Employing Virtual Models in Pediatric Clinical Trials and Combating Off-Label Use
I recently viewed the video “Pediatric Medicines – Prescribing Drugs ‘Off-Label’” reported by R. Frederick in Science [1]. The video highlights the issue surrounding off-label prescribing of medications to pediatric patients and summarizes the history and need for further inquiry. Briefly, the lack of pediatric-friendly formulations places nearly 40% of the world’s population at increased risk for non-compliance, decreased access to new medicines, suboptimal dosing, and avoidable side effects [2]. Although this issue has been a topic of hot debate for over a decade and incentives were put in place with the FDA Modernization Act of 1997, we are less than four years away from the expiration of Acts enacted by the US Congress that require pediatric clinical trials (namely, the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA)) [3]. One of the provisions that permits waiver of the PREA regulations is if pediatric studies are deemed impossible or highly impracticable. We must make strides in improving our ability conduct pediatric clinical trials. One technology may help in this respect.
The only innovative change highlighted in the video is virtual modeling of medications in pediatric populations being carried out by Professor Geoff Tucker of Simcyp (UK), a research-based company providing predictive pharmacokinetic services. The Simcyp Paediatric Simulator permits physiologically-based pharmacokinetic modeling and the prediction of drug absorption, distribution, metabolism and excretion based on either in vitro findings or adult in vivo data. As reported recently by Simcyp, the FDA has renewed its contract with Simcyp and has increased the number of various licenses to use their simulator [4]. An initiative by Pfizer is also yielding strong results, as reported in the British Journal of Clinical Pharmacology, identifying drug-drug interactions as shown by a Simcyp application [5]. Familiarizing the pediatric community in the US with Simcyp will be an important next step to help in bringing research together to gather results for the medical community.
In my opinion, the traditional reluctance to enroll children in clinical trials has had the effect of increasing, not decreasing, their vulnerability as a special population. Overall, I commend the European community for taking measures to establish definitions that can be used in the healthcare community [6]. It is imperative that the American medical community join in these efforts as this is a worldwide issue. It seems everyone is aware of the issue and being able to define the parameters will bring the healthcare community together.
It is true that research done on children is ethically questionable but the medical community and critics should be aware that innovative non-invasive measures are being used worldwide to help make medications safer for children. The great myths in pediatrics – children are little adults and children can be prescribed a lower dose of the same drug – have been widely dispelled [7]. But, we must now measure pharmacokinetic, pharmacodynamic, and response effects across different age ranges and establish the true differences of drug effects on adult and pediatric populations. Perhaps virtual models can place us one step closer to this goal.
Shaheen Lakhan is currently Executive Director of the Global Neuroscience Initiative Foundation based in Los Angeles, California.
slakhan@gnif.org
References
1. Frederick R. Video: pediatric medicines–prescribing drugs “off-label”. Science. 2008 322(5899):209.
2. Milne CP, Bruss JB. The economics of pediatric formulation development for off-patent drugs. Clin Ther. 2008;30(11): 2133-45.
3. Law Strengthens FDA. 2007; http://www.fda.gov/oc/initiatives/advance/fdaaa.html
4. US FDA renew contract with Simcyp. 2008; http://www.simcyp.com/News/20081008_FDA+renews.htm
5. Youdim KA et al. Application of CYP3A4 in vitro data to predict clinical drug-drug interactions; predictions of compounds as objects of interaction. Br J Clin Pharmacol 2008;65(5):680-692.
6. Neubert A et al. Defining off-label and unlicensed use of medicines for children: Results of a Delphi survey. Pharmacol Res. 2008; 58(5-6):316-22.
7. Lakhan SE, Hagger-Johnson GE. The impact of prescribed psychotropics on youth. Clin Pract Epidemol Ment Health. 2007;3:21.