FDA proposes plausible mechanism pathway for ultra-rare disease therapies

The US Food and Drug Administration (FDA) has proposed a new pathway for developing individualized therapies based on a plausible mechanism framework. If finalized, the guidance would lay out a path for the agency to authorize individualized drugs and biologics targeting specific genetic conditions with known biological causes.

Health and Human Services Secretary Robert Kennedy Jr. spoke about the pathway at a press conference on Monday. He said the new framework aligns regulations with biology and noted that randomized controlled trials are often not feasible to support authorization of treatments for ultra-rare conditions, and that such treatments may be approved based on a single well-controlled clinical investigation supported by confirmatory evidence.

“For decades, families heard the same thing, ‘There are not enough patients. The proof will take too long. You just have to wait for the science to catch up with your child.’ That ends today,” said Kennedy. “A disease with 100 of the same mutations on the same gene will no longer require 100 clinical trials.

“When the biology is clear, and the science is sound, we will evaluate therapies based upon strong evidence and not arbitrary barriers,” he added. “Individualized medicine is no longer theoretical.”

FDA Commissioner Marty Makary also spoke at the press conference and said that 30 million Americans have a rare disease, which amounts to approximately 1 in 11 people. He added that the current medical system is designed for common diseases, leading to underfunding of treatments for rare diseases.

“Historically, rare diseases have been at the FDA an afterthought with rigorous, elaborate standards so high they're just not practical for many of the therapies for rare diseases,” said Makary. “But today, treatments for rare diseases have powerful incentives, expedited reviews, tax credits for clinical trials, extended market exclusivity, and a powerful incentive, if the drug is approved, a pot of gold of $100M and $200M in the form of a transferable priority voucher.

“For the first time, the FDA is issuing guidance where we're giving drug developers of ultra-rare disease therapies a path to accelerated or traditional approval based on the experience of individuals,” he added. “We can learn from individuals. I have learned from individual patients of mine, and when you see something amazing right in front of your eyes, that is a type of evidence. It's time that the FDA recognizes it.”

Guidance

The guidance defines individualized therapies as treatments that target a specific pathophysiologic abnormality underlying a disease or condition affecting a small number of patients, for which a randomized controlled trial is typically not feasible. It states that the individualized therapies must target a specific genetic, cellular or molecular abnormality, and should be designed to correct or modify the underlying cause of disease.

While it specifically discusses genome editing and RNA-based therapies such as antisense oligonucleotides, FDA notes that it also leaves open the potential to use the framework for other tailored therapies that address the underlying cause of a disease. The framework requires sponsors to provide results of nonclinical and clinical data and chemistry, manufacturing, and controls (CMC) data to support the treatment’s approval.

"For sponsors who intend to submit a marketing application for an individualized therapy, planning for evidence generation to support the efficacy and safety of the product should ideally begin as soon as the patient and genetic target are identified," said the guidance. "Given the inherent limitations in the size of clinical development programs, early planning will allow more robust collection of data from various sources, which have the potential to be leveraged as evidence to support a future marketing application.

"Planning should also include establishing the appropriate chemistry, manufacturing, and controls (CMC) needed to support the generation of safety and efficacy data and subsequently, product approval/licensure," the agency added.

To qualify for the new pathway, sponsors would need to identify the disease-causing abnormality, demonstrate that their treatment targets the root cause or proximate biological pathway, base their evaluation on well-characterized natural history data in untreated patients, and show that their treatment is successful in treating the patient. For traditional approval, sponsors need to demonstrate improvement in clinical outcomes, disease course, or biomarkers if those are established to predict clinical benefit.

“Because genome editing technologies are designed to be highly specific to unique DNA sequences, a product targeting different mutations in a single gene could be included in a single product application and potentially evaluated through the use of master protocols that evaluate these product variations in a single trial,” said FDA in a statement announcing the draft guidance. “A highly supported ‘plausible’ mechanism of action may then be used to support the addition of other such genome editing product variants, intended to treat patients with mutations that were not included in the clinical trial used to support the original approval.

“The FDA recognizes that an adequate and well-controlled clinical investigation in this context will include a small sample size, therefore, investigation results should be sufficiently robust to exclude chance findings,” the agency added. “When determining effectiveness, the FDA considers the specific disease, the strength of the evidence and the challenges of conducting clinical investigations for individualized therapies.”

Tracy Beth Høeg, acting director of the Center for Drug Evaluation and Research (CDER), emphasized during the press conference that FDA's standards for evaluating treatments using the plausible mechanism framework have not changed. She also noted that it will allow the agency to look at the diseases as a collection of diseases in one clinical trial, since they use similar gene-editing or antisense oligonucleotide treatments.

“I was part of this effort in CDER and CBER cross-center effort to write this plausible mechanism framework draft guidance,” said Høeg. “I think we sense that this is going to be a transformational draft guidance in the sense that it's going to inspire industry to start developing these treatments in a way that we haven't seen before.

“We all feel, ...that the FDA is likely going to be overwhelmed with applications for these treatments for these rare diseases, and that's wonderful and exciting,” she added. “And we're going to need to be creative in the way that we meet this new demand.”

Høeg also said that FDA is hoping the plausible mechanism framework will "dramatically" speed treatment approvals because the agency will be able to lump together treatments and products and move seamlessly from the investigational new drug (IND) phase to phase 2 and 3 trials.

Draft guidance

FDA proposes plausible mechanism pathway for ultra-rare disease therapies

Related topics

Recommended content

Welcome to the new RAPS Digital Experience