Off label prescribing in childrenBMJ 2002; 324 doi: https://doi.org/10.1136/bmj.324.7349.1290 (Published 01 June 2002) Cite this as: BMJ 2002;324:1290
A view from the United States
- William Banner Jr, medical director
Three papers in this issue, one from Germany and two from the Netherlands, highlight the problem of off label prescribing in children. 1 2 At first reading these manuscripts were a confusing “tower of Babel” for a reader from the United States, but the problem being discussed is all too familiar. In the United States the Food and Drug Administration has responsibility for the licensing process for all drugs. The term “approved” is used for a drug that has been deemed to have safety and efficacy for a particular disease process. Until recently, the drug need only to have been studied in the adult male population. Yet once a drug is approved it may be prescribed by a physician for any population or disease state desired. The term “off label” has been applied to describe the use of these drugs in either populations or disease states not listed as indicated in the package insert. While attempts have been made to use the term off label to imply recklessness in the medical malpractice arena, the American Academy of Pediatrics has also pointed out that failure to use off label drugs where appropriate under the standard of care may also constitute malpractice.4 The common use of the term “unlicensed” in the United States is linked to rare pharmaceuticals not approved for any use. Extemporaneously prepared liquid preparations of approved drugs from tablets are so common that we hardly recognise that they are not adequately studied as to stability and absorption characteristics and are unlicensed.
To its credit the Food and Drug Administration in the United States has tried to deal with this problem. In 1994 regulations were established “requiring” the manufacturer to determine whether data existed to permit modifying the labelling of an approved drug to include children. For example, dopamine is widely used as an inpatient agent for hypotension in children. But despite its extensive use it is currently not labelled for use in children. By taking the existing body of published literature the Food and Drug Administration is legally allowed to consider a manufacturer's submission and modify the label to include children. As the drug is currently available as a generic preparation there is little or no incentive for any manufacturer to pursue any additional requirements of Food and Drug Administration that might lead to such labelling. Thus, though this process exists it has rarely been used to alter labelling.
Recognising this failure and with the encouragement of the American Academy of Pediatrics, the FDA Modernization Act of 1997 (FDAMA) provided that manufacturers of drugs under patent could seek a six month patent extension for performing studies leading to labelling in children. Although six months may seem short, the financial windfall for many of these drugs is a strong incentive. Some manufacturers may choose to wait until patents are about to expire to initiate these studies. Concerns were raised over this approach when omeprazole (Prilosec, Losec) was studied in children after its success was well established in adults and received a patent extension giving them a potential “two billion dollar sales windfall.”5 This gives them more opportunity to pick drugs that are sure to be profitable to study in children. Unfortunately, drugs with limited potential for financial gain will not be studied even though they may have a potential benefit for children.
To level the playing field further, the Food and Drug Administration rules went into effect in 1999 permitting the agency to mandate paediatric studies if the product is likely to be used in a substantial number of children.5 They may also decide that a meaningful therapeutic benefit to children exists and mandate studies.6 As these regulations come into effect, President Bush is considering reversing these requirements under pressure from the pharmaceutical industry. We can only hope that the best interests of children are put first in his consideration.
The outcome of these changes at the Food and Drug Administration thus far is slightly encouraging. Several new drugs have included studies in children leading to labelling. On the other hand, some disappointing decisions have hurt the process. For example, recombinant activated protein C was approved for adults and had ample safety and pharmacokinetic data in children but was rejected for paediatric labelling on the presumption that mechanisms of severe sepsis were sufficiently different in children that efficacy could not be extrapolated from the data in adults. As a paediatrician, I find that an extreme view that may inhibit the use of a potentially beneficial therapy for children. Furthermore, there is increasing pressure by healthcare insurance providers to limit reimbursement only to labelled indications and populations. High technology drugs such as this come at a high price and limitations on payment will not help children.
Off label use of drugs is expanding for the paediatric population rather than decreasing.7 The use of psychotropic drugs has literally exploded in behavioural and psychiatric practices in the United States. In some cases the off label use may be based on both age and diagnosis such as in attention deficit in children. Unfortunately it will take a concerted effort and a great deal of funding to correct this problem. For new drugs reaching the market we can hope that the Food and Drug Administration will continue to receive the authority to mandate consideration of children in addition to the carrot of patent extension to promote appropriate labelling for children and other disenfranchised populations.
The FDA has announced that it will suspend the enforcement of the paediatric rule for two years while it examines its necessity. (Pediatric News 2002;36(4):60.)