Pivotal Trials Are Cheaper For Unmet Needs And Orphan Drugs, JAMA Study Finds
Executive Summary
Analysis of clinical trial costs for CDER’s 2015-2016 novel therapeutic approvals finds pivotal studies are most expensive when a new agent has a similar benefit to already marketed products with well-established clinical profiles.
The first systemic evaluation of the cost of pivotal clinical trials illustrates the economic logic focusing new drug development on rare diseases and unmet medical needs.
The study, published in JAMA Internal Medicine on Sept. 24, “provides a different perspective to the widely held assumption that elaborate and expensive clinical trials are the main reason for the high costs of developing a new drug,” researchers from George Washington University and Johns Hopkins concluded.
“High-cost trials occur,” the article states, “but usually when drug effects are small or a known drug already provides clinical benefit.”
The study calculated the median estimated cost of a pivotal efficacy trial at $19mil. Half of the trial cost estimates ranged from $12mil. to $33mil., but the researchers noted more than 100-fold differences at the extremes – from the estimated $2.1mil. cost of the 4-person trial supporting uridine triacetate’s approval for a rare hereditary metabolic disorder to $346.8mil. for the pivotal trial for Novartis AG’ chronic heart failure drug Entresto (sacubitril/valsartan).
The researchers, led by Thomas Moore of GWU and the Institute for Safe Medication Practices, assessed 138 pivotal clinical trials supporting 59 novel therapeutics approved by FDA’s Center for Drug Evaluation and Research in 2015 and 2016. Clinical trial costs were calculated using
IQVIA’s CRO CostPro Mid-Level Tool, a cost estimation software system that incorporates benchmark cost data from historical CRO contracts.
The analysis dovetails with FDA concerns about long-term trends in novel drug development. “Follow-on drugs and biologics to compete with the first in class have been arriving more slowly,” FDA Commissioner Scott Gottlieb told a July 25 House subcommittee hearing, citing a soon-to-be-published FDA analysis of innovative competition in approvals from 1991 to 2010.
“Rising trial costs and complexity undoubtedly impacts market competition and drug pricing,” Gottlieb stated. "It's becoming harder and harder to be second, and that's a problem.” (Also see "US FDA's Gottlieb Touts 'Seamless' Clinical Trials, Worries About Second-To-Market Products " - Pink Sheet, 25 Jul, 2018.)
Concern about the downside to the drop-off in follow-on or “me-too” products – the type of drugs that require expensive trials against a known drug with clinical benefits – is not new. It was a theme for former Office of New Drugs Director John Jenkins, who once said that “it always makes us nervous at FDA to see a drop off in me-too’s or advances in class, because sometimes the first member in class isn’t the best member of that class.” (Also see "More Me-Too Drugs Please, FDA’s Jenkins Asks Industry" - Pink Sheet, 12 Dec, 2013.)
The Gold Standard Is Not Standard
Almost half of the 59 novel therapeutics – 27, or 45.8% – were approved with evidence from a single pivotal trial, Moore et al. found. Close to three-quarters of the approvals (43, or 72.9%) were granted “one or more forms of expedited reviews or legal exceptions to the primary standard of two well-controlled trials.”
The 2015-2016 novel therapeutics cohort included 35 priority reviews, 17 breakthrough therapies, 21 fast track designations and 12 accelerated approvals. Only 21 approvals did not use an expedited review pathway, the article notes. Close to half of the approvals – 27 agents (45.8%) – were orphan drugs.
The JAMA Internal Medicine study demonstrates the monetary value to finding indications for new drugs where controlled clinical trials can be avoided.
“Costs were lowest when the new therapeutic agents were approved by the FDA based on uncontrolled trials without any of the major protections against bias,” like randomization, a comparison group, or blinding, the study concluded. The researchers identified 18 agents that were approved based on pivotal trials without a control group, and calculated a $13.5m mean cost for the 26 trials supporting those approvals.
In contrast, the 112 controlled trials in the study had a mean cost of $35.1m.
The researchers broke down the controlled trials group into studies with a placebo control (77 trials supporting 33 approvals) and studies that compared the investigational drug against an active control (35 trials supporting 21 approvals). The placebo-controlled trials had a mean cost of $28.8m, while the active controlled trials had a $48.9m mean cost.
Clinical Outcomes Are Costly
“An end point of clinical outcome more than doubled the mean trial cost compared with trials using either surrogate outcomes or clinical scales,” Moore et al. reported. The 27 pivotal trials that measured a clinical outcome, representing 19.6% of the trials analyzed, had a mean cost of $64.7m.
The rest of the trials used a surrogate outcome (73 trials, or 52.9%) or a clinical scale (38, or 27.5%). Costs for the two categories were similar, with a mean of $24m and $20.5m respectively.
Greater length and size of trials were also, unsurprisingly, associated with higher costs. Overall, the analysis found a median (interquartile range) of $41,117 per patient and $3,562 per patient visit.
The researchers calculated a mean cost of $19.7m for the 89 trials (64.5%) with a treatment duration of 26 weeks or less. The 49 trials with a longer duration had a $51.7m mean cost.
Cardiovascular Development Is Especially Costly
While it was not a primary objective of the study, the JAMA Internal Medicine article provides an interesting look at the cost of pivotal trials by therapeutic area. (See interactive chart, below.)
Only five novel cardiovascular drugs cleared CDER in 2015 and 2016, but the mean cost of the pivotal trials stands out: $157.2m.
The authors use two CV approvals to illustrate their conclusion that “pivotal trials were expensive when the benefits of a new agent were similar to those of agents already available with well-established clinical benefits.”
Novartis’ Entresto, with the costliest trial, had to show non-inferiority to enalapril in cardiovascular mortality and other clinical benefits, the authors note. Despite the high cost of development, Entresto has struggled to find a foothold in the market, requiring further investment by Novartis to show pharmacoeconomic benefits. (Also see "Real World Data Helping To Drive Rise Of Novartis' Entresto" - Scrip, 29 May, 2018.)
Daiichi Sankyo Co. Ltd.’s Savaysa (edoxaban) had an estimated mean clinical trial cost of $174.3m, Moore et al. calculated. “Its higher costs were a result of the requirement for clinical benefit and noninferiority compared with the proven anticoagulants heparin and warfarin,” they said. Savaysa’s development was further complicated by its status as the fourth novel anticoagulant reviewed by FDA, which raised issues about its efficacy and safety given the availability of satisfactory alternatives. (Also see "Savaysa Shows The Good And Bad Of Being Late In Class" - Pink Sheet, 27 Apr, 2015.)
A ‘Realistic Price Tag’
The authors emphasize that “the intent of this study was to put a realistic price tag on one essential component of the drug development process that had not been previously evaluated” – the cost of pivotal trials – not to capture the entirety of the R&D and approval process.
Nonetheless, the authors concluded that “in most instances, the current costs of pivotal clinical trials appeared to comprise a modest portion of published estimates for overall costs of drug development.”
“Costs were increased when larger patient enrollments were required to detect a difference from placebo or active drug comparator,” they stated. Trial costs also rose when a study “required larger patient populations to achieve statistical power to document smaller treatment effects or accrue infrequently occurring end points.”
However, “pivotal trials for novel drugs with substantial clinical benefits can be conducted at a lower cost,” Moore and colleagues concluded.