FormalPara Key Points

Patient engagement in drug development is evolving, as the design and running of clinical trials change. There is a need to demonstrate the value of this.

Technology-assisted ways of working, societal demand to improve inclusivity and diversity of patients in clinical trials present new opportunities for the incorporation of patients’ lived experience, preferences and needs into clinical trial design, implementation, and dissemination.

1 Introduction

The development of medicines was historically the domain of regulators, researchers and healthcare professionals. Patients who took part in the research were ‘subjects’ who remained anonymous and ‘complied’ with the protocol. Things changed following the AIDS epidemic in the early 1980s. Suddenly, patients and their community demanded to know what academia, regulators and industry were doing to find a treatment for the disease that was killing so many, and to have a say in that research [1]. From those early days of assertive advocacy, patient engagement (PE) in clinical development has evolved to the point where patients expect and demand that they are recognised as legitimate stakeholders who can contribute positively across the whole Research & Development (R&D) process. Indeed, some have argued that participation in clinical research is a societal obligation [2], and that the ability to do so should be a patient right [3]. It might follow, that the inclusion of patients in the design, execution and evaluation should equally be both an obligation and a right. The ‘PE movement’ referenced by Getz and others [4] focuses on the recognition that collaborating with patients (individual patients, their carer and their representatives) as genuine partners, incorporating their preferences, insight and lived experience into all aspects of clinical research is wanted, needed, important, and adds value [5,6,7,8,9].

The impact could be the improved use of patient-relevant outcomes and endpoints, more patient-convenient protocols and data collection methods, and faster study recruitment and retention rates—impacts that can be readily recognised as beneficial for patients and others alike [10]. Softer measures of impact such as improved patient empowerment and equality, where the patient voice is reflected in the decision-making process [11] can increase a sense of ownership of the data, contributing to mobilisation and diffusion of learning and knowledge, and reinforce the need for PE systematically, across the R&D process.

Following a period of hesitancy, the prominent rise of PE in R&D, and in many other aspects of healthcare over the last decade, has been driven by many sweeping changes to reciprocal partnerships between patient organisations and others, including industry, regulators, health technology assessment bodies (HTA), and academic research organisations. Globally recognised initiatives have provided frameworks, tools, and training to support and systematise PE. For example, the training of patients (e.g., European Patients’ Academy on Therapeutic Innovation [EUPATI] [12]), the proposing of standards and processes (e.g. Patient Focused Medicine Development [PFMD] [13] and National Health Council [NHC] [14]), the identification of optimal input into clinical trials (e.g. Clinical Trials Transformative Initiative [CTTI] [15], TransCelerate [16], input into regulatory discussions (e.g. Food and Drug Administrations’ [FDA] Patient Focused Drug Development [PFDD] [17]), and into research funding activities (e.g. Patient Centered Outcomes Institute [PCORI] [18] and the UK’s National Institute for Health Research [NIHR]) [19].

Despite progress over the past decade, PE in clinical research is still regarded by many as “fragmented” [11], adopting an “experimental posture” [4] and, “…embedding and systemising it in organisational decision making remains challenging…” [8]. This sentiment may reflect that some niche areas of PE (e.g., children and young people, elderly, parents of neonates) still require a more fundamental shift in mindset, strategy, and implementation before a truly systemic approach to PE can be realised.

In the last few years, the COVID-19 pandemic has accelerated changes in how clinical trials are performed, in ways that were previously either rejected out of hand or seen as highly speculative options for the future. These changes are reflected to a certain extent by a broader societal shift in accepting healthcare priorities, new technologies and ways of working [20]. Many clinical trials are also becoming more complex and expensive, partly due to the increase in innovative trial designs, a trend to decentralisation, and the study of complex, combination, and advanced therapeutic medicinal products (ATMPs) in potentially smaller populations [21].

These factors have led to a re-thinking and re-orientation of how clinical research is undertaken, and in turn how patients and their lived experiences and perspectives can be sought and integrated more intuitively in clinical research for better outcomes.

A number of questions are emerging for the near future that are relevant to PE across clinical research; How and when can technology-assisted PE be optimised? How can better equality, diversity and inclusivity of patients be realised? And how can the return on (patient) engagement be better demonstrated?

In this paper, the authors will reflect upon these last few years, the emerging trends in how clinical research is changing and some of the evidence being used to inform the design of clinical trials. In turn, we highlight some of the opportunities that this presents to improve PE in clinical trial design and conduct now and where we may expect PE in clinical research to progress in the near future.

2 Incorporating the Patient Perspective

2.1 A Matter of Terminology

The ability for PE to improve research is only as good as the way it is defined and operationalised [22]. While there is broad agreement that PE across all stages of research should be impactful, meaningful and measurable [5, 6, 11, 23,24,25,26], a number of terms such as patient engagement, patient involvement, or patient centredness have been used interchangeably by some, whilst others see subtle differences in terminology and context to be important. Some have argued that this led to the inappropriate and incomplete application of the underlying principles of meaningful PE [22, 27] and slowed progress. A recent systematic review from the Professional Society for Health Economics and Outcomes Research (ISPOR) patient-centred interest group highlighted differences in definitions of PE in published literature that relate to the healthcare delivery setting, compared with those that were specific to the research setting. A distinction emerged from the review between patient engagement specific to the healthcare setting (i.e., patient centred and patient as participant) and patient engagement specific to the research setting (i.e., patient as partner). The authors proposed a definition of patient engagement in research as follows; “The active, meaningful, and collaborative interaction between patients and researchers across all stages of the research process, where research decision making is guided by patients’ contributions as partners, recognising their specific experiences, values, and expertise” [22]. The important element proposed in the definition by Harrington et al is the patient as a ‘partner’ (i.e., where patient contributions are given equal weight to those of other contributors). The emphasis on PE as a partnership in the research setting, rather than a more general patient-centred approach is a helpful distinction to follow in the context of PE in R&D [11, 28].

If this unified definition of PE across the whole of research cycle is accepted then the principles of PE must be accepted and integrated at the organisational level, and guidance is now available, such as PFMD’s Book of Good Practices [29], PCORI’s framework and rubric [30], NIHs PE rubric [31] and EUPATI’s resources and modular training [12]. However, context matters. Different stakeholders apply PE principles to their needs and preferences, and given the independence and differing culture of the various stakeholders, acceptance of such a wide-ranging partnership definition may not be universal. A single industry-wide process map is unrealistic but cross-industry consortia and non-profit organisations such as TransCelerate Biopharma have developed a suite of evolving frameworks and guidelines to help the pharmaceutical industry move forwards. Public–private partnerships (PPP) such as the EU’s Innovative Medicines Initiative (IMI) and now Innovative Health Initiative, continue to provide a rich ground for multi-stakeholder progress on such matters [12, 32, 33]. Perhaps together they can set minimum expectations for PE, moving from a patient-centred approach towards a patient as a partner, and better ways to measure the impact of those partnerships on improving clinical research and its outcomes.

2.2 Patient Preferences and Patient Reported Outcomes

There has been a heavy focus on PE in clinical trial protocol design, and recruitment, retention and running of trials (e.g., enhancing data quality, frequency of sites visits, etc.) particularly in the later Phase II/III studies where the needs of regulators have to be met, and increasingly with an eye to the data needs of payers and HTA bodies. Arguably, more could have been done to incorporate patient perspectives much earlier, to inform early clinical development (such as Phase I/II trials), and even the setting of research priorities and questions that could better shape the research.

Improving the incorporation of patient preferences and patient reported outcome (PROs) into early clinical trial design and implementation may be an opportunity.

Patient preference information is defined by the Food and Drug Administration (FDA) as “qualitative or quantitative assessments of the relative desirability or acceptability to patients of specified alternatives or choices among outcomes or other attributes that differ among alternative health interventions” [34].

The potential role of incorporating patient preferences into decision making is gaining traction, and the value in clinical trial design is several-fold. For example, they can be used to help determine which research questions are more important to patients, which clinical endpoints are most relevant to patients (and indeed, those that might not need measuring), developing composite outcomes and defining the minimum clinically important difference [35, 36]. This may, in turn, inform sample size, enrolment criteria, and sub-groups for enrichment and analysis [37], interpretation of the results by researchers [38], and help ensure that studies meet the needs of the regulators [34].

Patient reported outcomes provide reports from patients about their own health, quality of life, or functional status associated with the health care or treatment they have received, with no prior data interpretation (by for example, a clinician) [39]. Patient reported outcomes have become commonplace to inform benefit and risk of treatment, real-world evidence generation, and as an input for clinical decision tools [40]. They can also complement patient preferences in clinical trial design such as during Phase I/II trials, by facilitating the assessment of preliminary efficacy and tolerability and using patient experience to inform dose selection for later-phase trials and future data collection strategies [41]. For conditions without objective outcome measurement, PROs can be used as primary outcome measures. Patient reported outcomes can also be used to complement primary outcome measures such as survival rates as they reflect components important to the patient such as symptoms and quality of life [39]. Patient reported outcomes can be accepted by regulators to inform decision making [42] but they can also inform payer, future provider and patient discussions, where a positive impact on what matters to the patient may be a critical ‘value add’.

3 Capturing the Value and Measuring Impact of Patient Engagement

The intrinsic value of dedicating time, resources, and money to systematically capture the patients’ lived experience into organisational processes and decision making remains challenging for many, particularly where it is seen as another ‘hurdle’ to get over in an already complex and time critical development process. Reported barriers to adoption include legacy culture and practices, lack of senior management buy-in, lack of organisational vision, lack of authority to drive cross functional support and implementation [43, 44], and the additional considerations and accommodations required when engaging with vulnerable and underrepresented populations (e.g. children and young people, elderly, parents of neonates) [11, 45].

One long-standing challenge is the lack of agreement as to what constitutes a return on engagement (RoE) from PE activities and how to evaluate impact [46,47,48,49]. In the absence of published evidence of financial value or a well-defined value proposition, systematic attempts have been limited [41]. Others argue that this is simply ‘the right thing to do’—transparently including patients in a multi-disciplinary process which will improve the quality and relevance of research [49]. Patient engagement should not be seen as an intervention to be evaluated—but as a process of knowledge exchange needed to integrate patient perspectives, needs and priorities [46].

One attempt to provide details of a RoE in financial terms used a standard risk-adjusted financial modelling to assess the hypothetical impact of a PE activity on a typical oncology clinical development programme entering Phase II and Phase III trials. Investing in a PE activity that avoided one protocol amendment and improved enrolment, adherence and retention was modelled to save $2.5 million and predicted accelerated development through to launch [44]. While a useful modelling exercise, the limitations of this exemplar are several-fold, not least that the modelled benefits are hard to prove and fail to capture the less tangible benefits such as improved data quality. There have, of course, been no examples of running a clinical trial twice—with and without PE. Additionally, PE rarely occurs in a vacuum—other activities to accelerate R&D are always ongoing in the background, yet often supported by very limited empirical and published data [50,51,52]. It is difficult to link PE activity to binary measures of saved time and money.

A review of PCORI’s evaluation framework for assessing long- and short-term impact of engagement in PCORI-funded comparative effectiveness research (CER) projects recognised that engagement improved refinements to research questions, design, study process and outcomes as well as improved recruitment and retention in clinical studies [53]. The self-reported nature of data in this evaluation, and that the feedback was given to the research funder, might have led to overestimates. Also, the contextual application to CER may limit its applicability and transferability to different contexts such as clinical trials of investigational medicines and devices.

A collaboration between the Drug Industry Association (DIA), the Tufts Centre for the Study of Drug Development and others took it one step further, to try to find a way to demonstrate when patient-centric initiatives (PCIs) can be practically implemented and to demonstrate the RoE. They defined 30 evidence-based metrics and performance indicators. Of the 8 metrics ranked most highly, 4 specifically relate to clinical trial design and implementation, and 5 are quantitative (changes to cost, patient numbers, drop-outs, protocol changes, and study duration) [54]. This not only identifies impact measures that industry could collect to help assess the RoE, but also identifies low-cost and high-impact PCIs, as well as those that are easy to implement. These include patient advisory boards and the use of social media for trial recruitment. Those that could result in high impact with sufficient resources and expertise include open design and crowd-sourcing clinical trial protocols.

A more holistic and contextual approach to demonstrating a RoE has been taken by the—funded IMI consortium PARADIGM, in developing a monitoring and evaluation (M&E) framework within a co-produced toolbox [32]. Using participatory action research and case studies, the consortium developed a M&E framework and a suite of metrics applicable to all stakeholders that can help with the measurement of different qualitative (e.g. patient knowledge and experience) and quantitative (e.g. patient adherence and compliance rates) components of PE activities that can be applied in different therapeutic areas and settings This has also been used by some partners at an organisational level [49]. The framework focuses on earlier phases of the research, including priority setting and early engagement with HTA bodies as well as clinical trials themselves. The framework stresses the need to prospectively identify the metrics to capture and measure before the PE activity takes place.

A successful legacy from PARADIGM has been the continuation of the Patient Engagement Open Forum [55]—an open, non-commercial, platform led by PFMD, EUPATI and the European Patients’ Forum (EPF), aimed to co-create tools to shape the PE ecosystem. While metrics are not explicitly used within the forum to capture the co-design improvements to those tools, the implicit value of co-creating solutions in real-time with large, global and diverse system stakeholders—including patients—is undeniably substantial.

The PARADIGM M&E framework is now being developed into an interactive metrics selector to help operationalise the framework further. Organisations can identify a multitude of possible key performance indicators (KPIs) or measurements that can be applied to a variety of situations, select KPIs based on different segmentation criteria, and have the flexibility to apply some metrics to activities that have not been specifically designed for (e.g., clinical or commercial settings). The metrics selector can be considered as a way of bringing many of the current methods, metrics and monitoring approaches together to help increase organisations’ PE intelligence as part of a more holistic approach to monitor PE practices and process and learn from them—this is called a ‘Monitoring to Learn Strategy’ [56]. It continues to use the open forum platform for maximum reach.

Recent efforts like this can help demonstrate and embed the value proposition of selected PCI that have the greatest impact on clinical research and to all the organisations involved. In turn, this can help organisations reorient and restructure cross-functional teams more dynamically to optimise their PE strategies and reflect the changes in the types of patients they engage with.

4 Technology-Assisted Clinical Trial Design, Conduct and Transformation

Continuous technological advancements, accelerated by changes adopted during the recent pandemic-related global disruptions to clinical trials, have significantly transformed the way that society interacts with each other and has presented opportunities for improving ways in which clinical trials are designed and conducted [57]. Some of these changes can also help accelerate PE in clinical trial design, conduct and dissemination. Changes range from new regulations (such as the Clinical Trials Regulation in Europe [58]) that encourage sponsors to include information in the clinical trial application as to the patient involvement in the design of the protocol, improved study design and retention to better match the characteristics of the trial populations to the real-world populations [59], and the adoption of technology-assisted solutions.

Flexibilities introduced by many global regulators during COVID-19 related to clinical trial disruption, attempted to maintain trial continuity and patient safety. These flexibilities included, for example e-mailing of consent forms, shipping drugs and devices to participants’ homes, data collection through electronic participant-reported outcomes, and remote monitoring visits via digital access to electronic health records [60,61,62]. Trials without face-to-face interactions are not new, and have been gaining traction for some time to address some of the long-standing limitations of site-based trials such as poor recruitment [63,64,65], exclusion of participants in full-time employment, disabilities, carer responsibilities or other characteristics that make involvement difficult. Employing digital and other innovations to move clinical trial activities to a participant’s home or local setting—remote decentralised clinical trials (RDCTs) may be preferred by many trial participants [66], improve recruitment and retention rates, and earlier trial completion [67]. One large public-private partnership, Trials@home [68] is exploring ways to implementing RDCTs and identify the value of engaging patients in activities such as identifying the research question, creating recruitment materials, designing apps and websites (where patient interface occurs with study materials e-consent, survey completion, including PROs and routinely collected data), and providing ongoing feedback to trial participants.

The adoption of technology-assisted solutions in clinical trials such as smartphone apps and wearable devices has increased and has been largely well received by a diverse population of patients [69]. The inclusion of convenience-enhancing solutions offers the parallel opportunity to co-create those solutions with patients, covering issues such as work schedules, social media habits, childcare needs, and caregiver involvement [70].

Not all types of trial or elements within a given trial naturally lend themselves to successful remote function—from the patient’s perspective at least. Patient input can highlight those aspects that are most suited to either fully remote, hybrid or traditional site-based running. However, the optimal mode of engagement relative to the patient population, and the engagement activity, have yet to be properly explored beyond some rudimentary guidance [71]. The impact of the transfer of trial activity burden onto participants and remote-working research staff [72] will be important to consider.

5 Broadening Inclusivity in Clinical Research and PE

Broader use of technology-assisted methods and tools for PE can be used to increase not only inclusion (although some argue it can lead to digital exclusion) but equality and diversity—especially in populations that have long been under-represented or that carry a disproportionately high burden of chronic diseases [73]. The underrepresentation by ethnicity has been shown in a study of new drug trials in the USA in 2020 where only 8% were Black, 6% Asian, and 11% Hispanic [74] compared to census data of 14.2, 7.2 and 18.7%, respectively in the population [75]. Women, elderly, children, and those with physical or mental disabilities are also often underrepresented in trials [76,77,78]. Some of these issues can be attributed, at least in part, to a lack of trust between some patient communities and the pharmaceutical industry. However, most can be attributed to ways in which trials are designed and delivered—examples are: strict eligibility criteria, clustering of trial centres in central urban locations—often in university hospitals (excluding those in less accessible or under-served areas), and the assumption that later clinical studies can address the earlier exclusion of some key populations [78,79,80,81,82]. This can lead to a lack of data, both safety and efficacy, beyond those patients studied.

Strategies to improve inclusion in clinical trials are complex, multifaceted, and contextual, but PE strategies and practices can also play a part here. For example, in supporting transparency and improved communication, establishing and maintaining diverse community advisory panels in the clinical research process and co-designed recruitment protocols are useful [83, 84].

Recent guidance from the FDA [85] and funders such as the UK’s NIHR launched the INCLUDE ethnicity framework and toolkit in 2020 [86] detailing more inclusive trial enrolment practices. While much is focused on steps to improve diversity of participants in clinical trials [87], those principles and approaches should be adopted in end-to-end PE practices, process, and organisational alignment towards them. It seems logical that the greatest chance of the success of a clinical development programme (from development to patient and population health improvements) is to have the bidirectional engagement, education and partnership with the patient communities that are likely to benefit the most from the innovation being developed. For example, community-based participatory research has been shown to improve recruitment of underserved minority groups [88], and can help alleviate long-standing issues of mistrust and exploitation of some groups [89,90,91].

5.1 Paediatric Needs

Beyond diversity are attempts to better balance the number of paediatric-specific clinical trials and better incorporate the voice of youth populations in clinical trial design and dissemination. Significant numbers of children (~ 50%) and neonates (~ 90%) are still treated with medications that are not approved for use in their age group, due to a lack of clinical trials involving younger children and neonates [92]. Almost one-fifth of paediatric trials fail, mainly due to recruitment problems [93] because the protocol design is not suitable for the paediatric population. Marketing authorisation applicants are now obliged to include a paediatric investigation plan (PIP) in the regulatory submission if the disease also exists in children.

Groups such as the International Children’s Advisory Network (iCAN) [94] and European Young Person’s Advisory Group Network (eYPAGnet) [95], Paediatric Clinical Research infrastructure Network (PedCRIN) [96], and Conect4children (c4c;Collaborative Network for European Clinical Trials for Children) [97] provide advice, tools and education, and involve children and families in the design and delivery of paediatric clinical research. The International Children’s Advisory Network and eYPAGnet have frequently explored ways in which researchers may be able to improve the design and create content for assent forms for various clinical developmental stages (age and language appropriate) [98, 99]. Engaging youth in clinical research design (shorter, more frequent clinical visits, engagement that does not impact school attendance or work balance of parents) and using technology and social media assisted engagement as appropriate [11] are possible approaches.

6 Policy and Regulation Changes in Trial Conduct and Reporting

The year 2022 marks the evolution in clinical trials in Europe with the implementation of the EU Clinical Trials Regulation (CTR) and Clinical Trials Information System (CTIS). Legislative and non-legislative changes come into full force focusing on the increasing need for transparency in clinical trial reporting and creating new opportunities for PE—most notably in requiring trial sponsors to publish their results in lay summaries for all new clinical studies. For clinical trials in adults, the lay summary must be submitted no later than 12 months from the end of the clinical trial—irrespective of the trial outcome, and within 6 months for paediatric studies [100]. Developing clear, transparent, timely, publicly-available information, and if co-created with patients [101], becomes a valuable mechanism for dispelling public concerns that trials are part of an opaque black-box procedure and could improve trial recruitment, retention and inclusion of underserved population [102]. The UK’s regulator, the MHRA is consulting on something similar, by requiring the involvement of “people with relevant lived experience in the design, management, conduct and dissemination of clinical trials…”. This moves beyond the current Research Ethics Committees expectation, but not yet a legal requirement, for patients and the public to be involved in those research processes [103].

The FDA’s methodological patient-focused drug development (PFDD) guidance on collecting and submitting patient experience data from patients and caregivers for medical product development and regulatory decision making continues to gain traction [17], and related guidance is finally expanding to solidify PE in medical device clinical trials [104]. Furthermore, the EMA are continuing to take steps to improve the collection and use of patient experience data in the end-to-end medicine development and regulation in the EU [105]. At the same time, the rare disease legislation is under review in the EU. While it does not specifically cover PE in clinical trials, moves to incentivise clinical trials in rare diseases and paediatric populations could have positive effects on PE in those populations [106] and further close the gap of the required mind shift for meaningful engagement with these populations.

7 Future Perspectives

From modest beginnings a decade ago, the benchmark has been set by those such as EUPATI (celebrating 10 years in 2022) and others to help embed PE beyond just clinical trials. Increasingly, organisations are orienting themselves strategically and structurally around evolving a more holistic PE approach. Now more than ever, all actors can leverage booming technology-assisted methods to capture and integrate the patients’ lived experience across the whole of R&D. With these opportunities comes greater responsibility and public accountability that clinical trials are designed, delivered, and disseminated appropriately to meet the needs of the population(s) where the innovation is ultimately intended. This requires a sustainable shift in mindset in capturing and incorporating the patient voice within and across clinical trials with the patient as a partner. In many aspects, progress in clinical trials has perhaps been the most visible to date, but more work needs to be done with traditionally under-represented populations. Sustaining these partnerships long term may allow improved representation and trust.

Questions remain how the top down (legislative) versus bottom up (ecosystem evolution) levers for incorporating PE in clinical trials will balance out over time. It is also uncertain what the natural limits might be to technology-assisted ways of working, such as crowd sourcing patient input into clinical trial design, electronic consent, remote trial data collection and clinic visits, or using block chain technology to match patients to clinical trials using patients’ electronic health data.

8 Conclusion

What is clear is that opportunities to enhance PE in clinical trials have improved—but more needs to be done. The expectations of patients, regulators, payers, and funders alike continue to shape many of the opportunities for improved PE. The momentum of progress is increasing, but it needs a shift in mindset, followed by strategic and practical approaches. The implications of this should be that the rationale, methods, and value of incorporating the patient voice as a legitimate stakeholder in clinical trials will be uniformly accepted, broadly streamlined, and will contribute to driving more effective and responsible innovation.