Both clinical and surrogate endpoints are acceptable targets for trials investigating gene therapies (GT) for neurodegenerative diseases, according to finalized FDA guidance on developing these products.

The document updates and finalizes draft guidance that was filed last year.

Products advancing through the traditional approval pathway will need to show a significant effect on a clinically meaningful endpoint. But surrogate endpoints can be used to support a marketing approval under the accelerated approval pathway, under some circumstances.

A surrogate endpoint might be the best choice in cases where a GT product “directly targets an underlying, well-understood and well-documented monogenic change that causes a serious neurodegenerative disorder,” the guidance says. “In these cases, the GT product could alter the underlying genetic defect and thereby treat or cure the disease.”

Sponsors that intend to employ surrogate endpoints need to alert the FDA as early in the development process as possible and well before clinical trials begin.

By the time human studies commence, sponsors should have solid animal data that confirm dosing regimens and a proposed route of administration. These preclinical findings also need to support patient eligibility criteria and identify potential toxicities.

Because of the significant differences between human and rodent neurophysiology, animal studies of GT may be better conducted in larger mammals or non-human primates.

Using larger animals can also allow sponsors to evaluate delivery systems, whether those are surgical or via device. Drug/device compatibility needs to be demonstrated before initiating a phase 1 safety study.

“If use of a delivery device falls outside the cleared or approved indications for use or if the delivery device has not been cleared or approved by the FDA for any indication, we recommend early discussion with FDA to determine the additional information that may be needed to inform FDA’s safety evaluation of the delivery device when used with the investigational product for the proposed clinical study,” the agency notes.

All these requirements contribute to a strong body of preclinical data, which is especially important when the first-in-human clinical trial will be conducted in children.

“To justify conducting a pediatric first-in-human clinical trial … the preclinical program should include studies designed to demonstrate a prospect of direct benefit of the investigational GT product. Preclinical evidence to support a prospect of direct benefit is most important when clinical evidence of effectiveness is not available from adult subjects with the same disease.”

Ideally, the guidance says, a GT trial should be conducted in an adult population before the product is studied in children. When there are no adult data, sponsors need to explain why adult studies aren’t possible.

Read the final guidance here: https://bit.ly/3guoXEP.