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Less is more: how risk-based monitoring is changing trials

A quality risk management approach is one of the biggest drivers for change in clinical research
Less is more: how risk-based monitoring is changing trials

For decades, trials sponsors have monitored patient safety and data integrity in clinical trials through the use of frequent site visits and 100% source data verification (SDV), in other words comparing data in case report forms (CRFs) with the original source of information.

This labour-intensive process makes up a sizeable chunk of the cost of running a trial and is sometimes criticised for giving a better view of sponsor and site diligence than a read-out on the quality of the data itself. Moreover, relying on clinical research associates (CRAs) to monitor sites generally means there is little opportunity for cross-trial perspective, unless the trial is very small.

For some time the clinical research sector has been considering ways to improve this process, and a shift to centralised monitoring of trends that can be used to guide less frequent site visits and SDV monitoring has emerged as the way forward.

This allows sponsors to see which investigators may be struggling or which data points are giving rise to a problem, for example, and also to allow clients to amend, suspend or terminate a trial if it veers off course. It also brings the promise of greater efficiency, potentially reducing development costs and improving cycle times.

A guidance document issued by the US FDA in August 2013 - as well as a reflection paper on the topic from the EMA the following November - set a regulatory stamp of approval on risk-based monitoring (RBM) and has encouraged pharma companies and contract research organisations to start building it into trial designs.

“RBM is not a new concept - companies have been looking at it for 15 years or more - but the recent regulatory guidance has thrown it into the spotlight,” said Martin Robinson, executive vice president and co-founder of the International Academy of Clinical Research (IAOCR).

Technological advances such as increased use of real-time electronic data capture (EDC) in trials, which allows the studies to be monitored almost in real time, has made RBM feasible and without doubt accelerated its uptake, he added.

The last couple of years has seen increased adoption of risk-based monitoring

With the regulators wishes now evident, industry responded fairly quickly, and the last couple of years has seen increased adoption of RBM. For example, Novartis has indicated that it intends to move 50% of its EU studies to RBM by the end of 2015, while Eli Lilly said recently it has already applied it to 40 trials.

CROs too have been quick to embrace RBM and have been working hard to develop EDC systems for targeted monitoring - allowing them and their clients to have ongoing insight into trial data - and setting up central monitoring departments that deal with the data being generated and relay information to the sponsor's monitoring team.

“We are encouraging our customers to move to the more patient-centric risk-based approach,” says Steven Cutler, chief operating officer of ICON, who indicated that interest in RBM is growing despite the inherent conservatism in the pharma industry.

“We believe there is benefit to them, both in terms of the quality of the … operational management of trials, the price they are paying and the value they are getting.

“It's certainly moving faster than electronic data capture did 20 years ago,” he added, noting that it is likely that ICON will move most of its trials to an RBM approach within the next five years, although “some trials just aren't appropriate for it.”

The key to success of RBM however, lies in developing the efficiency of clinical trial sites so that the number of 'risk flags' coming from the centralised oversight initiative is reduced, ideally to zero, according to Chitra Lele, chief scientific officer at Indian CRO Sciformix.

“As the initial euphoria over technology-based drivers of RBM settles, CROs are realising that a strong focus is required to get sites to high competency levels [and] keep the RBM trends analysis flags-free,” she said.

Savings potential
According to Cutler, SDV can cost as much as $90m for a phase III trial, and the industry as a whole something between $10bn and $14bn a year based on 100% SDV rates, so the opportunities to sampling using risk-based principles is significant.

For example, Merck Serono has completed a pilot study on RBM - conducted with strategic CRO partner Quintiles - which reduced SDV to just 25% of trial participants, with reversion to 100% SDV only in cases where a quality issue was detected.

A Cancer Research UK pilot which completed in January 2014 showed that it was possible to reduce the average number of monitoring visits conducted across all studies by 20% and sped up eCRF completion and query resolution times from nine days to seven.

The approach has led to faster recruitment, and sites reported that CRAs were able to focus their time more effectively to provide the most value to investigator staff. As a result, the approach has been rolled out across all of the studies conducted by CRUK's Centre for Drug Development (CDD).

Amgen started to implement RBM in 2012, according to Keri Aitchison, director of the company's global development operations.

However, rather than rely on systems developed by CRO partners Amgen opted for an internally-developed platform that relies on modelling trial design, feasibility and cost simultaneously, as well as the use of predictive analytics to drive decisions and tightening the connection between the design and operational teams. In doing to it identified more than 200 opportunities to deliver significant savings. Among the benefits from working in this way included removing the need for manual checks and unnecessary oversight, and the elimination of non-essential work.

While there is no doubt that RBM is gaining traction among CROs, pharma's adoption of the process remains patchy, according to Robinson.

“Pharma companies in some cases haven't quite grasped the concept yet - some organisations are looking for a magic formula, but this doesn't exist and you need to redevelop a risk-management plan tailored for each study,” he pointed out.

Echoing that sentiment Tarek Sherif, chief executive of Medidata Solutions, said: “People talk about doing RBM, but typically they're doing it on spreadsheets. That's not scalable, when you think about the thousands of trials that are out there.”

Companies wishing to take the plunge in RBM can get a leg-up thanks to work being carried out by TransCelerate, which was set up in 2012 as a collective pharma industry initiative to improve the efficiency of drug development.

RBM was one of the first topics tackled by the group, which has been working on models for adoption including a plan for central monitoring and a review of technological considerations when selecting risk-assessment tools.

More generally though, it is recognised that effective RBM often needs a champion or leader to take control of coordinating the programme, for example by acting as a go-between between the various functional groups within and outside an organisation and making sure lines of communication are reliable.

However, “the key is a change in mentality, not just a re-engineering of processes,” according to Robinson. 

Phil Taylor is a freelance journalist specialising in the pharmaceutical industry

15th December 2015

From: Research

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