GAITHERSBURG, MD—There is an admonition that pediatricians can frequently be heard to say to other physicians: “Children are not just small adults.” This is no truer than when dealing with prescription drugs. Children are not immune to serious illness and disease—the kinds of disease that require powerful pharmaceuticals. But many times no pediatric formula exists and parents and physicians are left to play a guessing game: dividing up the adult dosage according to the size and age of the child; finding a way to make the medication palatable; and getting the child to keep the medication down. And when a drug company begins studies on a pediatric version of a drug, it is usually after the adult version has come to market, leaving pediatric patients to wait longer than their adult counterparts.
To open the discussion on pediatric drug formulas and nail down exactly what the issues are in developing such formulas, the FDA’s Pediatric Oncology Subcommittee held a hearing here recently, inviting researchers and industry representatives to speak about what should be done.
Not Just Small Adults
Creating a pediatric formula of a drug is not as simple as scaling the dosage down proportionately, explained Anne Zajicek, MD, PharmD, acting branch chief of the Obstetric and Pediatric Pharmacology Branch within the National Institute of Child Health and Human Development. There is actually a long laundry list of factors to consider in creating a pediatric dosage. The formula needs to be easy to swallow; palatable; safe; have adequate bioavailability; stable in high heat and humidity; and commercially available.
Most of those considerations are scientific or technical, Zajicek noted. Within NICHD, a number of working groups made up of representatives from FDA, NIH, academia, and pharmaceutical companies have been prioritizing what issues need to be addressed first. One of the most important considerations—one championed by the WHO—is the need for drugs that do not require considerable infrastructure to be kept viable.
“While it would be nice to have a liquid formulation that you can stick in the refrigerator, this is not necessarily the be-all, end-all for the rest of the world,” Zajicek explained. Such considerations might require investigators to start with the formulation platform first, and work through the rest of the problems thereafter. “Once you’ve got a molecular structure you can figure out what part of that structure would lead to solubility permeability, stability, and taste problems,” she said. Subsequently researchers can address possible solutions.
And these concerns do not just apply to pharmaceuticals for children. Dosage and swallowing concerns extend to other patients as well. “What’s going on here is not news,” Zajicek declared. “People have been talking about formulation problems for 30 or 40 years. It’s not just a pediatric problem, it’s a swallowing problem. [There are] similar problems with elderly patients.”
However, NIH and other research institutions can only go so far, she said. “There needs to be collaboration with the pharmaceutical industry, because at the end of the day, it will be pharma that produces these products. At the end of the day, there needs to be some plan for successful commercialization, and that really seems to be a problem.”
While most of Zajicek’s concerns are of a scientific nature, the big problem is one of commercial viability. Drugs need to be sold in large quantities for a company to see much of a profit. But there would be a limited target audience for such drugs. And because many such drugs will likely be in a liquid formula, it would be difficult to keep them on shelves for an extended period of time before they expire.
Debra Pereira, RPh, who presented the industry perspective to the subcommittee, agreed with Zajicek that pediatric formulas continued to be a challenge for companies, and said that one of the largest industry considerations was to understand the need of local markets in the long-term, and the needs of researchers in the short term.
“We aim to develop products for global markets, but need to consider local market preferences and needs,” Pereira explained. “Is clean water freely available? If we’re creating a liquid that requires the addition of water, we need to know that the market it’s intended for has access to water.”
In addition to the obvious size/weight ratio considerations, as well as the ability of each age group to take particular dosage forms—infants could not be given pills, for example—there is also the challenge of taste masking, which differs from region to region. “Taste preferences in children are different than in adults. And there are differences in taste preferences in different parts of the world,” Pereira explained.
While common practice has been to wait for a drug to be on the market before initiating a pediatric formulation, there has been a trend in recent years to initiate pediatric studies while the adult formulation is still in development, Pereira said. To do this, researchers need ad hoc pediatric formulas that will enable them to conduct their studies.
For example, FDA requested that Pfizer create a simple liquid as a pediatric formula that existed for adults in capsule form. The enabling formulation used in the clinical study involved opening the adult capsule and sprinkling a portion of its contents onto applesauce or yogurt.
In addition, while the number of considerations researchers need to examine is already numerous, there are always additional roadblocks that arise. In this case, the drug being studied was not stable in solution, strongly colored, and stained anything it touched. “No parent would like to have their child spit out their medicine, and stain everything it touches,” Pereira noted. And it is likely that a lot of spitting would occur, since previous studies have shown that the drug has a bitter, metallic taste. “We’re looking at other options, including film-coated minitabs and film-coated granules that can be sprinkled on food,” Pereira said.
The lessons Pfizer has learned along the way, she said, are to have your pediatric strategy as part of your development plan; consider the overall risk/benefit; seek flexibility and compromise; and apply good scientific principles.
Embracing the Ad Hoc
For researchers, the ad hoc methods of administration remain a necessary evil. However, researchers “can’t let the best be the enemy of the good,” explained Malcolm Smith, MD, PhD, associate pediatrics chief at the National Cancer Institute.
The alternative to using an ad hoc delivery method is to limit eligibility in studies to children old enough to swallow tablets. However, in cancer research, that can be a serious disadvantage, because there are some cancers where the patients can be five years of age or younger, he noted.
“This leaves us with the option of allowing the use of ad hoc formulation for children not able to swallow tablets,” Smith explained.
It’s a temporizing measure, he admitted. But pediatric clinical trials nearly always begin prior to the development of pediatric formulation. “However, once an agent is known to be effective in a pediatric population, the expectation is that there should be a true pediatric formulation that can be administered at home,” Smith said.
But the ad hoc methods of administration are not limited to clinical trials. Caregivers and patients frequently have to become familiar with those methods when dealing with adult prescriptions being given to a pediatric patient, explained Ravie Kem, PharmD, senior NCI research pharmacist.
There is the common practice of opening capsules and adding contents to food or juice. Temozolomide is frequently given mixed with applesauce or juice. There is also the method of dissolving capsules and tablets in a solution—dissolving dasatinib tablets in lemonade, for example. “Pharmacists can also compound the agents,” Kem said.
However, there are a number of problems with ad hoc dosing. Imprecise scoring of tablets—especially with tablets that do not come with a score line—can lead to unequal dosing. When given in a liquid, the active ingredients can adhere to the wall of the glass, depriving patients of a full dose. Also, the pharmacokinetics of the ad hoc formulation may differ from that of an intact tablet or capsule.
“We require short-term stability data on ad hoc formulations,” Kem declared. There is also a limited amount of preparation and handling information for patients and caregivers, something that NCI has been able to address. “We came up with a patient/caregiver leaflet. It answers the dose uniformity issue. It lists the exact equipment that is needed, and addresses the appropriate dosage and safety of how to prepare drugs. It also addresses precautions and safety issues and how to take the medication.”