Why were we abandoned? Orphan drugs in paediatric pain

Prescribing medications for children requires considerable creativity. When working in the field of paediatric pain, creativity and adaptability are even more crucial because very few medications are either created specifically or labelled for use in children, especially for the treatment of pain. Orphan drugs are usually defined as drugs that have been abandoned, or ‘orphaned’, by major drug companies. However, this definition can be extended to medications that could be useful to a minority of the population (ie, orphan group), such as children, physically or cognitively disabled patients, or the elderly, if the medications were available and approved for those groups. The practice of paediatrics requires frequent ‘off-label’ use of medication (ie, outside of the terms of the product approval). The younger the patients are, the more frequently this happens, with 80% to 97% of infants in neonatal wards receiving at least one off-label or unlicensed drug (1). As if those issues were not enough, children face another challenge when it comes to pain medication: few companies offer ‘child-friendly’ paediatric formulations, such as suspensions, small dosage tablets or capsules, that can easily be opened. This last factor results in an even greater reduction in the number of medications that are practical or approved to treat pain in children. Why are licensed and labelled medications to treat paediatric acute and chronic pain so rare? Why are data from clinical trials lacking? Although we know that treating paediatric pain has an immediate positive effect and can prevent long-term consequences (2), the financial market for pain medication for children and youth remains limited compared with the adult one. This limited market is nevertheless substantial, especially with increased availability and use of pain medication for children. Until recently, there was little incentive for major pharmaceutical companies to produce paediatric dosing guidelines and indications. Clinical analgesic trials in children still represent ethical, logistical, financial and legal challenges (3) that no company wishes to undertake without the potential for financial gain or legal requirement. Legislation on this subject has evolved over the past two decades (4). In the United States, paediatric labelling has been required since 1994. Starting in November 1997, the Food and Drug Administration Modernization Act (FDAMA) offered six months of marketing exclusivity to manufacturers for voluntarily conducting paediatric studies for certain drugs identified as potentially beneficial for children by the United States Secretary of Health and Human Services. This successful program provided important information on medications used for children, including ibuprofen, gabapentin and sevoflurane (5), and has been extended until October 2007 via the Best Pharmaceuticals for Children Act (BPCA) (6). This 2002 Act also added neonates as a specific age group and extended the FDAMA to off-patent drugs. Finally, in 2003, the Pediatric Research Equity Act (PREA) (7) gave power to the FDA to request paediatric data for all applications for drugs and biologicals, even for off-label uses of a product, which is a common situation in paediatric pain management. The major difference between the PREA and the BPCA is that PREA excludes orphan drug products (for affected populations of less than 200,000) and is limited to medications under development. In Europe, the situation is a little different because there is still no legislation on paediatric studies. A draft regulation was presented in 2004 with an estimated date for adoption as a law in 2006 (8). This law would require paediatric data for all medications with an active patent, whether in development or already approved, and would include orphan drugs. Off-patent drugs could be included on a voluntary basis. A European paediatric clinical trial register has also been created and is accessible through the Internet (9). There is still no specific Canadian law that requires paediatric data for new drug approval, although a proposal was published in June 2006. This new legislation would be similar to the BPCA, offering a six-month patent extension to companies who submit description and results of clinical trials in relevant paediatric populations within the first five years of the patent (10). When we look more closely at the medications most often used to treat paediatric pain in Canada, it is unfortunate to see how few of them are approved for use in children, or even contain good data from clinical studies. In fact, many of the products we commonly use for chronic pain management or as adjuvants for acute pain (eg, gabapentin or amitriptyline) are not even labelled for pain treatment in adults. When they are labelled for the treatment of pain (eg, celecoxib, pregabalin or diclofenac), the indication is only for adults (11). In 2007, children and youth are still therapeutic orphans for pain medication. The FDAMA/BPCA legislation proved that a combination of law and financial incentive can motivate pharmaceutical companies to provide paediatric data. This was a first step toward equity between adults and children. However, stronger regulations, with mandatory rather than optional requirements, are necessary to ensure the safe use of existing and under-development analgesics for children. In addition, internationally harmonized legislation would not only protect children of countries who are not under the legislation of the FDA or the European Medicines Evaluation Agency, but would also facilitate collaboration in international multicentre trials, the latter being necessary to achieve an adequate number of patients for study. As clinicians and researchers, we can help by informing politicians and the public of the need for legislation, by identifying those medications that need more investigation and by participating in pharmacological studies and clinical trials.

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