Background

Rare diseases are a global public health concern, affecting an estimated 350 million individuals. The definition of a rare disease varies internationally [1]. In the United States, a disease is considered rare if it affects fewer than 200,000 individuals at any given time; in the United Kingdom, rare disease is defined as a disease that affects fewer than 50,000 individuals. Although the number of patients with each specific rare disease is small, collectively, rare diseases affect about 30 million people in the United States and another 30 million in Europe [1].

In the United States, the Orphan Drug Act was designed to provide incentives to manufacturers to conduct research and development for rare disease therapies [2]. Although the submission and approval rates for orphan drugs in the United States have increased since the passage of the Act in 1983 [2, 3], only 5% of the approximately 7000 rare diseases identified currently have a treatment approved by the US Food and Drug Administration (FDA) [1].

Rare diseases are confronted with some of the most complicated scientific and medical challenges of today. There are numerous barriers to the development of new and meaningful treatments, including unanswered scientific questions; a lack of data on disease epidemiology, pathophysiology, and natural history; a lack of clearly defined biomarkers to measure disease activity; and difficulty in identifying clinical trial endpoints and measurable and validated disease outcomes [1, 4, 5]. The technical challenges are compounded by limited research funding for rare diseases compared with that provided for more common diseases, and by difficulty in finding and recruiting patients to participate in clinical studies [3]. Finally, patients with rare diseases and academic experts are often geographically dispersed, making it more difficult for drug developers to locate and engage with them. Expertise in the care and management of a particular rare disease is often concentrated in a small number of academic centers that may not be experienced in clinical research or development, adding to the time and costs of starting and implementing clinical trials. Patient advocacy associations are a key interface between patients and providers.

Solving the challenges posed by rare diseases requires the collaboration of multiple stakeholders: biopharmaceutical companies, academic researchers, clinicians, patient advocacy organizations, patients, and regulators. Yet collaboration, while essential, is often challenging. The highest personal, professional, and business stakes are at play; considerable ethical and legal issues exist; incentives can be misaligned; and the environment is both incredibly complex and rapidly evolving.

Patient organizations are playing an increasingly important role in addressing and overcoming the challenges of drug development. About half of all known rare diseases are represented by a disease-specific patient advocacy organization [1]. This number is growing. Although the history of patient advocacy organizations lies in grass roots efforts and family fundraising events, the sophistication of the patient community has increased to match its ambition to find effective therapeutics. Many patient advocacy organizations today are led by professionals, are meaningful and empowered stakeholders in the development of treatments, and have a large impact on research [5,6,7].

Indeed, today, one of the most important factors in the development of new therapies is the positive influence of patient advocacy organizations on research and development, clinical trials, and governmental regulations [7].

Patient advocacy organizations perform many functions that enable drug development and access, including the following [5,6,7]:

  • Educating patients, physicians, and the community about a disease and innovations in its management and treatment

  • Pushing the pace of research by championing and directly funding efforts to increase the understanding of the cause of a disease and to develop new therapies

  • Forming connections between disease experts and drug developers

  • Providing drug developers with relevant insights into the patient community to enable the development of therapies that best meet the community’s needs

  • Advocating for and influencing changes in regulations to expedite research

  • Facilitating and/or sponsoring patient registries and natural history studies to aid in the development of treatments

  • Helping to ensure that patients have access to treatments

With the evolution of patient advocacy organizations and the increasing activity of biopharmaceutical companies in the development of novel therapies for rare diseases, collaborations between patient advocacy organizations and biopharmaceutical companies have become more common. However, many organizations face uncertainty in addressing the complex and important day-to-day issues that arise within the context of these collaborations.

Although guidance documents exist, most either are directed at the biopharmaceutical industry, are specific to the European healthcare system [8, 9], or are too general to serve as a roadmap for day-to-day decision-making for patient advocacy organizations. Given the important and dynamic nature of their work and the complexity of collaboration in the development of treatments for rare diseases, many patient advocacy organizations are seeking clarity and guidance concerning approaches to industry collaboration.

Guidelines are needed now more than ever, especially with healthcare regulatory bodies increasingly restructuring themselves to put the needs of patients first. The European Medicines Agency (EMA) established the Patients’ and Consumers’ Working Party (PCWP) in 2006 to provide a platform for information exchange between patients and the Agency. The US FDA enacted the US twenty-first Century Cures Act in December 2016 [10]. The Act seeks to make improvements throughout the entire research and development system, from discovery, to development, to delivery of new medical products [10]. The policy reforms in the Act are meant to strengthen patient centricity in the areas of biomedical product development and regulatory approval and to catalyze innovation in clinical trials and regulatory approval. Such innovations would include promoting FDA qualification of biomarkers and other drug development tools and the study of how best to use innovative clinical trial designs and the real-world evidence that is generated during product development and regulatory approval [10, 11]. In 2016, the EMA and the FDA established a new ‘cluster’ on patient engagement. This cluster is intended to provide a forum to share experiences and best practices on the way the two agencies involve patients in development, evaluation, and post-authorization activities related to medicines [12].

The great need for guidelines was most recently emphasized by the publication of an article in March 2017 in The New England Journal of Medicine addressing conflicts of interest that may arise when patient advocacy organizations interact with industry [13].

In order to address the need for guidelines, we convened an Independent Expert Panel of leaders from patient advocacy organizations and the biopharmaceutical industry to develop guidelines on effective collaborations between these two stakeholders. This report presents the objectives and guiding principles developed by the Independent Expert Panel, the process used to develop the guidelines, a summary of points raised during the Panel discussion, and the finalized guidelines.

Objectives

The objectives of the Independent Expert Panel meeting, titled “Principles for Interactions With Pharmaceutical Companies: Guidelines for Patient Organizations,” were as follows:

  • To create guidelines directed at day-to-day decision-making for rare disease patient advocacy organizations for use in working with industry partners

  • To capture comments and suggestions from participants for use in developing a white paper on the principles of interactions with industry to support the guidelines

  • To determine next steps regarding finalization and dissemination of the manuscript and the guidelines

Methods

Nine experts chosen for their expertise and availability participated in the Independent Expert Panel: four leaders of patient advocacy organizations and three leaders in the pharmaceutical industry who interact with patient advocacy organizations. The Panel also included two facilitators, one with experience in such collaborations at both a patient advocacy organization and a biopharmaceutical company (EB) and one from a medical communications company specializing in rare diseases (SS).

The Independent Expert Panel meeting utilized a roundtable discussion format. The meeting was held via a 2-h web conference, ensuring that each participant was given the opportunity to provide input into the guidelines. The agenda included background and introductions, questions for discussion, a session on other comments and suggestions, and next steps.

Prior to the meeting, the Panel was provided with and asked to review the known guidance documents available on this topic (Table 1) [13,14,15,16,17]. The Panel was also provided with a set of guidelines previously developed by the International Fibrodysplasia Ossificans Progressiva Association (IFOPA), a nonprofit patient advocacy organization for this rare disease founded in 19889 (see www.ifopa.org), titled “The International Fibrodysplasia Ossificans Progressiva Association’s (IFOPA) Guidelines for Engagement with Pharmaceutical Companies” [18].

Table 1 Background materials for the Independent Expert Panel meeting

The IFOPA guidance document provided a foundation from which the Panel was asked to build a set of guidelines for use by the entire rare disease community. The IFOPA document was chosen because it reflects many of the broader principles described by the known guidance documents listed in Table 1. The facilitators discussed and raised key questions for each of the five sections of the IFOPA guidance document (Table 2) [18]:

  1. 1.

    Identification and Engagement of Companies

  2. 2.

    Patient Engagement

  3. 3.

    Financial Contributions

  4. 4.

    Clinical Trial Communications

  5. 5.

    Patient Privacy

Table 2 Discussion questions posed to the participants of the Independent Expert Panel meetinga

During the meeting, the Panel addressed the key questions (Table 2) and provided comments and revisions to the IFOPA document. Based on input from the Panel, the authors developed a first draft guidance document.

Results

The Independent Expert Panel reviewed and revised this first draft. A second draft was also reviewed by six independent experts from patient advocacy organizations and the biopharmaceutical industry. The Guidelines were finalized in October 2017.

The Guidelines produced by the Independent Expert Panel, titled “Guidelines for Interactions Between Patient Advocacy Organizations and Biopharmaceutical Companies,” are provided in the Appendix to this article. The Panel adapted the original five sections of the IFOPA guidelines into four sections:

  1. 1.

    Identification and Engagement With Companies

  2. 2.

    Patient Engagement and Patient Privacy

  3. 3.

    Financial Contributions

  4. 4.

    Clinical Trial Communication and Support

The Guidelines address the day-to-day considerations, choices, and consequences for patient advocacy organizations in their engagement with biopharmaceutical companies. The Panel agreed that all interactions between the patient advocacy organization, industry, and the disease community should be transparent; should enable trust, accountability, and shared learning; and ultimately should work most efficiently and effectively toward advancing meaningful treatments for patients. The Guidelines strive to achieve these objectives while recognizing that every relationship is unique and that there are a variety of ways to partner successfully.

The recommendations contained within the Guidelines are relevant for any paid or volunteer leader of a patient advocacy organization, including staff, board members, and committee members. The Guidelines are intended to be a living resource that can be revised and expanded as the environment evolves.

Participants in the Expert Panel stressed the importance of having the Guidelines available and published in the literature. The Panel also provided the following overarching comments:

  • Patients and industry cannot “go it alone.” Both need patient advocacy organizations.

  • Patient advocacy organizations may not realize their value and how important they are to industry.

  • Successful collaborations between patient advocacy organizations and biopharmaceutical companies are achieved when they have reciprocal relationships in which both parties recognize the value of the other.

  • Mutual respect is essential, which requires honesty and authenticity. Transparency and commitment from both parties should begin on day one.

The Independent Expert Panel provided Probing Questions for possible use in conjunction with the Guidelines (Table 3). The Panel also recommended that patient advocacy organizations develop educational resources for patients (Table 4).

Table 3 Probing questions from the Independent Expert Panel meeting, for possible use with the Guidelines
Table 4 Education and resources that patient advocacy organizations can provide and share

Discussion

Collaborations between patient advocacy organizations and the biopharmaceutical industry, which have become increasingly more common, are needed now more than ever to overcome the challenges of developing treatments for rare diseases. The increasing focus on patient engagement by healthcare regulators highlights the need for guidelines to facilitate this collaboration. Although collaboration is essential, it is also poses challenges. The Independent Expert Panel developed Guidelines that are intended to help address these challenges. The Guidelines presented here are directed at day-to-day decision-making for rare disease patient advocacy organizations for use in working with industry partners. Comments and suggestions from the members of the Independent Expert Panel were included in the Guidelines, and the Expert Panel reviewed and finalized the Guidelines. Additional comments on the draft Guidelines were provided by independent experts from patient advocacy groups and the biopharmaceutical industry.

Various limitations to the development of these Guidelines exist: the complexity of collaborations between patient advocacy groups and the biopharmaceutical industry, the dynamic nature of the work of patient advocacy organizations in the development of therapies for rare diseases, and various regional differences such as those between the United States and Europe related to interactions between these types of groups. However, these Guidelines are intended to be freely available for use as a living document, with the potential for regular revisions and updates. Future versions of the guidelines should explore regional differences and needs in how patient organizations interact with pharmaceutical companies, particularly between the United States and Europe.

Conclusions

The Guidelines described here are intended to guide collaborations between patient advocacy organizations and the biopharmaceutical industry in an ethical and transparent way for the benefit of patients who desperately need novel and meaningful therapeutics. The Guidelines recommend best practices and standards for interactions between patient advocacy organizations and the biopharmaceutical industry that will ultimately have a positive effect on the development of novel treatments.