In this series - The Pain Clinic - Kate O’Brien, formerly a senior research nurse and now a site consultant, examines the most common problems facing clinical trials today and what the potential solutions to them are (read the previous posts here). This month she speaks to two experienced ex-investigators and a research nurse about the challenges they are facing in clinical trials today.
Recent conversations with ex-colleagues brought to my attention that highly experienced investigators are deciding to discontinue their involvement in clinical trials. As these are precisely the sites that are vital to recruitment and the delivery of quality data this is an alarming fact. This article focuses on why this is happening.
Two investigators, Dr Bhavesh Bodalia and Dr Phil Marazzi, who have over 25 years of experience each, have been kind enough to discuss with me their reasons for withdrawing from commercial research. Other input has been provided by sites that will end their involvement when a key member of staff retires.
Dr Bhavesh Bodalia, based in Coventry, could easily be described as the perfect PI. Extremely hands on, he would see patients early in the morning, in the evening or at weekends to fit in with their daily lives. Much of what is now being discussed as Patient Engagement, Dr Bodalia was practicing years ago. His recruitment figures were phenomenal, for the ARRIVE trial he recruited 110, my site managed 36 from a much larger patient pool. Much of this can be credited to the fact that he spoke to the patients personally, taking time to fully explain everything as their doctor. His patients all had his mobile number in case of problems, it was rarely needed but this meant reassurance for them, plus any issues could be quickly resolved. Speaking to Dr Bodalia his passion for research and that this was an opportunity to provide the best possible care for his patients shone through.
Dr Phil Marazzi, based in Guildford, was early to identify the benefits to his patients of their involvement in clinical trials and he was a founding member of Profiad. His site had been participating in research since the 1970s. Again, Dr Marazzi had a highly professional attitude to conducting trials, recognising the need to work with an experienced research nurse and ensuring that the quality of data collected was top quality. His expertise in managing trials was widely recognised.
I have also included comments from another research nurse with over 25 years of experience. Here they will remain anonymous (referred to only as Research Nurse X) as the site will also cease their involvement in clinical trials when that person retires, but are currently still engaged.
What are the changes you saw over your research career?
Dr Bodalia: “We have seen a progressive move towards increased monitoring of research, a heightening of standards with increased protection for trial subjects, increased documentation at every level, more policing of research activities and a constant requirement to prove credibility. Significantly, most of the evolution has made the clinical research industry more robust and credible in the eyes of the public and reassuring for those who volunteer to participate and so is a positive evolution. We have always welcomed this as this gave our research subjects the reassurance that they are safe. Additionally, there has been a transition from paper-based records to electronic records which has also been a positive evolution. The downside for us in this arena is that we found ourselves doing much of the work that previously was done by data clerks which again is something we support.
However, we have found that funding did not follow proportionally to the work involved and indeed, research funding has fallen to a point that it is difficult to have a research team "ready" to deliver studies without the guarantee of work to come or a reassurance of funding. If a site encounters a year when work levels are low, then we have clinical research staff sat doing nothing and this becomes an unmanageable cost pressure which forced many research sites to abandon research work. We have been fortunate and despite concerns, always managed to secure projects in time to avoid "downtime", but with the unreliable nature of the arena, we also decided to finally retire from clinical research.”
- "Increasing standardisation and globalisation: These are good, but mean that inclusion/exclusion criteria can be much more difficult as may not ‘apply’ in our patients due to different clinical practice for example. This was a massive problem as even with our population of 10,000 patients, there were often only very small numbers meeting the criteria, and only a proportion of them would agree to a trial. When I started doing trials, investigators could influence the criteria to help make them ‘real’. Investigator meetings were earlier in the process and allowed a protocol to be carefully looked at in practical terms and then amended. Later, we were just presented with the final product and no possibility to amend it, especially in bigger multinational studies.
- Huge increase in admin and ‘paperwork’: We were approaching a stage where my research nurse was spending up to 75% of her time doing admin and only a small proportion seeing patients.
- Reduction in fees paid by pharma: The timings used by pharma/CRO to calculate fees became based largely on face to face patient contact time and not all the admin. This meant that actual payments remained virtually constant over 20+yrs even though inflation and amount of work we were doing was MUCH greater. We used to negotiate the investigator fee, but I think that ‘standardising’ it was actually a way of reducing it! It became non-viable as a business in primary care as we did not have enough patients for enough trials to cover costs at some points. ‘Feast or famine’. No trials for a while then several in the same therapy area competing for the same patients. More time was needed to find patients and the increasing demands of NHS general practice made this difficult. In order to take more time out for trials, you need more income to cover the NHS work. If the trial income is not regular, you run the risk of the whole process actually costing money, not making it.
- Hospitals and phase 1 units starting to do ‘primary care’ type trials causing loss of opportunities: When I started, we used to do a lot of phase 2 work, with PK studies etc. That stopped completely.”
Research Nurse X: “The expectations placed on investigators - to be far more involved on a daily basis than they might have been previously and as a very busy GP, that is not always possible. And as for paperwork - once upon a time you would have one site file for a study, now there are five or six in some cases!”
Do you feel that the relationship with the industry is now different?
Dr Bodalia: "The relationship with the industry is more intense and timeline pressures are a constant. There is often a failure in the industry to recognise the need to guarantee projects at site level so research sites can offer assurances over job security for staff. The industry needs to establish more financial certainty for small independent centres so that it can maintain diversity amongst its research centres and recruit appropriate selections of subjects for the clinical research."
Dr Marazzi: "CRAs expect more to be done in less time. It was always better working with big pharma direct, the minute CROs became more and more involved, the knowledge and quality of staff started to drop. Staff from pharma had better knowledge of the drugs, trials and so on, so were generally of a higher standard."
Did you notice a change in the complexity of the Protocols (that may not have corresponded with a change in income)?
Dr Bodalia: "Yes. Protocols became more complex, increased use of IT (often unreliable and time consuming) and not adequately supported by the funding. We have had occasion to give up on a study because of this."
Kate O'Brien: "The inclusion and exclusion criteria have become more restrictive which limits the pool of patients available to enrol. Then as the Protocols are more complex, this involves lengthier visits that deters patients. Often when I completed a feasibility, I did not have the final Protocol, by the time this was produced the original figures predicted were obsolete."
How easy is it to find experienced research nurses and study co-ordinators?
Dr Marazzi: "Staffing was not easy though I did manage to keep some very good nurses. They required quite high pay however and so this was a problem.
Kate O'Brien: "I found it impossible to attract experienced research staff on the salary I was permitted to offer. This resulted in employing staff with no experience, having to train them from scratch with no idea if they would demonstrate any aptitude for research or commitment to the job."
What are your thoughts on costings and payments?
Dr Bodalia: "It needs better consideration at site level. It costs the same to set up a trial that recruits two patients as recruiting 20, but obviously the former is not practical to run."
Kate O'Brien: "Negotiating costings in order to make a trial viable to run at a site was time consuming and consideration is not given to a site’s experience."
How do you view the increasing use of technology?
Dr Bodalia: "A necessary facet of research in the future. Sites need to embrace this but ensure the time it takes is factored into their costs."
Dr Marazzi: "Different IT systems is not a major problem but an irritation. A good nurse could always cope with different systems/couriers/labs etc."
Research Nurse X: “Definitely a growth area with increasing use of electronic diaries etc for patients. Also a big growth in the number of vendors involved in studies - for example, we have just started a study that involves the eCRF (RAVE), IWRS (clinphone), a study portal (intralinks), an adjudication website, and a website for viewing patient diary data. That's five vendors requiring setting up (and remembering passwords!!)"
What are your thoughts on the Clinical Research Networks?
Dr Bodalia: "These networks are good as they provide good support for sites. We, as a site, did not take any significant projects from these networks as we had robust relationships with the Pharma companies and CROs."
Dr Marazzi: "NIHR (our SE network anyway) didn’t do much to help. Initially all the work was more academic and generally very poorly paid. Little more than a distraction. Not sure if that has improved."
Research Nurse X: “Mixed thoughts really - they've raised the profile of research, which is good, but I can't help thinking that they're an additional layer of red tape. We've had a couple of run ins with our local CRN."
Kate O'Brien: "I echo all of the above, the networks are useful for inexperienced sites but those with a strong background gain little. Pressure to take on low paying non-commercial work that is often set up inefficiently is unhelpful. This occurred as these studies often required large numbers of recruits which boosted the overall recruitment figures to meet national targets."
Why did you decide to end your involvement in clinical trials?
Dr Bodalia: "We decided that the level of regulation, the complexity of the protocols and our motivation to constantly deliver timelines on the backdrop of a busy general practice and a failure of research companies to recognise this, finally dealt the blow to give up research. The difficulty is that the companies fail to recognise that research takes resource and to meet deadlines often means that it costs sites to back fill their normal daily work. I found that the recognition by research companies of the commitment required began to fail. For example, being constantly audit ready for inspection takes resource."
Dr Marazzi: "We stopped because the flow of work was irregular, the income inadequate, NHS pressures increased, difficult trial design in populations that were ‘well treated’, and increasing admin. I was very sorry to stop as I felt that I had really contributed to some good work but could not guarantee to make it viable any more."
Kate O'Brien: "Following the retirement of the PI who set up the unit, priorities changed to focus more on profit making and less on producing quality data. It became harder to maintain standards, the investigators didn’t seem to take research seriously, one regularly slept through investigator meetings and would only attend site meetings if lunch was provided! I was working with staff that I was unable to trust, and research is too important for that."
Would anything make you reconsider?
Dr Marazzi: "I wonder if the only real possibility now would be to run studies across a very local network, for example a group of practices with 50-100,000 patients. I am still not sure how financially viable it would be, but would be nice to try!"
Dr Bodalia: "No. The increased regulation, difficult timelines, increasing complexity of protocols and expectations which are not matched by an equivalent increase in investment in sites by Sponsors has made research increasingly difficult to deliver by smaller research sites and has made research not viable for investigators such as myself. I would not return to research until this balance has been redressed. Should this balance be redressed, then there is a great potential for experienced mentors and new investigators to become involved in clinical research at general practice level in the future. Perhaps this is a thought for the Sponsors to take back to the table when considering how to reach out to future research sites in the UK."
Kate O'Brien: "I recognise that there are some excellent sites with committed investigators and am happy to bring these to the attention to Sponsors. Using my experience to look at problem solving is enjoyable, I wouldn’t return to the problems of trying to manage a difficult site."