekar et al.: Unlicensed and off-label drug use in children
from drug studies, or is it important to evaluate drugs ad­
equately in children before they are used in pediatric practice,
is being resolved in favor of the latter. Historically, the phar­
maceutical industry has been less enthusiastic in conducting
clinical trials in children as they are costlier and logistically
more challenging to undertake. The fact that the pediatric
market-share is miniscule as compared to the adult market also
acts as a dampener.
Non-availability of pediatric formulations is a common reason
for unlicensed drug use. Young children require liquid prepa­
rations and dispersible tablets. For many molecules, such prepa­
rations are not available. Hence, extemporaneous dispensing
in the form of crushing tablets or opening capsules and sus­
pending contents is resorted to so as to produce a liquid prepa­
ration that a child can take.
Associated Risks
Given the fact that over 70% of all Physicians’ Desk Reference
(PDR) entries do not have adequate pediatric labeling,[25] off­
label and unlicensed drug use becomes a necessity. However,
such use is not without its risks. When extemporaneous dis­
pensing is resorted to, there is little information regarding the
drug’s bio-availability and stability. It is possible that the child
might receive an unstable and hence an ineffective drug. The
medium used to dissolve the drug powder, if inappropriate,
could cause adverse reactions. When pediatric dose has not
been established, doctors calculate pediatric dose on the basis
of adult dose. This could be hazardous as children are not just
miniature adults. Their body composition changes over the
years and so does their drug-metabolizing capability.[24] The
practice could result in children receiving sub-optimal or ex­
cessive doses. Even use of unlicensed topical preparations could
result in unexpected events. For example, given their greater
surface area as compared to body mass, relatively larger
amounts of topically applied dermatological preparations could
get absorbed systemically. It should be borne in mind that some
studies do indicate that the frequency of adverse drug reac­
tions is higher with unlicensed and off-label drug use.[22,26] In
some countries, insurance companies do not reimburse ex­
penses incurred on off-label and unlicensed drugs, putting
families at a financial disadvantage.
Concerns for the Treating Doctor
It is true that the terms ‘unlicensed’ do not imply disapproval
or that the practice is improper. They only imply that pharma­
ceutical companies have not performed clinical trials and,
therefore, evidence of tolerability and efficacy is not available
to satisfy licensing authorities.[24] Such data may not be really
available or the concerned pharmaceutical company may not
be interested in submitting this data for improving pediatric
labeling. Whatever be the reason, when a drug is used outside
the limits of its label, neither the company nor the authorities
take any legal or ethical responsibility for the occurrence of an
unexpected event. It may still be proper and lawful for a doc­
tor to prescribe an off label drug,[17, 25,27] but the responsibility
lies entirely with the prescriber. In addition, the doctor has to
� 250
250 CMYK
spend more time with parents explaining to them why a drug
does not have adequate pediatric labeling. On the other hand,
a doctor deciding to prescribe drugs only as per label would
find his therapeutic armamentarium greatly curtailed. And
such an approach besides being impractical, is untenable. It is
not ethical for a doctor to withhold using a potentially useful
drug in a patient, just because it would amount to off-label
use.
This puts doctors caring for children in an unenviable situa­
tion. Given the large number of drugs without adequate
pediatric labeling, they are frequently called upon to use their
judgment regarding the use of these drugs. It is expected that
the decision to use the drug and its dose be based on evidence
and authoritative professional opinions. But in reality, the li­
censing authorities do not seem to have enough evidence about
the drug’s efficacy, safety and risk-benefit ratio, the label on
the drug does not indicate a particular dose, the scientific in­
formation available from medical literature is confusing at best
and there is hardly any single authoritative source of reference
available. The doctors fear that they could be sued for mal­
practice for indulging in off-label drug use should an unex­
pected event occur. It needs to be emphasized that the doctor
could justify such use, provided the decision is based on what
is good medicine and what is best for the patient regardless of
conforming to labeling. In a liability suit, drug labeling may
have evidentiary weight, but it, per se, is not intended to set a
standard for good medical practice.[25] In fact, a doctor could
be subjected to claims of malpractice if a patient is denied the
best potential treatment just because it was unlicensed or off­
label.[24,25]
Remedial Actions and Future
Although, statements from professional bodies highlight that
unlicensed and off-label drug use is a vital part of children’s
drug therapy and that this practice should use the best infor­
mation available and should be justifiable as being in accord­
ance with a respectable, responsible body of professional opin­
ion; it is not a desirable state. Complacency about the lack of
evidence-based information on drugs for the children is unac­
ceptable, as the practice does expose children to drugs whose
efficacy, safety and risk-benefit ratio are not known and puts
undue stress on the treating doctors. As pointed out by Boos,[28]
a widespread off-label use of drugs makes mockery of licensing
and its declaration of bankruptcy. In this situation, the label is
off use in that it leads to a general tendency to ignore the pack­
age inserts and the guardians not finding any relevant infor­
mation in the package. More important offshoots of this kind
of practice will be that the physicians having to take on more
legal responsibility, the authorities not being able to control
the market and the companies not knowing what happens with
their drugs.
The society, the lawmakers and the pharmaceutical industry
need change their attitudes and mindset and should under­
stand and acknowledge that children have as much right to
effective, safe and quality drugs as adults. To ensure that this
fundamental right to safe therapy is protected, we need to act
J Postgrad Med December 2005 Vol 51 Issue 4

through two pathways. One is through steps intended to gen­
erate more pediatric data on safety and efficacy of drugs
through pediatric clinical trials and the second by making ef­
forts intended to make off-label safer.
Several innovative steps have been taken in the western coun­
tries to coax, entice, stimulate and even compel the pharma­
ceutical companies to undertake clinical trials in children.
Having failed to elicit the desired effect by asking the drug
companies to provide pediatric indications and dosage in the
label based on evidence derived from adequate and well-con­
trolled studies in the pediatric population, the FDA came out
with the voluntary pediatric exclusivity (PE) clause within the
FDA modernization Act (FDAMA) 1997. It provided exclu­
sive rights to the company to market a drug for an extended
period of six months, if the company made a fair attempt to
generate pediatric data regarding the drug by undertaking
pediatric clinical trials. The approach was innovative: the FDA
acknowledged that undertaking pediatric clinical trials put fi­
nancial burden on companies and hence attempted to provide
compensation / fiduciary incentive. The limitations included
its voluntary nature and its ineffectiveness with regard to off­
patent drugs. Through Pediatric Rule (PR) that came into ef­
fect in 1999, the FDA moved forward by mandating manufac­
turers to submit safety and effectiveness data on relevant
pediatric age groups before approval. The PR applied to
biologicals as well and could be applied multiple times during
the life cycle of a drug. The two measures (PE and PR) were
successful with FDA getting several requests for conducting
pediatric clinical trials. The Best Pharmaceuticals for Children
Act (BPCA) established an office of pediatric therapeutics and
created a Foundation of National Institutes of Health (NIH),
which would generate funds for the study of drugs (including
important off-patent drugs), in children. The Pediatric Re­
search Equity Act (PREA) re-established the FDA’s authority
to mandate pediatric drug development and made a pediatric
assessment mandatory at the pre-IND meeting with FDA. The
European countries have also taken steps to ensure that
pediatric studies are conducted more often. Prioritizing build­
ing infrastructure for such studies, they have concentrated on
developing network of pediatric clinical investigator and pro­
viding training in pediatric clinical pharmacology.[29,30] Having
seen the failure of “European guidance on clinical investiga­
tion of medicinal products in children” in stimulating phar­
maceutical industry to improve pediatric labeling scenario, the
European Union Council has published a consultation docu­
ment “Better medicines for Children” which it is hoped would
result in legislation to improve the situation.[24]
Compelling and motivating companies to undertake pediatric
clinical trials is not the whole answer to the issue. There is a
need identify and address factors that make the conduct of
pediatric clinical trials difficult. The factors responsible include
those related to difficulties in recruitments, obtaining ethical
clearance and having sensitive and trained investigators. These
could be tackled by providing community education regard­
ing need for undertaking clinical trials in children, providing
risk categorization guidelines to Institutional Review Boards
(IRB), training and sensitizing members of the IRB regarding
J Postgrad Med December 2005 Vol 51 Issue 4
Bavdekar et al.: Unlicensed and off-label drug use in children �
risk assessment and scientific issues related to children’s rights
as participants and providing training to investigators. The
FDA has provided broad guidelines regarding factors to be
considered (degree of risk involved, possibility of direct ben­
efit to the participant and prospect of generating vital
generalizable knowledge) while providing ethical clearance.[29,30]
But these need not to be made more precise. The importance
of conducting these studies with greatest degree of profession­
alism, while adhering to the highest level of ethical standards
cannot be over-emphasized. Any slacking in this regard could
lead to public outcry that would set the clock of readiness for
conducting trials back by decades. Therefore, the IRB will have
to become more pro-active and assume their monitoring role
with greater alacrity.[31] Boos in a thought-provoking editorial
has pointed out that testing indication by indication and age
group as pre-condition for labeling cannot work in rare dis­
eases and the expectation to supply standard data sets with
hundreds of patients is difficult to attain in severe or rare
pediatric illnesses. In these circumstances, conducting stud­
ies with lower level of significance or lower power would be
worth thinking about; but is likely to invite opposition since
nobody wants to systematically reduce the standards for spe­
cific patient groups.[28] Although, randomized controlled in­
terventional trials have been the standard design used for de­
termining efficacy and safety; under special circumstances, we
should determine if we could use alternative (epidemiology
and prospective observational cohort) designs for generating
vital efficacy and safety data.[32]
If we intend to rid of the off-label use, we will have to indulge
in, “out of box” thinking and devise novel approaches. At the
moment, only the concerned pharmaceutical company can
initiate the process of label change. But given the economic
considerations, why should a company be interested initiating
this costly process, if the drug is being used any way and is off­
patent? To counter this phenomenon, legal provisions should
be enacted that would require pharmaceutical companies to
summarize published data, medical guidelines and other clini­
cal experience with respects to their drug product and submit
this information to the authorities, who could eventually le­
galize the broad off-label therapeutic experience, whenever
possible. [28] Secondly, newer legal provisions should allow
pediatric and medical societies to review available evidence
and initiate label changes.[28] These societies should also en­
courage its members, who choose to prescribe a meditation
with no or limited pediatric data to document and publish
experiences from such off-label use.[32,33] In fact, the societies
could also maintain registries for certain critically important
drugs, where pediatric data needs to be generated.
We should assess the effectiveness of the measures undertaken
to stimulate pediatric trials. However, given the backlog of drugs
that do not have pediatric labeling, inherent problems in con­
ducting pediatric studies and limitations of various initiatives,
it is possible that off-label and unlicensed drug use in children
would continue for several years. Hence, we should also try
and implement measures that would make such use as safe as
possible. Updated information regarding drugs of interest
should be provided to assist doctors take informed decisions
251 �
CMYK251
� Bavdekar et al.: Unlicensed and off-label drug use in children
regarding off-label drug use. Although medical literature does
not offer this information; a newsletter dedicated to publish­
ing such specific data regarding drugs likely to be used for off­
label indications would be of great use to doctors. The
pharmacopias should improve pediatric coverage[25] and WHO
and UNICEF should develop a pediatric-specific essential
medicine list. This would help to increase the awareness of
the need for pediatric specific medications and highlight ar­
eas of priority where medications or formulations are lacking.[34]
The pediatric societies should provide evidence-based guide­
lines for appropriate drug choice and use in pediatrics on the
lines of Medicines for children produced by Royal College of
pediatrics and Child Health. These would reflect the expert
professional opinions that doctors can depend upon. In addi­
tion, drug information services provided by pharmaceutical
companies and clinical pharmacology units of academic in­
structions should be optimized. Guidelines for preparation of
extemporaneous formulations, when no licensed preparations
exist need to be generated and disseminated to ensure that
children continue to receive safe medications in a suitable form.
The situation in the developing countries needs to be studied,
as, barring a few, all the studies on this issue have been carried
out in European countries, US and Australia. This noteworthy
absence of studies from developing countries could be indica­
tive of lack of awareness or interest amongst health care pro­
fessionals. Either way, this is a worrisome phenomenon. If doc­
tors in the developing world are not aware of or are not sensi­
tive to the issue of unlicensed and off-label drug use in chil­
dren, they are likely to prescribe these drugs even when a
proven, safe and effective option is available, thereby expos­
ing children in these countries to unproven therapies. The
consequences could be graver with lesser awareness amongst
the general public and the medical profession and ineffective
implementation of inadequate legislation. Just one example
would be sufficient to emphasize that different and more steps
would be required to tackle the issue: in most advanced coun­
tries, detail men employed by the pharmaceutical industry are
prohibited from briefing doctors about off-label use. However,
in developing countries these detail men routinely inform
medical practitioners about off-label indications, without cat­
egorizing them as “off-label” (personal experience).
Although, it is heartening to note that the issue of off-label
and unlicensed drug is receiving attention from several quar­
ters and that some well-intended steps are being taken, a lot
more remains to be done. Every segment concerned with and
about the health of the children like the government, the leg­
islative bodies, the regulatory authorities, the consumer or­
ganizations, the medical practitioners, the pharmaceutical in­
dustry and the academic institutions will have to work in tan­
dem and in collaboration to ensure that children receive effec­
tive, safe and quality drugs which is their birthright.
References
1. Cuzzolin L, Zaccaron A, Fanos V. Unlicensed and off-label uses of drugs in
paediatrics:a review of literature. Fundamental and Clinical pharmacology
2003;17:125–31.
� 252 J Postgrad Med December 2005 Vol 51 Issue 4
252 CMYK
2. ‘t Jong GW, Vulto AG, de Hoog M, Schimmel KJM, Tibboel D, van den Anker
JN. A survey of the use of off-label and unlicensed drugs in Dutch Children’s
Hospital. Pediatrics 2001;108:1089–93.
3. ‘t Jong GW, Eland A, Strukenboom MCJM, van den Anker JN, Stricker BHC.
Unlicensed and off-label prescription of drugs to children:population based
cohort study. BMJ 2002;324:1313–4.
4. Dick A, Keady S, Mohamed F, Brayley S, Thomson M, Lloyd BW, et al. Use of
unlicensed and off-label medications in pediatric gastroenterology with a
review of the commonly used formularies in the UK. Aliment Phrmacol Ther
2003;17:571–5.
5. Carvalho PRA, Carvalho CG, Alievi PT, Martinbiancho J, Trotta EA. Prescrip­
tion of drugs not appropriate for children in a pediatric intensive care unit.
Journal de Pediatria 2003;79:397–402.
6. Pandolfini C, Impicciatore P, Provasi D, Rocchi F, Campi R, Bonati M, Italian
Paediatric Off-label Collaborative Group. Off-label use of drugs in Italy:a pro­
spective, observational and multicenter study. Acta Paediatr 2002;91:339–
47
7. Chalumeau M, Treluyer JM, Salanave B, Assathiany R, Cheron G, Crocheton
N, et al. Off-label and unlicensed drug use among French office based
pediatricians. Arch Dis child 2000;83:502–5.
8. McIntyre J, Conroy S, Avery A, Corns H. Choonara I. Unlicensed and off-label
prescribing of drugs in general practice. Arch Dis Child 2000;83:498–501.
9. Bucheler R, Schwab M, Morike K, Kalchthaler B, Mohr H, Schroderer P, et al.
Off-label prescribing to children in primary care in Germany:retrospective
cohort study. BMJ 2002;324:1311–2.
10. Schirm E, Tobi H, de Jong-van den Berg LTW. Unlicensed and off-label drug
use by children in the community:cross sectional study. BMJ 2002;324:1312–
3.
11. Conroy S, Choonara I, Impicciatore P, Mohn A, Arnell H, Rane A, et al. Survey
of unlicensed and off-label drug use in paediatric wards in European coun­
tries. BMJ 2000;320:79–82.
12. Turner S, Gill A, Nunn T, Hewitt B, Choonara I. Use of ‘off-label’ and unli­
censed drugs in paediatric intensive care unit. Lancet 1996;347:549–50.
13. Turner S, Longworth A, Nunn AJ, Choonara I. Unlicensed and off-label drug
use in pediatric wards:prospective study. BMJ 1998;316:343–5.
14. Coroy S, McIntyre J, Choonara I. Unlicensed and off label drug use in
neonates. Arch Dis Child:Fetal Neonat Ed 1999;80:F142–5.
15. Wilton LV, Pearce G, Mann RD. The use of newly marketed drugs in children
and adolescents prescribed in general practice. Pharmacoepidemiol Drug
Safety 1999;8:S37–45.
16. ‘t Jong GW, Vulto AG, De Hoog M, Schimmel KJM, Tibboel D, van den Anker
JN. Unapproved and off-label use of drugs in a children’s hospital. N Engl J
Med 2000;343:1125.
17. American Academy of Pediatrics Committee on Drugs. Unapproved uses of
approved drugs:The Physician, the package insert, and the Food and Drug
Administration:Subject Review. Pediatrics 1996;98:143–5.
18. Gavrilov V, Lifshitz M, Levy J, Gorodischer R. Unlicensed and off-label medi­
cation use in a general pediatrics ambulatory hospital unit in Israel. Isr Med
Assoc J 2000;2:595–7.
19. Craig JS, Henderson CR, Magee FA. The extent of unlicensed and off-label
drug use in the pediatric ward of a district general hospital in Northern Ire­
land. Ir Med J 2001;94:237–40.
20. O’Donnel CPF, Stone RJ, Morley CJ. Unlicensed and off-label drug use in an
Australian Neonatal Intensive Care Unit. Pediatrics 2002;110:e52 (http://
pediatrics.aappublications.org;last accessed on 23 Sep 2005).
21. Schirm E, Tobi H, de Jong-van den Berg LTW. Risk factors for unlicensed and
off-label drug use in children outside the hospital. Pediatrics 2003;111:291–
5
22. Neubert A, Dormann H, Weiss J, Egger T, Criegee-Rieck M, Rascher W, et al.
The impact of unlicensed and off-label drug use on adverse drug reactions
in paediatric patients. Drug Safety 2004;27:1059–67.
23. Turner S, Nunn, AJ, Fielding K, Choonara I. Adverse drug reactions to unli­
censed and off-label drugs on pediatrics wards:a prospective study. Acta
Peadiatr 1999;88:965–8.
24. Conroy S. Unlicensed and Off-label Drug Use. Issues and recommendations.
Pediatr Drugs 2002;4:353–9.
25. Blumer JL. Off-label uses of drugs in children. Pediatrics 1999;104:598–602.
26. Horen B, Montastruc J-L, Lapeyre-Mestre M. Adverse drug reactions and
off-label use in paediatric outpatients. Br J Clin Pharmacol 2002;54:665–70.
27. Hill P. Off license and off label prescribing in children:litigation fears for phy­
sicians. Arch Dis Child 2005;90:17–8.
28. Boos J. Off label use-label off use? Ann Oncol 2003;14:1–5.
29. Chesney RW, Christensen ML. Changing requirements for evaluation of
pharmacologic agents. Pediatrics 2004;113:1128–32.
30. Steinbrook R. Testing medications in children. New Engl J Med
2002;347:1462–70.
31. Bavdekar SB. Protecting children participating in Research trials:Review
Boards should take up Pro-active Role. Indian Pediatrics [in press]
32. Wong I Sweis D, Cope J, Florence A. Paediatric Medicines Research in the
UK. How to move forward? Drug Safety 2003;26:529–37.
33. Committee on Drug, American Academy of Pediatrics. Uses of drugs not
described in the Package Insert (Off-Label Uses). Pediatrics 2002;110:181–
3.
34. Beggs SA, Cranswick NE, Reed MD. Improving drug use for children in the
developing world. Arch Dis Child 2005;90:1091–3.