Among the 9 orally administered anti-hypertensive agents, there were 24 clinical study reports, including 9 safety and efficacy studies, 9 single-dose or multi-dose pharmacokinetic studies, and 6 bioequivalence or bioavailability studies. Twenty-five percent of the studies were bioequivalence or bioavailability studies and were performed in adults, while the remaining studies (75%) were performed in children. Of the 9 anti-hypertensive agents studied, 7 underwent successful labeling changes as a result of the studies.3, 9
Two drugs did not undergo labeling changes and were found to have insufficient data to support safe and/or effective use in children. Further studies were recommended for these 2 agents (). These results may have been due to ineffective dosing.
Anti-hypertensive studies and labeling changes following response to written request
Study reports summary
The 24 trials enrolled 2506 children. Twenty-one hundred children (84%) completed the studies. Efficacy studies enrolled approximately 4 times as many children as pharmacokinetic studies (efficacy = 1962, pharmacokinetic = 544). Approximately 20% (399/1962) of children enrolled did not complete the efficacy studies, but nearly all enrollees of the pharmacokinetic trials completed the studies (537/544; 99%). The median number of enrollees per antihypertensive agent for all agents reviewed was 51 (range: 16–441), with a median of 143 subjects (range: 110–441) enrolled in efficacy and safety studies and 30 subjects (range: 24–74) enrolled in pharmacokinetic studies (). The median duration for all of the studies was 17.5 months (range: 5–50 months). The time to complete efficacy studies was approximately 50% longer in duration than pharmacokinetic studies (median: 24 months vs. 16 months). The median duration of bioequivalence studies was 6 months (range: 5–7 months).
The median number of case report forms completed per child was 50, and the median number of tables, figures, and listings per study was 51 for all studies. A subject visited a study site a median of 7 times throughout a trial. Efficacy studies included a greater number of tables, figures, and listings (107) than pharmacokinetic studies (27) (P = 0.0014). However, there was no statistically significant difference in the number of case report forms (P = 0.46) or in the number of visits completed by subjects (P = 0.48).
Study costs, sales, and cash flows
The median cost per written request to evaluate a particular anti-hypertensive drug in this cohort was $6 million (range: $3.8 million–14.2 million). These costs included estimated coordinating center, sponsor management, site payment, and central laboratory costs (when applicable) adjusted to 2005 dollars. The median value to conduct efficacy and safety clinicaltrials per drug was $4.3 million (range: $2.1 million–12.9 million), while a similar estimate for pharmacokinetic studies was $862,000 (range: $556,000–1.8 million). The median single- or multi-dose pharmacokinetic study cost was $1,117,092 (range: $634,396–1.8 million), while the median cost for a bioequivalence or bioavailability study was $731,856 (range: $555,663–862,457). The difference in study cost for single-dose or multi-dose pharmacokinetic studies versus study costs for bioequivalence and bioavailability studies was statistically significant (P = 0.026). The median cost per enrollee for efficacy studies was $31,546 (range: $18,941–$51,179), while the median cost per enrollee for pharmacokinetic studies or bioequivalence/bioavailability studies was $28,982 (range: $13,356–$47,311) and $30,071 (range: $23,851–$35,977), respectively. After-tax cash outflow, study costs adjusted for inflation and an industry average tax rate of 30% were $4.8 million (range: $2.7 million–10.4 million).
Drug sales also varied extensively. The median annual sales value per drug was $687 million (range: $218 million–$2.4 billion). There were 2 blockbuster anti-hypertensive agents with sales exceeding $1 billion (). The median 6-month cash inflow per drug was $60 million (range: $17.5 million–$320 million).
Coordinating center, site monitoring, and central laboratory financial costs
Average sales by drug class were also variable, but formal significance testing of this difference was not performed due to small sample sizes.
Net economic return and net economic return-to-investment
Net economic return for 6 additional months of marketing exclusivity varied by antihypertensive drug but remained positive for all drugs for the 6 months of additional exclusivity (). Variation in net sales return greatly exceeded the variability in the cost of performing clinical trials: the standard deviation for cash inflow was $93 million, while the standard deviation in cash outflow per written request was $2.8 million. All studies resulted in a positive net return according to our analysis during the 6-month period of additional marketing exclusivity. The range in net return-to-investment after adjusting for discounts, taxes, and inflation far exceeded the cost of studying the drug and ranged from $14.5 million to $316 million (median: $53 million). For every $1 invested, 4 of the 9 agents studied had a return of less than $10, and 5 out of 9 had a return of greater than $20 for every $1 invested. The overall range was $4 to nearly $70 per $1 invested. Sensitivity analyses that adjusted discount rates for values between 5% and 20%, as well as adjustments in the contribution margin for values between 40% and 60%, also revealed positive net returns for all anti-hypertensive agents reviewed (, error bars).
Dollars in net return for each dollar invested
Study cost predictors
Coordinating center, site management, and pharmaceutical costs generated using Fast Track Systems revealed that, among these cost variables, coordinating research center (CRO) costs comprised the greatest proportion of the total. Forty-one to 73% percent of the total cost for studying an anti-hypertensive agent was related to coordinating center incurred costs (). A review of coordinating center costs revealed that, for the majority of studies, site management and project management contributed the greatest percentage to the total cost estimate ().
Breakdown of study costs (efficacy studies only)