Though medication non-adherence has been discussed with growing interest for several decades, the topic remains an important focus of the pharmaceutical industry. In 2012, it is estimated that 8% of the total healthcare spending in the United States – more than $200 billion – was spent on improper or unnecessary use of medications.1 Though many different patient subsets continue to be affected by poor adherence, children present a unique challenge.
Children remain a distinct challenge because of their fluctuating development, as well as the variable number of caregivers and treatment locations that may be involved.2 In the United States alone, more than 200,000 out-of-hospital medication errors per year have been reported to the National Poison Data System (NPDS), the American Association of Poison Control Centers’ (AAPCC) proprietary database since 2003. Approximately 30% of those reports have involved children 6 years of age or younger.3
Improving medication adherence requires the active participation of all involved parties. The pharmaceutical industry is well positioned to enact change at this level by focusing on formulations, simplified dosing regimens and packaging improvements to enhance caregiver convenience and understanding.
Significant Dosing Challenges
Children and adolescents are often physically limited in their ability to ingest larger solid dose medications, which has led pharmaceutical manufacturers to consider alternate forms of administration; different or limited taste preferences also pose a challenge.2 Syrups and suspensions offer greater flexibility, as a dose can be adjusted to account for weight or flavored for taste. However, both are also difficult to measure, easy to spill if a child is resistant, and offer little in the way of tracking from one dose to the next. Ensuring that accurate dosing cups, spoons, oral syringes, or droppers are provided can help to improve accuracy and eliminate the use of household measuring devices (e.g. teaspoons).
Of the medication errors documented in the NPDS from 2002-2012, over 80% involved liquid medications.3 Additionally, 20% of all dosing errors were categorized as the result of an accidental double dose.3 Offering multiple dosing options – tablets/capsules, chewables, granules and/or injectables, along with suspensions and syrups, can help to minimize many of the issues associated with liquid dosing; but dose size and accuracy are only part of the challenge.
The physiological differences in children may make certain excipients unsuitable for pediatric consumption, presenting an entirely different set of challenges for pharmaceutical and biopharmaceutical manufacturers.2,4 A child’s size changes dramatically – an increase of up to 1900% during growth; the dose increase that should correspond with this may approach 100-fold.4 This leads to significant pharmacokinetic differences in young children, including drug metabolism, transport expression, renal clearance, gastrointestinal permeability, and drug absorption (based on surface area).4 With many of these differences constantly in flux, it can be difficult to ensure that a given medication will meet toxicity and excipient requirements. Thoroughly understanding pharmacokinetic impact on pediatric patients is important, but pediatric drug testing adds to development costs and has only recently started to increase.
The pharmaceutical industry has historically viewed the pediatric market segment as only offering small financial benefits.5 To further complicate the issue, studies conducted on children present unique challenges related to both informed consent – with children 7 years of age and older being allowed to independently assent or dissent – and challenges with even the most routine procedures, including blood draws and urine samples.5 However, FDA regulations are working to increase pediatric studies to benefit patients and pharmaceutical companies alike. Though these studies place added responsibility on manufacturers, they help clinicians make more informed decisions, offering caregivers additional peace of mind.
In particular, the voluntary Best Pharmaceuticals for Children Act (BPCA) has been significant, potentially offering six months of additional marketing exclusivity on drugs in pediatric studies, as well as all additional forms / formulations containing the same active-ingredient moiety.5 Both pharmaceutical companies and the FDA can initiate a pediatric trial under BPCA, but the FDA ultimately determines the potential pediatric health benefits of the drug. However, after voluntary measures in the 1990s failed to produce results, the FDA became aware of the need for mandatory research in addition to voluntary programs and, as a result, the Pediatric Research Equity Act (PREA) was signed into law in 2003. PREA aims to protect pediatric patients by allowing the FDA to require pediatric studies on both pharmaceuticals and biopharmaceuticals if it believes the substance will likely be used in a pediatric setting or could provide benefits in such a setting.5
Patient-Friendly Packaging and Labeling
Following trials, one of the most significant ways pharmaceutical manufactures can help combat non-adherence is through improvements to both primary and secondary packaging. According to the 2016 Nice Insight CDMO Outsourcing Survey, many manufacturers are already turning to manufacturing partners for solutions in this area; compliance and adherence solutions were outsourced by 42% of respondents, while 39% outsourced child resistant and compliance prompting packaging.6