As of Monday, the ClinicalTrials.gov database listed 132,387 pharmaceutical and biologic trials worldwide, not including studies listed in non-US databases. A hefty percentage of those studies are industry-sponsored, for which drugmakers often outsource various functions to one or more contract research organizations — or CROs – to manage everything from individual tasks like data management to the entire trial.
And yet, doctors expressed deep frustration with experiences they’ve had in clinical trials, blaming CROs and drugmakers alike.
Over time, CROs have become a crucial component of drug development, ensuring proper compliance from all parties with study protocols and requirements from regulators like the Food and Drug Administration. According to trade group the Association of Clinical Research Organizations members conduct more than 9,000 trials with over 2 million participants in 140 countries annually, generating an estimated $27.8 billion in revenue in 2016.
But on the ground, despite acknowledging CROs’ importance, some doctors grumble about problems like poor communication, unnecessarily repetitive tasks and rickety technology. At the same time, they said the fault does not lie entirely with CROs, and a common perception was of poor coordination between the service providers and the drugmakers sponsoring trials.
In an almost “Office Space”-esque June 2017 editorial titled “Contract Research Agonizations,” Cleveland Clinic hematologist-oncologist Dr. Mikkael Sekeres wrote in the American Society of Hematology’s ASH Clinical News of burdensome requirements the CRO placed on him and his staff and employees who appeared unprepared. These included having to repeatedly sign documents and a staffer unfamiliar with the disease of the trial, leukemia. Another editorial with possible solutions followed six months later.
The industry took notice.
One of the biggest CROs, PRA Health Sciences, has adopted Sekeres’s editorial for its onboarding of new employees. “Admittedly, global CROs are in a difficult position with our placement in the drug development cycle,” said Michael Brooks, PRA’s executive vice president for product registration in the Americas, in an emailed statement. “Some of the causes are rooted in the original CRO business model, while others are a result of regulatory bureaucracy and biopharma client expectations.”
Despite such acknowledgment, on an industry-wide level, things haven’t changed much, Sekeres said in an email.
“I still see colleagues complain about CRO requirements on Twitter, and as recently as this month, a CRO asked me to re-sign and date a document because they felt the date I had originally provided wasn’t neat enough,” Sekeres said, adding that his cardiologist and neurologist colleagues report similar headaches.
When he refused to write a new signature and date, the CRO staffer making the request had to get permission from a supervisor to allow the refusal. “I still sign and initial multiple forms multiple times each, for no appreciable reason other than for a CRO employee to ‘check a box’ and say it’s done.”
Sekeres’s sentiments are echoed by other providers.
“I could not agree more – I could have written that piece myself,” Virginia Commonwealth University cardiologist Dr. Antonio Abbate said in an email, referring to Sekeres’s June 2017 editorial. Many CRO employees suffer from “mission creep” and develop an obsessive-compulsive view of their job.
“They get so close to the tree that they lose sight of the forest,” Abbate wrote.
That, in turn, discourages physicians from embarking on clinical research and prevents patients from enrolling in trials.
A New Orleans endocrinologist, who asked not to be named to avoid jeopardizing professional relationships, cited what she called a particularly egregious case of poor communication. In one trial, she and her clinical research staff needed to make sure they had a copy of a protocol amendment – meaning a change in the trial’s design – but repeated emails to the CRO went unanswered, forcing them to contact the sponsor’s medical science liaison.
“It was just like, come on, do people not have an outgoing email – I’m either on vacation or no longer here?” she said in a phone interview. To this day, she said, the CRO has not responded.
And it’s not as if this phenomenon was one bad apple, she said. The problem seems to be across the board among CROs, where “you find the left not talking to the right,” with the CRO having no idea what the trial sponsor is saying or vice versa.
In other cases, these service providers reach out to doctors requesting information identical to information provided to them in previous trials. The various headaches cause trial sites to waste time and resources, leading to delays and forcing timelines to be pushed back. Patient recruitment in particular is hampered, doctors said, when they find themselves spending time performing tasks they say add up to repetitive busywork, like filling out endless forms and being quizzed on what they regard as insignificant topics.
In a Sept. 6 tweet, Dana-Farber Cancer Institute hematologist-oncologist Dr. David Steensma sarcastically posted a screenshot of a true-or-false question about a program used to sign forms in order to proceed in a Phase I trial in myelodysplastic syndrome and acute myeloid leukemia. In a follow-up tweet in the same thread, he called that requirement “bureaucratic silliness.”
One problem, he said in a phone interview, is that all the CROs have different, proprietary systems for signing off. In some cases even having two trials with the same CRO means having to train on the same system twice.
“I think it’s the right hand not talking to the left hand,” he said. While signing-off requirements are understandable from a Good Clinical Practice standpoint, he said it’s the training and bureaucracy for entering electronic case report forms that is not well-designed or thought out. “It’s challenging for our research coordinators as well – they really struggle,” Steensma said.
The Association of Clinical Research Organizations did not respond to multiple requests for comment.
Shoddy information technology is another complaint that Steensma and the endocrinologist cited.
Programmers fresh out of college and lacking clinical experience are being tasked with building the IT systems, Steensma said. “Or it’s something they don’t care about and don’t invest resources in making it intuitive.” Issues include frequent calls to the IT department, expired passwords, improper administrative permissions, being assigned the wrong trial or being unable to open a page because it only works on Microsoft’s discontinued Internet Explorer 8. “There’s nothing about it that enhances trial conduct or safety. It always takes so much time, even though it sounds like it doesn’t, to sign off,” he said.
“It’s very frustrating,” agreed the endocrinologist. “In the middle of trying to sign off on stuff, these are the things that take up so much time.”
But blaming various problems on the CRO is unfair, akin to blaming the waiter for a bad restaurant meal, said Kenneth Getz, a CRO industry expert at the Tufts University Center for the Study of Drug Development, in a phone interview.
“I don’t want to make excuses, but the CRO is often caught as a go-between,” he said.
A lot goes on behind the scenes that investigators are unaware of, and often the CRO doesn’t know much more than the clinical trial site does, meaning the sponsor can be part of the problem as well, Getz said.
In aggregate, he said, his studies over the last 15 years have shown that they offer faster speed and cost advantage at comparable quality to clinical trials run directly by sponsors. There are indeed individual challenges that can be incredibly frustrating, but it’s not fair to pin all the blame on the CRO. In fact, a lot of the burdensome paperwork doctors complain about are imposed by sponsors themselves.
Dr. Dennis Bourdette, chair of the Department of Neurology at Oregon Health & Science University, also said reports of poor performance were inconsistent with his experience. While he had experienced site visits that didn’t run smoothly or in which CRO staffers were focused on details in a way that drove his study coordinators crazy, he emphasized the crucial role such companies play.
“The fact is that the CROs are paid a lot of money by industry to ensure that the clinical trial is performed to the standards that the FDA requires,” he said in a phone interview. “Unfortunately, we know of instances where study sites have fabricated data and done a sloppy job of filling out forms.” This requires supervising sites to ensure they’re kept to certain standards.
Surveys of investigators’ interactions with CROs have shown improvement over the years, but indicate there is room for more. An April 2015 study of 1,900 investigative sites by CenterWatch found that the proportion of site respondents giving the average CRO an excellent rating nearly doubled, from 25 percent in 2003 to 45 percent in 2015. But while the average CRO improved its performance, remaining areas of improvement included ensuring study monitors are well-trained and understand the protocol, resolving problems quickly, adequate patient recruitment support and timely grant payments.
Photo: pictafolio, Getty Images
