For Veteran PI, Research Requires Motivation, Dedication, And CRO Support

A conversation with Dr. Luke Twelves, general practitioner and medical director

Becoming a clinical trial principal investigator is no small task and often a fraught decision for most practicing physicians with even the strongest desire to pursue research. There’s plenty to consider — confidence in oneself, financial stability, and availability, to start. And the question is no easier for doctors who haven’t been exposed to research during their schooling or early in their careers. But the path for Dr. Luke Twelves has, fortunately, been a bit different.

Having had mentors at both Oxford and Cambridge universities conducting clinical research, Twelves experienced early career exposure that led to a career-long interest in clinical trials. In this Q&A, Twelves talks about those experiences as a student and young doctor, highlighting how he remained motivated to continue conducting trials and sharing insights into what he thinks will inspire others to do the same.

Reflecting on your early career, what motivated you to explore clinical research?

My choice of medical schools helped pique my research interest considerably. At Oxford, as a third-year medical student, I shadowed and supported Ph.D. students in labs run by eminent researchers. For example, one of the projects I supported was in the laboratory of Sir Colin Blakemore. I saw early phase and academic trials at the coal face at an early stage of my training. At Cambridge, as a clinical medical student, I learned directly from the researchers and was often tutored by research clinicians. This ensured, right at the start of my career, I had not only a clear understanding of the importance of research but also an interest in trial delivery.

This interest continued when I was a hospital doctor, in addition to supporting my consultant colleagues with research, and I was fortunate to be able to sit on the local medical ethics committee. This gave me valuable insight into a wide range of trials and a solid grounding in the ethical aspects of trial delivery.

Tell us about your first trial. What was your experience like? And what challenges did you encounter?

My first trial was quite some time ago (I qualified in the 1990s), but my overriding memory was of mixed emotions — being involved in trials was enjoyable, a break from the usual routine of clinical practice, a chance to flex my brain differently. The administration was, however, huge, with a lot of repetitive paperwork, and there also was a feeling of doing work in a vacuum, with little connection to the wider trial team.

After the study closed, what motivated you to continue serving as an investigator?

Firstly, a work ethos: Always when trying something new, give it a chance. After all, things and systems can be improved and issues can be ironed out. Secondly, I fundamentally felt it was important to be involved in research to help advance medicine. Thirdly, the academic challenge helped improve my clinical practice and skills.

Have you ever been involved in a trial in a therapeutic area that was not your area?

I am a generalist. I had originally started training to be an anesthetist and intensivist, which requires a broad understanding of every specialty so you can be safe and effective when anesthetizing or managing patients in ITUs. I then retrained as a general practitioner, which also requires you to have some understanding of every specialty, so being a generalist has been a key aspect of my career.

This could be seen as a disadvantage, but being a generalist is very useful, as it is exceptionally rare that there will be a clinical trial in an area I know nothing about, and I can bring different viewpoints and learnings to a trial. I work closely with specialists to get the best result for both the sponsor and participants, for example, by bringing my expertise in primary care recruitment. For trials where I have been the lead investigator, I always have ensured that the trials have been in areas that fit within my core expertise — areas that are common presentations or are typically managed by GPs/family practitioners.

As an experienced investigator, what advice do you have for prospective or naive investigators?

There are investigators with far more experience than me, and I would say an experienced investigator is someone whose entire career has been focused on research and has hundreds of papers to their name! That said, the key message I want to get across is “go for it” — but to go into it with your eyes open and to remember it gets easier! The more prep you do for your first trial the better, and it’s best to make the up-front time investment by completing the courses and setting up the processes that should make your first trial run smoothly.

After you have done your first trial, then each trial is incrementally easier. It's also sensible to start with a simple trial and then fine-tune and develop your systems as your trial complexity increases. When deciding to get involved or to continue in research, you need to recognize the broader benefits. I found that my involvement in research has beneficially altered my interactions with patients outside of the research itself, as well as ensuring that I stay fresh and enthusiastic about medicine.

What do you feel is the most common misconception research prospective or naive investigators have about clinical research?

There are two common opinions that are at opposite ends of the spectrum: The first one is that it's low effort or that it's easy income. It is not, and you can’t do this in a halfhearted way; the regulations are the regulations, and you need to follow them, and the safety of participants and the integrity of the trial are sacrosanct. This requires you to set up systems and processes in your practice that ensure you follow the regulations and deliver safe, effective, reliable trials.

The other opinion is the opposite — that it's so hard to start in research, that it’s a bit of a closed club, and that it’s impossible to do without a huge investment in infrastructure and staff and without established connections and research teams. This is also not true, because the regulations and requirements are clearly laid out, there is plenty of training available, and good support systems are fairly easy to access. It’s also sensible to start with a simple trial and then build on your experience.

Current data tells us that many, if not the majority of, investigators do not conduct a second trial. Why do you feel those investigators are “one-and-done”? In other words, what causes them to quit clinical research after just one trial?

There are broadly two groups. The first group is those who were motivated to do a piece of research in a specialist interest. For example, they come up with a patentable idea and want to research it, so they are particularly motivated to do that one specific piece of research. The second group tries the research and then, for a myriad of reasons, struggles with that trial and feels the next trial would be too much of a hurdle.

Along those lines, why do you feel investigators are so hard to recruit these days for clinical research?

It's a combination of research and non-research reasons. The non-research reasons are well recognized: Life as a clinician is exceptionally busy, with pressure and expectations on all clinical services being very high, especially post-COVID. This results in research being pushed down the priority list.

On the research side of things, the effort required to start in research has increased compared to 20 to 30 years ago, so this has created a hurdle to entry for those considering research. I would argue that there are very good reasons for this, but there is no doubt that now you must positively decide to make the effort to do research and make the time, effort, and investment to do so. I would also say that the current way trials are typically run by a CRO also can add considerably to the researcher’s workload burden.

What can sponsor companies do to identify, onboard, and retain investigators? And, from your perspective, what are the most common challenges PIs face when working with CROs and how can these challenges be addressed?

These two questions are linked: If you solve the challenges that investigators face, then you will help attract and retain good investigators. In terms of identification of investigators, there are no simple answers, especially for new investigators. Clearly, if you are well-published, then you can be found relatively easily, but for new investigators, you will need to be proactive and reach out to CROs. It's also key that professional profiles indicate the desire to get involved in or conduct more research. In addition, CROs can search through professional directories that prospective investigators sign up for. The CROs, however, must play their part by making it easy for potential investigators to contact them and then keep potential investigators informed of upcoming trials.

More generally, the research community needs to make the research easier for potentially interested clinicians. The common issues of poor communication, isolation, administrative workload, unnecessary clinical workload, and the need for realistic costs are well recognized. But other aspects should be considered, such as, for example, the complexity and practicality of delivering a particular protocol. The issues surrounding the identification, onboarding, and retention of investigators are multifaceted and, therefore, the solution needs to be multifaceted, too - from removing the myths around research and the work of an investigator to supporting researchers and reducing the burden on them once they start working with a CRO.

For example, when I am working on a protocol with my colleagues, the impact of a trial on the participant, the investigator, and their team is considered. We always look at ways to reduce investigator burden, especially when it comes to paperwork and administrative tasks, i.e., how can we ensure the investigator is only being asked to do things that they can add clinical value to? The broader aspects are also important. Is the research interesting? Will it potentially benefit their patients and wider team aspects — especially in group offices and practices? How will the research impact and interest the wider team? Finally, the research finances need to stack up, too, of course.

What feedback/suggestions would you offer to CROs looking to enhance their partnerships with PIs for more efficient and successful clinical trials?

My colleagues and I spend time listening to investigators and valuing their feedback, which we then incorporate into future studies. We also spend time and effort engaging with both the investigators and their teams to build and sustain relationships with them. We help connect investigators to help spread best practices and learnings and keep them informed of upcoming trials and happenings through newsletters and open days, for example. Fundamentally, it's about valuing the PIs and treating them as valued members of the wider team rather than items on a spreadsheet.

What role should they (CROs) play in providing training and educational resources to PIs, especially those new to clinical research?

In medicine, I always have considered the teaching and development of medical students and trainees of all specialties key to the future of healthcare. This same consideration is true in research, too. We need to support the next generation of researchers, as it's an investment in the future. My colleagues and I have helped develop new investigators, for example, by involving them in recruitment work and then supporting them as they build up to becoming investigators. We connect them with mentors and provide them with the tools and systems to ensure they deliver high-quality research. Supporting investigators, especially those new to clinical research, is important, and the support can be multifaceted. CROs are a key part of the clinical research ecosystem and they must be involved in nurturing the next generation of researchers.

About The Expert:

Dr. John Luke Twelves is a general practitioner (GP) and medical director at Lindus Health, where he combines both strategic and operational initiatives. Previously, Twelves was the CEO of a healthcare provider providing dermatology, ENT, diagnostic, and general practice services to the National Health Service (NHS) in England.