Pediatric Centric Drug Design

Historically, only a small fraction of all marketed drugs have had clinical trials performed in pediatric patients and a majority of marketed drugs were not labeled for use in pediatric patients. Accordingly, many drugs were administered to children in an off-label fashion without adequate understanding of appropriate dose, safety, or efficacy. The first initiative took place in 1994 when the Pediatric Labeling Rule was issued, requiring drug manufacturers to survey existing data and to determine whether those data are sufficient to support additional pediatric use information in the drug's labeling. Under the Pediatric Labeling Rule, if a manufacturer determines that existing data permit modification of the label's pediatric use information, the manufacturer must submit a supplemental new drug application (NDA) to FDA seeking approval of the label change. The Pediatric Labeling Rule allowed the labeling of drugs for pediatric use based on extrapolation of efficacy in the adult population and additional pharmacokinetics, pharmacodynamics, and safety studies in pediatric patients , but only if the course of the disease and the response to the drug were known to be similar in children compared to adults. Although this rule was designed to improve pediatric labeling, it resulted in only a small number of well-designed and well-conducted studies. Since the approach under the Pediatric Labeling Rule was entirely voluntary, it did not substantially increase the number of products with adequate pediatric labeling.

Over the past decade, regulatory legislations for drug development in pediatric patients were passed worldwide, dramatically increasing the number of drugs tested in and labeled for children. Both, the Food and Drug Administration (FDA) in the United States(U.S.), and the European Medicines Agency(EMA) in the European Union (E.U.), established approaches that have been successful in generating important new information about the safety and efficacy of drugs used by children. Transparency and accountability of pediatric drug development has improved and the amount and quality of pediatric information has increased by an elevated number of clinical trials in children in recent years.

The progress has been achieved by combining requirements for pediatric drug development with incentives for the pharmaceutical industry to (at least partly) cover the additional investment for testing drugs in children. There was and still is effort needed to harmonize the regulatory framework for pediatric drug development, but as of today pharmaceutical companies are still facing the problem that the regulatory requirements differ between FDA and EMA and that the development of a new drug in the pediatric population has to be in line with requirements from both authorities. Enforced by the authorities - in particular the EMA - pediatric aspects have to be integrated early in the development process of a new drug and the general strategy has to be part of the overall development program.

Drug development for pediatric patients is accompanied by various challenges for pharmaceutical companies. Clinical studies in children are different from studies in adults and the planning and conduct of a pediatric study needs special attention since the patient population is more vulnerable. Practical and ethical considerations are prominent and the latter receives particular attention in the regulatory guidance documents. As a consequence, the main challenges are to define the first dose in children, to find appropriate sampling strategies, to choose the right methods for data collection and analysis, to generate knowledge about safety, efficacy, pharmacokinetics, and pharmacodynamics of a drug in children, and ultimately to determine the right dose and dosing regimen.

To comply with regulatory requirements and to optimize pediatric drug development - in terms of ethical, operational, and scientific aspects - pharmaceutical companies have to develop new and appropriate strategies for clinical studies in children. Modeling and Simulation (M & S) techniques are beneficial tools for optimization of the design, increasing the knowledge gained from pediatric studies. Since several regulatory guidance documents refer explicitly to M & S methodology, there is a clear regulatory basis and a need for using M & S in pediatric drug development.

Towards a Renaissance of Pediatric Pharmaceutical Development
Successful drug delivery to pediatric patients depends on overcoming basic differences between children and adults. Pharmacokinetic and pharmacodynamic differences can make developing drugs very challenging for young patients. One can think of pediatric medicines as one of the last uncharted frontiers in patient-centric drug development.

Oral dosage forms, the preferred administration route, may not always be palatable or available in doses appropriate for children. Thus, pills and tablets are often manipulated in ways that are not ideal for delivering safe , effective, and consistent doses. Compounding pharmacies can help but their results are not always reproducible. Parents often resort to dividing doses, crushing and dissolving them in liquids, and administering drugs in quantities that have not been adequately tested.

Alternative delivery vehicles are similarly problematic. Rectal dosage forms provide consistent dosing but are not patientfriendly. Younger children in particular have problems with nebulization masks that do not fit their face properly or cause them distress. Achieving reliably metered therapeutic dosages is complicated when small gaps exist between the mask and the patient's face.1

Most issues in pediatric drug development arise from the fact that drugs are traditionally developed for adults and not children. However, many improvements in pediatric drug development have occurred during the last 15 years.

Development-Stage Incentives
Several regulatory changes have resulted in the recent development of close to 600 drugs supported by new pediatric studies. For example, the US has:
  • Best Pharmaceuticals for Children Act(BCPA) - The 2002 law established a program for pediatric drug development, provided mechanisms for studying on- and off-patent drugs in children, and offered an additional 6 months of exclusivity for on-patent pediatric drugs.
  • Pediatric Research Equity Act (PREA) - Passed in 2003, PREA requires sponsors to test new drugs in children under certain circumstances. Testing must occur with the same drug and for the same indication for which the drug was approved in adults.
BCPA and PREA have a sound scientific basis. The occurrence of suicidal thoughts in children taking the antidepressant Paxil was not uncovered until FDA ordered sponsor GSK to conduct pediatric studies. The result was an FDA warning, in 2008, for prescribers to consider the risks of prescribing Paxil to patients younger than 18.

Before BCPA and PREA were enacted, as many as 80 percent of drugs prescribed to children were untested in that patient population. By 2008 between 50 and 60 percent of such medications had been studied at some level in children. Nevertheless, children have been described as the 'orphans' of drug development.2

A bioavailability classification system (BCS) is not yet available for classifying the suitability of biopharmaceuticals for pediatric administration. However, preliminary investigations suggest that such a system may be available within a few years.3

Delivery Hurdles
Many shortcomings of pediatric-administered medicines arise from less-than -perfect dosage forms and delivery mechanisms. Improvements in these areas could be achieved with minimal regulatory risk.

Unpleasant taste is a perennial issue for many drugs administered to children . Clindamycin, an antibiotic for treating Gram positive and anaerobic infections, has a particularly bitter taste and unpleasant smell. Dosing is frequent and of long duration. Moreover the drug is available only as a dilute suspension requiring large administration volumes, which for young patients amplifies its negatives and complicates administration of therapeutic doses. Other antibiotics routinely administered to pediatric patients have similar issues.

Sabril (vigabatrin; Lundbeck LLC), which is prescribed for infantile seizures , is a classic case of a drug that has not been ideally formulated for its intended patient population. Sabril is available as a 500 mg tablet or a 500 mg packet. The tablet is too large for very young children to swallow. Parents must suspend the packet contents in relatively large volumes of water , which introduces issues previously mentioned. It also requires caregivers to perform a multistep process in order to mix and measure the prescribed dose.4

Infant acetaminophen, available in several liquid formulations, comes with no directions for parents. While a dosing syringe is provided, there is no indicated dose for the age-group for which this product is intended.

Other important medications commonly prescribed for children also require liquid compounding. These include Lamotrigine, Topiramate, Tacrolimus, Metronidazole, Lansoprazole, Spironolactone, and many others. As always, compounding carries inherent risks in preparation and administration such as inadequate shaking and errors in calculations and measurements.

Measuring volumes of liquid pediatric medicines is critical for delivery of safe, effective doses.5 Available metering devices include cups, syringes, droppers, and vials, and the ubiquitous teaspoon. Only 12.8% of pediatric oral prescription liquid products come with measuring devices, and pharmacists only occasionally provide them. Even when available, the devices' inherent inconsistencies can result in under-or over-dosing. 6

Improvement on the Way?
Thanks to regulatory and market incentives, more drug developers than ever are tapping into the potentially lucrative and medical need-fulfilling pediatric drug market.

The Michigan Pediatric Safety Collaboration was founded to address the lack of standardization for oral compounded liquid pediatric medicines. The state -wide, FDAfunded pilot program maintains a database of more than 100 recipes for pharmacies to refer to, ensuring consistency in compounded formulations in the state.

Drug developers are doing their part as well. The benzodiazepine Midazolam, for example, was approved as a rectal formulation in 1997 but presented the usual problems. The drug is administered to children who are experiencing seizures. An intranasal form of Midazolam, delivered through an atomization mister, was found to be as effective as the rectal dose and much easier to administer, however a commercially available product is still needed.

For drugs most suitable for administration by tablet or capsule, orally disintegrating tablets have shown benefit. Lansoprazole, prednisolone, and ondansetron are now available in this format, providing an attractive alternative dosage form for these pediatric-relevant products.

Even with dedicated development programs, pediatric drugs present numerous obstacles. Pharmacokinetic and pharmacodynamic studies performed within ideal clinical settings may not reflect real-world results. Additionally, dosage form and delivery platforms require close consideration in children. Industry and regulators recognize these facts, and are working harder than ever to introduce safer, more effective pediatric medicines to address specific patient-centric issues.