Pediatric clinical trials are unique in that not only do you need to consider the patient, but also the caregiver of the preparation, dosing and administration of investigational products.
When planning clinical supplies, there are also other factors relating to neonates, infants, children, and adolescents that do not normally apply to adult populations.
This article will present factors to consider when designing supplies for caregivers, having critical discussions and communications with the physicians responsible for protocol development, and ensuring that solutions are considered for situations likely to occur in the trial.
The scope of this article will not involve choice of formulation, which is a topic unto its own. This article will assume the formulation is chosen, and the IMP kit box packaging and labeling needs to be designed.
The Pediatric Clinical Environment
When designing Investigational Medicinal Products (IMPs) for pediatric trials, it is important to understand the clinical environment in which your supplies will be stored, prepared and used.
The ICH E11 (2000) guideline on Clinical Investigation of Medicinal Products in the Pediatric Population (CPMP/ICH/2711/99) is an excellent first step in understanding the pediatric clinical environment. In the guideline, the following age groups are defined in relation to developmental stages:
- Preterm newborn infants
- Term newborn infants 0-27 days (also called Neonates)
- Infants and toddlers (1 month to 23 months)
- Children (2-11 years)
- The age group 2-11 years could be further subdivided in terms of the child’s ability to accept and use different dosage forms, e.g. into pre-school children (2-5 years) and school children (6-11 years), having some consequences on compliance
- Adolescents (12-16 or 18 years)
It is important that the clinical supplies manager be involved in study synopsis and protocol development. The patient is not the only focus of the dosing instructions. The possibility of a home caregiver must also be accommodated, so your IMPs must contain unambiguous, well-illustrated instructions for dose preparation and administration.
The one common factor across formulations and presentations is that the dose may need to be adjusted according to the changing body weight of the patient, especially if they are in a stage of rapid growth and changing size.
I was involved in designing the IMPs for a trial, in which the drug product was a powder in a vial, with a bottle of solvent (large enough to be the mixing bottle) that needed to be mixed to make an oral solution (which could also be dosed via a feeding tube). There were enough vials and bottles in a kit box for eight cycles of 14 weeks.
Also provided in kits were two sizes of oral dosing syringes and a cap for the bottles that facilitated the withdrawing of the solution. It was pre- and post-operative treatment, with a daily dose, and parents/caregivers would have to administer a once-daily dose if and when the patient went home. The IMP kit box, about the size of a box of men’s shoes, had the instructions for dose preparation and administration (with graphics) printed on the top.
In the trial, the patient population consisted of both neonates born with a condition that needed surgery within days after birth, and/or children undergoing the follow-up procedure done at approximately four years old. Considering the stressful situation of the parents/caregivers, the objective should be to make the instructions for dose preparation and administration of the IMPs as clear and distress-free as possible.
In our trial, parents/caregivers were provided with:
- A tabletop scale, to weigh infants.
- A chart that cross-referenced the weight of the infant to the quantity of solution to be administered
- A DVD with instructions on weighing the infant, preparing, and administering the dose. A TV production crew was hired and a professional actress performed the weighing of the neonate/infant, the recording of the weight, the mixing and measuring of the powder and solution, and the dosing and administration of the oral solution. The video was shot in a kitchen, most likely the room that a parent/caregiver will most likely prepare the dose, and is a relatable, reassuring setting
- An instruction card illustrated with screenshots of the video, so that they could correlate the step being described with the video
Dosing Infants is Different!
Babies grow. In our trial, infants were weighed every 14 days, and the dose was adjusted. On the label of the mixing bottle was a space left blank for them to write the weight, the dose (in mL) to be given, and the date in which they mixed the powder and solution. The label had a statement of “Do not use more than 14 days after mixing.”
Infants often regurgitate some of what they ingest after feeding. After dosing an oral solution, it is necessary to decide (with the lead Clinical Pediatrician) what the allowable time before regurgitation that a child is considered “dosed.” In our trial it was 20 minutes. That is, if the child regurgitated within 20 minutes of dosing, they should be re-dosed. If 20 minutes have elapsed, the child is considered dosed.
Injectable formulations in a vial, as well as pre-filled syringes and pens should be relatively simple and straightforward, unless there is a lyophilizate to be reconstituted. In that case it is not much different from the oral solution scenario described above, except extra syringes and needles should be provided. The dosing syringe should not be the same as the mixing syringe.
Solid Dosage Formulations
Flexibility should be a main consideration here if multiple strengths of capsules/tablets are available. Again, the kit will have to be designed so that the achievement of the proper dose is clear. Color coding strengths of blisters (matching the dosing chart which is also-color coded) can help a parent/caregiver do this.
Before any project level commitment to taste-masking syrups, full due diligence should be performed. If a pediatric trial will demand flavored syrups for taste-masking, flavored syrups are not universal, so it is NOT recommended to source these centrally. Registration of these products outside of their marketed countries is a challenge.
For instance, there are U.S. manufactured syrups that are not allowed to be imported into the EU. Period of use needs to be defined once a syrup bottle is opened. It is better to identify what syrups are available, have the CMC/Product Development perform any compatibility/taste-masking/indistinguishability/period-of-use tests as early as possible, and let the sites source the syrups from an approved list.
Putting yourself in the mindset of a parent/caregiver is a great start to designing value-added IMPs to pediatric clinical trials.
Understanding your customers is paramount. Since pediatric trials most likely happen in the late stage of your project, this is an important opportunity to put the company’s best foot forward, as your IMPs are the physical representation of the customer-focus of your company. Given the financial benefits of an additional six months of market exclusivity in the U.S., the return on investment for what would normally be “extras” or “upgrades” are well justified.