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After the US Food and Drug Administration (FDA) solicited comments on an educational program for a new Empower Rare Disease Drug Developers (LEADER 3D) initiative in the Accelerating Rare disease Cures (ARC) program, nearly two dozen stakeholders offered feedback on what topics they believe are important for inclusion in educational materials on rare disease drug development.
FDA’s Center for Drug Evaluation and Research (CDER) asked for comments from rare disease stakeholders on knowledge gaps in rare disease drug development, including regulatory knowledge gaps. Such gaps may include non-clinical and clinical pharmacology considerations, clinical trial design and interpretation, and regulatory considerations for development of drugs for rare diseases, the agency said.
“With input from rare disease stakeholders who design and conduct rare disease drug development programs (academics, industry, patient groups, other federal partners, etc.), FDA believes we can better understand and address knowledge gaps for external stakeholders,” the agency said in a docket description for the LEADER 3D initiative.
General comments
The Dravet Syndrome Foundation highlighted the importance of patient input for rare diseases, as literature reviews and expert opinion are unlikely to yield a complete understanding of an unmet need for a rare disease.
“The voice of the patient is critical to garnering a full picture of the impacts of rare diseases on medical care and quality of life,” they said. “Early-engagement of therapeutic developers with patient populations and patient advocacy groups will facilitate a development process focused on improvements that are truly impactful to rare disease patients.”
To aid in opportunities for collaboration, the American Society of Clinical Pharmacology and Therapeutics (ASCPT) proposed the use of more cases studies when possible to educate sponsors on examples of both successful and failed cases of rare disease drug development.
“It is important for these sessions to not only bring the successful case studies that emphasize the FDA’s flexibility, but also identify the enablers for such flexibility by showing failure cases. In addition, we acknowledge the difficulty to achieve full harmonization in all aspects. To the extent possible, we encourage the FDA to share case studies that may help the sponsor navigate such differences or potentially, reach a middle ground with regulators,” ASCPT said.
The National Organization for Rare Disorders (NORD) said it is important to create educational materials for rare diseases that are accessible to an adult lay audience, including individuals with disabilities, and publish the educational materials in a space where they can be easily found and shared, such as the front page of a centralized website like ARC’s. “The best educational materials are useless if the intended audience cannot find them,” NORD said.
In their comment, NORD also noted a top gap identified within their patient group and small biotech industry membership is an ask for more guidance and best practices for engagement with sponsors, FDA, and other stakeholders. The request for more guidance was reiterated among many stakeholders who responded to FDA’s request for comment. “The need for better tools and more guidance on how to work together effectively on the development of rare disease drugs is universal and largely unmet,” NORD explained.
Considerations in clinical and non-clinical pharmacology
One major issue is an inconsistent definition of the term “rare disease” across the agency, Praxis Precision Medicine said in their comment. “Ensuring a flexible, yet consistent interpretation of the definition for rare diseases will ensure that patients with life-threatening and severely debilitating diseases … are able to more quickly access treatments that could be life-altering,” they wrote.
The Rare Disease Company Coalition (RDCC) brought up the issue of gaps in guidance in their comment, mentioning that problem areas include biomarker qualification for clinical trials, difficulty in obtaining clinical samples and in enrolling an adequate patient population, variation in disease severity and underlying disease cause, and challenges in modeling clinical outcomes due to unpredictability.
In a joint comment, the Pharmaceutical Research and Manufacturers of America (PhRMA) and Biotechnology Innovation Organization (BIO) wrote that there are often no relevant animal models for nonclinical studies. “As use of animal testing alternatives increase, we recommend FDA provide information on the use of alternative methods to support rare disease drug development,” they wrote.
A lack of guidance on dose finding and exposure-response for rare disease studies is another consideration, PhRMA and BIO said. “We note that while recent guidance has referenced dose finding and exposure-response studies in rare disease contexts, the guidance does not expand on regulatory flexibilities for clinical pharmacology studies in rare disease populations,” they explained. “Thus, we recommend FDA develop educational materials that specifically address the challenges of assessing dose response and exposure in small patient populations.”
Design and interpretation of clinical trials
Recruitment for rare disease trials can be an issue, Boehringer Ingelheim noted, as some patients have the perception that trials for rare diseases are unsafe or they fear receiving a placebo. They suggested education within specific patient communities and building relationships may be worthwhile to improve engagement with patients and their caregivers.
“[P]atients need education and support to understand the benefits to society and to the community when they participate in trials. It is also important for patients to understand that clinical trials are heavily regulated and that participants are not ‘guinea pigs’, but rather receive a high level of care, independent of the treatment they get in the trial,” the company said.
In terms of designing clinical trials, Chiesi Global Rare Diseases outlined four major challenges they face in the development of a rare disease therapy, including limitations of double-arm placebo trials, endpoints, adhering to diversity requirements for clinical trial participants with rare diseases, and use of real-world evidence (RWE). “These challenges can make rare disease-based clinical trials very time and resource intensive,” Chiesi said.
To address the issue of a comparator group in rare disease trials, PhRMA and BIO proposed the agency use case studies to describe when an external control group, natural history data, or real-world data use is warranted. “Information about approaches and/or methodologies and tools to support development of databases, the conduct of natural history studies, and other studies which would be adequate to support regulatory decision making would also be helpful,” they said.
RDCC said they agree with the use of RWE as “supplementing data to support regulatory decision making for rare disease clinical trials.”
“Natural history data and RWE can help to define rare disease progression, novel biomarkers, genetic relationships, and treatment effects. We support the increased use of RWE data as an important tool in helping to confirm the surrogate endpoint’s predicted clinical benefit(s) for rare disease,” RDCC said.
Regarding the development of endpoints, PhRMA and BIO asked FDA to describe under what circumstances novel surrogate endpoints are appropriate and to provide materials for “the appropriate qualitative research methods that sponsors can use to provide a holistic patient evaluation.”
Biopharmaceutical company Anavex Life Sciences noted that any pivotal endpoints developed should be done with the collaboration of therapeutic area experts and “use of clinical relevance as determined by experts in the field/disease to support use an end point or scale.”
Another concern raised by rare disease stakeholders is that the usual regulatory requirements surrounding development of drugs for pediatric populations would likely need to be changed for rare diseases.
“To support rare disease drug development for pediatric populations, we recommend FDA develop materials to explain how sponsors may extrapolate clinical data from adult to pediatric populations and consider additional recommendations for when [pharmacokinetic] PK-only bridging from adult population to specific pediatric subgroups may be appropriate,” PhRMA and BIO wrote.
Regulatory considerations
More broadly, Chiesi encouraged the agency to adopt an agency-wide approach to rare diseases, which includes clarifying the role of the Office of Orphan Products Development (OOPD) during the review of an orphan drug.
“In particular, we believe it would be beneficial for the FDA to provide a case study of OOPD involvement in discussions and finalization of a successful trial. The case study could be used by orphan disease drug sponsors to determine best practices for orphan drug clinical trials,” Chiesi said.
Some rare disease stakeholders encouraged the continued use of the agency’s accelerated approval pathway for development of rare disease drug products, while others, like the Minnesota Rare Disease Advisory Council, proposed the creation of a new pathway specifically for rare diseases. “There is a necessity for alternative approval pathways that match the unique characteristics of the rare disease community because what is common sense when approaching common diseases is not common sense for addressing rare diseases,” they wrote.
FDA’s Center for Drug Evaluation and Research (CDER) asked for comments from rare disease stakeholders on knowledge gaps in rare disease drug development, including regulatory knowledge gaps. Such gaps may include non-clinical and clinical pharmacology considerations, clinical trial design and interpretation, and regulatory considerations for development of drugs for rare diseases, the agency said.
“With input from rare disease stakeholders who design and conduct rare disease drug development programs (academics, industry, patient groups, other federal partners, etc.), FDA believes we can better understand and address knowledge gaps for external stakeholders,” the agency said in a docket description for the LEADER 3D initiative.
General comments
The Dravet Syndrome Foundation highlighted the importance of patient input for rare diseases, as literature reviews and expert opinion are unlikely to yield a complete understanding of an unmet need for a rare disease.
“The voice of the patient is critical to garnering a full picture of the impacts of rare diseases on medical care and quality of life,” they said. “Early-engagement of therapeutic developers with patient populations and patient advocacy groups will facilitate a development process focused on improvements that are truly impactful to rare disease patients.”
To aid in opportunities for collaboration, the American Society of Clinical Pharmacology and Therapeutics (ASCPT) proposed the use of more cases studies when possible to educate sponsors on examples of both successful and failed cases of rare disease drug development.
“It is important for these sessions to not only bring the successful case studies that emphasize the FDA’s flexibility, but also identify the enablers for such flexibility by showing failure cases. In addition, we acknowledge the difficulty to achieve full harmonization in all aspects. To the extent possible, we encourage the FDA to share case studies that may help the sponsor navigate such differences or potentially, reach a middle ground with regulators,” ASCPT said.
The National Organization for Rare Disorders (NORD) said it is important to create educational materials for rare diseases that are accessible to an adult lay audience, including individuals with disabilities, and publish the educational materials in a space where they can be easily found and shared, such as the front page of a centralized website like ARC’s. “The best educational materials are useless if the intended audience cannot find them,” NORD said.
In their comment, NORD also noted a top gap identified within their patient group and small biotech industry membership is an ask for more guidance and best practices for engagement with sponsors, FDA, and other stakeholders. The request for more guidance was reiterated among many stakeholders who responded to FDA’s request for comment. “The need for better tools and more guidance on how to work together effectively on the development of rare disease drugs is universal and largely unmet,” NORD explained.
Considerations in clinical and non-clinical pharmacology
One major issue is an inconsistent definition of the term “rare disease” across the agency, Praxis Precision Medicine said in their comment. “Ensuring a flexible, yet consistent interpretation of the definition for rare diseases will ensure that patients with life-threatening and severely debilitating diseases … are able to more quickly access treatments that could be life-altering,” they wrote.
The Rare Disease Company Coalition (RDCC) brought up the issue of gaps in guidance in their comment, mentioning that problem areas include biomarker qualification for clinical trials, difficulty in obtaining clinical samples and in enrolling an adequate patient population, variation in disease severity and underlying disease cause, and challenges in modeling clinical outcomes due to unpredictability.
In a joint comment, the Pharmaceutical Research and Manufacturers of America (PhRMA) and Biotechnology Innovation Organization (BIO) wrote that there are often no relevant animal models for nonclinical studies. “As use of animal testing alternatives increase, we recommend FDA provide information on the use of alternative methods to support rare disease drug development,” they wrote.
A lack of guidance on dose finding and exposure-response for rare disease studies is another consideration, PhRMA and BIO said. “We note that while recent guidance has referenced dose finding and exposure-response studies in rare disease contexts, the guidance does not expand on regulatory flexibilities for clinical pharmacology studies in rare disease populations,” they explained. “Thus, we recommend FDA develop educational materials that specifically address the challenges of assessing dose response and exposure in small patient populations.”
Design and interpretation of clinical trials
Recruitment for rare disease trials can be an issue, Boehringer Ingelheim noted, as some patients have the perception that trials for rare diseases are unsafe or they fear receiving a placebo. They suggested education within specific patient communities and building relationships may be worthwhile to improve engagement with patients and their caregivers.
“[P]atients need education and support to understand the benefits to society and to the community when they participate in trials. It is also important for patients to understand that clinical trials are heavily regulated and that participants are not ‘guinea pigs’, but rather receive a high level of care, independent of the treatment they get in the trial,” the company said.
In terms of designing clinical trials, Chiesi Global Rare Diseases outlined four major challenges they face in the development of a rare disease therapy, including limitations of double-arm placebo trials, endpoints, adhering to diversity requirements for clinical trial participants with rare diseases, and use of real-world evidence (RWE). “These challenges can make rare disease-based clinical trials very time and resource intensive,” Chiesi said.
To address the issue of a comparator group in rare disease trials, PhRMA and BIO proposed the agency use case studies to describe when an external control group, natural history data, or real-world data use is warranted. “Information about approaches and/or methodologies and tools to support development of databases, the conduct of natural history studies, and other studies which would be adequate to support regulatory decision making would also be helpful,” they said.
RDCC said they agree with the use of RWE as “supplementing data to support regulatory decision making for rare disease clinical trials.”
“Natural history data and RWE can help to define rare disease progression, novel biomarkers, genetic relationships, and treatment effects. We support the increased use of RWE data as an important tool in helping to confirm the surrogate endpoint’s predicted clinical benefit(s) for rare disease,” RDCC said.
Regarding the development of endpoints, PhRMA and BIO asked FDA to describe under what circumstances novel surrogate endpoints are appropriate and to provide materials for “the appropriate qualitative research methods that sponsors can use to provide a holistic patient evaluation.”
Biopharmaceutical company Anavex Life Sciences noted that any pivotal endpoints developed should be done with the collaboration of therapeutic area experts and “use of clinical relevance as determined by experts in the field/disease to support use an end point or scale.”
Another concern raised by rare disease stakeholders is that the usual regulatory requirements surrounding development of drugs for pediatric populations would likely need to be changed for rare diseases.
“To support rare disease drug development for pediatric populations, we recommend FDA develop materials to explain how sponsors may extrapolate clinical data from adult to pediatric populations and consider additional recommendations for when [pharmacokinetic] PK-only bridging from adult population to specific pediatric subgroups may be appropriate,” PhRMA and BIO wrote.
Regulatory considerations
More broadly, Chiesi encouraged the agency to adopt an agency-wide approach to rare diseases, which includes clarifying the role of the Office of Orphan Products Development (OOPD) during the review of an orphan drug.
“In particular, we believe it would be beneficial for the FDA to provide a case study of OOPD involvement in discussions and finalization of a successful trial. The case study could be used by orphan disease drug sponsors to determine best practices for orphan drug clinical trials,” Chiesi said.
Some rare disease stakeholders encouraged the continued use of the agency’s accelerated approval pathway for development of rare disease drug products, while others, like the Minnesota Rare Disease Advisory Council, proposed the creation of a new pathway specifically for rare diseases. “There is a necessity for alternative approval pathways that match the unique characteristics of the rare disease community because what is common sense when approaching common diseases is not common sense for addressing rare diseases,” they wrote.
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