Human chain

The impact of Covid-19 on clinical research is still being felt around the world. Whether their sites were forced to close by the pandemic or utterly swamped with work directly related to it, investigators everywhere are reeling. Their experiences, however, highlight a point that is all too often forgotten: the strength of any system is in its connections and, more importantly, the people it links.

In that sense, the virus could be said to have had a positive impact on the clinical study environment. Regulators have been more responsive than ever in signing off on study proposals and providing clear guidance on how trials should be managed, while research teams across the pharmaceutical industry and academia have broken speed records in developing, disseminating and initiating innovative protocols. But the added urgency hasn’t changed the fact that Covid-19 trials are still made up of the same unwieldy set of moving parts and partners as their pre-pandemic equivalents. They link pharma companies, academics, contract research organisations (CROs), vendors and trial sites – and to succeed, they need to get each node communicating transparently and working towards a single goal.

Indeed, the speed and success of Covid-19 vaccine trials is directly related to the way the pandemic has remade everyday life, aligning everyone’s objectives in the process. Usually that’s up to CROs, which rarely carry quite the same clout. Even when sponsors keep their studies in-house, the part of the business that fills the CRO role can’t rely on top-down orders – it needs to connect the entire supply chain with good communication and efficient processes. The failure to do so can doom a trial.

Yet, as tempting as it might be to entirely outsource that burden, Jim Kremidas, executive director of the Association of Clinical Research Professionals (ACRP), warns it isn’t simply a case of appointing a CRO and expecting it to pick up the work. Both he and Kate O’Brien, a senior research nurse turned site performance consultant, agree that as the nature of clinical trials evolves, there are two linked issues for professionals across the industry to reckon with: the nature of the relationships between sponsors, CROs and trial sites; and the ongoing flux within the investigator workforce.

Red flags

There’s no time to waste. Already, the global supply of clinical researchers is becoming stretched. According to ACRP figures, the number of clinical trials is rising by around 12% a year, while the number of investigators is only growing by 9%. That’s a clear red flag for Kremidas. “I think, as an industry, we need to really look at how we ensure we have the capacity in the workforce to get all of the studies done, faster than we have in the past,” he says. As he sees it, the rush to get through the backlog of trials delayed because of Covid-19 will likely expose the shortages in the months to come.

The problem is compounded by the fact CROs and sponsors still struggle to understand how best to work with trial investigators. Though Kremidas believes CROs and sponsors almost always have strong working relationships, O’Brien notes that their shared ignorance of trial sites often result in misunderstandings that put CROs in difficult positions – not facilitating links and communication between the sponsor and the trial sites so much as getting caught between them. “They may be working within tight timelines without having all the information,” she explains. “Final versions of the protocol may not be available to them early enough in the set-up process, and then there are changes which affect sites, predicted recruitment and trial delivery, which impact the CRO’s agreement with the sponsor.” As a first step for mitigating the impact of late changes, O’Brien recommends naming specific points of contact at the CRO and site. All vendors and partners should be made fully aware of these communication pathways and have a clear understanding of the chain of command – who reports to who, what on and when. “It makes life easier if there is one link overseeing the whole set-up,” she explains. “It is also helpful to sites if there are not frequent changes of monitor and the allocated monitor is fluent in [their] principal language.”

Making sure investigators can actually hold conversations with their points of contact is relatively simple, but it’s symptomatic of a deeper issue around communication. A less tractable expression of it, explains Kremidas, is that clinical research itself is still something of a “cottage industry”, and the way sponsors and CROs work with one site might not have any relevance to the operations of another. “Not all sites are the same,” he stresses. “They all have their own operations and ways of doing things.”

Much of this variation is down to the relatively informal structure of the workforce, something Kremidas and O’Brien agree needs to be addressed. “Research involvement is very different to nursing, and holding an RGN [registered general nurse] qualification does not qualify you as a good research nurse,” says O’Brien, who notes that she is far from the only one struggling to find the right people. Kremidas, for his part, highlights the “oneand- done phenomenon”, whereby an investigator has such a bad experience with their first study that they never return for another. “Why?” he asks. “Because they don’t know how to do clinical research. Just because you’re a doctor that does not mean you know how to do clinical research. And if you don’t have the infrastructure and the right people around you, then you’re going to fail.”

Kremidas believes the first step is instituting specific qualifications for clinical research. “There’s literally no consistency in the study coordinator workforce,” he continues. “We need to do something about that: there needs to be some minimum requirements; there needs to be a good, healthy understanding of the operations, patient safety and how to manage data.” He wants the research sector to set up professional bodies that can take on the responsibility for training its members and overseeing their work, which would enable sponsors and CROs to insist that investigator sites have staff with appropriate training. The Joint Task Force for Clinical Trial Competency has gone some way to defining universal standards, but it doesn’t test or certify against its framework. Fittingly, though, communication – both within the site and with external partners – is one of its eight listed competency domains: investigators, like everyone else, need to understand the teamwork skills necessary for conducting a clinical trial.

On the money

With professionalisation, however, comes a greater focus on money. Even today, when trial site work doesn’t require any extra training or expense, O’Brien sees it as the biggest issue affecting recruitment. “It’s impossible to attract high-calibre staff if the wages offered are poor,” she says. As sites are typically paid quarterly (and sometimes even less regularly), many struggle to maintain the cash-flow required to employ specialists for the duration of a trial. Most sites prefer to work to a monthly payment schedule, a fact O’Brien believes sponsors and CROs need to take into account more often, perhaps while putting specific systems in place for their preferred sites. “This would have the added bonus of [ensuring] a site was trained on the required systems and had the capacity and capability to deliver,” she explains. “However, they have to be aware how much the situation can change when key personnel leave.” Being more closely involved would help with that, and a more personal relationship with trial sites could help counterbalance some of the more corrosive effects of money on the ecosystem.

Indeed, focusing too intently on earnings can cause its own issues. “I was lucky enough to start my career with an investigator who prioritised the patient experience and delivering good quality data” recalls O’Brien. “Sadly, this changed when he retired and the focus became profit-orientated.” Note that down as another factor in the rise of the one-anddone phenomenon.

Not that financial issues are restricted to one node in the clinical network. Reasonably, Kremidas points out that there’s no business relationship that isn’t impacted by money. “Having been on both sides, CRO and sponsor, I can tell you that often sponsors do not trust CROs,” he sighs. Much of that comes down to the fact that sponsors often believe CROs are focused on extracting as much money from them as possible. “That may be true in some circumstances, but in most cases CROs know that if they don’t deliver what they promise, they’re probably not going to get work downstream,” Kremidas continues. “They don’t want to lose future business: they want to deliver on today’s and know they’ll be used again in the future.”

That sort of distrust is symptomatic of an issue that Kremidas believes has become endemic in clinical research. “Unfortunately,” he grimaces, “way too often in our industry people are so focused on their metrics and their little piece that, instead of using good project management techniques, they get their part done and throw it over the fence to the other group. Then, when things don’t go right, they blame the other group.” Typically, that other group is the one at the trial site – but the underpaid, untrained foot soldiers of clinical research probably shouldn’t be the ones carrying the can for strategic failings. As it is, the existence of the one-and-done phenomenon becomes less and less surprising.

In order to combat it, Kremidas recommends that all elements of the trial chain come together at the earliest opportunity to understand the aims of the study and their part in achieving them. “They’ll understand, ‘Okay, this is why we need to do this or this is why we need to change that’, so they can be more efficient downstream,” he explains. “That can really enhance things – I’ve seen it work. It’s communication and trust.”

At the very least, it’s a start. Professionalising clinical investigators won’t bring an end to the blame game, but it will likely mean there is less blame to go around. As there would be if sponsors or CROs communicated more openly with investigator sites, taking a continuing interest in what they’re doing, how they’re doing it and the difficulties that might be ahead, instead of looking back with an outstretched index finger once it’s too late to make a difference.

It’s worth remembering that clinical trials exist to find ways to improve people’s lives. Working on them shouldn’t have the opposite effect. Directto- patient and telehealth tools will continue to change the investigator role going forward, but ignoring it in the hope that new technologies enhance trial procedures simply by limiting human involvement could be disastrous. “I’ll be honest with you,” says Kremidas. “Often, as an industry, we get caught up in the technology and the processes, [but] the piece of the puzzle that really needs more emphasis is the workforce.”