We were provided access to individual patient data for each of the Type C efficacy trials submitted for pediatric exclusivity from 1998 to 2005, inclusive. The primary endpoint for these trials was a dose-response change in sitting blood pressure between low, medium, and high dosage groups. We found that 3 trials (enalapril, lisinopril, and losartan) were successful. These trials had several design components in common: all used diastolic blood pressure as the primary endpoint, were characterized by a larger range in amount of agent given to low dosage vs. high dosage groups, and used a pediatric formulation in their efficacy trial.
Pharmaceutical companies continue to apply for pediatric exclusivity in the United States for antihypertensive agents, and an analogous program is now in place in the European Union. We believe that these results have several important implications for the design of future pediatric antihypertensive trials.
These data support use of reduction in sitting diastolic blood pressure, rather than systolic blood pressure, as the primary study endpoint. Diastolic blood pressure has less physiologic variability among observations within a subject than does systolic blood pressure in children.14-16
This reduction in variability may have contributed to the success of diastolic blood pressure as the primary endpoint. Systolic hypertension is approximately 3-fold more common than diastolic hypertension,17
and the motivation to use systolic blood pressure as the primary endpoint derives from feasibility, a common problem in conducting pediatric drug trials. However, the underlying causes of systolic and diastolic hypertension may differ (e.g., abnormal aortic compliance versus elevated systemic vascular resistence), and this may become a significant factor depending on the patient population (e.g., systolic hypertension is more common in elderly patients). A primary study endpoint of mean arterial blood pressure that incorporated both systolic and diastolic blood pressure values might prove advantageous, and this possibility should be explored in future trials.
The incentives in place for the Pediatric Exclusivity Program are designed to encourage trial completion; sponsors are given exclusivity if the trials are completed, and the decision to grant exclusivity is not dependent on product safety or efficacy. Feasibility is therefore of far greater importance to sponsors than optimal trial design. Eligibility for exclusivity regardless of outcome is a major advantage of Type C trial design because it is considered interpretable regardless of outcome; avoiding the use of an explicit placebo arm makes this type of trial more appealing to parents of potential subjects and institutional review boards.
Our results indicate that future pediatric antihypertensive trials should incorporate a wide range of doses and use information from adult trials to account for potential pharmacological differences between adult and pediatric populations. For example, the lowest clinical trial dose should be lower than the lowest approved dose in adults, and the highest clinical trial dose should at least be twofold higher than the highest approved dose in adults, unless contraindicated for safety concerns.
None of the failed trials investigated dose ranges higher than the corresponding adult doses. For example, the highest irbesartan dose was 4.5 mg/kg, while adult data indicate that most adults need doses up to 150–300 mg (≈ 2–4 mg/kg for a 75 kg child) for better blood pressure control.18
Data obtained from irbesartan use in adults showed that effects on blood pressure increase at doses up to 600 mg (approximately 8 mg/kg for a 75 kg child), and the maximum irbesartan dose studied in adults was 900 mg.
In contrast, the 3 successful trials provided large differences among low, medium, and high dose strata. All 3 successful trials employed doses much lower (nearly placebo) than the doses approved in adults. For example, the recommended initial lisinopril dose in adults is 10 mg and the usual dose range is 20–40 mg. The lowest dose used in the clinical trial was 0.625 mg, thus providing a wider range for exploring dose response. The selection of wide dose ranges is important for pharmacokinetic reasons, as closely spaced doses yield overlapping exposures among dose groups. If overlap is substantial, the dose response could appear flat and thus fail to demonstrate a significant dose-response relationship.
Further, 3 of these orally administered antihypertensive agents (those used in the failed trials) did not develop a pediatric (e.g., liquid) formulation and thus exhibited a wide range in exposure within each weight stratum. Development of a liquid formulation is often challenging: bioavailability can be unreliable, and dissolving the agent in liquid can require high concentrations of alcohol. Stability and bioequivalence testing of liquid formulations also require additional time and expense. Still, pediatric formulations should be requested in the Pediatric Exclusivity Program whenever possible. Development of these formulations is now more economically feasible because of benefits provided to companies for successfully completing trials requested by FDA as part of this program.
It is possible that the failed trials were unsuccessful because the agents do not work (or do not work well) in children. Each trial had a placebo-withdrawal stage to address this concern. Amlodipine and fosinopril, neither of which showed a dose response, both reduced blood pressure compared to placebo.7,8
The third agent that failed, however (irbesartan), did not show a clinically meaningful reduction in blood pressure in the placebo-withdrawal stage.19
One potential flaw in the conduct of these studies is the overall approach of study sponsors to compliance with FDAMA requirements: these studies are often designed and executed at the end of the product’s period of marketing protection. This problem is not limited to antihypertensive agents, but exists across all products, and can result in trials that fail to provide optimal data for the practicing clinician.
Failure to document dose response has been noted in other FDA-approved study designs and is not confined to Type C trials. One solution might be to encourage lowering of blood pressure compared to placebo (e.g., over a 4-week period) with subsequent follow-up studies to determine long-term safety. This would eliminate reliance on dose-response findings and put greater emphasis on long-term safety exposure.
Our study is limited by the fact that we conducted a post hoc analysis of only 6 trials. However, there are very few pediatric efficacy trials, and if we are to improve trial design, post hoc analyses will need to be completed after relatively few studies.
In conclusion, acccess to protocols, final study reports, and individual patient data for each trial was crucial to our investigation. Our analysis highlights potential improvements in trial design, accurate assessment of product efficacy, and improved public health when access to data across trials is granted to investigators.
Poor dose selection, failure to fully incorporate pediatric pharmacology into trial design, lack of pharmacokinetic information, and use of systolic blood pressure as the primary endpoint likely led to the failure of several antihypertensive pediatric exclusivity trials. Complete access to patient-level data allowed us to fully examine trial results, and may result in better design for future studies. Our data may be applicable to efforts to improve pediatric clinical trial design by government agencies, clinicians, and pharmaceutical sponsors in both North America and Europe. In the future, we recommend that pediatric antihypertensive trials should 1) develop an exposure-response model using adult data and published pediatric data, and employ this model to perform clinical trial simulations of pediatric studies and to explore competing trial designs and analysis options; 2) work with FDA to design pediatric trials by leveraging prior quantitative knowledge; and 3) routinely collect blood samples at informative time points to assess the pharmacokinetics in each subject to ascertain exposure response analysis.