Some gene therapies no longer require clinical trials, thanks to new FDA rule. Is this safe, and who will it help?
The Food and Drug Administration (FDA) is implement a new strategy provide experimental gene therapies to patients with rare diseases without going through clinical trials. This framework could allow these patients to access individualized therapies, but experts are divided on whether the regulatory change is safe enough for patients.
Dr. Senthil Bhoopalana genome editing expert at St. Jude Children’s Research Hospital in Tennessee, said that while the framework is still emerging and the details require more discussion among the public and stakeholders, “this is an exciting step in the right direction.”
Arthur Caplanmedical ethicist at New York University, said increased pressure to allow access to new therapies has led the FDA “to allow more risk to subjects, and more risk of failure after approval, by being willing to accept weaker evidence.”
Before receiving FDA approval, most therapies require clinical trials with hundreds or thousands of participants to demonstrate that a drug is safe and effective. In some cases, the agency grants accelerated approval for interventions that appear to show benefit in small trials, when patients are very ill and have no other treatment options.
However, the new strategy, called plausible mechanismwould allow the FDA to authorize the use of therapies that have not been tested in humans but could likely be successful.
The sector would only apply to certain treatments, such as gene therapies which correct single-letter DNA errors where large-scale clinical trials would be impossible. Take the example of cystic fibrosis. Around 40,000 people in the United States suffer from this disorder, but hundreds of mutations can cause it, Bhoopalan said. Therefore, you cannot use a single gene therapy formulation to treat every patient.
However, if a gene-editing tool and delivery technique proves safe in earlier human trials, the pathway would allow drug developers to modify the sequence-specific element of the formulation, as a guide. RNA which tells the DNA “scissors” where to correct a mutation. Then, the specific gene editing tool, such as a base editor, could be customized for specific mutations in each CF patient. This is similar to how food producers only need to demonstrate that an ingredient is safe once before including it in multiple food products.
“It’s possible that over time we’ll see that they’ve lowered the bar.”
Dr. J. Paul Taylor, neurologist at St. Jude Children’s Research Hospital.
“The safety data can be extrapolated if you use the same distribution mechanism,” Bhoopalan said. “Really, you’re just changing guides.” If the change you’re making in the body is to replace a faulty mutation with the form that healthy people have, you don’t expect side effects, he added.
Caplan agreed that this particular use of the trail does not appear, at first glance, to pose a high risk. However, the security of core editors has so far only been tested in relatively small trials, with no more than 15 participants. With such a small sample size, it is difficult to demonstrate that a given gene therapy resulted in positive health outcomes. Additionally, without conducting larger-scale trials involving hundreds or thousands of participants, it is impossible to know whether core editors cause rare side effects.
For example, at least 65 small-scale tests studied the use of certain viruses as vehicles to deliver liver-targeted gene therapies to treat hemophilia. Although most of these studies are promising, one larger test involving 134 participants, revealed rare side effects, such as elevated liver enzymes, inflammation and allergic reactions.
“The level of risk doesn’t keep me up at night, but there are unknowns,” Caplan said. “I think it would be very important to have serious follow-ups after the drug is approved by the FDA.”
This is where he sees the potential for problems. Post-approval monitoring of drugs has “never been done seriously,” despite promises made by pharmaceutical companies. “If we want to take more risks to move faster upstream, you need to reinforce what is required and what will be monitored downstream, after approval.”
This does not mean, however, that the level of post-approval monitoring will be lower than before.
“It’s possible that over time we’ll see that they’ve lowered the bar,” said Dr. J. Paul Taylorneurologist who treats genetic neurodevelopmental disorders at St. Jude Children’s Research Hospital. “But the stated intention is not to change the level of substantial evidence [through post-approval monitoring]”.
Who will this help?
In an article published last November in The New England Journal of Medicinethe FDA has specified the criteria that a disease must meet to benefit from this pathway. The plausible mechanism would be ruled out for disorders whose causes are unclear, such as dementia, Taylor noted.
“It’s great for single gene disorders, that are caused by mutations in a single gene,” Bhoopalan said. It would be more difficult to use this pathway for polygenic diseases, caused by a set of mutations, he added, because you would have to successfully correct multiple mutations to see a benefit.
Rather than correcting a faulty mutation, gene therapy could be used to “turn on” a backup gene in spinal muscular atrophy, Taylor said, which is fatal in children who do not receive treatment.
“I think we need to start looking at this as an inevitable next step.”
Dr. Senthil Bhoopalan, genome editing expert at St. Jude’s Children Research Hospital
There are, however, certain single-gene disorders that may not meet this criterion. Diffuse intrinsic pontine glioma is a brain tumor that appears in young children carrying a defective gene. Taylor said specialists are divided on whether reversing this mutation alone could shrink tumors or whether other mutations appearing as the tumor grows could continue to cause cancer even if the original mutation was corrected.
Another FDA criterion requires doctors to confirm that the patient’s tissues have been altered. “It can be more difficult to quantify when you’re changing a critical organ like the liver, because you can’t get a piece of liver and measure how much has been changed,” Bhoopalan said.
Doctors may need to take tissue samples from patients multiple times, studies in mouse have shown that gene therapies can diminish over time, suggesting that some may not work as a “one-and-done” treatment. This would be much more difficult to achieve if you could only harvest tissue through invasive surgery.
Some places in the body may be difficult to target with gene delivery systems in the first place. Blood, bone marrow, liver and lungs could be easy targets, Bhoopalan said. The heart, on the other hand, could be difficult to modify because a layer of very compact cells creates a barrier which prevents gene therapy vectors from entering heart tissue.
Although further discussions are needed to clarify which disorders can benefit from this accelerated approval and how patients’ health can be monitored afterward, experts hope this new path could help people with rare diseases.
“I think we need to start looking at this as an inevitable next step,” Bhoopalan said.
This article is for informational purposes only and is not intended to offer medical advice.
