Perspective Chapter: Patient Advocacy - From a Seat at the Table to Equal Stakeholders

Abstract

Much has changed in individual and policy level patient advocacy in the years since the late 1980s when HIV/AIDS activists challenged the United States medical product regulator and aspects of how randomised controlled trials are conducted. Delays in access to innovative, life-saving medical interventions continue to be a key topic. We provide storylines to explore three interrelated pathways. The first follows the involvement of patients in the medical product lifecycle and clinical trial regulation, where the biopharmaceutical industry is a major stakeholder. The second follows the course of evidence-based practice and patients, the need for outcome measures of patient experience data and patient-relevant outcome measures that incorporate the patient voice into person-centred models of healthcare; and how regulators and HTA bodies are accelerating access to innovative medical products. The third storyline uses the European Union with its public-private funding of medical and healthcare research as a case study to highlight how patient advocacy is changing. Following the maturation of patient advocacy from patients as research subjects to patient involvement and centredness throughout the medical product lifecycle, we suggest possible next steps to continue to evolve patient advocacy into equal stakeholders within healthcare and innovative medical product development.

1. Introduction

1.1 The beginnings

In 1978 the World Health Organisation (WHO) Alma Ata Declaration introduced the concept of citizens having both the duty and right to participate in the implementation and planning of their healthcare [1]. It was in 1998 that the global worldwide disability movement took on the slogan ‘nothing about us without us’. This slogan embodies the principle that no health policy, programme or other initiative that has a potential impact on patients should be undertaken without the participation of those patients [2, 3]. Principles behind involvement and engagement with patients include justice, equity and inclusion, diversity, and to counter any systemic discrimination [4].

We live in a world with ever-increasing patient-clinician expectations, a strong biopharmaceutical industry and growing inequalities in healthcare. Digital technologies, machine learning and artificial intelligence (AI) are seen as essential tools to help with maintaining healthcare. We need patients as equal stakeholders. Health services have over recent years shifted from paternalistic approaches to healthcare that dictate treatment regimens to placing patients at the centre of their care [5, 6]. Patients have a right to a voice in their own healthcare, and the policies and decisions that govern that care, but only some have the knowledge and resources, or capacity, to contribute in an active and productive manner. Empowerment is a multidimensional process that helps people gain control over their lives and increases their capacity to act on issues that are important to them [7]. Patient advocates can speak on behalf of other patients and, by working together in groups or organisations patients can provide mutual support and a stronger patient voice. Collective empowerment is a process through which individuals and communities can express their needs, present their concerns, devise strategies for involvement in decision making, and take political, social, and cultural action to meet those needs [8]. Patient advocacy covers the full span of healthcare including individual care, services and how healthcare is delivered, interventions and treatments that are available, and the policies that direct health services and the health system. The connections between the different parts of a healthcare system, and patient involvement across them, can be limited even though the system as a whole is looking to improve healthcare and outcomes for patients [9]. Engagement in care at a service level, the organisation and the health system are treated in separate streams with little attention paid to the interaction of patient engagement efforts at the different levels [10]. At service level, hospitals are challenged to address ‘what matters to patients’ and provide kind and considerate, value-based patient-centred care [11, 12]. Within health services, public and patient and carer engagement is expected to contribute to health system transformation but has had limited influence on overall healthcare delivery and design [13]. Over the years the focus has moved from people’s management of chronic diseases to quality and safety improvements [14, 15] to determination of value, co-design and co-production, but with underutilization of patient experience and patient-reported outcome measures [9]. Patient engagement is generally provider-led in its initiation, by invitation, and within specified areas of service delivery [16, 17]. The negative impact of the COVID-19 pandemic on patient engagement in healthcare highlighted that patient participation was not well established in the work routines of providers, institutions and governments [18, 19, 20, 21].

People’s initial expectations and the health system’s response to those expectations can determine the responsiveness of a health system [22]. Both past and current care encounters influence expectations, framed by social structures and relations. Individually, socioeconomic status, age, health status and past experiences shape our expectations, influenced by wider social, cultural, historical, and political contexts. Expectations are formed within a social construct, with social accountability and a collective nature that can be contested and negotiated through broad, equitable participation [23]. Collective judgements are reinforced by the authorisation of higher authorities. Perceptions of ‘legitimacy’ can change in line with individual and collective-level social norms and values [23]. Deliberation and decision-making about health financing are shaped by the political environment, and power asymmetries in society that can increase or decrease equity of access to healthcare. The potential of medical innovation is limitless, as evidenced by the websites of the European Federation on Pharmaceutical Industries and Associations (EFPIA) and the Pharmaceutical Research and Manufacturers of America (PhRMA) in their missions of patient-centred innovation and access to life-saving medicines [24, 25].

In this chapter we address the role of meaningful patient advocacy to strive for equitable, fair and just access to innovative medical products. We start with the AIDS activists in the 1980s and 1990s, evidence-based medicine and the regulatory pathway, through to how patient advocates and leaders are changing the spheres of action for collaborative efforts with the biopharmaceutical industry, using the European Union as a case study. Our approach is that of storylines in a meta-narrative pragmatic review of the literature [26], as adapted by Ulster and Denis [13]. A storyline is the unfolding ‘plot’ as set out in key publications. Our storylines follow the literature from a patient advocacy perspective in three interrelated but distinct pathways.

2. Storyline one. Access to innovative medical products: from AIDS activists to key players in this space today

2.1 AIDS/HIV activists and the US food and drug agency (FDA)

Access to new and innovative medical products was key for acquired immunodeficiency syndrome (AIDS) activists with the onset of the AIDS epidemic in the 1980s. At this time the affected community was being devastated with many dying as a result of contracting the mysterious illness. Many activist leaders were young to middle aged, relatively affluent, and well educated white gay men. The first cases in the United States of America (US) became evident in 1981. The term AIDS was established in 1982 and human immunodeficiency virus (HIV) was identified as the cause of AIDS only in 1984. The AIDS movement called for heightened commitment to studying this new condition and the provision of resources including research funding. People with AIDS became knowledgeable and involved in the clinical trials for the development of antiviral medications. The HIV/AIDS epidemic extended from the 1980s to the early 1990s in the US and during this time the activists changed the medical research paradigm. The focus of discontent was the slow regulatory process and the randomised controlled trial (RCT). Initial eligibility criteria meant that although AIDS was a life-threatening disease, the comparator was standard available treatment or placebo. Furthermore, trial participants were not permitted to take other medications during the trials (even though they also needed to use treatments to deal with opportunistic infections that were also killing people). And so, many refused to enter the trials. Through their activism the inclusion criteria were expanded and they were able to keep people in trials to fulfil the government regulator the US Food and Drug Agency (FDA) requirements so that the drugs could be marketed [27, 28].

The first antiretroviral drug for HIV/AIDS was approved by the FDA in 1987, and the Investigational New Drug (IND) Program was initiated based on surrogate outcomes rather than clinical outcomes, and compassionate use of treatments became available. The AIDS Coalition to Unleash Power (ACT UP) was established in the same year. This group brought a very sophisticated understanding of the situation and specific problems concerning the scientific and regulatory issues associated with making medications available. They educated themselves, found mentors to help them, opened the door to the regulator and introduced a new model of advocacy that included the patient expert. As patient advocates, they learned the concepts and language and overall gained scientific and research knowledge. In this way they were able to give alternative suggestions, ask reasonable questions, push for specific changes, and became positive contributors to the process. In the process they were able to build a community to focus people’s fear and anger. People did not feel alone and developed fellowship. The movement had an inside and outside strategy. Over time, AIDS/HIV went from a death sentence to a chronic manageable illness [27].

2.2 Women with breast cancer claim their seats at the table

Breast cancer activists in the US quickly stepped in during the early 1990s. They wanted to actively contribute to the research process and for more women to be included in clinical trials [29]. The women adopted a ‘seat at the table’ approach to their advocacy with the development and implementation of an intensive science training course for breast cancer activists by the National Breast Cancer Coalition (NBCC) [30]. It was clear to these advocates that if they wanted a seat at the table where research decisions were being made—and to participate fully in making those decisions—they had to adapt to the dominant culture and understand the science. The programme termed Project LEAD (leadership, education and advocacy development) was developed offering in-depth immersion in epidemiology, molecular biology, clinical trials, and evidence-based healthcare, and building a base for ongoing learning [31]. To have a seat is a status within a group that gives one sufficient authority to be taken seriously, give a group perspective, to listen and be heard, share, define and influence, and make a difference. Through this approach, the NBCC was successful in gaining specific funding for breast cancer research through the US Department of Defence [29].

One breast cancer advocate who held a formal role with the FDA shared her experiences. She was able to work with industry and research groups to offer feedback on clinical trial design, serve on data monitoring committees and on steering committees for registry studies. Her questions included: should we wait for larger studies to provide conclusive evidence or take a chance that data will eventually confirm what we all hope to be true? Do the studies measure outcomes that actually help patients? Should we heed the speakers in the Open Public Hearings (a part of every FDA advisory committee) and get the proposed drug to market at the earliest possible moment or are there imperatives to wait for longer-term safety and efficacy data; and what about extenuating circumstances where alternative treatments do not exist? [32].

2.3 FDA committed to patient-focused drug development (PFDD)

The FDA as a government agency and under its congressional funding arrangement of accepting fees from medical product sponsors (Prescription Drug User Fee Act or PDUFA) launched the Patient-Focused Drug Development initiative (PFDD) in 2012 [33]. Public meetings have an important role and are designed to engage patients to elicit their perspectives on the most significant symptoms of a health condition, its impact on their daily life, and their views on current approaches to treatment [34, 35]. As a result, patient preferences, patient-reported outcome measures, patient experience data, and tolerability are patient-relevant clinical outcomes systematically included in clinical trials as part of drug development and evaluation. The FDA states that “as experts in what it is like to live with their condition, patients are uniquely positioned to inform the understanding of the therapeutic context for drug development and evaluation”. This patient-centred approach has been developed to facilitate enrolment in clinical trials, reduce the burden of participation, and provide an understanding of trade-offs between treatment benefits and harms. A series of methodological guidance and core outcome sets have been developed, and the FDA continues to set up health condition-based meetings to gather patient experiences [33]. The Patient Engagement Collaborative (PEC) is a legislated joint project between the FDA and the Clinical Trials Transformation Initiative (CTTI) that was initiated in 2017. Its purpose is to provide an ongoing, shared setting in which the patient community (PEC members), FDA, and CTTI can discuss topics for improving communication, education, and patient engagement related to medical product regulation [36]. The PEC was modelled on the European Union regulator the European Medicines Agency’s (EMA) Patient and Consumer Working Party, formed in 2014. The FDA and EMA have collaborated on patient engagement since 2016 [37]. They were both aware of the importance of public education resources and knowledge about the role of regulators and the safe use of medical products.

The EMA considers patient engagement along the regulatory lifecycle of medical products to be an integral part of its work, where patients and caregivers bring a unique perspective and offer real life insights including quality of life issues, unmet needs and the current therapeutic environment [38]. Representative patients first became scientific committee members in 2000; and the EMA has had a patients and consumers working party of patient organisations since 2006. As a community, patient advocates are on the Management Board, involved in consultations and workshops, and act as patient experts in various activities (scientific advice procedures; expert meetings; committee consultations; review of documents). EMA recognises the importance of patients working with clinicians and now better informs patient advocates with improved access to some of the data in the clinical reports submitted to the agency [39]. A biennial report summarises interactions with patients, consumers, healthcare professionals, academic researchers and their organisations, incorporating both quantitative and qualitative data [40].

2.4 Perceived and real competing interests

As is common practice, including for regulatory and payer or health technology assessment bodies, EMA takes care to ensure that its staff, scientific experts and board do not have any financial or other interests that could affect their impartiality. EMA’s policy on handling competing interests allows it to restrict or exclude the potential involvement of an expert or scientific committee member with interests in the pharmaceutical industry or in the medical-device industry [41]. The relevance of competing interests was noted by the breast cancer advocate referenced earlier: “it is impossible not to be acutely aware of the ways in which financial incentives shape both the conduct and outcomes of research. In an age when clever marketing and clinical trials are sometimes so intertwined as to be indistinguishable, trained advocates would do well to question the source of data and the design and conduct of trials. But it’s hard to maintain a critical perspective, to be the sceptic when others are so hopeful about this or that promising new agent…” [32]. These remarks apply not only to patients but the desire of patients to find relief and to participate in research and clinical trials can be inaccurately interpreted as competing interests.

Patient organisations face many challenges including a lack of formal recognition. The associated lack of resources and funding is an ongoing problem [42]. Many patient groups receive some funding from the pharmaceutical industry, either on a project basis or for operational activities. Others receive government funding aligned with current health policy and political interests. To maintain transparency and mitigate any perceived competing interests, patient organisations develop clear rules for ethical conduct and terms of engagement. Some groups choose not to accept such funding. Government, public health, and health research funding is limited, and donations and philanthropic funding are not enough [8]. Questions about the independence of groups that accept industry funding are raised. Patient organisations that are aligned with companies’ approved drug portfolios and research and development pipelines, including rare diseases, appear more likely to receive funding [43]. Industry funding can decrease public trust in the independence and the representativeness of those organisations yet patient organisations are expected to make themselves available and to act in a professional manner in health policy debate [8, 42]. A balance is needed because as groups acquire the highest levels of integrity and competence, and become more ‘professional’, they can become distanced from their patient members and so lose their representativeness and familiarity with the everyday needs of patient, carers and families [8, 42].

In the past, biopharmaceutical codes of practice and regulations covering engagement with patients and patient groups were in the marketing domain and were bureaucratic and restrictive. This has led to a lack of information on new and innovative medical products for patients and patient advocates wishing to give input to HTA bodies on the potential value of those products [44]. The restrictions also interfered with patient involvement in clinical trials and drug development research [45], as highlighted in a survey of patient groups, industry and academia in the US identified through the CTTI and Drug Information Association (DIA) [46]. Growing numbers of clinical trial sponsors recognised the benefits of continuous and meaningful patient group engagement in clinical trials. There was some resistance [47], as well as mismatched expectations [48]. Engagement activities have the potential to avoid protocol amendments, improve clinical trial enrolment, adherence, and retention could add considerable financial value [49, 50]. Overall, a culture change was needed [51].

2.5 The biopharmaceutical industry - what is the price?

The biopharmaceutical industry develops new and innovative medical products to counter disease and life-threatening conditions. Severe acute respiratory syndrome (SARS) is a viral respiratory disease caused by the SARS-CoV-2 coronavirus. During the COVID-19 pandemic, the biopharmaceutical industry was able to provide rapid access to innovative vaccines [52]. These received emergency use approval by regulators and funding from payers and so could be used to decrease the severity of infections and the number of deaths. The pandemic raised public awareness of the role of regulators in ensuring the safety of new vaccines and treatments, and the role of innovation. Innovation is often derived from publicly funded scientific research, including from patient groups, and numerous research and development-intensive start-up companies come out of academic institutions [53, 54]. It is possible that some end-products may therefore be largely due to decades of research funded by public investment, billions in grants for development and production, and tens of billions in Advanced Purchase Agreements (APAs) with governments [55]. Legal issues are a part of its business. The industry is looking to ‘game-changing science’, new breakthrough therapies and, eventually, large company profits [54]. One company can control the market. An example is the situation with innovative medications for the treatment of cystic fibrosis (CF), an hereditary condition present at birth that markedly reduces lifespan. New medications are very effective and significantly extend life expectancy. The CF transmembrane conductance regulator (CFTR) modulator drug combination is only available in high income countries [56].

3. Storyline two. Adapting evidence-based practice to be more relevant to patients with timely access to innovation

3.1 Evidence-based practice in healthcare

The term ‘evidence-based medicine’ (EBM) was introduced in the 1990s to formalise the scientific basis of medicine. The intent was to move away from expert opinion, actions led by individual senior physicians, and ingrained behaviours, which were causing waste and unwarranted variations in care [57, 58]. EBM was envisaged to reduce uncertainties in medical decision-making and to improve the quality of care [59, 60]. It was defined initially by Sackett as “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients” [61] and subsequently modified to include clinical expertise and the patient’s views and preferences, or values. The best available evidence comes from randomised controlled trials (RCTs). These are carefully controlled studies in which participants are randomly allocated to ‘intervention’ and ‘control’ groups, where the control group receives an inactive placebo or ‘standard treatment’. The participants are systematically followed, and predefined quantitative outcomes measured over a set time period generally up to 1 year. Bias, or factors that can influence the findings and result in systematic deviation from the true findings are in this way minimised. EBM operates at the population level but is applied to individuals, and healthcare is delivered within relationships, meaning that values, including patient values, are an inherent part of EBM [62]. Healthcare interventions can be multifactorial and complex, making it difficult or impractical to carry out definitive RCTs [63]. Long-term effects of interventions are also difficult to follow, as are any potential adverse effects. Greenhalgh et al. highlighted ‘biases’ against patients and carers in EBM including limited patient input into published materials, low value put on patient or carer experience, power imbalances that may suppress the patient’s voice, hard-to-reach populations may be missed, and the humanistic, person-centred aspects of clinical consultations (empathy, compassion, the therapeutic alliance) may be overlooked [64].

3.2 Need for measurable, standardised patient-relevant outcomes that give patients a voice

It is the patient who best understands the life experience of living with a disease or health condition. Quality of life measures and other patient-reported outcome measures (PROMs), patient-reported experience measures (PREMs), patient experience data and patient preference studies [65, 66, 67, 68] provide ways in which a person-centred approach to regulatory assessment can be incorporated [69]. Such measures can help clinicians to understand patient experiences and needs, and so enhance consultations and the delivery of individualised care [8, 70]. They also provide a person-centred approach with standardised tools for clinical trials [71, 72]. Patient-relevant outcomes capture patient data on the burden of disease and its treatment by following symptoms, ability to function, experiences and health-related quality of life over time and with interventions. New and innovative medical products, such as immuno-oncology treatments for cancer and weight reduction medications, can have high toxicities for some patients. Development of tolerability patient-reported outcomes (PROs) are therefore also important [73].

These measures are now collected electronically (as ePROs), which improves adherence to their collection, increases reliability, and reduces data entry errors [74]. Information can at the same time be gathered about the data collection process itself and device setups can be altered, training and resources provided, and better PROs developed as a result [74]. Overall, remote data gathering reduces the participant burden of collecting the data and in interpreting outcomes [75] to inform research and clinical services. Industry has the adaptability and resources to involve patients to provide specific validated tools that capture patient experience data and new methodologies in clinical trial design, particularly involving digital technologies. The in-depth descriptions of how companies invest into going deep into experiences of the health conditions and their treatment to develop PROMs [71] and patient preference studies [67, 72] are good examples. It is important that patients can relate to the measures, that they are relevant to them and capture what matters to them so including their voice [76].

3.3 Access to innovative medicines: what makes one need this?

The biopharmaceutical industry needs rapid access to market to maximise sales during the patent protected period [77]. From the patient perspective, accelerated or early access schemes have value when targeted toward innovative technologies with the potential for significant clinical benefit. This is particularly so for people with serious disease burden and high unmet needs where the stakes are high, if the medical product goes on to deliver significant clinical value [78]. Patients, medical professionals and their clinical communities, policymakers and the manufacturers of innovative technologies are all seeking rapid access to new medical products, and regulators, reimbursement or HTA bodies and payers are working to meet these demands [79]. Early access requires investment from payers and is associated with significant risk, since not all technologies will go on to be routinely reimbursed or show benefits over existing treatments [80, 81] and only be slowly withdrawn from the market worldwide [78]. Furthermore, complex technologies may present a significant step-change in care that poses challenges for implementation with alterations to health services, diagnostic requirements or treatment pathways. With early access schemes, payers need to determine the period of reimbursement, ensure fair competition for comparators, and consider both the possibility of new competitive technologies and future innovation in the area. The corporate relative balance of risks and benefits of early access schemes may vary according to the strategic importance of the healthcare system for industry, and patients may find their access to the medical product stopped at the end of contractually agreed early access scheme [82]. It is also relevant that shorter time to medical product regulation can mean that less clinical evidence is available on regulation and for funding approval considerations. This makes it difficult for HTA bodies and payers, patients and medical practitioners to understand the full profile of the product compared to existing treatment approaches.

The WHO’s health systems framework emphasises the importance of a well-functioning system that provides equitable access to essential medical products, vaccines, and technologies with assured quality, safety, efficacy, and cost-effectiveness, while promoting their scientifically sound and cost-effective use [83]. Healthcare systems are often passive, unplanned recipients of innovation. The activities of regulators and HTA bodies are very much set by companies, as they determine the medical products they seek market approval for, and for which indications [62]. Health Technology Assessment (HTA) provides a method to determine the clinical utility and value of a product within a health system to inform payment or reimbursement. It can also determine cost-effectiveness. A multi-stakeholder committee that often includes patient or public members appraises the evidence [84]. HTA has the potential to create a balance between population health and individual patient needs, so that limited resources are equitably distributed and people with, for example, rare diseases are considered [75]. Medical product lifecycle activities can, however, map poorly to need in terms of the burden of disease and so represent an opportunity cost for patients and health services. If biopharmaceutical science is defined in terms of commercially viable innovations, there will be less available funding or political will to address other areas of healthcare and the greatest societal good. The ways in which evidence is generated and interventions are developed and implemented for common chronic diseases including heart disease, cancer, Alzheimer’s disease, diabetes, and chronic lung, liver, and kidney diseases leave room for improvement [85] as does how they are prioritised for value assessment [86].

Governments want to be able to provide innovative medical products and make them available to their people. Australia, for example, has a National Medicines Policy that provides a highly supportive medicines policy environment to support better healthcare and reduce regulatory costs [87]. The European Commission in its proposed revised pharmaceutical strategy for aims to make sure all patients across the EU have timely and equitable access to safe, effective, and affordable medicines with secure supply; and continue to offer an attractive and innovation-friendly environment for research, development, and production of medicines [88]. To reduce medical product development time, both regulatory and HTA bodies need to adapt their processes. This was evident when the FDA approved a drug for Alzheimer’s disease before good clinical evidence was publicly available, effectively supporting ‘compassionate use and hope’ [11, 79, 89, 90]. Regulators are harmonising their work across comparable jurisdictions, through agreements such as with Project Orbis for promising new cancer treatments [91]. The initial stages of HTA in Europe are being brought together through EU Joint Clinical Assessments working closely with EMA and Regulation (EU) 2021/2282 on health technology assessment (HTAR) [92]. Regulators and HTA bodies use horizon scanning and offer early scientific advice to help with evidence generation challenges and new types of evidence [75, 82, 93, 94, 95]. Patient input adds value as it can offer a different perspective to other experts; bring experience of living with the condition and its treatment into the discussion, and leads to concrete additions to the final scientific advice given [96].

Real-world data sources include electronic medical records, billing and registries. Gathering real-world data to develop real-world evidence is a key priority area for investment [82, 97] but which requires protection of patients [75]. While RCTs are good for studying causal effects, real-world studies offer the ability to follow larger populations of patients for longer periods of time to capture the lived experience of patients. Registries and large databases can be used for less common and rare diseases [98] as well as capture less-common events such as side effects and exacerbations of disease. Making PROM data available beyond clinical trials can capture how people feel and function, reported by the patients themselves [66]. Not doing so is a missed opportunity for learning about the therapeutic use of interventions. Patient experience data reflect patients’ lived experience, their symptoms, interactions with the healthcare system, information-seeking behaviours, any misdiagnoses, lifestyle changes, treatments, side effects, and comorbidities adding to the completeness of the data to enhance person-centred care [99]. Patient groups themselves can collect data, as with Duchenne disease [100].

4. Storyline three. Empowering patient advocates in medical product research and development: the European Union as a case study

The European Patients Forum (EPF) was formed with the backing of EU institutions, including with commercial interests, as a pan-European umbrella body for patients, with national bodies as its members and not individuals. Early in its existence concerns about the independence of patient organisations from the drug industry and the power of more established interests within the healthcare system were seen by academic researchers as serious challenges [101]. Patient organisations focus on representing, mobilising and empowering patients and advocate for their rights. They are able to ‘speak with one voice’, with visibility and credibility, and ensure a coordinated presence of patient-related issues in health and non-health policies and programmes. While patient advocates and patient organisations are routinely challenged on their representativeness and ability to distinguish between personal and collective views, other stakeholders are not [8].

EPF has been a strong facilitator in placing an emphasis on collaboration and new ways of working, including working with EFPIA to build opportunities [51, 102]. They recognised that irrespective of the strong rationale for engagement, any relationship between patient organisations and pharmaceutical industry can be seen as commercially motivated. To encourage interactions and ensure ethical practice, EFPIA co-created with its Patient Think Tank a set of principles to govern relationships between patient organisations and the pharmaceutical industry (Working together with patient groups, September 2017) and principles for renumeration, with recognition of work of EUPATI, The Change Foundation, PFMD, and WECAN (Working together with patients. Principles for renumerating, June 2019). In 2019, the EFPIA board endorsed its patient engagement strategy (relationships). These documents are in addition to the EFPIA Code members for the Promotion of Medicinal Products to healthcare professionals (HCPs) and the interactions with HCPs, healthcare organisations and patients’ organisations [103].

4.1 European Union: innovative medicines initiative and EUPATI

The Innovative Medicines Initiative (IMI) programme, now the Innovative Health Initiative, is a public-private partnership between the European Commission and EFPIA to improve the drug development process by supporting a more efficient discovery and development of better and safer medicines for patients. The programme was launched in 2008 to support collaborative research projects, develop networks of industrial and academic experts in Europe as a way of boosting innovation in healthcare and to build a more collaborative ecosystem for pharmaceutical research and development. In 2010, an applicant Consortium of umbrella patient advocacy groups operating at European level submitted a project entitled ‘Fostering Patient Awareness on Pharmaceutical Innovation’, in the third IMI call for projects [104]. The patient groups were involved with EMA, active in EU Pharmaceutical Policy (that dictates EMA activities), and with academic partners, DIA and the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). The project, which set up the European Patients’ Academy on Therapeutic Innovation (EUPATI), ran from 2012 to 2017, extended to 2020 and beyond. An infrastructure was built for educational materials and develop patient experts through education and training - provide resources to learn the technical skills to aid them in being full participants in a relationship where each side has knowledge that the other does not - and a common language to communicate effectively with each other. It was important that the project was accepted by the patient community and was seen to be objective, transparent, and independent. The project coordinator and executive committee were appointed through EPF. The project also had a Steering Committee and Advisory Board. Well-balanced working parties or task forces from a network of all stakeholders and chaired by the coordinator and other patient experts were tasked with developing the EUPATI course. The course objective was to promote knowledgeable patient advocates and patient support groups to work effectively with government authorities, healthcare professionals, and industry to meaningfully contribute to medicines research and development [105].

Parsons et al. [106], as part of the EUPATI work, provided an academic perspective and identified that the pharmaceutical industry was becoming increasingly interested in how medicines research and development could with patient involvement be patient-centred. Such involvement could also have other benefits such as identifying new areas of research, promoting innovation, providing new insights, identifying solutions to problems in running trials, and improving acceptability of new medicines to patients. Companies previously had little contact with patients in their day-to-day working. The authors also identified a need to work with media to build understanding and communication about medicines research and development, to build public trust.

A large number of EUPATI graduates now hold leadership positions in patient organisations [75]. They ensure patients’ needs are at the heart of drug development, by joining science, ethical and regulatory committees and getting involved in clinical trial design. The EUPATI programme currently includes an in-depth training course, an e-learning platform (Open Classroom), an online toolbox, national platforms and more. It has been a game-changer for patient empowerment in Europe and beyond. Japan now has its own national platform. EUPATI became an independent, non-profit foundation toward the end of 2020. A subsequent project, IMI PARADIGM, Patients Active in Research and Dialogues for an Improved generation of Medicines (2018 to 2020) was co-led by EPF and EFPIA to further patient engagement and involvement in research priority setting, design of clinical trials and early dialogue for regulatory and HTA purposes by developing processes and tools. A set of metrics to measure the impact of patient engagement was also produced [107]. In 2019, IMI PARADIGM, EUPATI, and EPF joined forces with Patient Focused Medicines Development (PFMD) to initiate the Patient Engagement Open Forum (PEOF) to hold regular events [108]. These provide opportunities to share patient engagement tools, discuss challenges and facilitate collaboration.

Patient Focused Medicines Development (PFMD) was established in 2015 under the umbrella of The Synergist, an incubator that brings key players together in ‘people-public-private’ partnerships to solve societal problems through collective action [109]. It is working collaboratively with stakeholders to develop patient engagement tools, frameworks, training and events [110, 111]. Their work includes a Patient Engagement Quality Guidance (PEQG) tool [112], ‘how-to guides’ for patient engagement in medicines development [113] and a Global Patient Experience Data Navigator tool [114] as well as Patient Engagement Country Guidelines to help navigate country codes of conduct and other regulations. A co-created Fair Patient Engagement (PE) Planner applies activity and expertise frameworks to support patient engagement partners in defining the level of expertise required for activities, an important step. This will enable dialogue among patient involvement partners to agree on fair renumeration [110].

At an international level, patient involvement in HTA processes is well established [115, 116, 117] but is largely concentrated on the appraisal stage of an assessment. This leaves room for broader involvement at all stages of an HTA [69, 118]. Public knowledge about HTA is still limited. Following the successful negotiation for the new EU Regulation on HTA, EUPATI [119] and EUCAPA, a collaboration between EPF, EURORDIS and Tyrolean Private University (UMIT) [120], have been funded under the EU4Health programme to provide training.

4.2 We have moved a long way from patients as subjects in clinical trials

It can be asked why the biopharmaceutical industry has taken so long to consult and partner with its end users. EUPATI provided opportunities for biopharmaceutical company representatives to work closely with patient advocates and leaders. At the same time, public knowledge is being increased about medical product development in the EU and beyond. Patient-centred healthcare recognises individual patient preferences, needs, and values in the context of their own social worlds. Inclusion of patient voices helps develop treatments that improve people’s lives and in ways that matter most to them, how they feel, function, and set their personal goals. It also makes good economic sense [75, 82]. Industry is making patient-centredness its’ goal and now biopharmaceutical companies can empower patients by including them throughout product development [51]. While advances made in recent years are promising, there is still a long way to go to secure the systematic involvement of patients across companies and as true partners at many levels of internal decision making.

Patients can use their insights to identify target areas/questions that have meaning for them, and inform clinical trial design [51, 95]. Relevant outcome measures must relate to patients’ experiences, perspectives, needs, and priorities – and be seen as meaningful to patients - core outcome assessments for clinical trials that form part of the regulatory submission [51]. Patients can help identify biases in large datasets, so that they can be corrected, anticipate barriers to applying results that others could miss, and assist in safety surveillance during trials. On study completion, patients can take part in interpreting results and then go on to communicate with their communities and increase health literacy and knowledge [75]. Patient input is required for economic models to reflect true value based on lived experience and produce more realistic models [75]. Social media provides a way of gathering perspectives from informal conversations, and the use of language. Adverse events can be detected in postings on public sites. This is particularly useful for pharmacovigilance because historically patients do not routinely report side effects [75]. Interests, perspectives or insights relevant to more than one person are mobilised and acted upon, with validation through interactions with other patients and gathering community knowledge [111].

5. Conclusions: vision for the future, possible steps

Patient advocates deserve recognition as equal stakeholders and partners in promoting fair and affordable access to quality innovative products across diverse populations. If the impact of their involvement is to be measured then so should that of all stakeholders. The issue of competing interests needs to be re-assessed and declarations co-designed by regulatory and HTA bodies, academia, patients and patient groups, and industry for all stakeholders. Patient advocates and their patient groups need funding considerations with development of models that allow for best practice management that allow them to be equal stakeholders.

Are we trying to solve the right problems, and is it time for process improvement? We need accountable care – where providers, both healthcare and medical product providers, are enabled with advanced technologies that help them communicate with, engage, and inform patients so that they become empowered with information. Their behaviours can then better align with actions that improve healthcare. Healthcare currently falls well short of having truly informed patients and patient advocates. We need multidisciplinary ownership of the care experience over time, greater information sharing across all dimensions of care, a focus on patient, family and support systems, a true measure of outcomes, and a strong focus on improvement and affordability. We would benefit from strengthened relationships with healthcare professionals themselves.

• Many tools and resources have been developed to help different stakeholders work with patient advocates. How can these be collated into a searchable library that enables easy access? We would benefit from improving the links between advances being made in industry with patient involvement within health services, to better meet the needs of patients, for example PROMs and related materials, patient education and training, funding opportunities, recognition as partners and opportunities to become patient experts and leaders including in less-well serviced communities.

• Greater transparency and availability of information on new medical products (e.g., less commercial in confidence materials/redacted information in EMA reports) to enable patients and their organisations to assess the value of the products from their own perspective and for their voices to be heard more meaningfully on access within health systems.

• Reassessment of competing interests in relation to participating in the research undertaken by bio-pharmaceutical and related companies comparable to healthcare professionals. And recognition of patient advocates as able to make their own carefully considered decisions on competing interests, as with clinicians. At the same time identify the power base from which people come, to give greater accountability. Work collaboratively to identify other funding models of patient groups as recognition of their evolving place within health systems; allocating budgets to build their skills and capacity.

• Provide clear information on medical product mechanism of action, possible interactions with other medical products and the level of overall scientific development. When medical products have the same mechanism of action as existing medical products highlight any real and potential differences e.g. route and frequency of administration, possible side effects. Make public the marketing strategies for new medical products, in which countries and where, to inform access and enable action to promote diversity. Enable patients and patient organisations to be co-decision makers and arbiters on access to medical products. Work on a disease basis in lifecycle negotiations, aligned to clinical services.

Acknowledgments

We would like to thank the people in the global HTA patient advocacy community who helped construct this chapter through many hours of discussion and learning experiences. We particularly thank Neil Bertelsen, Heidi Livingstone, Catherine Voutier, and Stella O’Brien. We are also grateful to Trisha Greenhalph for her fresh thinking in approaching methodological issues in evidence-informed healthcare.

Conflict of interest

No funding was received for the development of this manuscript. Janet Wale is a previous chair of the HTAi Patient and Citizen Involvement in HTA Interest Group and a current active member of the Cochrane Collaboration and declares no conflicts of interest.

Dominique Hamerlijnck (DH) is a member of the patient advisory boards for European Lung Foundation (ELF), European Federation of Allergy and Airways Diseases Patients’ Associations (EFA), Dutch Lung Foundation, EU Innovative Health Initiative, Global Initiative on Asthma (GINA). She is an independent patient advisor to Novartis, Chiesi, Pfizer, and Roche; and a member of the patient advisory board for the following projects: EU SafePolyMed, ERS Severe Heterogeneous Asthma Research Collaboration, Patient-centered, IMI/IHI 3 TR, IMI/IHI Mobilise-D, IMI/IHI Digital and data DAG+. DH is also a member of scientific advisory committees for ZonMW (Dutch organisation for funding of research). She is a member of HTAi and ISPOR.

Nomenclature

The term ‘patients’ is used to refer to patients, caregivers, consumers, potential patients, and any organisation that represents people who use health services.