Measuring the Incidence, Causes, and Repercussions of Protocol Amendments

Abstract

Measuring the Incidence, Causes, and Repercussions of Protocol Amendments Drug development companies frequently amend finalized clinical trial protocols. Yet the incidence, causes, and impact of protocol amendments have never been quantified. Tufts Center for the Study of Drug Development (Tufts CSDD) conducted a study, in collaboration with 17 large and midsized pharmaceutical and biotechnology companies, examining more than 3,400 clinical trial protocols across development phases and therapeutic areas. Data on protocol characteristics, the number of amendments, the nature and incidence of changes per amendment, the causes of amendments, and the time and cost to implement amendments were among those analyzed. Tufts CSDD found that more than 40% of protocols were amended prior to the first subjedfirst visit, and one third of amendments were avoidable. Each amended protocol had an average of 2.3 amendments resulting in 4 months of incremental time to implement. Protocol amendments translate into significant unplanned expense and delays for research sponsors and unexpected burden for investigative sites. These findings underscore the substantial impact of protocol amendments on drug development efficiency and present an opportunity to realize substantial cycle time and cost savings.

Assessing the Financial Impact of Reusing Electronic Health Records Data for Clinical Research: Results from the EHR4CR European Project

“…The EHR4CR platform also enables the identification of eligible patients in relation to the clinical trials' inclusion and exclusion criteria in order to ensure their timely recruitment, as well as efficient clinical data exchange for facilitating clinical trial execution and SAE reporting. Accordingly, and as reported by Kalra et al, EHR4CR solutions are expected to deliver important benefits [5], such as improved clinical study planning, reduced number of protocol amendments (the cost of one protocol amendment being estimated at more than €400,000 (USD 450,000), with Phase III trials exceeding on average 3.5 amendments per trial [14,15]), reduced administrative burden, better patient and investigational site targeting, faster patient recruitment, seamless study conduct, reduction in clinical research actual person-time and costs, reduced clinical trial cycle time, etc.…”

Clinical trial metadata: defining and extracting metadata on the design, conduct, results and costs of 125 randomised clinical trials funded by the National Institute for Health Research Health Technology Assessment programme

“…Given that ClinGov has moved towards requiring inclusion of results, CCT may move in a similar direction, in which case some of the headings in the database could be used. l Make comparisons with other research, such as the cost casemix study of RCTs in the USA 132 and the analysis of cohorts of RCTs (as in the Cochrane Review by Djulbegovic et al…”

“…132 This work, being carried out for NIH in the USA using a portfolio of commercially funded trials, should be monitored and compared.…”

Drug development study designs have reached the danger zone

“…Tufts CSDD found that one out of every four (24.7%) procedures performed in Phase III protocols supported tertiary and exploratory objectives and end points. The average cost to administer procedures supporting these 'Non-Core' objectives and end points represented 18% of the entire study budget, or $1.7 million per Phase III protocol [10]. This figure grossly underestimates the total cost of performing less essential procedures because it excludes all indirect costs for personnel and infrastructure required to capture, monitor, clean, analyze, manage and store extraneous protocol data and it does not begin to estimate the unnecessary risk to which patients may be exposed.…”

“…Tufts CSDD found that complex protocols are amended on an average of 2.3-times at a direct cost of over $1 million per protocol and 4 months of incremental time to resolve. The implementation of amendments is highly disruptive causing significant unplanned expense and delays for research sponsors and unexpected burden for investigative sites [10].…”