By William van’t Hoff, M.D., consultant pediatric nephrologist at Great Ormond Street Hospital (GOSH) for Children and director of the National Institute for Health Research (NIHR) GOSH Clinical Research Facility
Good recruitment and retention is critical to the success of clinical trials. Get it right, and a trial will likely achieve its primary objective; get it wrong, and the time, effort, expense, and any patient participation is likely wasted. This article discusses how a new national approach to involving patients and the public in the U.K. is helping life sciences companies get it right the first time.
In the U.K., huge efforts have been made to improve recruitment into clinical trials and had justifiable success. Last year, the National Institute for Health Research (NIHR),1 which supports and monitors 70 percent of the clinical research in England,2 published record levels of research participation. A total of 725,333 people took part in clinical research (both commercial and non-commercial) during 2017-2018, a 22 percent increase from 2010-2011. For commercial contract research alone, there has been an impressive 258 percent increase in recruitment to 50,112 participants in 2017-2018 from 13,987 over 2010-2011.
However, there is still much work to be done. Alongside growing public awareness campaigns, work is underway to develop patient/public engagement activities to become more impactful in supporting recruitment and retention. To understand how such activities can achieve this aim, we first need to examine some of the issues that affect a patient’s decision to participate in, and complete, a research study. Some factors are specific to patients, some relate to the study design or processes, some affect the ability of healthcare staff (usually — but not exclusively — doctors) to conduct the study, and others pertain to societal attitudes toward research or standards for research.3
Study Protocol’s Impact On A Patient’s Decision To Participate
The study protocol is the key determinant in supporting successful recruitment. For instance, an early-phase study will usually be intense and designed primarily around safety rather than benefit. In this situation, patients and their physicians need to feel that the intensity is relevant and acceptable to the condition being studied (e.g., cancer or other life-shortening disease). Conversely, a study for an intervention in healthy people (e.g., vaccination, contraception) should recognize the normality of their lifestyle, focusing on data collection in the home or community and minimizing hospital visits and invasive tests.
Study design and conduct is led by the research team but also strongly directed by other influences, including safety issues, scientific and statistical requirements, practical constraints, sponsor timelines or imperatives, and, importantly, regulatory authorities. All of these affect protocol development.
While the overall aim of both the researcher and regulators is to ensure a safe and effective study, some elements of study design can disproportionately affect recruitment and retention. For example, the Paediatric Regulation, which came into force in the EU in 2007, obliged companies to screen their product for potential use in children and, where relevant, to undertake prescribed studies in children prior to marketing authorization. Overall, this has been positive for children’s medicines and research. However, there have been instances where the complexity and intensity of the trial, as required for regulatory submission, have been seen by investigators and potential participants as too burdensome and resulted in the trial being stopped because it failed to recruit. In short, despite the best of intentions, a study aiming to improve patient care can become so complex that the very patients it seeks to support are unable to participate.
Finalizing the protocol to accommodate the aforementioned factors enables the information for potential participants to be written and, again, numerous factors determine the format and content. In parallel, potential sites and investigators are sought to conduct the study, traditionally with a preference for key opinion leaders in the condition or disorder being studied. While acknowledging their expertise, such leaders are frequently heavily committed with research programs and may not have capacity to prioritize study setup and recruitment which, in turn, can also affect the success of the study.
Finally, after all the approvals are in place, potential participants are invited for screening. This is often the patient’s first opportunity to have a say on a study designed for them but usually not with them. It seems a bit late at this point to find out the patient’s views on whether the study protocol and practicalities are appropriate for them to consider participation. The balance is weighted if the patient has a life-threatening or life-shortening illness. In these cases, any treatment option may be worth trying and “new” seems better to many than standard of care.
Not surprisingly, researchers are interested in why some research studies and trials fail. Cochrane Reviews, focus groups, and qualitative research methods are being applied to identify what does or doesn’t work and to determine improvements.4
Obstacles To Patient/Public Engagement
Given the factors described above, it would seem sensible to assume that focusing patient/public engagement activities at the protocol-development stage could make the study more patient-friendly than, for example, inviting patients to provide feedback on a leaflet after the protocol has been finalized.
However, such activities bring a different set of challenges and considerations, particularly where the research is funded and sponsored by a life sciences company, such as:
Keith Wilson, patient research ambassador for Liverpool Heart and Chest Hospital NHS (National Health Service) Foundation Trust, has helped to shape a number of clinical research studies in recent years and is now paid by the NHS to encourage patients to become involved in clinical research. He cites similar concerns from a patient and public perspective, particularly around the perceptions of the life sciences industry:
“I believe the main challenge in the past has been around trust. Patients/public have historically been wary of the life sciences industry, and some may still harbor some misconceptions. Through my work representing patients, I’ve learned life sciences companies are not just driven by profits; they want that next breakthrough, they want to make a good product, and they want to improve quality of life for patients. But these companies deal in commercially sensitive information which could be misconstrued as failing to be open or transparent, which reinforces those negative misconceptions.
“But patients and the public can be a real asset to life science companies. We have a very different views than clinicians and scientists, so we can spot the challenges to study recruitment and retention, and often the solutions, that companies sometimes miss. I find this is because companies tend to focus more on the end point than on how to get there. For example, the recruitment strategy for one study I helped review included giving contact cards to patients in the ward. We pointed out that hospital gowns do not have pockets and that most cards would end up being left behind in hospital bedside cabinets — something easily overlooked.”
A National Initiative Aims Increase Patient Engagement
In the U.K., a project is underway which aims to address some of the challenges and issues identified here, while simultaneously harnessing the power of the patient’s perspective. The ambition is to establish a national framework for patient engagement with a clear route for life sciences companies to engage with relevant patient groups that can help clinical trial design at the protocol development stage. Throughout 2018, the NIHR’s Clinical Research Network collaborated with a global pharmaceutical company, Pfizer Ltd, to design and pilot this new service and, having overcome compliance and legal challenges, the model is currently being tested by a number of early-adopter life sciences companies.
The service is a “cost-recovery” extension of the NIHR’s Study Support Service (which is free). It aims to create a level playing field on a national scale in which patient/public engagement activities can take place unhindered and comprises:
The pilot involved two Pfizer studies looking at a new treatment for atopic dermatitis (eczema), which are both pediatric and adult studies. Two facilitated meetings took place at Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, firstly with a group of young people5 and then with a group of parent/carers. The young people’s feedback was used to shape the informed consent and assent documents, and the clinical trial design was adapted following consultation with the parents/carers.
Sophie Evett, feasibility lead for Pfizer UK, who led Pfizer’s participation in the pilot, reflects on the benefits of being involved in the pilot from a life sciences company perspective:
“At the study level, the clinician who wrote the protocol met with both patient groups in person, as did my colleague who supports recruitment for Pfizer globally. They were surprised at some of the questions they were asked by the young people in particular. Some of the questions were very scientifically technical — for example, around how the drug might alter your immune system and what effects that might have on the body. The young people were not afraid to say what they felt and were very clear about what they wanted to see included in the informed consent and assent document. For the adult study, one element of the draft protocol relating to prohibiting other medications was amended as a direct result of engagement with the parents/carers, and the study has since been approved to move to site-selection stage.
“Looking at the pilot more broadly, it took a little longer than expected to satisfy our legal and compliance teams initially, mainly because it was a completely new way of working. However, it was a worthwhile exercise because it enabled us to work through the many legal and compliance challenges and develop documentation that we can use time and time again for patient engagement activities, regardless of the study, patient group, or therapeutic area.
“Throughout Pfizer, all studies now need to have some level of patient engagement into the protocol and study documents in order to achieve approval to proceed to execution. We are already planning to use the NIHR service again to help meet those requirements. We have several clinicians who are keen to learn more about the service and a number of studies in the pipeline that are suitable, including a Lupus study for which we already have a patient group that has expressed an interest in working with us.
“Other companies looking to engage with patients in the U.K. will certainly benefit from the work we have done and be able to quite quickly and efficiently engage with patients. I can’t image that we left any legal or compliance stone unturned, so I am reasonably confident that the service will fit their needs without having to do too many amendments to the service documentation.”
In the past, the idea of life sciences companies involving patients in the design and improvement of clinical protocols was virtually unheard of. However, like Pfizer, most life sciences companies are embracing the patient engagement agenda and, as a result, we are entering a new era of collaboration. #PatientCentricity has become the new conference buzzword, and many examples of the methodology behind patient engagement, and practical examples of how this works in practice, are emerging. A common theme in some of the more effective examples is the need for a trusted organization to act as a go-between — a role that the NIHR is undertaking.
Of course, it would have been absurd to develop this service without consulting patients/the public on the design and delivery, and Wilson is one of many patients who worked with NIHR to develop the pilot. “I thought the pilot was a great idea and long overdue,” he said. “But at the same time, I was initially skeptical that the project would achieve the desired outcomes. Having the NIHR — which has worked in partnership with our NHS for over a decade — facilitate the service has made an enormous difference. Patients in the U.K. love their NHS, and if the approach comes from the NIHR, patients and members of the public are more open to having those direct discussions with life sciences companies.
“My view is that the research should be designed to fit the patient, not the other way around. I firmly believe involving patients from the very beginning, at the protocol-development stage, increases the chance of getting it right the first time. We now have a genuine opportunity to further improve research recruitment and retention in England. Admittedly, it was a leap of faith initially, and without the NIHR we’d probably still be talking about it rather than doing it.”
About The Author:
Dr. William van’t Hoff is a consultant pediatric nephrologist at Great Ormond Street Hospital (GOSH) for Children NHS Foundation Trust, London, and director of the National Institute for Health Research (NIHR) GOSH Clinical Research Facility. He has also held local and national leadership roles in the NIHR Clinical Research Network Children’s Specialty. Van’t Hoff is an active paediatric researcher with a long-standing interest in involving young people in shaping clinical research. He has led the development of Generation R, a children and young person’s national initiative through which they can seek to improve research. In 2016, he was appointed clinical director for NHS Engagement for the NIHR Clinical Research Network, working across all ages and specialties to lead the strategy and coordination of the organization’s approach to helping the NHS recognize the importance of research in improving health.