The Food and Drug Administration (FDA) is implementing a new strategy to provide experimental gene therapies to patients with rare disorders without going through clinical trials. This framework could grant these patients access to individualized therapies, but experts are divided over whether the regulatory change is safe enough for patients.

Dr. Senthil Bhoopalan, a genome-editing expert at St. Jude's Children Research Hospital in Tennessee, said that, although the framework is still emerging and the details require more discussion between the public and stakeholders, "it's an exciting step in the right direction."

Arthur Caplan, a medical ethicist at New York University, said more pressure to permit access to new therapies has led the FDA "to allow more risk to subjects, and more risk of failure post-approval, by being willing to accept weaker evidence."

Before receiving FDA approval, most therapies require clinical trials with hundreds or thousands of participants to show a drug is safe and works. In some cases, the agency grants accelerated approval for interventions that appear to show a benefit in small trials, when patients are very sick and have no other treatment options.

However, the new strategy, called the plausible mechanism pathway, would enable the FDA to grant permission to use therapies that haven't been tested in humans but could plausibly succeed.

The pathway would apply only to certain treatments, such as gene therapies that correct single-letter DNA errors, where large-scale clinical trials would be impossible. Take cystic fibrosis as an example. Around 40,000 people in the U.S. have this disorder, but hundreds of mutations can cause it, Bhoopalan said. As a result, you can't use one gene therapy formulation to treat every patient.

However, if a gene-editing tool and delivery technique have been shown to be safe in past human trials, the pathway would allow drug developers to tweak the sequence-specific element of the formulation, such as a guide RNA that 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 cystic fibrosis patient. This is similar to how food producers need only show that an ingredient is safe once before including it in multiple food items.

"The safety data can be extrapolated if you're using the same delivery mechanism," Bhoopalan said. "You're really only changing the guide." If the change you make in the body is swapping a faulty mutation with the form that healthy people have, you wouldn't anticipate side effects, he added.

Caplan agreed that this particular use of the pathway doesn't seem, on its face, to be high-risk. However, the safety of base editors has been tested only in relatively small trials thus far, with no more than 15 participants. With a sample size this small, it’s difficult to show a given gene therapy led to positive health outcomes. What’s more, without performing larger trials involving hundreds or thousands of participants, it’s impossible to know whether base editors cause rare side effects.

For example, at least 65 small-scale trials have investigated the use of certain viruses as vehicles to deliver liver-targeting gene therapies that treat hemophilia. While most of these studies show promise, a larger trial involving 134 participants revealed rare side effects, such as elevated liver enzymes, inflammation and allergic reactions.

"The level of risk doesn't keep me awake at night, but there are unknowns," Caplan said. "I think it would be very important to have serious follow-ups following FDA drug approval."

That's where he sees the potential for problems to creep in. Post-approval monitoring of drugs has "never been done with earnestness," despite promises made by pharmaceutical companies. "If we're going to take more risk to go faster at the front end, you have to beef up what's required and what's going to be monitored at the back end, post approval."

Still, that doesn't mean the level of post-approval scrutiny will be lower than it has been previously.

"It's possible that in the fullness of time, we'll see that they've lowered the bar," said Dr. J. Paul Taylor, a neurologist who treats genetic neurodevelopmental disorders at St. Jude Children's Research Hospital. "But the stated intent is not to change the level of substantial evidence [through post-approval monitoring]."

In an article published last November in The New England Journal of Medicine, the FDA outlined which criteria a disease would need to meet to qualify for this pathway. The plausible mechanism pathway would be ruled out for disorders with unclear causes, such as dementia, Taylor noted.

"This is great for monogenic disorders, which are caused by mutations in a single gene," Bhoopalan said. It would be harder to use this pathway for polygenic diseases, which are brought on by an array of mutations, he added, as you would have to successfully correct multiple mutations to see a benefit.

Rather than correcting a faulty mutation, gene therapy could be used to "switch on" a backup gene in the case of spinal muscular atrophy, Taylor said, which is fatal in children who don't receive treatment.

There are some monogenic disorders that may not meet the criterion, however. Diffuse intrinsic pontine glioma is a brain tumor that appears in young children who carry a faulty gene. Taylor said specialists are split on whether reversing this mutation alone could shrink the tumors or if other mutations that appear as the tumor develops could continue to drive the cancer even if the initial mutation were corrected.

Another FDA criterion requires doctors to confirm that the patient's tissues have been edited. "It might be harder to quantitate when you're editing a critical organ like the liver, because you cannot get a piece of liver and measure how much has been edited," Bhoopalan said.

Doctors may need to repeatedly sample tissues from patients, as studies in mice have shown that gene therapies can wane over time, suggesting that some may not work as a "one-and-done" treatment. This would be much harder to accomplish if you could only sample tissues with invasive surgery.

Some body locations might be difficult to target with gene delivery systems in the first place. The blood, bone marrow, liver and lungs could make easy targets, Bhoopalan said. The heart, on the other hand, could be difficult to edit because a layer of tightly-packed cells creates a barrier that stops gene therapy vectors from crossing into heart tissue.

Though more discussion is needed to clarify which disorders can benefit from this expedited approval and how patients' health can be monitored afterward, experts hope the new pathway could help people with rare disorders.

"I think we have to start thinking about this as an inevitable next step," Bhoopalan said.