Parent and Patient-Driven Discovery and Research in Rare Diseases

By Simon Frost and Marshall Summar

Rare diseases, defined as conditions affecting fewer than 200,000 individuals in the United States, present significant challenges to the healthcare system. With limited financial incentives for pharmaceutical companies and sparse knowledge about these conditions, families and patients have by necessity often taken the lead in driving discovery and advancing treatments. Despite challenges facing parent- and patient-driven research initiatives, they regularly serve as a powerful and effective response, emphasizing the importance of patient-centered approaches, robust partnerships, and strategic planning.

Early Steps: Organizing Patient Groups

The foundation of any successful parent/patient-driven initiative is a well-organized patient group. These groups amplify the collective voice of the community, provide critical support networks, and lay the groundwork for research and advocacy.

Key Steps to Form a Patient Group:

1. Define a Clear Vision and Mission: Establish the group’s purpose early. A well-defined mission helps guide research and development efforts, align resources, and attract like-minded partners. It ensures everyone is working toward the same goals.
2. Understand the Science: Patient organizations can be highly successful partners and leaders in therapy development if they invest in developing foundational knowledge of underlying mechanisms and disease biology.
3. Develop a strategic plan to set clear priorities, define objectives, and guide investments. This plan should outline what success looks like and identify the essential components needed to achieve it. These components should include foundational research, toolkit development, biomarker identification, and multiple parallel approaches to therapeutic development.
4. Centralize Operations: Build an infrastructure that serves as a hub for the group’s activities. Bring together critical stakeholders, including scientists, researchers, and the patient community. Develop a coordinated strategy to:

·       Raise and allocate funds efficiently.

·       Centralize data, research repositories, preclinical tools, and therapies.

·       Accelerate mission execution by uniting resources and expertise under one framework.

1. Systematize the Approach: Develop structured methodologies to systematize key processes, including data collection, establishing research repositories, centralizing preclinical tools, evaluating and developing therapies, and designing and conducting clinical trials. This approach streamlines execution and minimizes duplication of effort.
2. Standardize Data, Tools and Processes: Establish consistent standards. Standardization creates efficiencies, ensures replicability, and facilitates comparisons across all aspects of research and development. Open access to high quality data and a standardized toolkit catalyzes advancements and encourages collaboration. A standardized approach across diseases supports broader, platform-based research. Internally, implementing standardized processes for proposal evaluation, research updates, and legal agreements enhances efficiency.
3. Optimize Systems and Processes: focus on continuous optimization to make systems and research and development processes as streamlined as possible.  Investigate failures, document them, learn from them, and correct them systematically.  Identify gaps and weaknesses and fill them.  Evaluate successes and build on them.
4. Grow Sophistication Over Time: As the foundation matures, formalize its structure with:

·       Bylaws and nonprofit or public charity status.

·       Scientific and medical advisory boards.

·       Professional support: engage legal advisors, data scientists, and regulatory experts to navigate complex healthcare systems and accelerate development.

·       Technological infrastructure: develop tools like patient registries, data visualization platforms, and telemedicine systems to enhance research capabilities and patient care.

·       Financial systems and advocacy expertise.

·       Capabilities in lobbying and educational outreach

Benefits to this approach:   Like the movie Field of Dreams, if you build it they will come.   In areas where there is not a lot of research or scientific/medical expertise, building a solid infrastructure of connected patients and data will bring them in.    It eliminates so much of the startup and organizational work they are not well trained or suited for.

Case Studies: Success Stories

1. Cystic Fibrosis Foundation (CFF):

Founded in 1955 by parents of children with cystic fibrosis (CF), the foundation’s mission was to improve care and drive research for CF patients. At the time, CF was a fatal childhood disease.  CFF created a centralized patient registry, established specialized CF care centers, and funded groundbreaking research.  Today, CF patients benefit from a robust portfolio of therapies, including:

·       Airway clearance techniques (ACTs).

·       Medications like mucus thinners and bronchodilators.

·       CFTR modulator therapies, such as Ivacaftor, Lumacaftor, Tezacaftor, and Elexacaftor.

·       Nutritional and breathing support protocols

·       Surgical interventions.

2. Friedreich’s Ataxia Research Alliance (FARA):

FARA began as a grassroots effort by families uniting to support research for Friedreich’s ataxia, a rare genetic disorder.  The alliance quickly gained momentum by collaborating with academic and industry leaders, prioritizing drug development, and launching successful clinical trials. FARA’s focused and strategic approach enabled the rapid advancement of research and therapeutic options for patients.

These examples highlight how patient groups can drive meaningful progress in research and therapy development, transforming the landscape for individuals affected by rare diseases.

Start With the Endpoint in Mind: Define Meaningful Treatment Goals

The definition of “success” varies by condition and patient priorities. While some diseases may benefit most from curative therapies, others may see life-changing improvements with symptom management or slowing disease progression.   To continue the baseball analogy, “swinging for the fences” is not always the best or most realistic strategy.

Examples of Patient-Centered Goals:

• Cystic Fibrosis: Early efforts focused on improving lung function and reducing infections. These priorities shifted as modulator therapies became viable, targeting the root cause of the disease.

• Friedreich’s Ataxia: Patients value treatments that preserve mobility and mitigate cardiomyopathy, even if the disease progression isn’t entirely halted.

How to Engage Patients in Goal Setting:

1. Create Patient Advisory Councils (PACs): Collaborate with patients to identify and prioritize treatment outcomes.

2. Use Surveys and Focus Groups: Collect feedback on what patients value most, such as pain relief, greater independence, or extended life expectancy.  Standardize and systematize this process: patient feedback should be treated as valuable data rather than anecdotal feedback.

3. Reassess Goals Over Time: Regularly update priorities as new therapies and treatments become available.

Survey the Landscape: Identify Available Therapies and Potential Therapies, and Perform a Cost-Benefit-Timeline Analysis

Rare diseases often have established pathways for developing therapies, including proof of concept, regulatory approval, and clinical trials. Accessible therapeutic options include gene therapies, knockdown approaches like antisense oligonucleotides (ASOs) and RNA-based treatments, gene editing techniques, and pharmaceuticals—ranging from repurposed drugs to novel compounds. Additionally, easily available solutions may include tailored nutritional plans, therapies effective for similar diseases, and symptom management protocols.

Steps to Evaluate Costs, Benefits, Timelines, and Risks:

1. Align Research with Patient Priorities: Focus on therapies and outcomes that matter most to patients.

2. List Currently Available Therapies: Identify existing treatment options that can inform your strategy.

3. Identify Potential Therapies for Development: Explore innovative approaches or repurpose existing drugs.

4. Assess Each Potential Therapy:

·       Risks involved

·       Expected costs

·       Likelihood of benefits

·       Timeline to clinical trials and regulatory approval.

5. Reprioritize Based on Feasibility: Focus on therapies with acceptable cost-benefit-timeline-risk ratios.  Pursue multiple approaches, when feasible, in parallel to maximize the probability of success and mitigate risk of failure.

Funding and Resources: Key Considerations for Cost Analysis

Patient- and parent-driven initiatives often require significant resources that exceed what individual families can provide. Critical elements include:

• Funding Sources: Secure diverse funding streams, from small donations to large grants. Consider venture philanthropy, like the Cystic Fibrosis Foundation model, which invests in biotech companies while retaining equity or royalties.

By thoroughly analyzing available and potential therapies and strategically managing resources, you can optimize the path to meaningful treatments while balancing costs, risks, and timelines.

After Finalizing a Strategy, Find and Align Research Partners

Partnering with the right research collaborators—whether academic institutions, pharmaceutical companies, or independent investigators—is essential for advancing rare disease research. Successful partnerships should be grounded in shared values, aligned goals, and transparent agreements.

Best Practices for Partner Selection:

1. Maintain the Highest Standards: Collaborate only with partners who demonstrate exceptional expertise, scientific rigor, integrity, ethics, professionalism, and a strong track record. Anything less introduces unnecessary risks and compromises outcomes.
2. Ensure Strategic Alignment: Choose research projects and partners that align with your strategic plan and long-term vision. When all collaborators work toward the same goals, synergies and positive outcomes naturally emerge.
3. Align on Values: Use a patients-as-partners model to center research on patient interests across the spectrum of research, from basic science investigation to clinical trial design. Establish expectations that this partnership will be robust and mutually beneficial.  Select partners who understand and prioritize the needs of the patient community. They should share a commitment to supporting vulnerable populations and advancing the broader field of rare diseases. For example, the Friedreich’s Ataxia Research Alliance (FARA) partnered with Reata Pharmaceuticals to develop treatments for neurodegeneration in Friedreich’s Ataxia—a mission both noble and practical.
4. Establish Clear and Shared Intellectual Property Agreements: Ensure that agreements protect the interests of the entire patient community. For example, the Cystic Fibrosis Foundation negotiated royalties from therapies it helped fund, reinvesting the proceeds into further research.  Make sure the data sets collected cannot be locked away either by a commercial or academic  partner.

Ethical Considerations:

• Avoid Exclusive Licensing Agreements: Ensure therapies remain accessible to all patients, avoiding restrictive terms that could limit access.
• Include Patient Representation: Involve patient representatives in decision-making to ensure the community’s interests are prioritized and protected.

By carefully selecting partners who meet high standards, align with your mission, and prioritize ethical considerations, you can create impactful collaborations that benefit both the patient community and the broader research field.

Build Your Preclinical Toolkit

Investing in a robust preclinical toolkit is essential for advancing research and therapy development for each rare disease. Centralizing, standardizing, and optimizing these tools ensures easy access and sharing, accelerates research efforts, and enables consistent comparisons across projects.

Steps in Building a Preclinical Toolkit:

1. Develop and Centralize Animal Models: Carefully design your portfolio of animal models, balancing the benefits of each model with development and maintenance costs.  Fully characterize and document the phenotype of each model to ensure reliability and reproducibility of research efforts.

2. Develop and Centralize Cell Lines: Test therapies in cell lines, especially patient-derived or isogenically corrected cell lines, as a critical step in therapy development. Consider the need for specific cell types, such as IPS cell lines, HEK293 cells, oocytes, or SH-SY5Y neuroblastoma cells, to support various aspects of preclinical research.

3. Establish a Biobank: Create a well-organized biobank to store and manage biological samples like tissues, blood, DNA, RNA, and cell lines, along with comprehensive donor data (e.g., medical history, genetic information, demographics). A biobank enables researchers to access standardized samples for consistent and collaborative studies.

4. Develop Assays and Screens: Design systems to assess function, dysfunction, and therapeutic correction in cells and animal models.  Aim for assays that are precise, easy to use, and cost-effective, as these will streamline preclinical testing and evaluation.

5. Establish Biomarkers: Invest in identifying and developing biomarkers—measurable indicators of biological states or conditions—that can demonstrate therapeutic efficacy or disease progression.  Robust biomarkers play a critical role in diagnostics, therapy development, clinical trials, regulatory approvals, and pharmaceutical collaborations.

By building a centralized and accessible preclinical toolkit, you lay the foundation for faster, more efficient, and highly collaborative research that drives meaningful progress in therapy development.

Build Natural History Studies

Natural history studies are critical to advancing rare disease research. They establish baseline knowledge about disease progression, variability, and biomarkers, which are essential for designing clinical trials and designing therapeutic protocols.  These studies should be prioritized early in the strategic planning process and developed alongside other research efforts.

Steps in Building a Natural History Study:

1. Define Goals and Stakeholders: Determine the key aspects to study, such as onset, progression rates, or genetic markers. Consider the needs of regulators (e.g., FDA) and pharmaceutical companies from the start, as they require specific data to evaluate treatment efficacy and safety. Example: In Friedreich’s Ataxia, natural history studies focused on tracking neurological and cardiac symptoms over time, establishing critical endpoints for regulatory and pharmaceutical evaluations.
2. Recruit Participants: Leverage patient group networks to encourage enrollment. Enhance participation by providing support for transportation, accommodations, or telemedicine options, ensuring accessibility for all patients.
3. Standardize Data Collection: Use validated instruments and protocols to ensure consistent and reliable data collection like the NORD IAMRARE program.

Example: The Cystic Fibrosis Patient Registry gathers longitudinal data on lung function, hospitalizations, and treatments, shaping clinical practices and trial designs. The data collected by the Cystic Fibrosis Foundation informed the clinical trials for Trikafta, a breakthrough combination therapy. Without decades of registry and longitudinal data, identifying suitable endpoints and measuring treatment efficacy would have been nearly impossible.

Natural History Studies: Challenges and Mitigation Strategies:

• Funding: Partner with organizations like NORD (National Organization for Rare Disorders) to access grants or shared infrastructure to reduce costs.

• Data Privacy: Implement strong protocols to protect patient data. Use platforms like IAMRARE®, which include built-in privacy compliance features, to ensure security and adherence to regulations.
• Data Access: Make sure that safeguards are in place so that data does not become embargoed or restricted through either a commercial or academic partner.    Decades of work can be lost if an investigator retires or moves without having planned for legacy data access.   The best model is for the patient organization to “own” the data and to make plans  in case even that organization goes away (IAMRARE® | Rare Disease Research Platform).

Select the Right Clinical Trial Partners

Choosing the right clinical trial partner is crucial for accelerating the development and delivery of life-changing treatments. The right partner can streamline the trial process, reduce costs, prioritize patient well-being, and maximize the chances of regulatory approval.   It should be remembered that an overly optimistic timeline is going to be a source of frustration and can result in wasted effort.   Also look for partners that are not trying to apply a common disease trial model to rare disease.  The two are very different in almost every aspect.

Steps to Design and Execute a Successful Clinical Trial:

1. Choose an Experienced and Specialized Team: Partner with a team that understands the unique needs of the rare disease community.  Look for expertise in rare disease patient care, experience with trials tailored for regulatory success, and the ability to design inclusive trials that prioritize both patient well-being and data reliability.

2. Tailor the Study Design for Your Diseases: Focus on measuring meaningful endpoints relevant to the disease.  Eliminate unnecessary or costly processes while ensuring the trial qualifies and treats the appropriate patient population.

3. Leverage Advanced Technology for Data Collection : Find a partner that uses sophisticated tools and systems to collect data accurately, securely, and efficiently, optimizing trial outcomes and compliance.

4. Implement Rigorous Subject Screening: Your clinical trial partner should routinely employ ethical, thorough, and efficient processes to identify and qualify trial participants, ensuring the best chance of success.

5. Evaluate and Optimize Trial Facilities: Identify a clinical trial partner that uses state-of-the-art, fully integrated facilities to conduct comprehensive and seamless trials that can collaborate with specialized external facilities to expand research capabilities and improve the quality and scope of the trial.

6. Conduct Thorough Post Marketing Studies: Make sure your clinical trial partner is well practiced in monitoring and evaluating the safety, effectiveness, and real-world performance of approved therapies to ensure sustained patient benefits and long-term success.

Clinical Trials: Avoiding the Pitfalls of Moving Too Quickly

While urgency can motivate action, rushing through key steps risks undermining long-term success. Common pitfalls include:

1. Poor Study Design: Hastily constructed studies can yield unreliable data, stalling progress. Engage experienced researchers early to ensure robust, well-designed trials.  Loading two many “interesting” data points in a study can make it impractical for patients to participate and seriously harm recruitment.    Remember that most studies fail from recruitment and retention rather than science.  The classic double-blind-placebo-controlled study is frequently not the best design for rare disease.   The regulatory agencies realize this and will work with the team, usually.    We strongly recommend an INTERACT meeting with FDA to discuss the study in a non-binding format.

1. Community Burnout: Demanding too much from families and patients without providing adequate support can reduce participation over time. Offering flexible engagement options and emphasizing self-care can help.

1. Ethical Risks: Patient-funded trials (PFTs), though appealing, can exploit vulnerable populations if not carefully regulated. Ethical oversight is paramount, as highlighted in Wenner et al.’s analysis of PFT vulnerabilities.   Also carefully consider the enrollment of patients in long-term therapeutic models where, after approval, there may not be a way to pay for the therapy.

By carefully selecting clinical trial partners with the right expertise, technology, and infrastructure, you can maximize efficiency, improve patient outcomes, and achieve regulatory success more effectively, while avoiding costly pitfalls.

Broader Impact and Future Directions

Parent- and patient-driven efforts are not just about developing treatments—they can reshape the broader landscape of rare disease care. Key areas include:

• Advocacy and Policy: Lobbying for expanded rare disease funding and faster regulatory pathways can yield systemic benefits.   The most powerful impact can be legislation aligning the regulatory requirements with the realities of rare disease trials.

• Global Collaboration: Initiatives like the European Reference Network for Rare Neurological Diseases demonstrate the power of cross-border partnerships.   Treatment standards like those in RARECAP can also both improve outcomes and identify gaps in treatment knowledge (RareCap – Clinical protocols for rare disease patient care).  They also serve to draw the professional community together.

• Education and Awareness: Educating healthcare providers about rare diseases improves diagnosis rates and patient experiences.
• Platform Approaches: Coordinated, systematized, standardized efforts by sophisticated patient-led groups can lead to high-quality research collaborations that explore networks, pathways and common pathogeneses of similar diseases.

These initiatives collectively enhance the quality, efficiency, and inclusivity of rare disease research and care worldwide.

Conclusion

Parent- and patient-driven initiatives have become transformative forces in rare disease research and care. By adopting a strategic, patient-centered approach, these efforts empower communities to tackle significant challenges, drive innovation, and advance meaningful therapies.

From organizing patient groups and building preclinical toolkits to conducting natural history studies and designing effective clinical trials, these initiatives showcase the power of collaboration, innovation, and determination. Success stories from organizations like the Cystic Fibrosis Foundation and the Friedreich’s Ataxia Research Alliance demonstrate how these approaches can lead to groundbreaking advancements. By building on past successes and addressing current challenges, patient-driven movements continue to deliver life-changing solutions for rare disease communities worldwide.

Beyond developing therapies, these initiatives play a vital role in reshaping the broader healthcare landscape. They advocate for systemic changes, foster global partnerships, educate healthcare providers, and improve research efficiency through standardized and platform-based strategies.

As these efforts evolve, their collective impact will drive better outcomes, raise awareness, and create a more inclusive and equitable future for rare disease research and care. By partnering with experts, leveraging advanced technology, and maintaining strong ethical standards, patient-led movements are not only accelerating treatment development but also setting new benchmarks for care and advocacy.

For more reading on these topics we suggest:

• Books: Rare Disease Drug Development: Clinical, Scientific, Patient, and Caregiver Perspectives by Raymond A. Huml. The Patient Revolution: How Big Data and Technology Empower Patients and Change Medicine Forever by Mohan Giridharadas. Rare Diseases and Orphan Products: Accelerating Research and Development by the Institute of Medicine (IOM).
• Articles: “Empowering Patients in Rare Disease Research: The Role of Patient Advocacy Groups” (Nature Reviews Drug Discovery). “Clinical Trial Design in Rare Diseases: Challenges and Opportunities” (Clinical Pharmacology & Therapeutics). “Ethics of Patient-Funded Trials” by Wenner et al. (Bioethics Journal).

Patient Groups and Infrastructure

• Guides and Platforms: NORD’s Diversity, Equity, and Inclusion (DEI) Toolkit – Part 1: A resource to inform and guide patient advocacy groups on DEI principles.

Rare Diseases

• EveryLife Foundation’s Advocacy Resources: Tools to empower the rare disease patient community in legislative advocacy.

Every Life Foundation

• RareConnect Platform by EURORDIS: Connects rare disease patient groups globally.
• Case Studies: Cystic Fibrosis Foundation: Details on their patient registry and research initiatives. Friedreich’s Ataxia Research Alliance (FARA): Insights into their collaborative model for therapy development.

Preclinical Research and Natural History Studies

• Books: Preclinical Development Handbook: Toxicology by Shayne C. Gad. Natural History of Rare Diseases (Journal Compilation).
• Platforms and Papers: IAMRARE® Platform by NORD: For setting up patient registries and conducting natural history studies. FDA’s Role of Natural History Studies in Rare Disease Development: Explores the importance of these studies in regulatory submissions.

Advocacy and Global Collaboration

• Organizations and Resources: National Organization for Rare Disorders (NORD): Advocacy toolkits and resources. EveryLife Foundation for Rare Diseases: Policy and advocacy resources. Global Genes: Toolkits and case studies for advocacy. Orphanet: Comprehensive resource on rare diseases and orphan drugs. European Reference Network (ERN): Frameworks for cross-border collaboration in rare diseases.

Clinical Trial Design and Ethical Considerations

• Books and Reports: The Design and Management of Clinical Trials by Davis and Soin. Optimizing Clinical Trials for Rare Diseases: Report by FasterCures focusing on accelerating rare disease trials with patient input.