Introduction

The goal of healthcare systems and practitioners has always been to deliver better health outcomes for patients. However, despite the best intentions of working to achieve this goal, healthcare has historically made decisions for patients without actively involving them (i.e., without patients co-creating and co-implementing care and research models). This omission was largely because the burden of illness used to be driven by acute diseases that required immediate care by the physician with little or no time for patient input. Twentieth century advances in medical interventions have led to the emergence of chronic diseases as the dominant cause of illness [1], a setting in which the patient has a significant role in both primary prevention and treatment, and therefore has valuable experiences and insights to share. Numerous studies have shown that partnering with patients to address their clinical health needs delivers better outcomes, including satisfaction by both patients and practitioners, and often at reduced cost to society [2,3,4]. The value of partnering with patients now extends beyond clinical care, into a wider range of healthcare decisions. A recent comprehensive report by the Council for International Organizations of Medical Sciences (CIOMS) highlights the importance of also involving patients systematically and meaningfully throughout medicines lifecycle and development, including in regulatory processes, and provides consolidated evidence for the benefits of patient involvement [5].

Patients and those who look after them (such as family members or friends) have unique and relevant insights into the ways that a condition and its management impact day-to-day life. As such, diverse health stakeholders are increasingly seeking to engage with the patient community for their lived experiences and preferences in terms of treatments, risks, and outcomes. According to the US Food and Drug Administration (FDA) Patient-Focused Drug Development guidance, patient engagement (PE) is defined as “activities that involve patient stakeholders sharing their experiences, perspectives, needs, and priorities that help inform FDA’s public health mission” [6]. The term patient involvement is also widely used, sometimes interchangeably with PE [5, 7] but also with a variable meaning that can encompass more than “engagement”, depending on region and stakeholders. Although the two terms may have slightly different interpretations and understanding [8, 9], they both refer to the concept of bringing patients and their experiences, insights, and perspectives into decision-making processes with the aim of ensuring that decisions are rooted in the needs and experiences of patients. Community engagement is also used as a wider term and encompasses a concept beyond the scope of this work; therefore, we have focused on patient engagement as only one part of community engagement. Regardless of the language used to define patient input, both the engagement of patients in the process (PE) and the consideration of evidence on the patient perspectives and impacts (patient experience data [frequently referred to as ‘PED’ but as ‘PXD’ in this article to differentiate from ‘PE’]) are required. The goal is to inform and drive evidence-based decision-making through the collection and consideration of patient insights provided from patient-involvement practices, alongside evidence and data that capture the real-world experiences, preferences, and needs of patients. In this paper we use the term PE to refer to not only the act of interacting with patients, but also to a more meaningful, active, long-term, two-way collaboration with patients as valued, true partners in the development of medicines and medical technologies throughout the entire product lifecycle. Our definition of patient involvement or PE describes meaningfully working with patients systematically, over a period of time with a focus on delivering better outcomes.

Health technology assessment (HTA) and regulatory practices are deliberative processes that make judgment calls on available evidence; they require different stakeholders to consider the relative importance and impact of the evidence under review. Many HTA and regulatory bodies have long recognized that patient input is needed to provide the patient context in these deliberations, and they are increasingly including patients in decision-making processes that impact medicine and technology development [10]. As such, PE in regulatory practices is not new and has been embedded in some decision-making bodies since the late 1980s, with one early example being the establishment of the FDA patient advisory committee on HIV/AIDS in 1988 [11]. While PE has been used to date, to provide the insights needed to inform regulatory and HTA deliberations, and patient groups contributed to these decisions with their own evidence, decision makers lacked a systematic framework for patient-focused evidence. The need for further well-designed, robust evidence to provide additional clarity on the patient perspective and across a wider group of diverse patients was identified as a critical gap. Moving beyond the ad hoc collection and occasional consideration of patient evidence, the term and concept of PXD as a class of evidence that needs to be considered has emerged. The FDA defines PXD as “information that captures patients’ experiences, needs and priorities related, but not limited to: (1) the symptoms of their condition and its natural history; (2) the impact of the conditions on their functioning and quality of life; (3) their experience with treatments; (4) input on which outcomes are important to them; (5) patient preferences for outcomes and treatments; and (6) the relative importance of any issue as defined by patients” [6]. In this article, which also provides an update of a previous landscape analysis [10], we examine recent developments and evolving PE and PXD resources by geography in regulatory and HTA processes.

Methods

Project Design and Structure

The project took a phased approach, starting with the collection of information/publications on guidance, initiatives, and resources for PE and PXD in regulatory and HTA processes. Approximately 100 contributors and collaborators were approached directly through the “Patient Focused Medicines Development (PFMD) PE and PXD Project” to provide their input and signpost to potentially relevant information. This information (along with results from the literature searches described later) was then compiled into a draft report and landscape analysis (by Daniela Luzuriaga and Gary Finnegan) and disseminated to approximately 25 contributors (who were all members of the PE and PXD Project) for review and consultation. Feedback on the draft report was received from 13 core contributors who further contributed to and refined the landscape analysis. The 13 core contributors represented seven different stakeholder groups: patient representatives/patient advocacy groups, regulatory, HTA, academic research organizations, pharmaceutical industry, consultancy, and PFMD (Supplementary Table 1; Fig. 1).

Fig. 1
figure 1

Breakdown of the 13 core contributors by stakeholder group. (Please note that one of the contributors falls under both academic research and patient organization, and so is counted twice). HTA, health technology assessment; PFMD, Patient Focused Medicines Development

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Contributing members of the PE and PXD project were identified through PFMD and PFMD member networks, through participation in previous PE projects, and contribution to SYNaPsE—a platform of PE practices and initiatives. Members were invited to participate in the project and contribute to the analysis based on their expertise in PE and/or PXD, prior experience in managing, collating, developing, and using PXD, and/or their lived experience as patients. In line with good PE practices, patients were active participants in the project throughout, alongside industry and other stakeholder-group representatives. The contributors pulled in insights and examples from their networks including Health Technology Assessment International (HTAi), the Centre of Regulatory Excellence, the FDA, and the European Medicines Agency (EMA). Per International Committee of Medical Journal Editors criteria [12], core contributors were also invited to be authors of this paper.

Identification of Global PE and PXD Resources

Google search engine was used to conduct a broad literature search (from August 2021 to January 2023) using keywords around PE and PXD, including “HTA”, “regulators”, “patient engagement”, “patient experience data”, “guidance”, “initiative”, “FDA”, and “EMA”. In addition, a search of “grey” literature (public information available outside of scientific or peer-reviewed journals) was conducted. This search scope included sources such as relevant research, annual reports, public hearings/conference proceedings, webinars, and data updates from the following government health authorities, professional organizations, and regulatory and HTA bodies: CIOMS, EMA, FDA, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), Medicines and Healthcare products Regulatory Agency (MHRA), Pharmaceuticals and Medical Devices Agency (PMDA), Canadian Agency for Drugs and Technologies in Health (CADTH), Center for Drug Evaluation (CDE), the Japan Agency for Medical Research and Development (AMED), Agency for Care Effectiveness (ACE), HTAi, Institute for Clinical and Economic Review, and Europe Network for Health Technology Assessment (EUnetHTA). Contributing members (see Supplementary Table 1) identified additional relevant resources and comprehensively evaluated the research.

Assessment of the Main Focus Area of Global PE and PXD Resources

We conducted a broad thematic analysis to assess the main focus area of each resource and whether there was systematic and clear integration of PE and PXD in the approach described. Resources were reviewed for alignment with the time period of the current analysis and relevant focus on PE and PXD, and were categorized by region and stakeholder group. Information and descriptions from the title, objectives, and (where available) outputs of the resource were used to categorize its focus area as either primarily PE, primarily PXD, describing both PE and PXD but separately, or describing an integrated PE and PXD approach. Each resource was reviewed separately by a subgroup of the project team comprising four PFMD members with multiple people reviewing different resources. Where the focus area was unclear, this was discussed within the subgroup to reach consensus on thematic interpretation; categorization results were also shared with core contributors for their review and validation.

Results

Global PE and PXD Resources in Regulatory and HTA Processes

The landscape review and analysis provided further evidence for the growing momentum to include PE in the decision-making of global regulatory and HTA bodies with an increase in the number of relevant resources and initiatives identified compared with the previous landscape analyses (53 vs 27) [10]. The current literature search yielded a total of 63 unique PE and PXD resources (comprising initiatives, projects, and papers) in regulatory and HTA decision-making. Of these, 10 were not included in this landscape analysis following review either because they were outside of the time period for the current analysis (five resources) or because they were not relevant for the focus of PE and PXD (five resources). This report focuses on the remaining 53 initiatives and projects, of which 14 were considered global, 11 were from North America, 11 were European in origin or focus, nine were from Asia, six were from the UK, one was from Latin America, and one was from Africa (Table 1). Examples of resources that represent current PE and/or PXD initiatives in different regions are summarized in the following sections and in Table 2 [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34].

Table 1 Current global patient engagement (PE) and patient experience data (PXD) resources in regulatory and health technology assessment processes
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Table 2 Examples of patient engagement (PE) and patient experience data (PXD) initiatives in different regions
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Initiatives in Europe

In the European Union, the EMA continues to make patient involvement and the collection of PXD a priority [35], including through the admission of patients as members of the EMA board and the decision to regularly invite patients to attend meetings and public hearings [36]. In addition, the EMA Engagement Framework provides a platform and roadmap for EMA’s engagement with patients and other stakeholders (Table 2) [16, 37,38,39]. HTAi has established several initiatives to explore optimization of patient ideas in terms of effectively incorporating them into decision-making, and to better understand the impact of patient input in terms of different stakeholder perspectives (Table 2) [17]. The Innovative Medicines Initiative-PREFER (IMI-PREFER) has produced a framework outlining how patient perspectives could be measured through patient preference studies and incorporated into regulatory decision-making [18]. The EMA acknowledged this as an important reference document but noted that there were some limitations in providing a concrete framework due to the limited experience with patient preference studies [40].

Schroeder and colleagues stressed the importance of multistakeholder collaboration in PXD approaches [41] and global health agencies have several ongoing initiatives to promote stakeholder collaboration in the use and generation of PE and PXD. In Europe, the EUnetHTA works toward building collaborations between various HTA agencies, and in September 2021, a 2-year service contract was signed by the European Health and Digital Executive Agency for the “Provision of Joint Health Technology Assessment (HTA) Work Supporting the Continuation of EU Cooperation on HTA”[19, 42]. This joint work plan has identified several areas of focus (including methodological deliverables and guidance for stakeholder interactions), and recognizes that implementation needs to be flexible, to support work towards a legislative framework on European HTA cooperation (Table 2). EUnetHTA has also developed 43 relative effectiveness assessments with an emphasis on patient involvement. The assessments are considered generalizable across countries, aiming to reduce duplication in HTA production [43]. However, it has been noted that timely patient involvement remains to be addressed along with guidance on how to demonstrate visibility of patient contribution [44].

In the UK, the MHRA aims to make consideration of patient perspectives a mandatory part of all clinical trials, and their Patient Involvement Strategy also establishes objectives for multistakeholder partnerships [20]. The UK’s Centre for Research in Public Health and Community Care provides advice to health researchers on giving feedback to patient and public contributors [21]. The National Institute for Health and Care Excellence (NICE) in England and Wales uses real-world evidence (RWE) including patient experiences to inform their guidelines and health technology appraisals, and it recognizes that such data could be used more routinely than currently to address gaps in evidence and speed up patient access to health interventions [22]. NICE therefore launched a framework in June 2022 to identify when RWE can be used to reduce uncertainties and improve NICE guidance, and to describe best practices for organizations to plan, conduct, and report studies (Table 2) [22].

Initiatives in North America and Brazil

In the United States, the FDA has published a series of detailed guidance documents as part of their Patient Focused Drug Development (PFDD) initiatives to help stakeholders collect comprehensive and representative data and answer the question of what matters most to patients [23,24,25,26]. In a study conducted by the Medical Device Innovation Consortium, a working group of 17 experts reviewed a series of case studies to help identify the best practice for using patient and public involvement (PPI) to inform clinical trials [45]. The study led to the development of a PPI-Clinical Trial Framework, which identified several considerations for regulators wanting to include PPI in clinical trial design (Table 2). The Patient Insights Database also aims to support early inclusion of patients in clinical trial design and resultant decision-making [29]. Strides in PE have been made in the rare disease sector, where patient populations are small but often highly motivated. Working alongside patients who suffer complex and rare diseases can be crucial to finding treatments and for disease management [46]. Nicod and colleagues have provided recommendations on appropriate use of patient-reported outcomes (PROs) and health state utility values in HTA decisions for rare diseases [47].

Ways to incorporate patient feedback and input into medical technology and devices are also being explored. For example, the FDA’s Center for Devices and Radiological Health released two guidance documents in 2022 on the use of PE in medical device development (Table 2) [30, 31]. Canada’s Drug and Health Technology Agency (CADTH) have included ‘partnerships’ with patient communities (including individual patients, their families and caregivers, and patient representatives) and a pledge to work together ‘to improve and strengthen the quality and significance’ of their work, as a key element of their 2022–2025 strategic plan [48]. In Brazil, a legislative mandate for social participation makes public involvement in HTA processes compulsory. Recommendations have been made for a more systematic approach through “expansion of communication, capacity building, and transparency”, to maximize benefit from such participation [49].

Initiatives in Japan, China, and Singapore

PPI in clinical trials/research in Japan is a relatively new endeavour [50], and until recently, examples of PPI in clinical trials were isolated cases [51, 52]. The starting point of national initiatives was a project led by the Japan Medical Agency and patient groups and supported by the Ministry of Health Labour and Welfare (MHLW) and AMED through a national survey held in 2017. The outcome of this survey, the PPI Guidebook, was published in 2019 in Japanese [53], and in 2022 in English [51]. The Ministry of Health Labour and Welfare has also emphasized the necessity of involving trained patients from the planning phase of clinical trials and in proposing patient-oriented outcomes [54, 55]. In addition to AMED, the PMDA in Japan has published a guidebook for patient centricity and is advancing PE in several sectors [32]; both organizations are beginning to collaborate with other stakeholders. China has also published guidelines around a patient-centred approach to drug development using PROs [33, 56]. With the aim of boosting patient participation in HTAs, Singapore set up the Consumer Engagement and Education agency, and in November 2021 a special dialogue was held for patient and volunteer organizations to publicize their work on PPI (Table 2) [34, 57, 58].

Initiatives in Africa

The African Medicines Agency (AMA)—the second African health agency to help regulate medical products—was recently established to “enhance regulatory oversight and facilitate access to safe and affordable medicines across the continent” [59, 60]. The agency will also focus on harmonizing current regulatory policies/standards and will provide scientific guidelines. Although this is not directly a patient engagement or PXD resource, it does signal a move towards a regulatory system built for and by African people themselves and will promote domestic production and development of medicines within Africa. In turn, this will provide opportunities for direct patient engagement locally, along with initiatives and development of medicines directed towards patients of African descent.

Emerging Global Initiatives

Clinical RWE and the incorporation of PE into the design of RWE studies are areas where PE/PXD is still limited; however, other regulatory authorities (in addition to NICE in the UK) are considering how RWE can inform regulatory decision-making. Following a workshop in June 2022, the International Coalition of Medicines Regulatory Authorities issued a statement identifying opportunities for regulatory authorities to collaborate in this area [13]. PFMD has co-created a Global Patient Experience Data Navigator tool to help navigate the increasingly complex PXD landscape and to add clarity and structure to understanding the “what, how, when, who, and why” of PXD. The Navigator has been designed to be relevant for diverse stakeholders and can be used to help ensure that PXD focuses on impacts that have been identified by patients as most important and meaningful, reviews available PXD measurement tools and methodologies, identifies which stakeholders are using PXD and how it is being used, and understands the impact of PXD use on decision-making [15].

Impact of Patient Contributions on Decision-Making

While there are many examples globally of patient contribution to regulatory decision-making, there is still limited documentation of the impact of such contributions [61, 62]. However, there are some insights; for example, in Europe, patient input is an established part of the medicine development process for all scientific advice provided by the EMA. A recent case study examined the extent and value of this input over a 4-year period [63]. The study quantified the number of patients involved and in which areas they contributed (Fig. 2). Importantly, patient input was shown to directly impact 52% of the cases, leading to further reflection, and in 20% of the cases, PE led to modification of the final advice letter, indicating a direct and tangible impact. The EMA also quantified the contribution of patients and healthcare professionals to their work during 2020–2021; it found that patient contributions outnumbered those of healthcare professionals across committee consultations and review of documents [64].

Fig. 2
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Case study of patient contributions to scientific advice provided by the EMA. The number of patient contributions and how they contributed to various aspects of scientific advice provided by the EMA was assessed as part of a 4-year case study. *In most cases where patient input did not make a change, most of the patients agreed with the development plan set out. EMA, European Medicines Agency

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In their guidance for providing patient input to inform reimbursement reviews, CADTH describes the development of patient input summaries and how the patient contribution is used by their clinical and economic teams, in the CADTH clinical report, and to inform development of the review protocol [65]. The Scottish Medicines Consortium encourages patient input through its patient group submission process and has established Patient and Clinician Engagement (PACE) meetings that can be used where more detailed input is valuable, such as in the rare disease setting [66]. A summary of patient input is made publicly available, and the PACE report is incorporated in documents for committee deliberations [62, 66]. Similarly, at NICE in England, patient advocates and expert patients are able to both submit written responses and provide testimony in the deliberative committee meeting, this too is made publicly available in the HTA reports [62]. In the US since 2017, the FDA have required incorporation of a table (the “PXD Table”) within the assessment report, tabulating the patient experience data included in the submission [67]. These examples indicate that while there is increasing acknowledgment of patient input, this is currently not consistently or systematically reported, and the impact of the contribution is rarely articulated. It is likely that clearer documentation of the impact of patient contribution, with feedback to patient groups submitting their input, would demonstrate transparency in the process and also provide contributors with practical examples of what inputs are most informative [62].

Assessment of the Main Focus Area of Global PE and PXD Resources

The collective value of PE alongside PXD is being increasingly recognized by diverse health stakeholders [41, 68,69,70,71]. There has been a call for multistakeholder collaboration and a more aligned approach to the generation, collection, and use of PXD that incorporates established elements of good practice in PE [41, 72]. The aim is to ensure that resulting insights reflect patients’ needs and priorities, meet the collective needs of diverse stakeholder groups, and minimize duplication of effort as well as burden on patients being asked for their insights [41]. We assessed whether this integrated approach is apparent in identified PE/PXD resources and found that the vast majority of resources focused either on PE or PXD; only very few had a joint focus on PE and PXD, or demonstrated an integration of PE and PXD. Of 53 resources included in this landscape review, the majority (26 [49%]) were categorized as focusing primarily on PE and 15 (28%) as focusing primarily on PXD. Overall, six (11%) resources were categorized as focusing on PE and PXD but not in an integrated approach, rather in separate sections of the resource. Only six (11%) resources were categorized as demonstrating a focus on an integrated and combined approach to PE and PXD that reflects the interdependency between the two.

Discussion

This landscape review of recent initiatives, papers, and publications confirms and extends previous accounts of increased attention to reporting both PE and PXD by regulatory and HTA organizations. Overall, we found that this attention continues to expand globally and also to evolve from interest and openness toward guidance and expectations. The guidance and expectations that are increasingly expressed by regulatory and HTA organizations around the world pertain to both PE and PXD, albeit to varying degrees and proportions. This observation raises the question of the relationship between, and the value of, both concepts.

The FDA initiative to hold PFDD meetings [73] was in many ways a milestone in highlighting the uniqueness, value, and need for PXD as part of the regulatory review process and to complement and augment insights gained from scientific and medical data. The success of the PFDD meetings in raising awareness of the importance of PXD was in no small part due to meetings being based on quality engagement with patients testifying as an essential and early step in the process, thus providing a strong example of the value of integrating PXD and PE. Our landscape review indicates that much effort has been invested in PE, which is the focus of many initiatives. Much effort has also been invested in clarifying the format, quality, and use of PXD. However, these are largely separate approaches where the patient often still is simply the data “source” for PXD; they lack the critical integration of PE into the design, generation, collection, interpretation and use of PXD. By focusing preferentially or almost exclusively on the “data” in PXD, there is the risk of repeating the historic omission of the “patient” in PXD, and thus potentially jeopardizing the quality, value, and usefulness of the resulting PXD. Quality PE is necessary for the generation of quality PXD, and in fact well beyond that stage. PE also has an important role in the interpretation and understanding of PXD (it can uniquely help to answer the “why” question and thus explain the relevance of the observed PXD) and in helping all stakeholders understand the evidence and agree on a course of action. PXD and PE are interdependent, and both are essential for better regulatory and HTA decision-making. However, our landscape analysis highlights that there are few resources or initiatives where this interdependence is highlighted and where both are optimally integrated or even recommended.

Health stakeholders are calling on regulators and HTA bodies to give definitive guidance on how and when to conduct PE and PXD, but these agencies cannot provide robust guidance without first gaining their own experience on how PXD insights can be combined with PE to improve the quality of their deliberative processes. While collaborative global efforts such as PFMD’s Global Patient Experience Data Navigator [15] aim to provide clarity and direction around PXD, there is still a long way to go toward robust guidance.

The collective value of PXD to diverse health stakeholders has been described [41]. This indicates that development of a collaborative framework to accelerate the learnings from ongoing PE/PXD initiatives would be beneficial, as proposed at a multistakeholder forum in 2022 [74]; for example, it could provide advice and best practice examples on the generation of PXD with PE and the use of PXD and PE in decision-making. We acknowledge that there may be some limitations to this landscape review in terms of researching and providing an overview of all relevant global initiatives. However, as there is not one global database to search for such initiatives, in order to find relevant programs, in addition to relevant literature searches, we drew on expertise globally through a diverse group of stakeholders whose collective aim is to widen the reach of their connections to maximise communication and patient engagement. So, to the best of our knowledge, we have included all available resources at the time of writing but would also like to emphasize that the onus is on everyone to connect, join larger networks and to share learnings and best practice, to prevent duplication of efforts and to maximise outcomes for patients. We appreciate there is also value in systematic monitoring of the rapidly evolving and maturing PE and PXD landscape to identify and share emerging trends and positive initiatives, resources, and tools. As such, the authors recommend and plan a regular evaluation and update of this PE/PXD landscape review and invite all stakeholders globally to join this collaborative effort and to share their resources and insights. At the same time, we recognize that major barriers stand in the way of a true global collaboration and that while we extend this invite, we recognize that an active approach to seeking out more diverse collaborators is needed and will collectively be working towards ways to address this.

We also acknowledge that the review will not directly advance scientific approaches, methods, and hypotheses suitable for concretely advancing the scientific field of patient involvement, as this falls beyond the scope of a landscape review. However, by providing a comprehensive list of resources we have created a de facto global database that lays the foundation for further analysis of each resource. Specific methodologies to advance patient involvement is also the focus of ongoing work, research, and development at many of the key organisations mentioned that continue to develop resources and guidance in this area. Hence, we recommend a call to action for existing organizations and new organisations to work together to develop suitable and credible guidance. It is also important to note that whilst patient engagement is a form of community engagement, it was beyond the scope of this review to specifically address all such community initiatives, including those associated with health equity and diverse populations.

Conclusions

Both PE and PXD are central to achieving an approach to healthcare that reflects and addresses needs, priorities, and outcomes that matter most to patients, in addition to clinical outcomes. The combination and integration of PE and PXD is needed to generate meaningful data that captures the patient experience and accurately reflects the patient perspective, and also to contextualise its interpretation within a deliberative process such as regulatory and HTA—ultimately leading to better quality (value-based) decisions. However, our landscape review demonstrates that the tendency has been to offer guidance/policies on either PE or PXD in isolation, and that the majority of approaches are not (yet) thinking about the benefits of combining the two. Although there are a few examples where PE and PXD have been integrated, such integration needs to be expanded and normalized. We are currently in a transition stage, where the supporting guidance has not kept pace and therefore, a key step forward will be developing robust guidance and evolving dynamic processes that can be adopted universally and in different contexts. For example, to recommend how and when to involve patients in the design, generation, collection, and application of PXD, and there are emerging tools that can support this integrated approach. To this end, multistakeholder co-creation of a framework for integration of PE and PXD is under way as part of PFMD’s PE and PXD project. Without this and other initiatives towards integration, we will lose key engagement opportunities and important patient influence on decision-making and slow progression towards building patient-centred healthcare systems. In addition, the PXD used by regulators and HTA are at risk of being of lower quality when collected (and interpreted) without patient engagement.