Pediatric patients are not simply small adults. Children differ from adults in both disease pathophysiology and pharmacokinetics/pharmacodynamics (PK/PD). Yet historically, 80 percent of medicines used in children had little to no data guiding prescribers on proper use. In this blog post, I’ll discuss the challenges of developing drugs for children and explain how quantitative pharmacology strategies can inform pediatric drug development.
Disincentives for pediatric drug development
Pharma has numerous reasons not to develop pediatric drugs. Often, pediatric indications are not particularly profitable, and pediatrics in the U.S. market represents only about seven percent of drug sales. Furthermore, conducting pediatric clinical studies poses both ethical and legal risks, and from a practical perspective tends to be a low priority for product development teams who are focused on gaining regulatory approval for adults.
The regulatory landscape
To address this market failure, global regulatory agencies have introduced a number of “carrot and stick” policies. The U.S., for example, provides incentives for studying pediatrics such as six-months of market exclusivity. These policies have had a positive impact. In the early 1970s, only about 22 percent of drug labels included pediatric information. By 2009, about half of drugs included this information. Similar trends have occurred in Europe. Despite progress made in older children, neonates remain an under-served population. In fact, many pediatric programs exclude neonates. Sponsors are granted waivers from regulatory agencies, and they exclude this sub-population from clinical trials.
Using adult data to bridge to pediatrics
Due to the inherent difficulties of pediatric development, the concept of extrapolation― bridging from adults― was proposed years ago. Decision trees illustrating the pediatric extrapolation algorithm help sponsors determine a development pathway that is scientifically robust, yet operationally feasible. In cases where disease progression and pharmacology supports a similar response to the drug, conducting efficacy trials in children isn’t always necessary. If you have a strong pharmacodynamic marker, then using robust PK/PD modeling approaches is possible instead. If an exposure-response relationship has been established in adults, and it’s reasonable to apply this to children, then simply dosing pediatric patients to achieve similar drug exposures is possible. Pediatric extrapolation provides a framework to bridge and scale from adults to children and has led to advances in both tools and methods.
Children are physiologically distinct from adults
Numerous physiological changes occur during development which can impact drug disposition. Maturation of metabolic capacity and renal function can impact drug clearance. In addition, changes in body composition can alter volumes of distribution, and changes in GI function can affect drug absorption. These factors must be accounted for when bridging from adults to kids. This information has become better characterized over time, and pharmacometric approaches incorporating these factors have become common place.
Pediatric drug development also requires consideration of pharmacodynamic factors such as the number of drug-related receptors present as a function of age, or the functioning of those receptors compared to adults. Often, these factors are unknown in advance.
Stocking the pediatric drug development armamentarium
Data from pediatric clinical studies are usually sparse and limited. Thus, we need methods that fill data gaps. Quantitative pharmacology meets this need and is a proven tool for facilitating pediatric development.
But pediatric development is still tough. The approach is never straightforward. It’s always done on a case-by-case basis and requires multidisciplinary expertise in clinical pharmacology, quantitative methods, and regulatory science. Pediatric drug programs often face capacity, capability, or capital constraints. The result is lost opportunities and delays in introducing important new medicines to the pediatric population.
Partnering with experts on pediatric components of programs can help expedite their development. These partnerships may include out-partnering entire programs or particular aspects of programs, such as formulation development/manufacturing, clinical development, all the way through to sales and marketing.
When should pediatric trials be started?
Ninety percent of investigational drugs don’t make it to market. Thus, sponsors often wait to expose children to new medicines until safety and efficacy has been established in adults. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Topic E11 provides guidance on when trials should be initiated depending on the indication and the state of existing therapies.
- For diseases affecting children exclusively or predominantly, the entire development program can be conducted in children. Often, these programs begin with a Phase 1 healthy adult volunteer study, if relevant.
- For serious diseases lacking treatments for children and adults, they recommend conducting pediatric studies early, after obtaining reasonable evidence for tolerability and efficacy from studies in adults.
- For diseases affecting both adults and children― which may be less serious or where adequate treatments exist― pediatric trials should be initiated after gaining substantial experience in adults.
The ability to bridge from adults to children, the amount of available data, and the assumption of risk changes as pediatric programs are initiated earlier. Conducting pediatric trials early is riskier. But these drugs have the highest probability of meeting an unmet medical need. These programs also benefit the most from scientific innovation.
A bright future for pediatric drug development
Studying drugs in pediatric populations has many challenges. The earlier studies are performed, the less information is available for guidance. Likewise, the ability to extrapolate from adult data varies by the indication. Careful and thoughtful drug programs can address important pediatric diseases sooner. These indications include diseases where no acceptable treatment options exist, (orphan diseases), childhood cancers, and medical countermeasures.
Constraints on capacity, expertise, and capital also may delay the availability of pediatric therapies. Sponsors’ constraints can be mitigated via partnering, outsourcing, and creative licensing approaches.
Clearly, newer tools and approaches to support pediatric drug development are needed. Emerging approaches include microdosing in pediatrics to characterize pharmacokinetics, further development of quantitative pharmacology methods, and advances in study design. Fortunately many opportunities for further innovation can happen in the pre-competitive space. Through collaboration and sharing of information, we can bring new medicines to children more quickly.
Learn more about quantitative pharmacology strategies for pediatrics
We recently presented a webinar on this topic. I hope that you’ll watch it, and let me know what you think in the comments section!