The Food, Drug and Cosmetic Act, first passed in 1906, was dramatically altered by the 1962 Kefauver-Harris amendments as a direct result of the thalidomide tragedy. This amendment required that drugs must be both safe and effective before marketing approval could be given. In addition, adequate animal, toxicology and fertility testing had to be concluded prior to the first dose in humans. Substantial additional testing in animals and in humans was required prior to marketing approval. This led to the era of the Science of Clinical Trial Design. Regrettably, the testing of drugs in children did not advance at a similar pace, and most drugs (unless specifically intended for children) were never tested in children by the sponsors of new medicines.
Physicians were thus forced to use most drugs 'offlabel' and extrapolate the child dose on a comparative weight basis from that in adults. This often involved parents splitting or crushing tablets, hiding medication in spoonfuls of honey, or sprinkling a crushed tablet onto a meal. Each time this happened, a little more confidence in and knowledge of the drug was gained, but each child was a 'one-off experiment' and only provided a learning curve for the individual physician. Eventually, academia would publish a series of cases, so giving guidance on dosing and likely toxic effects. Even so, the average pediatrician and family practitioner felt uneasy and legally vulnerable about off-label use.
A few drugs were developed for children in such categories as antibiotics, antihistamines, and antiepileptics. But otherwise, few firms undertook studies to develop full pediatric label instructions or even pediatric formulations. Liquid formulations did exist for some drugs, but mainly for use in the elderly. In 1975, Wilson surveyed the 1973 Physician's Desk Reference for labeling instructions for pediatric patients and pregnant or breast-feeding women. He found that 78% of listed drugs either had no information for pediatric dosing or contained a disclaimer. A subsequent survey by Gilman (1992) showed that this situation had not improved qualitatively and had also risen to 81%. Eventually, the FDA issued the 1994 rule, which sought to strengthen the 1979 guideline on pediatric labeling requirements (Fed Reg 1994).
The Pediatric Use Working Group, chaired by Miriam Pina (1995) (FDA Division of Pulmonary Drugs), examined data that the FDA had acquired on 1994 pediatric prescriptions from IMS. From these they identified the top ten drugs used 'off label' in children: Albuterol, Phenergan, Ampicillin i.m. or i.v., Auralgan otic solution, Lotison, Prozac, Intal, Zoloft, Ritalin (under 6 years old) and alu-pent syrup (under 6). A combined total of over 5 million of these 10 products were prescribed in 1994.
Clearly, firms needed further encouragement to submit additional pediatric data, so in 1997 Congress passed the FDA Modernization Act (FDAMA). This called for firms to submit data on children to support labeling for a new pediatric subsection before the drug could be approved. This applied to drugs that could be projected to provide therapeutic benefit to substantial numbers of children. In exchange, Congress felt that an inducement was required and wrote into the Act provision for an extension of a drug's patent life by 6 months if pediatric studies were done. For a $2 billion drug such as Claritin (Loratidine) 6 months' extra exclusivity is not 'small change'. The FDA was requested to provide guidance and, in December,
1998, it issued the Final Rule Amendments to the Pediatric Subsections to be implemented April
1999, governing the need for pediatric studies, and extending the requirements to biological drugs and already-marketed drugs. The FDA identified drugs for which supplemental data was still needed for pediatric labeling. The FDA has issued an annual list of 'priority drugs' for which additional pediatric information may be 'beneficial'.
FDA chose to interpret the patent life extension as applying to all indications, not just to pediatric use. As might be expected, the generic companies are appealing this interpretation of the pediatric rule.
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