Survey of unlicensed and off label drug use in paediatric wards in European countriesBMJ 2000; 320 doi: https://doi.org/10.1136/bmj.320.7227.79 (Published 08 January 2000) Cite this as: BMJ 2000;320:79
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Editor - Over recent years there has been increasing concern
expressed within the medical and pharmaceutical professions, and amongst
the public in general, regarding the fact that few medicines used in
secondary and tertiary care paediatrics are licensed in children. Studies
have been published which indicate that the extent of this problem is very
significant, not just in this country but throughout Europe. A recent
study1 has shown that on general medical wards two thirds of patients
received an unlicensed or off
label drug prescription (421/624;67%) and nearly half of all prescriptions
written were for unlicensed drugs or off-label use (1036/2262;46%).
Previous studies have shown that these figures significantly increase when
high dependency areas are studied2, 3.
Those of us working in paediatrics have been heartened by the fact that
pressure exerted from a number of directions, including the Neonatal and
Paediatric Pharmacists Group (NPPG) and the Royal College of Paediatrics
and Child Health (RCPCH) did seem to be generating a recognition that this
is a serious issue which must be addressed. However in recent weeks we
have had cause to temper our optimism.
On 14th. February this year Dr. David Jackson, the Medical Director of
GlaxoWellcome UK, wrote to the major paediatric centres to inform them of
a decision by the company to discontinue the supply of several unlicensed
tablet preparations which the company had been making available for many
years. The drugs concerned are Imuran, Lanvis, Puri-Nethol and Myleran.
Pharmacists will immediately appreciate that such preparations are used in
the treatment of some of the most sick children in our care.
Subsequently, a letter was sent to Dr. Jackson co-signed by the Chair of
the Paediatric Oncology Pharmacists (POP) group and the Secretary of the
UK Child Cancer Study Group (UKCCSG) expressing concern on behalf of the
paediatric community at this decision, which had been taken without any
discussions with the professions concerned. A number of points were made
to him explaining why it was felt that the discontinuation of these
problems would pose significant difficulties to clinicians and pharmacists
in the areas of organ and bone marrow transplantation, and cancer
Dr. Jackson's reply offered no hope that the decision to withdraw these
products would be reconsidered. But it was the reason given for the
decision which causes us such concern for the future. It appears that
UK has decided, as a matter of corporate policy, not to continue to supply
unlicensed medicines. In an increasingly regulated world this may seem
entirely reasonable. But the crucial point is that, in the cases of Puri-
Nethol and Lanvis in particular, these products have been used within
Medical Research Council (MRC) protocols, adopted on a national basis, for
the treatment of acute lymphoblastic leukaemia (ALL) in children since the
early 1980's. With some 400 children being diagnosed with ALL every year
the UK, GlaxoWellcome had the opportunity to use the wealth of data
collected on a potential population of at least 6,000 patients as the
basis for an application to license these two products.
Yet it chose not to do so, and instead will withdraw these two products on
completion of the current ALL study. The problems we are faced with
following the withdrawal of Myleran are more acute. Supplies of 25mg.
tablets are no longer available yet we have bone marrow transplant
patients requiring daily doses of 4mg/kg. as part of their conditioning
regime. The difficulty in administering such doses using 2mg. tablets are
there was the added advantage that we could make a suspension from crushed
25mg. tablets for those children would could not take tablets. This will
now be impossible due to the bulk of the powder containing the same doses
If a company with the resources of GlaxoWellcome is unwilling to seek to
license products used in children for which there is overwhelming evidence
of efficacy in large numbers of patients, there seems to be little hope
other suppliers will seek to license their products. In the absence of any
immediately apparent options for compelling suppliers to license their
products in children, recent experience would suggest that the pressure to
license medicines in children may have the opposite effect to that which
Specialist Clinical Pharmacist, Haematology
1. Conroy S, et al. Survey of unlicensed and off-label drug use
in paediatric wards in European countries. BMJ 2000;320:79-88.
2. Turner S, et al. Use of "off-label" and unlicensed drugs in
paediatric intensive care units. Lancet 1996;347:549-50.
3. Conroy S, et al. Unlicensed and off label drug use in the
neonate. Arch Dis Child Fetal Neonatal Ed 1999;80:F142-5.
Birmingham Children's Hospital NHS Trust,
Competing interests: No competing interests
The paediatric rheumatic diseases (PRD) are rare conditions,
associated with substantial morbidity, and monetary costs. Drugs for the
treatment of PRD are now being used in new dosages, new routes of
administration, new combinations and for complications of disease but data
regarding the safety and efficacy of these new treatment regimens tends to
be from small, anecdotal, uncontrolled, non-randomised case series.
Moreover all the drugs currently used for the treatment of the PRD in most
if not all the European countries, are used off label since no indication
for paediatric use is reported in the drug label.
Certainly chronic illnesses of childhood with the potential for
producing high levels of morbidity should be the target of intense
research aimed at amelioration and possibly curing the disease. Yet, for
many reasons, securing funding for conducting clinical trials in PRD has
always been difficult. The pharmaceutical industry for example, has little
interest in funding trials in PRD and for children in general: the
potential market in children is small, most of the childhood chronic
conditions are considered orphan illnesses, and moreover due to the rarity
of most of the paediatric conditions, enrolment periods must necessarily
be long while pharmaceutical companies demand a relatively short enrolment
To face these problems in May 1996 a European research network called
"Paediatric Rheumatology International Trials Organisation - PRINTO" was
founded initially by 14 European countries (now 32 countries world wide)
with the goal to facilitate and co-ordinate the development, conduct,
analysis, and reporting of clinical trials in children with PRD. PRINTO
was founded with the idea to perform clinical trials for the PRD with or
without the support of pharmaceutical companies.
In 1997 PRINTO obtained a 3 years grant support from the European
Union (EU) to conduct, a clinical trial entitled: "A randomised actively
controlled clinical trial in children with juvenile chronic arthritis
(JCA): parenteral methotrexate in medium versus higher doses in children
who failed on standard dose of methotrexate". Important funding are coming
entirely from the EU with no pharmaceutical company supporting the trial.
This trial is built on the current "standard of care" in such a way that
the cost of insurance coverage, the medication, clinic visits, and
laboratory monitoring, are paid by the usual method of cost reimbursement
for clinical care in each participating country. The amount of data to be
collected, in addition to that from routine follow-up, is minimal, and all
participants volunteer the effort. As of today we have been able to enrol
more than 250 patients from 18 countries world wide. Interesting ethics
committee approval has been denied in 4 other countries because of lack of
insurance coverage (to be covered internally by the participating
hospitals), because medication were not administered free of charge (to be
paid with the usual methods of cost reimbursement), because of lack of the
support from a pharmaceutical company.
The problems faced by PRINTO, and surely other paediatric
organisation in dealing with pharmaceutical companies and ethics
committees, clearly underline the difficulties to design and conduct
clinical trials for children with rare diseases and for children in
general, especially if the issue is a trial seeking for approval from
As stated by Conroy S et al 1 the "European Medicines Evaluation
Agency - EMEA"2 has issued the European guidance on the clinical
investigation of medicinal products in children 3, but this guidance
simply encourages pharmaceutical companies that wish to introduce new
products to investigate these in children when clinical appropriate. The
same difficulties lead the Food and Drug Administration (FDA) to issue the
so-called "paediatric rule"4. The "Rule," effective April 1, 1999,
specifies "Regulations Requiring Manufacturers to Assess the Safety and
Effectiveness of New Drugs and Biological Products in Pediatric Patients."
This regulation directs the manufacturers of certain products likely to be
used in children to study those products in the relevant paediatric
population, so that data and information sufficient to support directions
for paediatric use could be made available (modification of the Food and
Drug Administration Modernization Act of 1997 5; 6).
As Conroy et al we urge the European Union and the EMEA to issue a
similar paediatric rule for the European Community to assure children and
their families the same rights than adults to receive drugs fully tested.
1 Nicolino Ruperto, MD, MPH
2 Alberto Martini, MD,
Prof for the
"Paediatric Rheumatology International Trials Organisation -PRINTO"
1. Conroy S, Choonara I, Impicciatore P, et al. Survey of unlicensed
and off label drug use in paediatric wards in European countries. BMJ
2. European Medicines Evaluation Agency - EMEA. Report on the experts
round table on the difficulties related to the use of new medicinal
products in children held on 18 December 1997. EMEA 1998;27164/98 Rev. 1:
3. European Medicines Evaluation Agency - EMEA. Note for guidance on
clinical investigation of medicinal products in children. London: EMEA
4. Connor JD. A look at the future of pediatric therapeutics: an
investigator's perspective of the new pediatric rule. Pediatrics
5. Food and Drug Administration (FDA). Food and Drug Administration
Modernization Act of 1997. Food and Drug Administration Modernization Act
of 1997 1997;USA Public Law 105-115 Nov. 21, 1997:
6. Food and Drug Administration (FDA). Regulations requiring
manufacturers to assess the safety and effectiveness of new drugs and
biologic products in pediatrics patients (21 CFR Parts 201, 312, 314, and
601). Federal Register 1998;63:
Competing interests: No competing interests
EDITOR-Conroy et al show the widespread use of unlicensed or off
label drugs in children admitted to hospital . Whilst it is not illegal
to use medicines in this way, the responsibility for any adverse events
becomes the clinicians or the pharmacists, rather than the manufacturers.
However, much unlicensed use may be recommended in local or national
As part of our trust's response to unlicensed drug use in children, I
reviewed all drugs recommended in our local Paediatric Medical Guidelines.
These contained 69 guidelines for acute management and elective
investigation of children. The guidelines recommended 86 drugs, but only
47(55%) were licensed for use in children. A further 14 drugs were
licensed only for children above a certain age or weight, 24 were
unlicensed or off label and the status of one drug (methylcellulose) is
unknown. Five drugs used for investigations were not licensed or the
license was restricted.
National guidelines also recommend drugs that are unlicensed for children.
The British Thoracic Society guidelines for treating tuberculosis
recommend Pyrazinamide should be given routinely, despite the fact this
drug is not licensed for children . Primaquine is recommended by
national guidelines for use in Vivax malaria, but is unlicensed .
Paediatric guidelines (both local and national) need to acknowledge the
licensed status of the drugs recommended. Linking guidelines to the Royal
College of Paediatrics and Child Health's formulary (Medicines for
Children) might facilitate this.
F Andrew I Riordan
Dept of Child Health,
Birmingham Heartlands Hospital,
BIRMINGHAM B9 5SS
1.Conroy S et al. Survey of unlicensed and off label drug use in
paediatric wards in European countries. BMJ 2000;320:79-81
2. Joint Tuberculosis Committee of the British Thoracic Society.
Chemotherapy and management of tuberculosis in the United Kingdom:
recommendations 1998. Thorax 1988;53:536-548
3. Benign malarias (treatment). British National Formulary 1998;283-
Competing interests: No competing interests
Most people in developing countries equate developed western
countries with the epitome of scientific progress and ethical medical
practice. In India one often hears the phrase, "that would never happen in
the west". So when one reads that two-thirds of children in European
hospitals receive unlicenced drugs (1) one is petrified with disbelief.
And more so because of the realisation that the 624 subjects in the report
were from countries like Sweden (from where the Nobel Prize Awards are
distributed), UK (from where most of modern medical and nursing practice
orignated), Germany (where most of the multinational drug firms have their
bases), Italy (from where the Vatican dictates to the conscience of the
people) and Netherlands (which houses the International Court of Justice).
Church (2) expresses an even stronger observation that newborns are
prescribed drugs that are only tested in animals. In general, clinical
trials are not done on children and it is considered unethical to use
children as mini guinea-pigs (3). And, as Abraham emphasised (4) there
should be a transparency and accountability in medicines recognition in
But children do not seem to be the only ones who are les miserables!
It is claimed that at one time 70% of doctors treating medicare patients
in the US failed in an examination concerning their knowledge of geriatric
prescribing. Also, 22% of geriatric patients who were given three or more
prescriptions upon discharge had prescription errors that were serious or
life-threatening (5). So what was reported from European hospitals was
also confirmed in the US, but to a different scale and with a different
Does such statistics reflect the corruption within a health-care
system or the failure of the medical educaton process? Indian was often
considered to be the medical dump-yard where drugs which were banned or
bannable in other countries were promoted by multinational drug firms
through their outlets here. The scenario has now changed to a large
extent. But the tragedy remains - unlicenced drugs are being manufactured,
promoted and dispensed unashamedly! Perhaps, as Klein suggested, there is
a nexus between the markets, politicians and the NHS (6).
A more gruesome view of this report would be obtained is we were to
combine the statistics of the geriatric and the pediatric prescriptions:
it might be horrific to even imagine that practitioners of modern
scientific medicine might be involved in a large-scale calculated and pre-
meditated carnage, a holocaust which is being fully endorsed by the
depraved mind that wishes to satisfy itself with monetary gains and fully
subsidised by a health care system that is more concerned about systems
than about health care.
But all is not lost. With the startling statistics being made public
it is hoped that common sense and uncompromising policy-makers will
prevail. As Lord Mountbatten said at Strasbourg in May, 1979, "it is not
science fiction, it is a matter of fact. The world now stands on the brink
of the final abyss. Let us all resolve to take all possible practical
steps to ensure that we do not, through our own folly, go over the edge".
Mankind is on the brink of its own annihilation. Only God above can save
1. Conroy S, et al. Survey of unlicenced and off-label drug use in
pediatric wards in European countries. BMJ 2000; 320: 79-82
2. Church D. Newborns are prescribed drugs only tested in animals.
eBMJ, March 03, 1999, in response to: White C: Newborns prescribed drugs
only tested in animals. BMJ 1999; 318: 554
3. Oommen T. Mini guinea-pigs, eBMJ, March 03, 1999, in response to:
White C. Newborns prescribed drugs only tested in adults. BMJ 1999; 318:
4. Abraham J, et al. Rethinking transparency and accountability in
the UK. BMJ 1998; 318: 46-47
5. "The Licence to rip off the public". In, Amazing medicines the
drug companies don't want you to discover. University Medical Publishers,
Tempe, Arizona, 1993
6. Klein R. Markets, politicians and the NHS. BMJ 1999; 319: 1383-84
Competing interests: No competing interests