From Mr N. E. Ballantine, MRPharmS
SIR,-Over recent years there has been increasing concern expressed within the medical and pharmaceutical professions, and among the public in general, regarding the fact that few medicines used in secondary and tertiary care paediatrics are licensed for use in children. Studies have been published which indicate that the extent of this problem is very significant, not just in Britain 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 per cent) and nearly half of all prescriptions written were for unlicensed drugs or off-label use (1,036/ 2,262; 46 per cent). Previous studies have shown that these figures significantly increase when high dependency areas are studied.2,3
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 and the Royal College of Paediatrics and Child Health, 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 February 14 this year, Dr David Jackson (medical director of Glaxo Wellcome 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 sickest children in our care. Subsequently, a letter was sent to Dr Jackson co-signed by the chairman of the Paediatric Oncology Pharmacists Group and the secretary of the UK Child Cancer Study Group expressing concern on behalf of the paediatrics community at this decision, which had been taken without any discussions with the professions concerned. A number of points were made to Dr Jackson explaining why it was felt that the discontinuation of these problems would pose significant difficulties to clinicians and pharmacists practising in the areas of organ and bone marrow transplantation and cancer chemo-therapy.
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 Glaxo Wellcome 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 protocols, adopted on a national basis, for the treatment of acute lymphoblastic leukaemia (ALL) in children since the early 1980s. With some 400 children being diagnosed with ALL every year in the UK, Glaxo Wellcome 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 regimen. The difficulty in administering such doses using 2mg tablets are obvious, but there was the added advantage that we could make a suspension from crushed 25mg tablets for those children who could not take tablets. This will now be impossible due to the bulk of the powder containing the same doses from 2mg tablets.
If a company with the resources of Glaxo Wellcome 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 that 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 was intended.
Nigel Ballantine
Specialist Clinical Pharmacist (Haematology, Oncology), Birmingham Children's Hospital NHS Trust
| 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. |
Dr D. A. JACKSON (medical director, Glaxo Wellcome) replies: Thank you for the opportunity to reply to this letter which raises a number of important issues. I would like to take this opportunity to assure Mr Ballantine of Glaxo Wellcome's understanding of the difficulties they may be facing, and our commitment to help overcome any problems to ensure that patients continue to receive treatments which benefit them.
First, on the issue of increasing the number of new medications that are licensed for paediatric indications - Glaxo Wellcome is fully committed to supporting initiatives in this area. Examples of Glaxo Wellcome's commitment to developing new licensed medicines for use in paediatric populations include:
These examples should illustrate the continued commitment that Glaxo Wellcome has to reduce the use of unlicensed and off-label medications in paediatric populations and to increase the availability of licensed medications for paediatric indications.
The decision to withdraw supply of the unlicensed dosages of the medicines mentioned was taken only after considerable research to ensure continued availability of alternatives to the unlicensed medications would still be possible. I would like to stress that licensed formulations of these medicines continue to be available and are not affected by the withdrawal of unlicensed medicines.
After assurances were received on continued availability from alternative suppliers, the decision was made and communicated immediately to all UK institutions using these unlicensed medicines and support was offered to help overcome any difficulties foreseen. Naturally, it is disappointing to hear that this offer was not accepted by all - where institutions have entered into dialogue with Glaxo Wellcome UK about alternative dosing strategies, the outcomes have been positive.
On the issue of Puri-Nethol and Lanvis, prior to discontinuation of the unlicensed dosages, we carried out research to ensure that alternatives were available, and we are satisfied that this is the case. Unfortunately, the data generated from the MRC trials mentioned would not be sufficient to gain a licence for these formulations. These trials, conducted by an academic group, do not require the rigorous processes for conducting studies that registration trials require. The requirements of regulatory authorities today are such that licensing for indications outside currently licensed indications is only possible with evidence provided by a prospective clinical trial programme. At the outset of these studies, it was clearly understood that the data from the MRC study was not appropriate for a licensing application.
Our research into alternatives for 25mg Myleran tablets identified an IV formulation as an alternative to high-dose oral therapy for myeloablation. The IV formulation is approved in the US and is currently undergoing the regulatory approval process in Europe. The IV formulation is available in the UK on a named patient basis, prior to regulatory approval. The 25mg Myleran tablets have never been available in the US and institutions there have developed dosing strategies for myeloablative therapy using 2mg tablets or the IV formulation. As previously stated, we have entered into dialogue with institutions in the UK about alternative dosing strategies and these are now being considered for implementation by those institutions. We continue to believe that there are realistic alternative dosing strategies and that the experience of institutions using these can be shared to help ensure a smooth transition for all institutions to alternative dosing strategies.
As previously stated, we realise that discontinuation requires changes for those institutions using the unlicensed formulations and we remain available to all institutions requiring our assistance. We welcome dialogue with Mr Ballantine to help him overcome the difficulties he is currently facing.
Glaxo Wellcome remains committed to and will continue to support the important initiative of developing licensed medications for the paediatric population.