Considerations in View of the Lived Experience of Affected Individuals: Compliance in the Rare Disease Space 

Authors: Lori Alarimo, Ben Ehrhart, Patrik Florencio, Sheila Folayan, Michele Girdharry, Melissa Gothie, Michael G. Hercz, Chad Morin, Piyush Sharma, Sarah Whipple, Donna White, Jean F. Cambell, Jayne C. Gershkowitz, Barbara H. Wuebbels, Max Mulcahy, George Timmins, Esther van Weert, Gary Giampetruzzi, and Adam Gomes-Abreu

1. Introduction

A. Overview of Rare Disease

While we live in a time of unprecedented access to information, the tribulations attendant to treating and living with rare disorders are still not broadly understood.  Over 10,000 rare diseases are currently affecting more than 30 million Americans.  Little is known about rare diseases and perhaps even less is understood about affected individuals, their families, and their caregivers. Rare disease companies face numerous challenges developing treatments for remarkably unique affected individuals under an ever-evolving legal and regulatory framework.

In this article, we will discuss the role of critical stakeholders in the experience of people affected by rare diseases—Patient Advocacy Organizations (“PAOs”) and patient advocates.  PAOs are organizations that engage in a variety of activities related to the awareness and treatment of medical conditions, with the goal of taking actions to help patients affected by those medical conditions, their families, and caregivers.  Patient advocates are those individuals who educate, empower, and support others living with, or caring for those with, a disease by which they are affected in a meaningful way.  Here, we discuss the value of PAO and patient advocate expertise in the lived experience of individuals affected by rare diseases.  We also discuss the existing framework under which PAOs and patient advocates can interact with rare disease companies.

II. The Role and Value of Patient Advocacy Organizations and Patient Advocates

PAOs vary in shape, size, interest, and geographic coverage.  They are generally defined as “notfor-profit organizations which are patient focused, and where patients or caregivers […] represent a majority of the members in the governing body.”  Relatedly, patient advocates are caregivers, family members, friends, health care professionals, affected individuals, life science professionals, healthcare system navigators, or those who have simply been touched by the story of an individual affected by a rare disease, such as a case manager.  Patient advocates provide support to affected individuals in a variety of ways, including helping to navigate a complex healthcare system, communicating with physicians about treatment decision-making, or assisting with adherence to medication.

A. PAO Composition & Membership

PAOs vary in organizational structure and size, from small kitchen-table volunteer-operated nonprofits to large professional organizations.  There are PAOs that operate at a local level and others that have international operations.  Certain rare disease PAOs operate as more than informal collections of patient experts and caregivers.  

In some cases, licensed medical professionals, including geneticists, genetic counselors, and other medical professionals specializing in rare diseases, participate in the activities of rare disease PAOs.  Furthermore, medical professionals working within rare disease PAOs tend to also be organized under Medical Advisory or Scientific Councils, which guide and inform PAO activities from a clinical perspective.  Medical professionals may also sit on the Board of Directors for rare disease PAOs and some are even founders of rare disease PAOs.  Some medical professionals are Chief Medical Officers of rare disease PAOs and others are heads of research for rare disease PAOs—medical professionals work among the ranks of PAOs in a variety of capacities. 

Anecdotally, most rare disease PAOs are patient initiated, volunteer-led organizations, focused on raising money for research.  That informal group will reach out and build relationships with local experts in their disease areas to help inform the best areas of research investment.  Rare disease PAOs also serve as support groups and connect patients and their families with one another to help form a community. 

B. Disease State Awareness and Expertise

The lived experience of an individual affected by rare disease is difficult and may start long before diagnosis.  Unlike broader disease classifications, individuals affected by rare diseases can often live for long periods of time without receiving an accurate diagnosis (a recent survey suggests 5 years on average, which has held true for roughly 30 years).  Rare diseases may present clinically in seemingly unrelated or unusual symptoms, and many general practice or primary care clinicians may not have the knowledge or experience to recognize the physical manifestations of certain rare diseases and/or may struggle to accurately diagnose and treat the disease.  When an affected individual is clinically symptomatic and undiagnosed, it can be a very isolating and lonely experience for the individual and their family, and can often create an opportunity for misdiagnosis, incorrect treatment, or for the affected individual and their family to receive incorrect or incomplete information about their disease state or prognosis.  

Living with a rare disease, both pre and post diagnosis, can be a chronically socially isolating experience across the lived experience continuum if the affected individual hasn’t found a community for support.  When an affected individual receives an accurate initial diagnosis, PAOs and patient advocates are often the only stakeholders that can provide current and accurate information on the affected individual’s rare disease in the period between diagnosis and treatment by a specialist.  In many cases, PAOs are made up of caregivers.  For these caregivers, it can be exhausting to both care for an affected individual and manage or participate in a PAO.  These difficulties notwithstanding, PAOs and patient advocates for rare diseases have a deep understanding of prevailing clinical research and academic literature.  Furthermore, rare disease PAOs and patient advocates have decades of experience in understanding not only their own health situations, but also the lived experience of others affected by rare diseases.  

This experiential knowledge, coupled with scientific expertise, allows PAOs and patient advocates to understand accurately and holistically, and aptly communicate, the experiences of people living with rare diseases and the diseases themselves.  Sophisticated PAOs often make this information accessible through materials available on their websites, and typically provide this information in an FAQ format, including questions such as: “What is my rare disease?” “Is my rare disease life-threatening?” “What are the signs and symptoms of my rare disease?” “What treatments are available or in development?” and “Where can patients find support?”  These PAOs also host live and virtual patient education conferences and other enduring programs.  The transfer of prevailing disease information provides affected individuals with essential information for improving treatment and disease management outcomes.  For this reason, PAOs and patient advocates play a particularly vital role in an affected individual’s lived experience, as many PAOs, through their community and patient advocates, provide affected individuals and their caregivers the benefit of their collective knowledge.  This also includes offering assistance to affected individuals and their caregivers with services such as access to disease management resources, medication, and diagnostic services, clinical research, and psychosocial and emotional support services. 

C. Patient Engagement

Patient engagement continues to be considered “a critical part of a continuously learning health system.”  Through their interactions with affected individuals and their caregivers, rare disease PAOs and patient advocates play a critical role in facilitating engagement with affected individuals, with the aspiration of improving the design and delivery of rare disease treatments. This is not to say that PAOs and patient advocates in every instance have greater expertise than clinicians.  Rather, it suggests that clinical expertise and experiential expertise are different. While affected individuals and their stakeholders, in most cases, do not have formal training regarding the diagnosis and treatment of rare diseases, affected individuals and their stakeholders can acquire a significant level of expertise through “the trial and error of managing the lived experience of illness.”

Rare disease PAOs represent a massive repository of both clinical knowledge and knowledge learned through the lived experience of affected individuals. The National Organization for Rare Disorders (“NORD”) provides many resources to affected individuals, including the maintenance of a news-oriented website and active social media communities; providing publications and educational materials to affected individuals, caregivers, and medical professionals; and supporting over 330 affiliated PAOs.  Large, sophisticated PAOs, like NORD, also participate in national and international PAO alliances, such as the Alliance for Healthcare Reform and the International Rare Disease Research Consortium.  These alliances are critical for coordinating PAO priorities and advocacy strategies.  Many PAOs have also become deeply involved in the creation of specific repositories of information and toolkits to assist patient advocates.  One key example is that of Global Genes, a rare disease umbrella PAO that has committed to helping connect patients, including patient advocates, with a variety of critical resources such as white papers, trainings, podcasts, and even connecting them with recognized experts, medical students, and others.  Both NORD and Global Genes host annual conferences for education, networking, and advancing specific priorities for the rare disease community, such as health equity and drug development. 

Several organizations and training programs have been formed to further improve the professionalization of Patient Advocacy.  These include both domestic organizations, such as Professional Patient Advocates in Life Sciences (“PPALS”), and organizations based internationally, such as the European Patients’ Academy on Therapeutic Innovation (“EUPATI”).  PPALS is a non-profit organization committed to supporting the function of patient advocacy within the biotech and pharmaceutical industries.  PPALS supports patient engagement by acting as a liaison between patients and industry for the purposes of encouraging drug development.  PPALS uniquely supports the education and training of patient advocates by offering a Patient Advocacy Certificate Training (“PACT”) to enhance the professional development of patient advocacy professionals in life sciences and leaders of PAOs.  EUPATI is a public-private partnership in the European Union organized as a non-profit organization based in the Netherlands. The organization aims to provide education and training directly for patient advocates on the therapeutic development process to allow for greater accessibility and understanding for their Fellows to impact the rare disease research and development process.  EUPATI offers a 12–14-month training program, which includes a rigorous application process, online and in-person training modules, exams on course content, and a graduation ceremony.  As of this writing, six cohorts have graduated, with a seventh one completing training by the end of 2024, producing over 330 EUPATI Fellows across 46 countries and over 60 diseases.

D. Recruitment and Rare Disease Research Support

PAOs and patient advocates engage in medical clinical research initiatives and work with clinical research sponsors—although PAOs are often the engine behind both bench and clinical research.  For this reason, they are in a unique position to support people affected by rare diseases through research collaboration and generating awareness.  Historically, rare disease research has been neglected due to its limited target markets, patient reimbursement challenges, and treatment profitability.  Researchers for rare disease populations have typically followed the same recruitment methods used for broader disease classifications, such as recruiting patients in hospitals and medical clinics, recruiting agencies, newspapers, websites, and even social media.  Enrolling individuals living with rare diseases through these channels is challenging given the limited, and in some cases undiscovered, patient population.

Through transparent communications, in which the goals of the PAO are not subordinate to the goals of the researcher, PAOs collaborate with researchers and the pharmaceutical industry to identify effective recruitment strategies for rare disease patient populations.  This in turn improves the ability of both academic and industry researchers to develop therapies that will ultimately benefit those living with rare diseases.  PAOs and patient advocates can uniquely encourage affected individuals to participate in registries or biobanks that can both raise awareness of rare disease signs and symptoms and assist with research and drug development.  In turn, specifically as it relates to rare diseases with genetic causes, people living with rare diseases can facilitate the participation of family members in registries and biobanks.

While these interactions seem intuitive and productive, one of the more frustrating aspects of rare disease industry interactions with PAOs and patient advocates under the existing U.S. regulatory framework arises in the context of research and development (“R&D”).  While all physicians, including general practitioners, are free to engage in detailed conversations with rare disease companies in the pre-promotional phase of drug development, industry participants are limited in what they can share with PAOs and patient advocates, who, in some cases, have a deeper level of disease expertise.  While recent reforms in the U.S., such as the 21^st Century Cures Act of 2021 (the “Cures Act”), have attempted to enhance the role of PAOs and patient advocates in new product development, PAOs and patient advocates are still largely held at arm’s length in the pre-promotional phase of new product development.  It would stand to reason that a criterion could serve as a license to allow advanced discussions with PAOs and patient advocates in the pre-promotional phase of drug development.

III. Industry Interactions with Patient Advocacy Organizations

To develop innovative and potentially life-saving products, rare disease companies need to identify affected individuals who may be suitable for existing or investigational treatment options or clinical trials.  Similarly, affected individuals want to understand the entire spectrum of treatment options at their disposal.  Often, PAOs and patient advocates are more familiar with recent academic research for a given disease, and some may even have relationships with subject matter experts for certain rare diseases.  For this reason, PAOs are playing an increasingly important role in addressing challenges associated with rare disease R&D.  PAOs are uniquely situated to provide drug developers with relevant insights regarding the lived experience of affected individuals, including symptom and disease burden and preferences in treatment mechanisms, to guide the development of novel treatments.

A. Collaborating with PAOs: Existing Industry Guidance

While the existing framework for PAO and patient advocate interactions with biopharmaceutical manufacturers was developed to account for a vastly different lived experience than that of an individual affected by a rare disease, particularly as it relates to disease awareness and diagnostics, it is nonetheless instructive on how PAOs and patient advocates can interact with the pharmaceutical companies focused on rare diseases.  According to the Pharmaceutical Research and Manufacturers of America (“PhRMA”) Principles on Interactions with Patient Organizations (“PhRMA PAO Guidance”), all interactions between PAOs, at their core, must be consistent with the PAO’s mission and adhere to high ethical standards, and the independence of the PAO must always be respected.  Further, when working with PAOs, companies should ensure that both the involvement of the industry participant and the nature of their involvement be clearly documented from the outset of the engagement.

PAOs and patient advocates typically expect to be informed by pharmaceutical manufacturers about the latest scientific research and developments in disease states.  Pharmaceutical companies focused on rare diseases learn a great deal from affected individuals, such as disease state manifestations.  To cultivate relationships with these affected individuals, trust and transparency with PAOs and patient advocates is critical, as affected individuals will be interacting with PAOs and patient advocates, and affected individuals have a key voice with respect to the treatments that are ultimately used to treat their conditions. 

Pharmaceutical companies focused on rare diseases are also placed in an unenviable position of having to, in some cases, “police” communications between PAOs and affected individuals.  Companies need to be very careful to balance pre-approval communications with PAOs and patient advocates to ensure that pre-approval communications are not promotional in nature.  Further, PAOs may seek to coordinate with manufacturers post-approval to augment communications with affected individuals regarding what they can expect while on treatment.  Indeed, there are instances in which sophisticated PAOs that operate as hybrid research organizations (and may have been actively involved in the research and development of a manufacturer’s approved product) provide information to affected individuals about a treatment that goes beyond what is in approved labeling.  It could go as far as coaching affected individuals to adhere to treatment in early phases, when adverse events are at their worst, because of the long-term benefits of treatment.  This creates issues for manufacturers who closely monitor communications related to adherence to product labeling for which they could ultimately be held responsible, as these same manufacturers will want to avoid any inference that they are encouraging PAOs to engage in communications that could be considered promotional.  The foregoing notwithstanding, and for the reasons we have covered in this article, manufacturers do not want to impair or otherwise prevent PAOs from interacting candidly with affected individuals, especially when PAOs have deep clinical experience and may even have medical professionals among their ranks who treat affected individuals.  The issue is more acute when the PAOs seek to have manufacturers “refer” affected individuals to them for further information, either through formal channels like triaging responses that come to the manufacturer as medical information requests, or more informally by directing patients to the PAO for additional information.  

The PhRMA PAO Guidance also establishes principles for the financial support of PAOs by industry participants, which, in some cases, is critical for creating disease awareness, providing evidence-based education, and advancing R&D efforts.  As is the case with non-monetary interactions with PAOs, the PhRMA PAO Guidance states that industry participants providing financial support or in-kind contributions to PAOs should have written documentation setting out the nature of the support, including the purpose of any activity it is funding.  The primary purpose of the financial support being provided to a PAO must be of a professional, educational, or scientific nature, or it must otherwise support the mission of the PAO.  Further, no industry participant should require that it be the exclusive source of funding for a PAO or any of its programs.  Such an arrangement, on its face, would call into question the independence of the PAO.  However, in the rare disease sector, a company may be the only company working on a given disease state, and there may not be other companies available to help support the PAO.  Often these PAOs are newly established by caregivers, where the caregivers are trying to balance their roles as both caregiver and PAO operator. 

B. Developments in PAO Collaboration

Recently, more targeted rare disease-specific thought leadership and proposed industry guidance has started to emerge in recognition of the unique challenges faced by people living with rare diseases and the commonality between PAO-industry interactions in the rare disease sector.  This framework accounts for how rare disease PAOs may decide to proactively communicate with the industry, providing that PAOs contact industry representatives: (1) that show an interest in drug discovery, preclinical research, or clinical research, or (2) that may not currently be working on rare disease R&D but that have otherwise developed technology that could assist the treatment of people living with rare diseases.  This framework would also permit PAO leaders or community representatives to speak at internal industry participant meetings, public events hosted by industry participants, or meetings with regulatory agencies.  This framework would allow PAOs to interact with industry participants in the clinical trial setting, which would enable PAOs to appropriately share with industry participants community-wide observations, needs, and barriers to participation in clinical trials.

C. A Framework for PAO and Patient Advocate Engagement

The collective experience of rare disease PAOs and patient advocates could be an invaluable addition to rare disease product development initiatives.  Of course, it is important to note that not all PAOs and patient advocates possess a level of expertise that is worthy of extensive pre-commercial interactions with industry participants.  But for those who do, the question remains as to whether their expertise can be certified in such a way that could provide regulators with a level of comfort that would, in turn, enable PAOs and patient advocates to have advanced pre-commercial interactions with industry.  A consistent and structural approach in PAO-industry collaboration, which considers the lived experience and needs of affected individuals, would result in increased value and efficacy of rare disease product development initiatives, from design, planning, and execution until the dissemination of clinical trial results.  Moreover, this alignment would also benefit subsequent access and reimbursement determinations as regulatory agencies are increasingly requesting the input of affected individuals for key decisions, such as formulary decisions.  Formalized regulatory guidance for PAO-affected individual communications that draws a distinction between disease state education and product education discussions, and guardrails for what can and cannot be discussed in each context, would further ease the burdens currently placed upon pharmaceutical companies focused on rare diseases and interactions with rare disease PAOs. 

IV. Conclusion

Given the unique nature of the lived experience of individuals affected by rare diseases, namely the lack of disease awareness and availability of credible and reliable information, patient advocacy is a critical aspect of improving quality of care for people living with rare diseases.  In the small universe of rare diseases, PAOs and patient advocates offer a tremendous amount of valuable knowledge—often acquired through learned experience and independent academic and scientific research.

While incremental progress has been made with respect to involving PAOs and patient advocates in rare disease R&D, little has been done to reconsider the framework under which rare disease PAOs and patient advocates can interact with rare disease companies.  As more rare diseases are discovered, and even more therapies developed to treat these diseases, PAOs and patient advocates should be empowered and encouraged to continue their essential work of identifying and understanding the lived experience of affected individuals.

Footnotes

^[1] See About GARD, National Center for Advancing Translational Sciences, https://rarediseases.info.nih.gov/about (last visited Jul. 7, 2024). 

² See Stakeholders and communication division.  Criteria to be fulfilled by patient, consumer and healthcare professional organizations involved in European Medicines Agency (EMA), European Medicines Agency, https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/criteria-be-fulfilled-patient-consumer-hea lthcare-professional-organisations-involved-european_en.pdf (last visited Sept. 10, 2023).

³ See Lori Alarimo et al., Considerations in View of the Patient Journey: Compliance in the Rare Disease Space (Part 1), Pol’y & Med. Compliance Update (Jun. 2020).

⁴ See Major survey reveals lengthy diagnostic delays for rare disease patients, EURODIS Rare Diseases Europe (May 2024), https://www.eurordis.org/survey-reveals-lengthy-diagnostic-delays/#:~:text=Speaking%20about%20the%20survey’s%20findings,on%20demographic%20and%20geographic%20factors.

⁵ See Lori Alarimo et al., Considerations in View of the Patient Journey: Compliance in the Rare Disease Space (Part 2), Pol’y & Med. Compliance Update (Aug. 2020).

⁶ See National eHealth Collaborative, 2012 NeHC stakeholder survey results,http://www.nationalehealth.org/ckfinder/userfiles/files/2012%20NeHC%20Stakeholder%20Survey%20Results%20FINAL.pdf Google Scholar (last visited Sept. 10, 2023).

⁷ See Hartzler A and Pratt W, Managing the Personal Side of Health: How Patient Expertise Differs from the Expertise of Clinicians, J. Med. Internet Res 2011;13(3):e62, https://www.jmir.org/2011/3/e62; citing Coulter A.  After Bristol: putting patients at the centre.  BMJ 2002 Mar 16;324(7338):648-651

⁸ Id.

⁹ A white paper is a concise report or guide designed to inform the reader about an issue or topic. 

¹⁰ See https://ppals.org/about/.

¹¹ EUPATI Open Classroom, About Us, https://learning.eupati.eu/mod/page/view.php?id=1068&forceview=1 (last visited Mar. 1, 2024).

¹² Nguyen, Alba-Concepcion, Palmer, et al., The involvement of rare disease patient organisations in therapeutic innovation across rare paediatric neurological conditions: a narrative review, Orphanet J.  Rare Dis. 17, 167 (2022). https://doi.org/10.1186/s13023-022-02317-6.

¹³ Priscilla Auguste, MHS, et al., Working Together to Enhance Rare Disease Research — The Role of Patient Advocacy Organizations, The Evidence Forum, Evidera.com (Oct. 2014) https://www.evidera.com/wp-content/uploads/2015/04/The-Role-of-PAOs-in-Disease-Research.pdf#:~:text=Due%20to%20the%20rarity%20of%20these%20life-altering%20diseases%2C,or%20to%20rare%20disease%20umbrella% 20organizations%20for%20support.

¹⁴ See Pharmaceutical Manufacturers of America, Principles on Interactions with Patient Organizations Guidance, (Nov. 20, 2014), https://www.phrma.org/codes-and-guidelines/phrma-principles-on-interactions-with-patient-organizations.

¹⁵Stein, S., Bogard, E., Boice, N. et al., Principles for interactions with biopharmaceutical companies: the development of guidelines for patient advocacy organizations in the field of rare diseases.  Orphanet J.  Rare Dis. 13, 18 (2018). https://doi.org/10.1186/s13023-018-0761-2.

¹⁶ Id.

¹⁷ Id.