The Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) are the frameworks to ensure research quality, integrity, and safety in clinical research – and while Simon Rule agrees the principles are fundamental, he argues that the processes developed to ensure compliance with these principles “have been allowed to run out of control and are in danger of defeating their purpose.”
Rule is a clinical academic splitting his time between the Plymouth University Peninsula Schools of Medicine and Dentistry in the UK, where he is the director of R&D, and the National Health Service (NHS), running his town trials as well as pharma-sponsored studies.
Drawing on his more than 20 years of experience conducting research, Rule recently published an article in BMJ, making the case that bureaucracy is strangling clinical research – largely due to the massive increase in paperwork.
Rule also argues that many of the challenges are the result of drug companies outsourcing clinical research to contract research organizations (CROs), which he said have “developed and invented processes that create tier upon tier of bureaucracy.”
“Common sense is completely gone out of research,” Rule told us, citing the deluge of data facing clinical researchers, specifically information about side effects, many of which he said are of no relevance.
For example, he recently had to reconsent a patient in a trial because it had been described that patients were at an increased risk of “spider bite” and “road traffic incident” while taking a particular drug. This, because a patient had a car accident, an unexpected adverse reaction (UAR) not listed in the investigational brochure (IB), also known as a suspected unexpected serious adverse reaction (SUSAR), the definition of which Rule said has shifted to describe anything that doesn’t appear in the IB.
Adding to this, researchers must start recording adverse events the minute the patient signs the consent form, not after they begin taking the drug, he said: “You have a patient that falls over and bangs their head – before they start the drug – you have to file the paperwork.”
The forgotten patient
However, all of this is done in the name of patient safety, which is hard to argue with, Rule said. Though he counters that it’s not truly about the patients, but an excuse – and “what everybody hides behind.”
“Everything is justified as patient safety, and you can’t argue with that. But it’s actually making this less safe. You see so much information that you are now blind to the significant things,” said Rule.
“If you’re going to send me 100 adverse events, 95 of which I’ve known about for 30 years, and 3 have nothing to do with what I’m treating, how am I supposed to pick the 2 in the middle?
“The deluge of information about side effects which are of no value are so much that we lose the important message … the amount of paperwork involved in actually running these things is such that you have to have a big team about you to do it.”
And the paperwork isn’t just for the researchers, but for the patients, who must comb through lengthy contest forms and often must reconsent to a trial several times over the length of a study, said Rule.
“The cost of that is massive, massive,” he added. “And that is the just the tip of the iceberg … There are all sorts of analogous things like that that are getting more and more stupid.”
This includes mandatory retraining for any protocol amendments, a process that in one instance involved a presentation with 235 slides, he said, asking rhetorically: “If you spent 1 minute per slide how long is that?”
Additionally, as part of his job, many of the forms Rule fills out must be faxed or emailed to a CRO, before being forwarded to a medical monitor. Another example of the type of steps put in place in the name of safety and good patient management. “Meanwhile, in the days I’m waiting the patient has progressed and hasn’t gotten in the trial,” Rule said. “The patient is completely forgotten in all this now.”
More processes, more paperwork
Compounding these challenges is a complete lack of flexibility as well, he said. For example, working in lymphoma, Rule needs to complete CT scans of a patient within 28 days of starting a trial, at 29 days the patient must be scanned again. “The idea that you shouldn’t be repeatedly scanning people with radiation goes out the window,” he said.
Though perhaps one of the biggest issues is that most do not disagree that there is too much paperwork and not enough attention paid to the patient. Even big pharma agrees, said Rule, though he argues the industry in part created the problems by being too dependent on their legal departments – and passing clinical trials off to CROs.
“That’s been a big problem,” he said. “[CROs have] generated an industry out of processes. Their focus is not the trial or the drug or the patient. Their focus is the process because that’s how they generate their income.”
The consequences on the administrative side are massive, said Rule, who has four full-time admins on his team dedicated to data entry. Doing the work on his own would be impossible, though not all are in the same position, with a team providing support, and instead have had to stop conducting their own research.
“The paperwork has become significantly worse, so the cost has gotten significantly higher,” Rule said. “You’re going to find that the only trials that are going to be done in the near future are only going to be those run by drug companies, who are only going to be asking the questions drug companies want to ask.”
The end of independent clinical research?
Rule expects that independent clinical research is going to disappear due to a lack of time and effort, and not just in the UK, where he is based. In fact, the challenges might be greater in the US, he said.
So how does Rule propose the industry address bureaucracy in clinical research? Go back to where it all started from and ask, “Why are we actually putting these processes in place?” And if it’s about safety for patients, “let’s focus on things that are important,” he said.
Being patient-centric – among one the industry’s latest buzzwords – isn’t following a protocol without someone saying, ‘How can a spider bite be a side effect of a drug?’
“We need to strip all this back and say look, forget your tick box process, let’s just go back to what’s important,” said Rule. “It’s a tsunami of paperwork and no one is prepared to say, ‘Hang on, can we stop here?’”
Asking this question, the BMJ editorial has generated a lot of noise, with researchers around the world voicing support, the first step in tackling a challenge Rule described as not unlike a “runaway train.”
As for what comes next, Rule is among a group of a dozen senior clinicians working to promote change that won’t have any impact on the safety of patient, whom they also plan to include in future conversations: “What we want to do is include a patient group, so it’s not us saying it; It’s the patients saying, ‘I don’t need to know about this kind of thing.’”
Co-author Steve LeGouill also has had initial discussions with the European Medicines Agency (EMA), with a formal meeting now planned for June – an encouraging next step in the conversation Rule hopes to continue, ultimately making it easier and cheaper to run trials, and hopefully, getting more people involved. “Because patients benefit from clinical research,” he said. “We all benefit from it.”
Industry groups respond
Jim Kremidas, executive director at the Association for Clinical Research Professionals (ACRP) suggests that the root cause of many of these challenges is a lack of industry alignment around the competency requirements for the workforce.
“Everybody uses their own process and is convinced it’s the best and only way. Variance is the enemy of quality and the variance of competencies in the clinical research workforce is shocking,” he told us.
Douglas Peddicord, PhD, executive director, Association of Clinical Research Organizations (ACRO), said the organization agrees with the authors that reducing regulatory and administrative burdens on investigators and patients “is important to the health of the research enterprise.”
Peddicord cited the investment from clinical research and technology companies in developing and deploying new approaches to trial conduct, such as risk-based monitoring (RBM) tools and the use of mobile technologies to improve data collection and informed consent.
In the UK, ACRO has worked with the research arm of the NHS, the National Institute for Health Research (NIHR), which has invested in a Clinical Research Network, increasing clinical trial participation within the facilities of the NHS by more than 25% over the last seven years, said Peddicord.
He added, “The member companies of ACRO would be happy to be part of a multi-stakeholder review of ways to improve the focus on patients and continue to speed the development of new safe and effective drugs, biologics and devices.”
Bureaucracy is strangling clinical research
Authors: Rule Simon, LeGouill Steven