Advocacy groups ask FDA to share more information about rare diseases

Several patient and disease advocacy organizations have responded to the Center for Drug Evaluation and Research's (CDER) request for feedback on what it should provide as part of its Learning and Education to ADvance and Empower Rare Disease Drug Developers (LEADER 3D) educational materials.

In comments submitted to the agency, organizations recommended information specifically catered to patients and their healthcare providers, materials to clarify the agency’s product pathways, and external resources that may be useful to rare diseases stakeholders.

In February, FDA issued a request for feedback on what additional information it should include in its LEADER 3D project. The agency said the materials are intended to inform rare disease drug developers and asked stakeholders for feedback on the relevance and clarity of the existing LEADER 3D educational materials, the effectiveness of current media formats, and which other topics should be included.

The Lymphoma Research Foundation (LRF) wrote to FDA and emphasized the need to provide patient-facing educational materials on topics such as the plausible mechanism framework and comparing it to other regulatory pathways. The group said patient advocacy groups are familiar with the agency's guidance on expedited programs for serious conditions and said it has been helpful to understand different product development pathways.

"To help patients and patient advocates develop understanding of the Plausible Mechanism Framework and its relationship to other development pathways, a document should be developed that compares these pathways," said LRF. "We believe that such a document will assist patients and patient advocates in understanding the Plausible Mechanism Framework and its role in rare disease therapy development and regulatory review."

LRF also recommended including a patient-facing document on the site that explains natural history controls and how they may be used in rare disease drug development. The group said including information on natural history controls could be useful to patient groups and research foundations that maintain patient registries or other collections of patient data.

Finally, LRF said FDA should include information on listening sessions with patients and patient advocates to educate rare disease product developers as they develop materials to communicate risks and benefits of their products.

"We specifically recommend a listening session with lymphoma patients but believe that additional disease-specific listening sessions could be useful," said LRF. "We believe the deep experience of lymphoma patients in undergoing different treatments for their cancer and participating in the research and development process as trial enrollees and expert advisors should be mined and reflected in patient-focused materials that explain evaluation of risks and benefits of cancer therapies explain the potential risks and benefits of these treatments.

"Patient-facing materials on these therapies should address matters such as sequencing, long-term durability, one-time dosing paradigms, immunogenicity, and the implications of irreversibility," the group added. These materials should also address short- and long-term follow-up requirements."

The Save Rare Treatments Task Force (SRTTF) also said more guidance would be useful to stakeholders. The group said that while case studies are useful, they are not as useful as guidances to help rare disease sponsors figure out what is expected of them at each stage of the product development program.

"For smaller sponsors and organizations that are new to the regulatory process, what is most needed is clear, step-by-step process guidance: how to navigate the pathway from early development through FDA approval, including when and how to request different types of FDA meetings (INTERACT, Pre-IND, Critical Path Innovation Meetings), how to determine the appropriate evidentiary standard for a given program, and how to sequence the decisions around endpoint selection, trial design, and dose optimization," said SRTTF.

"We recognize that much of this information exists across multiple FDA guidance documents, and that the LEADER 3D User Guide helpfully catalogs many of these resources," the group added. "However, the guidance landscape itself can be difficult to navigate, particularly for the growing number of noncommercial and academic sponsors, patient advocacy organizations, and small biotech firms that are increasingly taking on drug development roles."

SRTTF also echoed other organizations in noting the need for more educational materials for patients and their caregivers to help them understand complex technical processes. The group also said that while the case studies presented by FDA are useful, they do not cover a wide enough area of research and recommended more case studies where the regulatory path was less straightforward, where patient advocacy played a critical role, and where innovative trial designs were required due to the ultra-rare patient population.

The Amyotrophic Lateral Sclerosis (ALS) Association said LEADER 3D materials on substantial evidence of effectiveness, clinical trial design, and endpoint selection are especially useful. The group noted that ALS trials face hurdles such as limited enrollment, ethical concerns regarding prolonged placebo exposure, and the rapid pace of disease progression, and case studies can be helpful to understand how FDA assesses single adequate and well-controlled studies that are backed by confirmatory evidence.

ALS Association said it would be useful to stakeholders if the LEADER 3D materials included information on how the FDA distinguishes between exploratory and confirmatory uses of natural history data, how it evaluates the strength and limitations of surrogate endpoints in progressive neurodegenerative diseases, and how it assesses safety and biomarker data collected from Expanded Access programs. It also recommended including educational materials that address how regulators assess disease severity, irreversibility, and limited life expectancy in benefit-risk assessments; their expectations for biomarker validation and use as surrogate endpoints; and how post-approval confirmatory trials fit into the regulatory lifecycle.

The Muscular Dystrophy Association (MDA) also stated that the LEADER 3D educational materials currently available are useful, especially the short and animated videos. The groups recommended that the FDA consider including the voices of agency leaders in the videos to give them greater weight and update them when they become outdated.

Furthermore, MDA recommended additional materials, including videos explaining different guidance documents, case studies of failures, and a decision tree outlining whom patient advocates can contact at the FDA regarding specific opportunities. The group also listed other resources available to patients and patient organizations who want to learn about rare diseases, including the National Center for Advancing Translational Sciences (NCATS), the Critical Path Institute, and Global Genes.

In terms of external resources, the National Organization for Rare Disorders (NORD) was among the groups that shared their own resources with the FDA to be included in the Rare Disease Innovation Hub. In particular, the group pointed to its video library, which includes materials on genetic testing, treatment types, and disease-specific videos. The group also recommended that, as the agency aggregates and shares educational material on rare diseases, it ensures that the materials are pertinent to both patients and product developers.

"NORD is grateful that the Rare Disease Innovation Hub provides so many resources to industry and patients," said the group. "We recommend that the Hub provide a central site for patient-focused resources across FDA product Centers – patients identify by disease-state or pathway, not Center."

NORD also commended the FDA for including case studies on its Accelerating Rare Disease Cures (ARC) program webpage, which it says demonstrates the agency's flexibility in rare disease product development.

"FDA’s choices provide much-needed insight on how industry can design well-controlled trials that are not randomized, placebo-controlled trials," the group said. "We respectfully request that, particularly as biotechnology allows for more tailored therapies, gene therapies and other emerging forms of treatment, that appropriate technologies are represented in the materials."

The American Society of Gene and Cell Therapy (ASGCT) was also shared a list of educational resources for patients and patient organizations, as well as for the Center for Biologics Evaluation and Research (CBER). The group listed its own resources focused on cell and gene therapy (CGT) educational materials, including the basics of CGT, viral vectors, and the clinical trial process. It also listed resources for CGT developers, including information on the foundations of CGT, viral vector content collection, and its regulatory webinar series.

"ASGCT’s quarterly Regulatory Webinar Series provides educational resources for developers across career stages and roles to support an informed and prepared workforce in the cell and gene therapy field," said ASGCT. "By pairing foundational sessions with deeper dives on advanced regulatory and CMC issues, the series helps stakeholders interpret evolving expectations, align internal teams, and apply practical frameworks relevant to development of rare disease biologics."

ASGCT emphasized that it supports educational exchanges among stakeholders through scientific convenings and other educational forums and highlighted its annual meeting as such a forum for researchers, developers, clinicians, and other stakeholders. Furthermore, it highlighted that its Policy Summit offers stakeholders a venue to discuss regulatory and policy issues, while its Empowering Patients Summit is intended to further conversations between healthcare providers, patients, and other stakeholders regarding the evolving therapeutic landscape.

"Together, these events contribute to a more informed community across the rare disease network, said ASGCT.

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