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The FDA is exploring ways to expedite the authorization process for certain personalized gene therapies.(Image credit: Hiroshi Watanabe via Getty Images)Share this article 0Join the conversationFollow usAdd us as a preferred source on GoogleSubscribe to our newsletter
The Food and Drug Administration (FDA) is initiating a new approach to provide experimental gene therapies to individuals suffering from rare conditions without requiring them to undergo clinical trials. This framework has the potential to grant these patients access to bespoke therapies, but specialists are divided on whether the regulatory adjustment is sufficiently secure for patients.
Dr. Senthil Bhoopalan, a specialist in genome editing at St. Jude’s Children Research Hospital in Tennessee, commented that while the framework is still in its early stages and its specifics necessitate further deliberation between the public and involved parties, “it represents an encouraging advancement.”
Arthur Caplan, a bioethicist at New York University, stated that increased pressure to permit access to novel treatments has prompted the FDA “to tolerate greater risk to participants, and a higher likelihood of post-approval failures, by accepting less robust evidence.”
Prior to securing FDA authorization, most therapies necessitate clinical trials involving hundreds or thousands of participants to demonstrate a medication’s safety and efficacy. In certain circumstances, the agency grants accelerated approval for interventions that show a potential benefit in small trials, particularly when patients are critically ill and lack alternative treatment options.
However, the newly proposed strategy, termed the plausible mechanism pathway, would empower the FDA to authorize the use of therapies that have not undergone human testing but possess a credible potential for success.
This pathway would be applicable exclusively to specific treatments, such as gene therapies designed to rectify single-point DNA errors, for which large-scale clinical trials would be impractical. Consider cystic fibrosis as an illustration: Approximately 40,000 individuals in the U.S. are affected by this condition, but it can stem from hundreds of distinct mutations, as explained by Bhoopalan. Consequently, a single gene therapy formulation cannot effectively treat all patients.
Nevertheless, if a gene-editing tool and its delivery method have previously demonstrated safety in human trials, the pathway would permit drug developers to modify the sequence-specific component of the formulation, such as a guide RNA that directs the DNA-editing machinery to the precise site of a mutation. Subsequently, the specific gene-editing tool, like a base editor, could be adapted for individual mutations in each cystic fibrosis patient. This operates similarly to how food manufacturers only need to establish the safety of an ingredient once before incorporating it into multiple products.
“It’s conceivable that in due course, we might find that the standards have been lowered.”
Dr. J. Paul Taylor, neurologist at St. Jude Children’s Research Hospital.
“The safety data can be extrapolated if the same delivery mechanism is employed,” Bhoopalan elaborated. “The alteration is primarily to the guide.” If the modification introduced into the body involves replacing a defective mutation with the healthy variant, adverse effects would not be anticipated, he added.
Caplan concurred that this particular application of the pathway does not appear inherently high-risk. However, the safety of base editors has thus far only been evaluated in relatively limited trials, involving no more than 15 participants. With such a small sample size, it is challenging to definitively establish that a given gene therapy has yielded positive health outcomes. Furthermore, without conducting more extensive trials with hundreds or thousands of participants, it remains unknown whether base editors may cause rare adverse reactions.
For instance, at least 65 small-scale trials have examined the use of specific viruses as vectors for delivering liver-directed gene therapies for hemophilia. While the majority of these studies show promise, a larger trial involving 134 participants identified infrequent side effects, including elevated liver enzymes, inflammation, and allergic responses.
“The degree of risk does not cause me significant concern, but uncertainties exist,” Caplan remarked. “I believe robust follow-up investigations subsequent to FDA drug approval would be crucial.”
This is where he perceives a potential for complications to arise. Post-approval drug monitoring has “never been pursued with genuine commitment,” despite assurances from pharmaceutical companies. “If we are prepared to accept increased risk to accelerate the initial stages, we must enhance the requirements and the monitoring protocols for the subsequent phases, post-approval.”
Nevertheless, this does not imply that the level of post-approval scrutiny will be less stringent than in the past.
“It’s possible that over time, we’ll discover they’ve lowered the threshold,” commented Dr. J. Paul Taylor, a neurologist specializing in genetic neurodevelopmental disorders at St. Jude Children’s Research Hospital. “However, the stated intention is not to compromise the standard of substantial evidence [through post-approval monitoring].”
Who will it help?
In a publication last November in The New England Journal of Medicine, the FDA detailed the criteria a disease would need to fulfill to be eligible for this pathway. The plausible mechanism pathway would not be applicable to disorders with ambiguous causes, such as dementia, Taylor pointed out.
“This is highly beneficial for monogenic disorders, which result from mutations in a single gene,” Bhoopalan stated. It would present greater challenges to utilize this pathway for polygenic diseases, which are influenced by a range of mutations, he added, as multiple mutations would need to be successfully corrected to observe a therapeutic effect.
Instead of rectifying a faulty mutation, gene therapy could be employed to “activate” a compensatory gene in cases like spinal muscular atrophy, Taylor mentioned, a condition that is fatal in children who do not receive intervention.
“I believe we must begin to view this as an inevitable progression.”
Dr. Senthil Bhoopalan, genome-editing expert at St. Jude’s Children Research Hospital
However, certain monogenic disorders might not meet the specified criteria. Diffuse intrinsic pontine glioma, a brain tumor affecting young children with a defective gene, is one such example. Taylor noted that experts are divided on whether correcting this specific mutation alone could reduce tumor size or if secondary mutations that emerge as the tumor progresses might continue to fuel the cancer even after the initial mutation is addressed.
Another criterion set by the FDA requires physicians to confirm that the patient’s tissues have undergone editing. “It may be difficult to quantify the extent of editing in a critical organ like the liver, as a tissue sample cannot be easily obtained for measurement,” Bhoopalan explained.
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Medical professionals might need to perform repeated tissue sampling from patients, as studies in mice have indicated that gene therapies can diminish in effectiveness over time, suggesting that some may not offer a “one-and-done” solution. This would be considerably more challenging to achieve if tissue sampling could only be performed through invasive surgery.
Certain anatomical locations might pose difficulties for gene delivery systems from the outset. The bloodstream, bone marrow, liver, and lungs are considered accessible targets, Bhoopalan stated. The heart, in contrast, could be challenging to edit due to a barrier formed by densely packed cells that impedes the passage of gene therapy vectors into cardiac tissue.
Although further discussion is required to clarify which disorders are eligible for this expedited approval and how patient health will be monitored subsequently, experts are hopeful that the new pathway may assist individuals with rare conditions.
“I believe we must begin to view this as an inevitable progression,” Bhoopalan concluded.