Debating a new pathway for ultrarare 

Woodcock, patient advocates, biotech leaders call for reforms

Science has repeatedly thrown patients with devastating ultrarare diseases a lifeline, but all too often it has been snatched away before they can seize it. Scores of ultrarare therapies have been abandoned or stalled over the past four years, and many others have been envisioned but never developed, despite evidence that they could be effective treatments or cures.

The bottleneck is especially frustrating for patients and their families because they’ve seen how public policy can stimulate drug development. Despair over market failures has, on several occasions, led patients and their families to demand economic incentives for orphan drug development. Congress listened, enacting laws over the past 40 years that provided market exclusivity, R&D tax credits, and rare pediatric disease priority review vouchers. Hundreds of drugs for orphan diseases have been brought to patients as a result. Yet drug development for the rarest of these conditions remains a nearly impassable road.

Moreover, these policies are under attack as skepticism about the need for economic incentives from a small, prolific group of academics and criticism of accelerated approval of Alzheimer’s drugs have resonated with pharma-bashing politicians. Rare disease patient advocates are fighting efforts to undermine accelerated approval and to eliminate economic incentives for orphan drug development.

At the same time, they are pointing to the need to go beyond economic incentives.

Transformational treatments for extremely rare conditions are just out of reach and are being held back because sponsors can’t meet regulatory requirements that were designed for a different era, patient advocates and biotech leaders believe.

The pipeline of therapies for ultrarare diseases is being crimped by approval standards that were crafted at a time when it wasn’t possible to diagnose extremely uncommon conditions, there was little understanding of how drugs worked, and attempts to market medicines for conditions that affected a few hundred or thousand people would have been inconceivable.

FDA has tried to adapt, but its attempts to exercise “flexibility” to fit therapies for extremely rare conditions into pathways created for more common diseases have created as many problems as they’ve solved. 

High-profile examples of FDA invoking flexibility have undermined confidence in the agency’s decision-making. Critics, including FDA reviewers, say the agency has quietly adopted an “empathy standard” that disregards legal approval standards and elevates unsubstantiated hopes over scientific realities. Patients and biotech executives whose pleas for flexibility have been denied accuse FDA of acting inconsistently by favoring products or diseases that catch the attention of top officials. And there are concerns that the backlash against accelerated approval will make the pathway less accessible.

Establishment of a distinct pathway for ultrarare disease therapies could dampen some of the criticism by creating clear boundaries between the small subset of products that are eligible and the majority of products that would be subject to standard approval criteria.

To explore proposals for addressing barriers to ultrarare therapy development, the EveryLife Foundation for Rare Diseases held a scientific workshop on May 21 on “Therapy Development for Small Populations: Evidence, Implications, & Policy in Characterizing Ultra-Rare.”

Discussions at the workshop revealed that calls for modernizing approval standards for orphan therapies that cannot be developed using standard criteria are resonating with FDA leaders. Although there are disagreements about how to go about solving the problem, and whether legislation is needed, current and former senior FDA officials agree with patient advocates and biopharma leaders that the system for regulating therapies for ultrarare conditions should be improved.

Former Acting FDA Commissioner Janet Woodcock proposed the creation of a new approval pathway for therapies when it is impossible to conduct trials required to meet standard requirements.

Woodcock sparked much of the controversy over regulatory flexibility in 2016 by overruling FDA staff and approving Exondys 51 eteplirsen from Sarepta Therapeutics Inc. (NASDAQ:SRPT) for Duchenne muscular dystrophy. Given the size of the DMD population, about 15,000 in the U.S., and the well characterized natural history of the disease, it isn’t clear that it would qualify for the pathway Woodcock is proposing.

Peter Marks, director of FDA’s Center for Biologics Evaluation and Research, agreed that the regulation of drugs for rare conditions needs to be revamped, but he believes the agency has sufficient authority to make the necessary changes without asking Congress to establish a new pathway.

Losing hope

Patient advocate Sharon King told the workshop about the human costs of stalled drug development for ultrarare conditions. She is chair of the North Carolina Rare Disease Coalition and a member of the North Carolina Advisory Council on Rare Diseases. 

King became a patient advocate after her daughter Taylor was born with CLN1 disease, a fatal genetic condition, also called Batten disease, that attacks the central nervous system.

King described how patients helped jump-start development of an AAV gene therapy for CLN1, celebrated early successes, and watched as its progress stalled, while her daughter and other patients suffered and died.

In 2013, the CLN1 community threw a party when mice with the disease lived year after treatment with the experimental therapy, four months longer than their expected lifespan. Three years later, the therapy was transferred to Abeona Therapeutics Inc. (NASDAQ:ABEO), and in 2019 Abeona received an IND.

Shortly after, however, Abeona put the trial on hold because it was unsure that it could manage the complexities and cost of a trial, King said.

The program was sublicensed in 2020 to Taysha Gene Therapies Inc., which made a trial protocol public a couple of years later. Families around the world, including a couple in Australia whose daughter has CLN1, began preparing to travel to Canada to participate. Eventually, that company too put its trial plan on hold. 

There were 12 programs underway in North America developing therapies for six of the 14 types of Batten disease in 2021. Today, King said, “there are only four active programs in the United States for three subtypes of Batten disease. One of those is an n-of-1 investigator-initiated trial for CLN1 disease.”

Patient advocates, including King, attribute the withering of the ultrarare disease pipeline in large part to demands from regulators for trials that are impossible, impractical or unethical.

“We’ve learned from painful experience that the clinical trial landscape continues to be volatile, unpredictable, and, yes, ruthless, particularly for very small populations,” King said. “Even as investment in rare diseases is beginning to wake to a new spring, patient communities, particularly those that are very small, have lost trust that the system can work for them. Hope and optimism may present the deepest loss of all.”

The situation with CLN1 is far from unique. The ultrarare landscape is littered with abandoned and stalled development programs for conditions such as mucopolysaccharidoses (MPS), GM1 gangliosidosis, and Niemann-Pick disease type C.

Ultrarare disease patient communities, King said, are “damaged and bitter, and surely, you can understand why. To know there is science with the potential to improve life significantly, yet you are forced to watch it shut down right before your eyes. These are real people, pulled to the edge of hope, only to be pushed from the cliff.”

Defining ultrarare

King concluded her remarks with the suggestion that the first step toward adapting the regulatory system so that it can support therapies for conditions like Batten disease is to define “ultrarare.”

“Before we can fix something, we need to define it, and we need to set measurable parameters. Right now, there’s no true distinction between a rare condition that affects a few people and one that affects 199,000 people. Without a consistent definition for what constitutes an ultrarare condition, it seems illogical to me to talk about pathways to treatments and cures.”

Emil Kakkis, president and CEO of rare disease company Ultragenyx Pharmaceutical Inc. (NASDAQ:RARE), says the definition should be 2,000 U.S. patients, a figure which is 1% of the threshold in the Orphan Drug Act and would include the majority of rare diseases. Kakkis did not attend the EveryLife workshop, but his ideas were presented.

He is trying to build support for legislation creating a new pathway for ultrarare diseases. It would create a “sufficient efficacy standard” based on the emergency use authorization standard. The idea is to approve therapies for ultrarare diseases if the known and potential benefits outweigh the known and potential risks and those of the disease it is treating. Under his proposal, approvals could be based on “one study of reasonable size, reasonable historical controls within patient or independent of patient with potential required postmarketing commitment to confirm clinical outcomes,” he told BioCentury.

A key part of his proposal is the qualification of primary disease biomarkers based on scientific and pharmacologic criteria without a requirement for proven long-term clinical correlate of improvement.

Benefit-risk standard 

Frank Sasinowski provided an overview of FDA’s framework for regulating drugs and presented a proposal for adapting it to the realities of ultrarare drug development. Sasinowski, vice chair of the EveryLife Foundation and a director at the law firm Hyman, Phelps & McNamara, said he was expressing his own views, not those of organizations he is affiliated with.

The foundation for U.S. drug regulation was poured in 1962 when Congress set the approval standard as “substantial evidence” of safety and effectiveness consisting of “adequate and well-controlled investigations.” FDA interpreted this to mean two adequate and well-controlled clinical trials that each met a prespecified primary analysis with a p-value of ≤ 0.05.

“In 1962,” Woodcock said, “we didn’t even know there was a genome, and even for the common diseases, we really had no idea of their biology. What was put in place was an empirical testing standard where you cast the dice,” measure an outcome, “and then statistically you said, does it look good?”

In 1997, Congress amended the law to give FDA additional authority to grant approvals based on “substantial evidence of effectiveness” based on a single adequate and well-controlled study with confirmatory evidence. And in 1998, FDA issued guidance stating that it could approve a drug based on a single trial where a statistically “persuasive” effect, defined as a p-value of ≤0.01, has been shown on mortality, irreversible morbidity or prevention of a serious disease and where a second trial would be practically or ethically infeasible.

FDA has also issued regulations acknowledging that a rigid application of approval standards could make it impossible to approve drugs under certain circumstances, and that “flexibility” should be used to determine the kind and quality of evidence required to meet the approval standards.

Flexible application of the requirement for an adequate and well-controlled trial may not be sufficient, Sasinowski suggested. A different approval standard may be needed, he said, when “small populations, heterogeneity among patients with the same disease or condition, lack of validated endpoints, poorly understood natural history of the disease” and other circumstances make it impossible to demonstrate substantial evidence of effectiveness using an adequate and well-controlled trial.

Sasinowski noted that EMA has adopted two approaches that are well-suited to these kinds of situations. EMA’s exceptional circumstances pathway allows for marketing authorization if it is not possible to provide comprehensive data on the efficacy and safety under normal conditions of use because the condition to be treated is rare or because collection of full information is not possible or ethical. EMA’s conditional approval hinges on a determination that available data indicate that a medicine’s benefits outweigh its risks.

As reflected by a slide presented at the workshop, Sasinowski suggested a new statutory standard for ultrarare therapies: “Whether the known and potential benefits of a therapy outweigh its known and potential risks, based on an assessment of all available scientifically valid evidence, such as mechanistic information (e.g., clinical pharmacology/biomarkers and animal models), real-world evidence and other externally controlled comparisons (e.g., natural history studies).”

Woodcock’s proposal

Building on Sasinowski’s account of the history of drug regulation, Woodcock described the mismatch between approval standards and the realities of ultrarare drug development.

“We’ve had accelerated approval. We’ve had regulatory flexibility. We’ve had one trial and confirmatory evidence. But basically, at the end of the day, the evidentiary standard is supposed to be that standard of adequate and well-controlled trials,” Woodcock said.

“This puts very rare diseases in a very difficult position,” she added, “because we may have very good mechanistic information, we may have reasonable biomarkers but they aren’t validated,” and there may not be enough patients to conduct a dispositive Phase III trial.

“We may have a very good story about why we should make that product available to those people,” Woodcock said, “but the reviewers are put in a terrible position. They’re told they have to uphold the standard, that the role of the FDA is to enforce the law.”

Woodcock said regulatory flexibility isn’t a viable policy and called for Congress to create a new approval pathway.

“What we’ve seen is a lot of cognitive dissonance internally, of people being asked on one hand to enforce the standards, and on the other hand to be flexible,” Woodcock said. “You can be flexible, flexible, flexible, and then pretty soon you’re going to break.”

Woodcock believes that Congress should carve out a distinct approval pathway for therapies that can’t meet existing approval standards, for example because there are too few patients and there are no predictive biomarkers. “I think it would be best to have a statutory pathway for diseases where there’s very strong mechanistic understanding and the totality of the evidence enables a reasonable prediction of benefit over risk.”

While other workshop participants presented proposals for establishing a numerical definition of ultrarare, Woodcock said the problem that needs to be addressed stems from difficulties in conducting trials that meet legal approval requirements, not necessarily from small populations.

She acknowledged concerns that inviting Congress to enact a new law could have unpredictable consequences, so FDA may prefer to proceed through regulation rather than legislation. “I don’t think there should be a numerical definition of ultrarare. I do think instead of changing the standard, having a slightly different pathway where it is not feasible to do adequate and well-controlled clinical studies and being very overt about that” should be the goal. “Whether it’s [accomplished] by regulation or by statute, could be finessed.”

The goal, Woodcock said, is creation of a “pathway that takes into account the totality of the evidence rather than a pathway that pretends to rest on adequate and well controlled clinical trials as a way to reach the market.” 

‘Defenders of the p-value’

Responding to Woodcock, CBER’s Marks agreed that there is an urgent need to modernize the review of orphan therapies but said he doesn’t believe FDA needs new legal authority.

“I worry less about our authorities, because I think we have tremendous flexibility that we can use, at least in my area,” Marks said. “I actually am more focused on the cognitive dissonance that you’re talking about because it’s very challenging.”

To illustrate the challenge, Marks recalled his first impression when he joined FDA. “I would go into people’s offices, and the first thing you’d notice is they’d have multiple years of the Code of Federal Regulations.” Reviewers, he said, viewed themselves as “defenders of the regs and defenders of the p-value.”

While regulations are important, Marks said his goal at CBER is to focus reviewers on patients, and to avoid fetishizing regulations. “It is true, the expanded access regulations, they’re very beautiful. But that said, who cares? It’s what you can do for a given patient” that is important.  

While “it sounds crazy,” because FDA staff “obviously know they’re dealing with patients,” Marks said that “it’s very easy with this cognitive dissonance to become the defender of the p-value of 0.05.”

Explaining why he believes new legal authority is not needed, Marks said, “we have people that are smart enough that we can focus on the patient and actually still stay on the right side of the regs. I think it’s just a matter of, in some cases, just changing how we think about things and how we approach them. I’m not saying that we don’t need progress.”

Marks warned of unintended consequences from creating a new approval standard. “My great concern about changing our standard is that right now we’re already seeing, in my area, insurance companies fighting against giving kids gene therapies that are potentially life changing because of their cost, and [skepticism over] accelerated approval.”

Payers are already questioning whether drugs that receive accelerated approval work, Marks said. “I don’t want to see us in a place where we have haves and have nots in this country, which I already am concerned we may see with Medicaid and gene therapies for sickle cell disease.”