Licensing of Medicines for Children in the USA. © Priory Lodge Education Ltd

Milap C. Nahata. Professor of Pharmacy and Pediatrics.
Colleges of Pharmacy and Medicine. The Ohio State University, USA.

Introduction

Betrween 29 June 1979 and 11 January 1995, the licensing of medicines for children generally required the completion of adequate and well-controlled studies in the paediatric population. Specific statements were required under the "Indications and Usage" and "Dosage and Administration" sections of labelling. Unfortunately the vast majority of drugs currently approved by the US Food and Drug Administation (FDA) for adults have not been approved for children. The most common statement in the labelling is "Safety and effectiveness in children have not been established".

Nearly 80% of the new molecular entities approved during 1984-89 in the US had no labelling for use in infants and children¹. During 1991-95, only 19% (25 of 130) of the new molecular entities contained paediatric use information in the labelling at the time of approval for adults (Table 1)².

Children suffer from many acute and chrronic illnesses, and clinincal use of the best available medicin cannot wait for its approval by the US FDA. Even commonly used drugs in paediatric practice; eg: salbutamol, captopril, cisapride, enalapril, dopamine, lorazepam, midazolam, morphine, ranitidine and warfarin do not contain information for use in paediatric patients. Use of medicines without knowledge about their optimal dosage guidelines may lead to toxicity or inadequate efficacy.

Table 1 Paediatric studies in new molecular entities approved by the US FDA ²
Status of paediatric studies**
Year	Number of drugs approved*	Done	Continuing	Not needed
1991	30	9	7	14
1992	25	4	10	11
1993	25	4	10	11
1994	22	4	11	7
1995	28	4	10	14
TOTAL	130	25	48	57

New Regulations

Since 12 January 1995, the US FDA has implemented new regulations for the licensing of medicines for paediatric patients³. The new rule is expected to encourage sponsors (ie: industry) to seek drug approval for children. These regulations will allow labelling of drugs for paediatric use based on adequate and well-controlled studies in adults and supportingstudies dealing with pharmacokinetics, pharmacodynamics and safety in paediatric patients., "provided that the course of the disease and the drug effects are sufficiently similar in the paediatric and adult populations". This wiull reduce the need for conducting comparative efficacy trials, and thus the time and cost required for drug approval. It is not certain, however, how the US FDA and the sponsor would evaluate the adult and paediatric populations. By 13 December 1996, each sponsor would be required to submit and./or develop information about paediatric use for their product if the medicine is widely used, represents a safety hazard or is therapeutically important in paediatric patients. It is un,clear, however, what criteia would establish wide usage, a safety hazard or therapeutic importance. In addition,hoe would the disagreement between th esponsor and the US FDA be addressed?

Although the new regulations may encourage the licensing of medicines for children, there are numerous impediments for making substantial progress in the near future. The approval process is very expensive. It may cost over $350 million to receive a US FDA approval and licensing of one medicine only for adults. A natural question arises (especially in these days of cost constraints) : why would one invest additional resources to conduct paediatric studies, realising that the market size is small in most cases. Despite the lack of US FDA approval, an important medicine will be prescribed for chil;dren, although the sponsor will not be laible for any legal claim for injury caused by the drug. An attractive incentive would be to provide tax benefits or patent extenstiom for the medicines which are approved for both adults and children.

Conclusions

The new US FDA regulations are encouraging but their enforcements would be difficult. The US FDA must work with industry, health care systems, professional assicaitions and the researchers to focus and set priorities for additional studies and subsequent licensing.

Paediatric research is challenging. Informed consents, placebo controls, justification for the use of volunteers, number of blood samples and amount of blood and funding needed for studies are among the difficulties which must be addressed in designing and conducting research in infants and children. Both government and private funding agencies, including the pharmaceutical industry must make a commitment to increase research support for studies in paediatric patients. This will indeed be the best investments for our future.

References

1. Kauffman RE. Remarks to Council on Competitiveness. Washington DC: American Academy of Pediatrics. 8 October 1991
2. Roberts R. Assessing safety of investigational drugs. Presentation at the Drug Information Association Meeting. Gaithersburg, Maryland, US. 15 April 1996
3. US Dept. of Health and Human Services, Food and Drug Administration, 21 CFR part 201 (Docket No. 92N-0165) Specific Requirements on the Content and Format of Labelling for Human Prescription Drugs: Revision of "Pediatric Use" Subsection in the Labelling. Federal Register 1994; 59 (No. 238): 64240-50