Stakeholders want more collaboration, regulatory flexibility in FDA’s new rare disease hub

Stakeholders want the US Food and Drug Administration’s (FDA) recently announced Rare Disease Innovation Hub to be based on more collaboration not only within the agency but also with outside stakeholders. They also want more flexibility and consistency in how reviewers oversee rare disease products.

On 16 October, FDA convened a public meeting to discuss its recently launched Rare Disease Innovation Hub, which is run by its Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER). In addition to the input received during the meeting, FDA sought comments from stakeholders in a public docket tied to the meeting announcement.

Several commenters emphasized the need for a collaborative atmosphere at the hub that draws on viewpoints and experiences from a wide spectrum of experts and stakeholders. The Biotechnology Innovation Organization (BIO) was one of the commenters who emphasized collaboration not only between CDER and CBER but also other FDA centers, such as the Center for Devices and Radiological Health (CDRH), Oncology Center of Excellence (OCE), and others. It argued that establishing cohesive collaboration principles among the different centers is vital to the hub's success, which ultimately will be tasked with developing standards and processes to accelerate the development of rare disease products.

“This unified strategy would alleviate the inconsistencies that sponsors encounter, leading to a more efficient and predictable regulatory landscape,” said BIO. “It could also address specific regulatory challenges, ensuring that insights and best practices from successful cases are shared and implemented widely, including appropriate regulatory flexibility approaches.”

“This consistency would assist sponsors navigating the evolving landscape and enhance efficiency in drug approvals,” the group added. “The Hub can also work to disseminate knowledge and expertise on rare diseases and share the best practices across the agency.”

The Muscular Dystrophy Organization (MDO) also asked for collaboration with the Office of Patient Affairs within the FDA Commissioner's office. It argued that the office has excelled at partnering with rare disease patient advocacy groups and has promoted intra-agency collaborations.

However, several commenters have called not only for intra-agency collaborations but also for greater collaboration with external stakeholders. MDO said it wants to see the Rare Disease Innovation Hub build direct relationships with other federal agencies such as the Center for Medicare and Medicaid Services (CMS), the Social Security Administration (SSA), and the National Institutes of Health (NIH).

“Collaborations with CMS could entail informing CMS’s coverage approaches, guidances, and regulatory requirements for covering rare disease therapies under Medicare and Medicaid,” said MDO. “Collaborations with SSA could inform SSA’s understanding of rare diseases when making Social Security Disability Insurance (SSDI) determinations, particularly for rare disease communities with approved therapies that may impact the community’s eligibility for benefits administered by SSA.”

“Collaborations with NIH could lead to better constructed NIH-funded studies and clinical trials in rare diseases that will accelerate drug development and lead to better outcomes,” MDO added.

Mary Kohler, an attorney and founder of Kohler Health Law, emphasized the need to find ways to collaborate with payors who tend not to see the potential benefits of products that have been approved based on data from small trials and an accelerated pathway. She also noted that they are hesitant to provide coverage for such products, especially if they are expensive and have a high chance of not working.

"I recognize payment is not your remit; and cost is not a factor in approval," said Kohler. "But approving drugs in isolation can yield products that later die on the pharmacy shelf. And that wastes precious development resources."

"Perhaps your hub could expand its notion of collaboration to include payors," she added. "To be clear, payors have little interest in watching the details of development unfold. But pinpointing their concerns earlier might give others a chance to resolve them before they eventually become commercialization mishaps."

Another key issue stakeholders raised in their comments is ensuring FDA officials who review rare disease products are consistent and flexible in their decision-making.

Sen. Bob Casey (D-PA), who sits on the Senate Health, Education, Labor and Pensions (HELP) Committee, said rare disease drug sponsors have told him there’s a lack of understanding among FDA reviewers about the science of small population trial design, lack of rare disease expertise, and inconsistency across the review centers.

“FDA employs the gold standard for approval, requiring drug and biologic sponsors to demonstrate substantial evidence of effectiveness, but FDA also has broad latitude to employ regulatory flexibility when reviewing medical products that address an unmet need, such as a drug for a rare disease,” said Casey. “Drug sponsor and patient groups have noted that certain review divisions, or even certain individual reviewers, have reputations for being more or less flexible than others. This is an urgent matter for the FDA to address, as it is having a significant impact on the agency’s credibility and reputation as a fair regulator.”

The Senator noted that sponsors have used alternative methods to design their clinical trials, such as crossover studies, natural history studies, and delayed start studies, in conjunction with new statistical modeling methods that can interpret data for small populations.

“While FDA can and has allowed products to come to market relying on data from these types of study designs and statistical analyses, it is clear that not all review divisions within CDER and CBER are equally comfortable with them and that some drug sponsors are being asked to continue testing their products even when a drug has been studied in as much as half of the entire patient population,” said Casey. “I believe that a robust and open discussion is needed to establish a shared understanding about when alternative study designs and statistical methods are appropriate and how product sponsors and FDA reviewers can best work together to agree on suitable study designs and analytical methodologies.”

While stakeholders tend to call for regulatory flexibility that is often supported by FDA itself, the Center for Medicine in the Public Interest (CMPI) argues that reviewers should go beyond flexibility and adopt regulatory nimbleness.

“Regulatory Nimbleness understands and respects the need for process,” said CMPI President Peter Pitts. “Undefined and anecdotal 'flexibility' leads to regulatory pandemonium.”

“Nimbleness enhances progress through process. Flexibility bends rules,” he added. “Nimbleness reads between the lines. Nimbleness looks to the spirit of the FDA’s mission. Experts are nimble.”

He said there needs to be clear definitions of terms such as what makes a disease ultra-rare. He recommended that the Rare Disease Innovation Hub form an intramural working group to develop definitions and answer major questions about rare diseases.

“The Rare Disease Innovation Hub mustn’t be dogmatic. Change is not an all-or-nothing proposition,” said Pitts. “Small movement in the right direction is the beginning of momentum. Small victories are better than explosive defeats.”

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Stakeholders want more collaboration, regulatory flexibility in FDA’s new rare disease hub

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