The patient’s voice

United States

The work of the FDA in regulating drugs and medical devices has been influenced in recent years by what has been described as an “explosion” of disease-specific advocacy groups. ¹¹ Before the 1970s, there was little direct involvement by members of the public in FDA decision-making, ¹² but that decade saw broader social shifts (including declining public trust in established institutions, the development of a more prominent rights culture, and increased availability of health information) ¹³ as well as early examples of activism by cancer patients and the feminist health movement ¹⁴ that set the stage for greater involvement. In the 1970s and 1980s, the increasing prominence of consumer and patient rights discourse and of health-related advocacy groups started to change the landscape. ¹⁵

The acquired immune deficiency syndrome (AIDS) epidemic in the 1980s is widely seen as a turning point in the relationship between patient groups and regulatory agencies. ¹⁶ AIDS research had many characteristics that made it unusually controversial, such as its connection to a “politicized social issue” and social movement, ¹⁷ and many of those affected were highly motivated and had social advantages (e.g. financial resources and education) enabling them to challenge traditional power relationships. ¹⁸ AIDS activists were able not only to bring public attention and political pressure to bear on the FDA and other agencies but also to engage in scientific discussions and regulatory decision-making processes in “unprecedented” ways. ¹⁹ Having educated themselves and gained credibility, activists became increasingly influential and participated directly in decisions about research and drug approval (e.g. as members of a National Institutes of Health (NIH) working group, ²⁰ NIH and FDA committees, and institutional review boards). ²¹ This was not the first time patient or consumer groups had taken prominent roles in influencing the FDA, ²² but AIDS activists “succeeded in changing the rules of the game, transforming the very definition of what counts as credibility in scientific research such that their particular assets would prove efficacious.” ²³ This shift has enabled patient representatives to become engaged in decision-making processes rather than simply trying to influence them from outside. The forms of direct involvement in FDA decision-making developed during this period provide a model that continues to be influential. ²⁴

In the 1990s, the FDA began to invite patient representatives to join advisory committees, ²⁵ starting with the Antiviral Drugs Advisory Committee for human immunodeficiency virus (HIV) and committees reviewing cancer therapies. ²⁶ Advisory committees provide a means for the FDA to get external input, since the committees are composed of independent scientific experts and other representatives, and provide advice on matters such as the safety and efficacy of an unapproved new product. ²⁷ These committees now regularly include patient representatives as well as “consumer” representatives. ²⁸ Patient representatives must have personal experience with the relevant disease (either as a patient or as a primary caregiver) and knowledge of treatment options for the disease and are expected to “offer the patient perspective, ask questions, and give comments to assist the committee in making recommendations.” ²⁹ Since the mid-1990s, patient representatives have had voting rights on many, though not all, advisory committees. ³⁰ Advisory committees also hold open public hearings, at which input from patients or other members of the public can be given orally or in writing. ³¹ In 2001, the roles of patient representatives were expanded to include providing input at drug development meetings between the FDA and product sponsors, as well as acting as consultants when products are reviewed. ³²

Several recent initiatives aim at expanding patients’ involvement in product development and regulation. A section of the 2012 Food and Drug Administration Safety and Innovation Act (FDASIA) directs the Secretary (of Health and Human Services) to “develop and implement strategies to solicit the views of patients during the medical product development process and consider the perspectives of patients during regulatory discussions.” ³³ Subsequently, the FDA sought public comments on these strategies and formed a working group to examine both existing and new approaches. ³⁴

FDASIA includes the fifth reauthorization of the Prescription Drug User Fee Act (PDUFA V) and third reauthorization of the Medical Device User Fee Act (MDUFA III), both of which contain specific commitments regarding patient involvement. Under PDUFA V, the FDA is committed to holding a series of public meetings to gather input from patients about their perspectives on particular diseases or conditions and the treatments available for them. ³⁵ At least 20 of these “Patient-Focused Drug Development” meetings are planned for the period 2013–2017, each producing a “Voice of the Patient” report on a particular disease or condition. ³⁶ These are intended to gather information about patients’ perspectives in a broader and more systematic way, beyond the context of a specific product application. ³⁷ The proposed 21st Century Cures Act, as recently passed by Congress, would require the FDA to build on this by elaborating processes for using patient experience data in assessing new drugs. ³⁸ Under MDUFA III, the FDA is also committed to seeking information about patient perspectives and increasing its use of patient representatives in the regulation of medical devices. ³⁹ It established a “patient preference initiative” to seek information about patient preferences that can inform assessments of benefits and risks for medical devices ⁴⁰ and published a draft guidance document on this topic. ⁴¹ More recently, a Patient Engagement Advisory Committee was established to advise on means of obtaining and using patient input in regulating medical devices, including the use of patient-reported outcomes and patient preference information. ⁴²

A novel and significant development in 2015 was an initiative by a rare disease patient organization, Parent Project Muscular Dystrophy, to produce a proposed draft guidance document for the FDA. The intent of this effort was to capture patients’ needs and preferences as well as current research on Duchenne muscular dystrophy, in order to inform all stages of product development. ⁴³ After an intensive collaborative effort, the proposed draft was presented to the FDA and released for public comment, ⁴⁴ following which the FDA published a draft guidance document informed by the proposed draft and comments. ⁴⁵ This could provide a model for other groups to follow, although it requires a substantial investment of time and resources. ⁴⁶

Europe

The EMA involves patients and patient groups in its activities in several different roles. Early in the Agency’s history, these developed in an ad hoc way, and the emphasis was on ensuring that patients and consumers were fully informed, as a way of fostering patient empowerment. ⁴⁷ As in the United States, the activism of “highly motivated and well-informed” people living with HIV and AIDS was an important catalyst for greater patient involvement and provided models for interaction. ⁴⁸ The framework for interaction with patients has evolved to include a broader range of objectives and of structured forms of participation. ⁴⁹ The Patients’ and Consumers’ Working Party, composed of representatives of patient organizations as well as the EMA’s scientific committees, is responsible for implementing and monitoring the framework and generally for advising the EMA on matters of interest to patients. ⁵⁰

The composition of EMA’s management board has, since 2005, included as members two representatives of patient organizations. ⁵¹ These representatives are fully involved as members of the board and are expected to provide “their views as users of medicines and as representatives of civil society.” ⁵² The enabling regulations of four scientific committees also stipulate that their membership includes representatives of patient organizations: the Committee for Orphan Medicinal Products, which was the first to include these representatives and has three patient representative members ⁵³ : Paediatric Committee, also with three, ⁵⁴ Committee for Advanced Therapies, which has two, ⁵⁵ and Pharmacovigilance and Risk Assessment Committee (PRAC), which has one. ⁵⁶ The patient representative members of these committees are full voting members and are expected to bring “unique and critical input based on their real-life experience of being affected by a disease and its current therapeutic environment.” ⁵⁷

In addition, the overarching regulation governing the EMA’s procedures directs the management board to “develop appropriate contacts between the Agency and the representatives of … consumers and patients,” including participation as observers. ⁵⁸ Further, it directs the Agency’s committees, working parties, and scientific advisory groups to “establish contacts, on an advisory basis, with parties concerned with the use of medicinal products, in particular patient organisations,” and authorize committee rapporteurs to establish contacts with representatives of relevant patient organizations “on an advisory basis.” ⁵⁹ These provisions act as the foundation for a range of activities involving individual patients and patient organization representatives. For example, they can participate in scientific committee proceedings as observers, providing advice as individual experts or group representatives. ⁶⁰ Patient representatives sometimes act as members of Scientific Advisory Groups, ⁶¹ or as experts providing input into scientific advice in Scientific Advice Working Parties ⁶² ; and patients or patient organizations are consulted on an ad hoc basis to review information that will be disseminated to the public, such as package leaflets or safety information. ⁶³

When the framework for interaction between the EMA and patients was revised in 2014, one of the objectives was to increase involvement of patients in assessment of benefits and risks. ⁶⁴ This involvement is recognized as important but complex, because of the potential diversity of views both among patients and between patients and other stakeholders. ⁶⁵ Patients already participate in benefit/risk assessment in various ways, such as through their involvement with Scientific Advisory Groups and Scientific Advice Working Parties or as members of PRAC. ⁶⁶ The Agency is seeking to develop and provide greater structure for this role, in particular for patients’ participation in the Committee for Medicinal Products for Human Use (CHMP), the central committee responsible for assessing medicines at the European level. ⁶⁷ A 2014 document sets out terms of reference, including a list of situations in which patients should be consulted, the forms of interaction, and methods of recruiting patients. ⁶⁸ Also in 2014, a pilot phase for more systematic involvement of patients in CHMP benefit/risk discussions was launched. ⁶⁹ Initially planned to run at least one year, ⁷⁰ the pilot is continuing in order to allow more cases to be analyzed. ⁷¹

The literature on public participation, which will be reviewed in the next section, is helpful in better understanding these various initiatives, their objectives, and the issues they raise.

Value and purposes of direct public or “lay” participation

Public participation in policy-making and decision-making processes is widely advocated and supported—“no one is against it in principle” ⁷³ —but the specific goals and expectations are often unclear. ⁷⁴ It is important to articulate these, since participation is less likely to be effective if there is a mismatch between goals, expectations, and methods. ⁷⁵

The value and purposes of public participation have been described and categorized in many different ways, within which two loose groupings can be identified. First, there are purposes that relate to democratic ideals or values. As a matter of principle, those who are affected by a decision or process are seen as having a right to participate in it. ⁷⁶ This can be viewed broadly, in the sense that the public should have some input into decisions affecting the public interest, or more narrowly in giving those with the greatest stake in a decision a specific entitlement to participate. ⁷⁷ Public participation also increases transparency and accountability in decision-making. ⁷⁸ This, in turn, can enhance the legitimacy of decisions and foster public trust in decision-making institutions and processes. ⁷⁹ In serving these purposes, participation is an end in itself with intrinsic value, but it can also be a means to other related goals, such as helping to promote public acceptance and support for decisions ⁸⁰ or informing and empowering citizens. ⁸¹

The second type of purpose focuses on the potential for public participation to improve the quality of decisions or outputs. ⁸² The involvement or input of members of the public—or some specific subgroup of the public, such as patients with experience of a particular condition—is valuable because these individuals have specialized knowledge or expertise that is relevant to the decision being made. ⁸³ Their unique perspective allows them to ask questions that might not otherwise be asked and reframe issues in a way that can improve outcomes. ⁸⁴ This purpose recognizes and validates the contributions of the “lay experts” ⁸⁵ or “expert patients” ⁸⁶ who, although they may not have professional or technical expertise, have useful knowledge by virtue of their experiences (“experiential knowledge” or “experiential expertise”).

Types of participation and participants’ roles

There is also great diversity in the forms public involvement can take and roles participants can play, many of which are not consistently or precisely defined. ⁸⁷ Discussions of these aspects often refer back to a typology introduced in Arnstein’s 1969 article on citizen participation in urban planning and community governance. ⁸⁸ Critically examining a range of citizen participation initiatives in this context, Arnstein proposed a “ladder” of participation, ranging from “manipulation” and “therapy” as forms of “nonparticipation,” through “informing,” “consultation,” and “placation” as “degrees of tokenism,” to “partnership,” “delegated power,” and “citizen control” as “degrees of citizen power.” ⁸⁹ Arnstein’s hierarchy focuses on the extent to which citizens exercise decision-making power. The lower rungs of the ladder represent forms of participation that allow decision-makers to claim that affected citizens have been involved or consulted, while denying any meaningful power or influence over decisions. ⁹⁰ Some of the middle rungs, such as informing or consulting citizens, can be important but are viewed more as a “step toward” full participation than as ends in themselves. ⁹¹ At the higher levels, power is redistributed, through sharing power in partnerships, delegating power over certain matters, or transferring power to full citizen control. ⁹²

As influential as Arnstein’s ladder model has been, its hierarchical structure and emphasis on degrees of decision-making power, to the exclusion of other relevant considerations, are significant limitations. ⁹³ Subsequent work has produced various refinements and adaptations of the model, ⁹⁴ some of which aim to capture other considerations and dimensions of participation. Several scholars have proposed multidimensional frameworks, adding variables such as the context or type of decision and the specific roles or perspectives of participants. ⁹⁵ For example, the conceptual framework proposed by Charles and DeMaio in the context of health-care decision-making includes three dimensions: decision-making domain, role perspective, and level of participation. ⁹⁶ The decision-making domain relates to the context or type of decision (e.g. treatment, service delivery, or system-level decisions). ⁹⁷ The “role perspective” dimension recognizes that lay individuals may adopt different perspectives or roles when they participate, such as patients, advocates, or taxpayers. The level of participation in the third dimension of their framework is adapted from Arnstein’s model collapsed into three categories: consultation, partnership, and lay control. ⁹⁸

The second dimension in Charles and DeMaio’s framework aims to capture the multiplicity of roles that participants can play. Discussions refer variously to “public,” “citizen,” “stakeholder,” “lay,” “user,” “consumer” or “patient” participation, often without clearly defining or distinguishing these roles. ⁹⁹ Furthermore, these groups and their roles can be described in different ways. For example, “lay” or “public” participants could be defined as those without vested interests, those who lack professional expertise, or those who receive rather than provide services. ¹⁰⁰ There are important distinctions between various types of participants, depending on the interests they are assumed to represent (“stakeholders” with specific interests as compared to a broader “public” interest, for example ¹⁰¹ ) or the type of knowledge or experience they can contribute. Finally, there is likely to be heterogeneity within each group, ¹⁰² and even as members of a particular group, individual participants can focus on their own personal interests and experiences or act as formal or informal representatives of the interests and perspectives of a group. ¹⁰³ It may not be clear which type of role they are expected to play and how, if at all, they can or should represent others’ perspectives. ¹⁰⁴ As this brief review shows, the role perspective dimension, along with the other dimensions of participation, can be complex. The next section will examine some of the issues and challenges that surround the roles of patient participants in the context of medical product regulation.

Understanding the role perspectives of patient representatives

Although patient and public participation are often discussed together, the distinction between patients and other members of the public can be significant. Both can be considered “lay” participants, but their interests and perspectives may be distinct—even conflicting ¹⁰⁷ —and the purpose of their participation is somewhat different. Although virtually all members of the public are or have been patients in some sense, in the context of medical product regulation, references to “patients” generally mean individuals with experience of a particular disease (or persons like primary caregivers of those patients who could share much of the same knowledge, particularly on behalf of patients who cannot participate, such as children). The role of patients can therefore be distinguished from other members of the public in two ways: they are most directly affected by the regulatory decisions in question (as potential users of the products) and they have specific relevant experiential knowledge. ¹⁰⁸ The participation of patients as a distinct group is usually sought “when the explicit aim [of involvement is] to grasp the experiential knowledge of a patient, or a well-described group of patients or carers.” ¹⁰⁹

The policies and practices of the FDA and EMA do generally separate the roles of patient representatives from other public or “consumer” participants, though some other jurisdictions seem to be less clear on this point. ¹¹⁰ FDA advisory committees include consumer representatives as well as patient representatives as distinct categories. ¹¹¹ The patient representatives, as explained above, must have personal experience with the relevant disease and knowledge about its treatments. ¹¹² Other initiatives such as the Patient-Focused Drug Development meetings also focus on relevant personal experience and knowledge. ¹¹³ Many EMA documents refer to “patients and consumers” together, but the prescribed members of the management board and scientific committees are specifically identified as patient representatives, in particular representatives of patient organizations. ¹¹⁴

Where both patient and public/consumer representatives are included, they can play distinct but overlapping roles and both are valuable ¹¹⁵ ; where only a patient representative is included (as seems more common in this context), the patient representative may, to some extent, be expected to play both roles. This is not necessarily problematic, since both relate to important purposes of democratic legitimacy, transparency, and bringing a fresh “lay” perspective to discussions. Particularly where there might be the potential for conflicting perspectives or interests, however, it is important that participants have a clear understanding of the role they are expected to fulfill.

Even when a participant’s role is clearly defined as “patient,” further questions about role perspectives can arise. Commenting on the EMA’s description of patient roles, van Thiel and Stolk suggest that the conceptual basis for patient involvement is “limited to reference to experiential knowledge of patients,” and it is not clear whether “patients [are] asked to bring forward only their personal experience… [or should] collect the experiences and preferences from the groups they represent.” ¹¹⁶ This question is very important in the context of medical product regulation. If the central role of the patient participant is to act as a conduit for experiential knowledge, it could sometimes matter a great deal whose experiences are shared with a committee or other body. References to “the patient’s perspective” ¹¹⁷ can obscure the heterogeneity of perspectives and experiences that exists even among patients with the same disease or condition.

Although the concern raised by van Thiel and Stolk is valid, the EMA has arguably done more than most agencies to define patients’ roles and has attempted to provide guidance on this point. ¹¹⁸ The patient members of the scientific committees and management board are explicitly designated as representatives of patient organizations or associations; input or advice can also be provided either by individual experts who “act on their own behalf” or by patient organization representatives. ¹¹⁹ This framework is designed so that the contributions of patient representative members can be supplemented by “ad-hoc involvement of the most adequate experts/representatives” to add specific expertise the patient representative members may not have. ¹²⁰

Notwithstanding these attempts to clarify and define role perspectives, questions about the “representativeness” of the patient representatives are recognized as among the challenges or matters of debate in the European context. ¹²¹ This can involve questions about whose interests those members are representing, which will be discussed further below. It is also quite possible that in practice, the expectations of patient representatives may not always be clear, for example, regarding the extent to which they are expected to provide their personal experiences and perspectives as well as representing the relevant group, and the efforts they are expected to take to gather information from the group.

Such questions are undoubtedly present also in the FDA patient involvement activities, where there seems to be overlap between the personal and representative role perspectives. FDA patient representatives are required to have personal experience with the disease (either as a patient or as a primary caregiver) but also to be able to objectively represent the views of other patients; applicants are asked to describe their personal experience but also to describe their “ability to represent patients and communicate their perspectives,” for example, through connections with patient organizations. ¹²² This implies that patient representatives have a mixed role, which includes acting in their personal capacity (providing their individual views and experiences) but also as representatives of relevant groups, although they are not formally required to represent patient organizations.

Both role perspectives—personal and representative—present their own challenges. The personal experiential knowledge of individual participants can be extremely valuable, but it is inevitably limited. It cannot be assumed that one individual’s experience is typical and relying on individual input “has the potential to be distorting,” which is particularly problematic if it conflicts with other evidence. ¹²³ Patient groups themselves have apparently raised concerns that input into FDA decisions “does not necessarily represent the broad spectrum of patient views.” ¹²⁴ There are indications that the agencies are aware of the heterogeneity of patients’ experiences and its importance, ¹²⁵ and participation could arguably increase regulators’ sensitivity to heterogeneity among patients in a positive way. ¹²⁶ It must also be remembered that patient participation fulfills other important purposes, beyond providing specific experiential knowledge. There is an obvious need for individuals’ personal input to be supplemented by broader perspectives, however.

When patient representatives are formally or informally expected to gather and provide input from a relevant patient group, other issues arise. These efforts, particularly if they are comprehensive, systematic, and meaningful, may impose demands that are not realistic in terms of the time, expertise, and resources needed for individual representatives and patient organizations to identify relevant group members and collect and synthesize their input. Furthermore, a host of ethical and legal issues arise when patient organizations or their representatives attempt to collect data about members’ health, such as whether research ethics approval is required and what measures are required to protect patient privacy, and adequate guidance on these issues may not be available. ¹²⁷ Confidentiality of patient information is a particular concern in the context of rare diseases, where small patient populations can make it difficult or even impossible to effectively de-identify patient data. Confidentiality constraints also operate in the other direction: patient representatives are generally constrained by confidentiality obligations from sharing information about the deliberations of scientific committees, for example. It may be difficult for them to consult effectively with a patient organization and its members when they cannot disclose information about the matters under discussion. This has been identified as an issue of concern in the EMA context. ¹²⁸ Finally, even when efforts are made and barriers are confronted, “there is no good mechanism for knowing whether the individuals who do participate reflect the views of the groups they represent.” ¹²⁹

Who do “patient representatives” represent?

Further concerns about the “representativeness” of patient participants involve other questions about the perspectives and interests they represent, particularly if they are (formally or informally) affiliated with patient organizations. Do “professional” or “expert” representatives adequately represent “average” patients and could input from representatives of patient organizations be affected by ties with the medical products industry?

A central part of the rationale for patient involvement in regulation of medical products is the ability of patient participants to contribute relevant experiential knowledge. References to the “expert patient” ¹³⁰ recognize that patients, by virtue of their experiences, have knowledge about medical conditions and treatments that can be as valid and important as professional “expert” knowledge. ¹³¹ Patients are “experts by experience.” ¹³² At the same time, however, it is widely recognized that in order to participate effectively, patient representatives often need to acquire some specialized knowledge through training and other supports. ¹³³ Participants can thus be considered “expert patients” in another sense—meaning that they have become experts through training or repeated participation. ¹³⁴ In the context of health research, it has been suggested that this creates a “paradox” in which training and “professional socialisation” can blur the lines between “lay” and “expert” participants, and potentially undermine participants’ ability to fulfill their expected roles. ¹³⁵ Similar concerns have been raised in HTA about “professionalisation” of public participants through “repeated involvement of individuals closely associated with HTA agencies and other governmental institutions.” ¹³⁶

This tension also exists in the context of medical product regulation. The paradigmatic example of AIDS activists’ involvement in the FDA and other organizations is a case in point: as some activists became highly educated and engaged in scientific debates, questions arose about the extent to which they represented other activists or people living with HIV and AIDS. ¹³⁷ As a core of activist leaders became “full-fledged experts,” the “expert/lay division” came to be replicated “within the movement itself,” with the expert group now including “a smattering of autodidact activists.” ¹³⁸ The risk of such divisions remains a concern. The EMA has recognized that the training needed by patient representatives to participate effectively in scientific advisory groups might give rise to “the development of a more permanent ‘expert patient’ representative role,” but that this would need to be supplemented with “additional ‘naïve patient’ representatives to counteract the risk of coming to adopt an overly regulatory viewpoint.” ¹³⁹ A critique of FDA patient involvement initiatives suggests that most patient representatives are people with whom the agency already has a relationship ¹⁴⁰ ; participants tend to come from “a small cadre of well-organized patient advocacy organizations” ¹⁴¹ and many are “professional advocates speaking on behalf of patients.” ¹⁴² Further, it suggests that “[n]either the agency nor any other group has attempted to assess whether the people and organizations represented on these committees are in any way broadly representative of the range of perspectives in the general public.” ¹⁴³

The significance of these concerns depends on the extent to which meaningful efforts are made to be inclusive in seeking and representing the views of other group members as well as on expectations of the roles and purposes of participation. It should be noted that the existence of a “paradox” of training and professionalization undermining the value of patient or public participation is contested; the amount of training required need not always be extensive, and participants do not necessarily lose their “lay” perspective when they gain other knowledge. ¹⁴⁴ The combination of professional and experiential expertise may allow them to occupy a “hybrid” position ¹⁴⁵ and develop a “sophisticated and reflexive awareness” of their potential contributions. ¹⁴⁶ However, attention should be paid to the risk that the requirement for scientific understanding could limit participation ¹⁴⁷ and affect participants’ roles, and deliberate efforts to broaden participation and input may be needed. ¹⁴⁸ Agency policies could also help, to some extent. For example, the EMA’s criteria for patient and consumer organizations eligible to participate in Agency activities include expectations of the organization’s representativeness and consultation with its members. ¹⁴⁹

The fact that many patient participants are representatives of or affiliated with patient organizations can raise other issues. There is widespread concern about the potential for patient organizations’ relationships with industry to affect the activities and positions of these organizations. ¹⁵⁰ The relationships between pharmaceutical companies and patient organizations are not only financial—patient organizations play important roles in disseminating information and recruiting participants for clinical trials, for example ¹⁵¹ —but funding of patient groups is a major concern that is particularly relevant to patient representatives’ participation in medical product regulation, ¹⁵² along with related areas such as government lobbying and HTA. ¹⁵³

Various studies have estimated that between 30% and 71% of patient organizations accept industry funding ¹⁵⁴ ; the proportion of an organization’s funds represented by industry support ranges from small amounts to a majority of annual budgets. ¹⁵⁵ Patient organizations’ approaches vary widely, with some accepting no industry or corporate funding, others accepting some (in varying amounts), and a few seeming to be almost entirely co-opted or even created by pharmaceutical companies. ¹⁵⁶ Industry funding tends to be in areas relevant to companies’ products, suggesting that their sponsorship of patient organizations is motivated by business interests as well as altruism. ¹⁵⁷ There are concerns that industry funding may influence patient groups to focus more on advocating for reimbursement and faster approval of drugs, ¹⁵⁸ and some evidence suggests that patient advocacy has influenced drug approvals. ¹⁵⁹

Given the value of new products in terms of research and development investment and potential profit, the stakes in approval decisions are sufficiently high that companies can be expected to exert influence in whatever ways will be most effective. Alliances with patient advocacy organizations can be valuable in this respect: “politically strategic pharmaceutical firms know that industry lobbying is less successful than patient advocacy, and their regulatory behavior adapts to this fact.” ¹⁶⁰ The formation of these alliances does not necessarily fall within the original, narrow understanding of “regulatory capture,” ¹⁶¹ and its purposes extend beyond influencing regulatory processes (its role in supporting marketing of new products is also important). ¹⁶² However, it does raise concerns relating to capture in a broad or general sense, ¹⁶³ or perhaps what some have called “deep capture,” a form of regulatory capture in which certain interests (here the medical product industry) capture institutions other than the regulator and do so through subtle and invisible influence over ideas, perceptions, and beliefs, rather than overt pressure or incentives. ¹⁶⁴ One feature of deep capture that is particularly relevant here is the creation or co-option of “credible messengers” who can further commercial interests. ¹⁶⁵

These concerns obviously extend far beyond the context of patient participation in medical product regulation, but failure to address them adequately could undermine the value and legitimacy of that participation. To suggest that industry funding could create the potential for real or perceived bias or contribute to regulatory capture is not to question the integrity or bona fides of patient representatives; the concern is a structural or systemic one, requiring structural or systemic responses—and, if understood as a form of deep capture, likely to be resistant to simple policy solutions. ¹⁶⁶ While some have argued that patient organizations should not accept industry funding, ¹⁶⁷ others reject this as unrealistic, given the limited funding sources available to these groups. ¹⁶⁸ There is broad consensus that transparency is essential, and some policies to promote it have been developed by both industry and patient organizations ¹⁶⁹ ; however, disclosure practices have been criticized as falling well short of full transparency. ¹⁷⁰ Other measures can be taken by patient organizations, such as having policies that limit the amount or type of industry funding accepted or attempt to separate fund-raising from other functions. ¹⁷¹

Regulatory agencies themselves have policies regarding conflicts of interest and disclosure of interests, which are clearly relevant, but have some limitations. The FDASIA provision mandating the FDA to further develop patient involvement specifically directs the agency to identify and enable the participation of patient representatives “who do not have any, or have minimal, financial interests in the medical products industry.” ¹⁷² Patient representatives who are members of FDA advisory committees have the status of “Special Government Employees” and as such are required to declare potential conflicts of interest. ¹⁷³ The focus is on financial interests of the member and his or her family, employees, or an organization of which the member is an employee (or officer, director, trustee, or general partner). ¹⁷⁴ A representative who has a “disqualifying conflict of interest” cannot participate in an advisory committee meeting unless a waiver is granted. ¹⁷⁵ A waiver can be granted if the interest is considered de minimis ¹⁷⁶ or if the committee’s need for the individual’s participation outweighs the potential conflict of interest. ¹⁷⁷ Waivers are reportedly fairly common, ¹⁷⁸ though there is a cap on the number of waivers that can be granted each year. ¹⁷⁹

Apart from the possibility of waivers, the focus on individual financial interests (e.g. owning shares in a company whose product is under consideration) limits the relevance of these requirements for the more indirect types of influence that might arise from affiliation with an industry-funded patient organization (e.g. the patient’s organization receiving substantial funding and assistance from a company whose product is under consideration). Furthermore, these rules apply to advisory committee membership but not necessarily to other forms of patient participation. Speakers at advisory committee open public hearings are “encouraged” to disclose relevant financial interests, but this does not appear to be mandatory. ¹⁸⁰ Similarly, there does not seem to be a requirement for disclosure of interests by participants in “Patient-Focused Drug Development” meetings. ¹⁸¹ Financial interests might be less of a concern in this context, given that these meetings are intended to discuss the needs and priorities of patients with a particular disease or condition rather than specific products, but relationships between participating patient advocacy organizations and companies developing treatments for that disease or condition could still be relevant, since input at the meetings may well influence future consideration of relevant product applications.

The EMA has a similar policy for individual committee members, requiring disclosure of financial interests; however, it is broader in that it includes both direct financial interests (e.g. employment, personal compensation, holding intellectual property rights or shares) and indirect interests, which could include pharmaceutical company funding to an organization of which the individual is a member. ¹⁸² Depending on the nature and timing of the interest, the type of committee (decision-making or advisory), and the type of action or decision before the committee, participation as a member may be excluded, limited, or permitted with disclosure. ¹⁸³ In addition, a separate EMA policy governs eligibility requirements for patient organizations that are involved in any of the activities of the agency. ¹⁸⁴ The eligibility criteria require organizations to disclose details of their funding (including donors’ names and amounts) to EMA, to publish sources of funding on their websites, and to follow a code of conduct on relationships with and independence from sponsors. ¹⁸⁵ This policy speaks directly to the concerns about potential bias from industry funding of patient organizations and helps to promote the type of transparency that many have called for, so it could be used as a model for other jurisdictions.

The type and domain of patient participation: A broader view

Convergent developments in patient engagement at various stages of medical product research and development may offer partial solutions to some of the issues identified above, while adding greater complexity in some respects. Patient organizations have become increasingly active in research, and at the same time, product sponsors and researchers are seeking new ways to integrate patients’ views and experiences into research and product development. Involvement of patients and patient organizations in research and development is focused primarily on the purpose of improving the decision or process—specifically, facilitating research and ensuring that it is responsive to patients’ needs and priorities—although other benefits such as increased transparency and mutual respect are also acknowledged. ¹⁸⁶ The involvement of patient organizations can make successful clinical trials more feasible by advising on trial design and helping with recruitment of participants. ¹⁸⁷ Patient input can inform the choice of outcomes measures or end points ¹⁸⁸ and help to ensure that research is relevant and will produce results that meet patients’ needs and expectations. ¹⁸⁹

Some efforts go far beyond the types of patient participation discussed above, as patient organizations, especially those for rare or ultrarare diseases, have funded, organized, and even conducted research studies themselves. ¹⁹⁰ In a few cases, this has taken the form of what has come to be known as “venture philanthropy,” in which patient organizations not only fund research but partner with companies and become involved in oversight and management. ¹⁹¹ Perhaps the best known example of this model is the partnership between the Cystic Fibrosis Foundation and Vertex Pharmaceuticals to develop Kalydeco, the first curative therapy for cystic fibrosis. ¹⁹² In other cases, patient groups conduct studies themselves, for example, through finding ways to systematically gather and analyze experiential knowledge that begins as “anecdotal” reports from patients. ¹⁹³

Such initiatives, and even less extensive funding and assistance by patient organizations, can exacerbate the conflict of interest concerns identified above, since a patient organization may now have a direct stake (sometimes a financial one) in approval of a new therapy. Of course, this does not mean these initiatives should not be pursued; it does, however, mean that their implications for patient representatives should be taken into account and addressed to the extent possible, for example, as a factor to consider in the structure of relationships between patient organizations and product sponsors. ¹⁹⁴ In other forms of engagement with research and development, issues similar to those discussed above will arise, such as the concern about “professionalisation” of participants and its implications for patient input. ¹⁹⁵ To the extent that the same participants are involved in various stages of research, development, and regulation, these concerns could be intensified.

Yet in other ways, patient engagement in research and development has the potential to alleviate some of the difficulties inherent in the role of patient representatives in regulatory processes. One of the most challenging aspects of this role is the expectation that an individual committee member or expert consultant can adequately represent the diverse views and experiences of patients with a certain disease or treatment history. As already noted, this presents both practical and ethical or legal challenges; in addition, the time it takes to gather and synthesize such information in a meaningful way may not be feasible in the midst of a product review process, particularly given that regulatory agencies are under increasing pressure to shorten review timelines. ¹⁹⁶ The collaborations among researchers, product sponsors, and patient organizations in research and development are beginning to develop more systematic and rigorous methods of collecting and using patient input at various stages: “What began as an extension of patient advocacy has evolved into an emerging scientific discipline aimed at understanding and incorporating patient needs into the processes of developing, regulating, and delivering new therapies.” ¹⁹⁷ The momentum behind this research agenda can be seen in major initiatives to develop methods of generating relevant evidence and engaging patients in research. ¹⁹⁸

This “paradigm shift” ¹⁹⁹ of patient engagement in research and development has important implications for product regulation and patients’ roles in that process. A better understanding of patients’ needs and priorities is obviously helpful at every stage, including but not only when new products are reviewed. Some of the recent FDA initiatives speak to this directly, notably the “Patient-Focused Drug Development” agenda and the involvement of patient advocates in drafting guidance for industry on Duchenne muscular dystrophy. The latter initiative aimed “to encourage clinical trial sponsors to work with patients and parents to understand patient preferences at the very outset and throughout the clinical development of new therapies” ²⁰⁰ and to “enable FDA to rely more heavily on data regarding the community’s preferences than on public testimony and anecdotes gathered during New Drug Application hearings.” ²⁰¹ In the EMA, the revised framework for patient and consumer involvement adopted in 2014 states that one of its objectives is to:

Facilitate participation of patients and consumers in benefit/risk evaluation and related activities, to capture patients['] values and preferences and obtain information on the current use of medicines and their therapeutic environment, all along the lifecycle of the medicines, from early development throughout evaluation and post-marketing surveillance. ²⁰²

There are echoes of Arnstein’s work on public participation in warnings about “token” attempts “to appear more patient-centric” in this context. ²⁰⁵ However, a narrow view focused on degrees of decision-making power would fail to capture the full value of consultation and input in the research and development process. Arnstein’s model would privilege the exercise of decision-making power, such as voting rights in committees, and tends to view decision-making as an adversarial power struggle, ²⁰⁶ whereas current efforts emphasize collaboration. ²⁰⁷ More recent scholarship gives greater attention to other dimensions of participation, such as the stage of involvement, which has been recognized as important in this and other contexts. ²⁰⁸ Broad consultation in the early stages of research and development, where it can influence the questions and goals that are pursued, might ultimately be more influential than participating in decision-making at a later stage.

There is a recognized need to develop a comprehensive framework to guide and structure patient involvement in research and development. ²⁰⁹ Given the synergies with patient participation in medical product regulation, such a framework should encompass involvement at all stages, from early research through to pre- and postapproval regulatory processes. This provides an opportunity to revisit and clarify the purposes, roles, and types of patient participation in product regulation and might entail rethinking these to some extent. As already noted, increasing participation at multiple stages may introduce further complexity, for example, regarding conflicts of interest, which will need to be taken into account. However, situating product regulation within the larger context could be very helpful in reducing the burden on patient representatives to collect and represent diverse views of other patients, since these would already have been integrated into the process at earlier stages and structures for collection and analysis of patient data would already be established. There could be less emphasis on contributing specific experiential knowledge as the primary function of participants, mitigating the difficulties of that role that were discussed above. Patient participants could still play important roles in raising questions from a broader lay perspective and their involvement would continue to serve other purposes, such as those related to democratic legitimacy and transparency.