By Lynn Gold, PhD, vice-president of CMC services and Kenneth V. Phelps, president and CEO, both with Camargo Pharmaceutical Services, and Peter R. Joiner, CEO of Madeira Therapeutics.Overview of pediatric drugs. There is a profound need for pharmaceutical products that have been tested and approved safe and effective for use by children. From 1973–1997, the percentage of approved drugs that contained no labeling information for children remained fairly stable at 71–81% (1). Of the 33 new molecular entities approved in 1997, 27 had potential for pediatric use, but only nine contained any pediatric labeling information (2). Two-thirds of the drugs that currently are prescribed to children have not been studied and labeled for pediatric use (3).
With so few medicines containing adequate labeling information to guide their use, off-label use of medicines has become, unfortunately, a necessary and accepted part of pediatric medical practice (4). Off-label prescribing includes the use of drugs for unapproved indications, in a different age group, or with a different dosage, frequency, or route of administration. Off-label prescribing also includes the administration of extemporaneous formulations (e.g., oral suspensions made from adult tablets) with untested bioavailability and stability.
Legislative activity. Recognizing the need to have a determination of pediatric applicability and adequate labeling instructions for children, Congress included incentives for conducting needed studies in the Food and Drug Administration Modernization Act of 1997 (FDAMA). Due to slow progress, Congress added additional incentives in the Best Pharmaceuticals for Children Act (BPCA) in January 2002. In essence, this act provided the innovator a six-month extension of exclusivity if adequate pediatric studies were performed and allowed FDA to formally request that such studies be performed. In 2003, Congress passed the Pediatric Research Equity Act (PREA), which provided FDA with the authority to use bridging data from adult studies in approving pediatric medicines. These three acts, together with continuing enabling legislation through the Prescription Drug User Fee Act (PDUFA) renewals, encourage the development of pediatric drugs. The Food and Drug Administration Amendments Act (FDAAA) of 2007 extended and amended BPCA and PREA.
Until these acts (BPCA, PREA, and FDAAA) were passed, the approach in pediatric drugs was first to develop a drug for adults and then adjust the dose to suit children. The thinking was if a drug were safe enough for adults, it would be safe enough for children. The three acts (BPCA, PREA, and FDAAA) make the development of an "age-appropriate formulation" a legal requirement if the drug under development is appropriate for children.
Penicillamine is a good example of a less-than-optimum formulation for pediatric use. Penicillamine tablets are too large for children and have to be crushed to administer them to children, leading to uncertainty of the actual dose delivered. Dosing of penicillamine is also required for extended time periods. The crushed tablet is foul smelling, and the taste and odor are unpalatable (5).
Pediatric drug development . The goal for any new drug product is a safe, effective dosage form that facilitates maximum compliance through the course of treatment. Formulations for pediatrics usually must cover a broad age range. Drugs that must be dosed based on body weight or endocrine status (e.g., puberty) require either solid doses that are scored or different doses. Children under 12 years of age often have difficulty swallowing capsules and/or chewing tablets. A liquid formulation, therefore, is often chosen for pediatric administration. Liquid formulations facilitate dose titration and are easily administered. Liquid formulations, however, have certain constraints. Taste is an important issue for pediatric formulations, and the more frequent the dosing, the more critical this issue can be. Stability of the liquid in multiple-dose bottles must be maintained, often by using preservatives. Taste-masking agents, preservatives, and solubilizing excipients must have an acceptable safety profile in pediatrics.
Special considerations must be taken to reformulate currently approved adult drugs to be a pediatric friendly product. As an example, Madeira Therapeutics is developing a pediatric formulation of a marketed statin for a population with an inherited cholesterol gene that often leads to early heart disease (6). This product requires flexibility in dosing as the amount of drug required can be variable. To meet the requirements of a flexible dose level and integrate the characteristics of the active pharmaceutical ingredient (API), an oral syrup formulation was identified as the target formulation. As expected, many of the formulation steps are the same as with any drug-development program. The physical and chemical properties, such as solubility, salt form, stability, and the taste of the API must be known or established.
The major difference for a pediatric formulation compared with an adult formulation is an added layer of investigation when choosing excipients. The traditional sources, the generally regarded as safe (GRAS) list (i.e., 21 CFR Parts 182, 184, and 186) and FDA's Inactive Ingredients Guide are based on the safety obtained primarily in adult subjects. Investigation into the safety data in the pediatric population available for the potential excipients to be used should be performed. The specific excipients chosen must be determined based on the drug under development as well as the pediatric product profile under consideration.