Efforts to reduce the number of phantom investigators—principal investigators (PIs) who are not adequately supervising their staff and clinical trials—appear to be having a measurable impact. But problems associated with, and the issues that cause, phantom PIs and their causes linger.
“We are still suffering from huge issues of PI disengagement,” said industry veteran Beth Harper, president of Clinical Performance Partners, a company that helps get sites back on track following large errors in their data or processes. “And I think, in part, we’ve created this problem.”
Harper points to the fragmentation in the industry that no longer has sponsors interacting with sites directly. Instead, CROs don’t actually talk directly with sites. They connect with them through email, portals and Web-based training, she said.
No touch, no success
What’s lacking are high-touch and systematic site-relationship management processes, said Harper. “Without that, we’re hurting sites, which then hurts patients.”
Monitors still come to the site, but nowadays they are often young, not very well trained and sometimes intimidated by the PI, said Harper. They may not even speak with the PI when onsite. This is a big change from just a few years ago when the monitor was much more involved, helping the sponsor select sites and then helping sites with startup, remembers Harper.
“Now things have gotten so fragmented that you have many studies where the PI may never have been engaged directly by a person from the sponsor or the CRO,” she said. “Their first face-to-face interaction doesn’t come until they get into trouble.”
And even less monitor interaction is on the horizon as the industry digests and begins to incorporate the concept of risk-based monitoring, which many companies interpret as only physically sending monitors to sites when the site is seen as high risk for data errors.
Are PIs just too busy?
Another factor that has lead to disengaged PIs: an untenable workload.
“Metaphorically speaking, PIs are running alongside their bikes and don’t have time to slow down and actually get on the bike and ride,” said Gretchen Bowker, chief operating officer of Pearl Pathways, Pearl IRB and Pearl ReGXP. Pearl ReGXP, which launched five years ago, performs rescue work at sites and has been overrun with business.
“PIs usually have way too much on their plates. They assume that the infrastructure they’ve created under them—the coordinators, the IRB—is good and is handling everything, but often it’s not.”
As may often be the case, a coordinator is under undue stress and gives notice, leaving a dangerous void. A new coordinator is hired who is altogether unfamiliar with the studies the PI has taken on, said Bowker. She added that PIs position themselves to be focused on the patient, not the paper, but it’s their signature on the paper.
This pervasive disengagement takes place across all types of PIs—from those in private practice and hospitals to those in dedicated research facilities and academia, said those interviewed for this story.
In fact, things may be getting worse in academia. Industry veteran Nikki Christison, now president of Clinical Resolutions but formerly a monitor and site coordinator, explained that grants from the National Institutes of Health are few and far between these days, which puts pressure on physicians in academia to take on industry work in order to keep publishing.
“They are pushed to take on trials from the industry when they might not even want to. Then they’re expected to oversee all parts of the trial. Instead, they delegate to staff that has no experience with the trial, Christison said. “It’s a bad cycle, one that’s getting worse.”
After a long period of investigator responsibilities being somewhat vague, in 2009, the FDA put out guidance on exactly what PIs need to do during the course of a clinical study, and what they are responsible for legally. The following year, the agency put out a FAQ document on Form FDA 1752, the form PIs sign when taking on a study pledging to adhere to FDA regulations. This left little to the imagination for PIs formerly wondering exactly what their responsibilities were.
These efforts may not have had the sweeping affect that was hoped for, as many factors—old and new—in the industry still work against PI engagement.
There is another type of PI—one who is engaged in the many facets of the study taking place at her practice, but who may not fully understand the importance of documentation. She may appear unengaged altogether.
“I talk to PIs who have a lot of internal meetings and hallway chats to touch base with staff during a study. The problem is that these meetings and chats are informal—nothing was documented or signed. And nothing gets placed in the regulatory binder. The Golden Rule of clinical research: If it isn’t written down, it didn’t happen.”
Another factor is faulty monitoring, said Bowker.
“The monitor goes to the site to check all the data to make sure the study is being conducted the way it should. But when things go wrong at the site, it often can be traced back to a monitor who didn’t catch problems early on or help the site understand what they’re doing wrong,” she said. “I’m seeing more and more of this.”
Compared to 15 year ago, when The CenterWatch Monthly first took a hard look at the problem of the phantom PI and found the landscape troubling, Christison said she saw a shift toward PIs having a much greater understanding of what will keep them from getting warning letters from the FDA. That awareness has lead to fear, which brings a certain level of engagement with the study, but it’s by no means ideal.
At the same time, protocols have gotten exponentially more complicated. It’s even more critical that the PI stays deeply engaged and not leave much of the study to the coordinator—who may or may not be trained to handle the complexity and may or may not stay on for the duration of the study.
Said Bowker, sponsors need to take a good, hard look at how many studies they’re giving to each site, and assess whether an untenable workload is causing a site to produce less-than-satisfactory work.
Is PI certification the answer?
There is currently no required certification program for PIs. The Association of Clinical Research Professionals (ACRP) has for many years offered such certification, but since PIs are under no pressure to become certified, few do.
ACRP executive director Jim Kremidas points to pivotal research done by the Nashville, Tennessee-based hospital group Hospital Corporation of America (HCA). David Vulcano, head of research there, and his colleagues looked back on three years of data from certified PIs working on multicenter studies and found that certified PIs had significantly more “No Action Indicated” (NAI) notices from the FDA following an audit.
The hope, said Kremidas, is that it will become clear to sponsors, CROs and PIs alike that PI certification just makes sense in this long-waged war to keep PIs doing their best work, to keep data clean and patients safe.
Clinical Resolution’s Christison agrees. “If there were more good models out there that show how this should be done, more PIs would do it, too,” she said.
Many sponsors “get it”
Who ultimately bears the responsibility? The sponsor. Said FDA spokesperson Tara Goodin, “It’s important to note that it is the responsibility of the sponsor to choose appropriately qualified clinical investigators and to appropriately monitor trials. Part of that monitoring would include assessing the clinical investigators conduct of the trial.”
There are a lot of sponsors and CROs who “get it,” said Harper, and they devote a tremendous amount of attention to keep PIs engaged.
Deirdre BeVard, vice president, development operations at Nektar Therapeutics said she’s never seen a disengaged PI on any of Nektar’s trials. That’s because the company’s methods are extremely high-touch.
Before starting a trial, said BeVard, Nektar brings groups of PIs to its headquarters and asks them what they think will and won’t work for the study, and involves them in the study’s design. At the study’s initiation meeting, those PIs help educate the rest of the PIs on the study. This very interactive initiation meeting, held in a theater-in-the-round environment, simulates the experience of conducting the study, with role playing and kiosks for handling the study materials in advance.
It’s definitely not just a 45-minute PowerPoint,” said BeVard.
Then, in conjunction with its CRO, Necktar sends its “customized concierge service” to help each site with startup in whatever way the site feels it needs help. Sites also get access to a social media-like online study community. Nektar posts updates in the online community and PIs and coordinators can respond and discuss.
Acting on feedback
After each milestone, Nektar calls the sites and talks to them for an hour to ask for feedback and assess the need for any additional help, said BeVard. She added that PIs are shocked to not only be listened to but to then have their feedback acted on during the study or in the design of the next study.
This is just what sites need to stay engaged in the study and to stay passionate about it, said Victoria DiBiaso, associate vice president and head of the Office of Patient Participation and Preferred Partnerships at Sanofi.
Sanofi, parent company of Genzyme, was an early adopter of site-relationship efforts. “Over the last 20 years, there’s one thing I’ve always heard PIs say, and that’s, ‘I desire a relationship with the sponsor,’” said DiBiaso. That’s what Sanofi aspires to give the PIs in its partner program.
As a direct result of feedback from PIs, Sanofi pulls them into the planning process on trials and stays in close touch with them throughout a trial. There is a wrap-up session at the end to see what the PI thought about the process, which also asks what could go better in the future.
Said DiBiaso, “We consider them the clinical extension of our project team, and their involvement, in turn, can help reduce protocol complexity.”
“Next time” is a key concept, she said. “PIs used to tell us, ‘I know I’ll be recruiting for trials at this time next year, I just don’t know what those trials are,” so Sanofi began sitting down with PIs and sharing information on the studies that are coming up so PIs can plan accordingly. This sounds basic, but few sponsors do it.
The outcomes are there. DiBiaso said Sanofi sees accelerated startup across its partner sites, with an average savings of 40 days across all disease areas. The company also sees better recruitment, with partner sites recruiting double the average number of patients. Another upside: fewer protocol amendments.
But will the rest of the industry eventually “get it?” That remains to be seen, and will look different for each company, depending on their mission, therapeutic areas, size and many other factors, said DiBiaso. She added that there are some common concepts that any company can adopt for greater PI engagement.
“Take the time to understand what is important to the PIs and their staff—why they want to be involved in each study and what elements of the trial make it the most meaningful for them,” she suggests. “What are their recommendations to reduce the levels of burden for them and their patients? Spend time with the site to hear what you as a sponsor can do to help them be successful in each study and act on it, and acknowledge their role as part of the extended study team.”
Above all, the PI should be treated as a very valued member of the clinical research enterprise rather than a person who’s primary task is to check boxes to push the study through.
“Clinical research is a collaboration, and we couldn’t do it well if we didn’t work closely with the PIs,” said DiBiaso.
Suz Redfearn is an award-winning journalist and former senior staff writer for ClinPage.com. Her articles have appeared in numerous publications, including the Atlantic.com, the Washington Post, Slate, Salon, Politico, Men’s Health, MedPage Today and Physicians Practice. Suz holds a degree in print journalism from Loyola University in New Orleans and has been a medical writer since 1990, focusing on clinical research since 2007. Email firstname.lastname@example.org.
This article was reprinted from Volume 23, Issue 04, of The CenterWatch Monthly, an industry leading publication providing hard-hitting, authoritative business and financial coverage of the clinical research space. Subscribe >>