Sarepta Trial Protocol Change Could Spur More IRB Referrals To US FDA

The US FDA’s speedy decision to allow in-dwelling ports in a Sarepta Therapeutics Inc. Duchenne muscular dystrophy (DMD) trial could encourage greater use of the investigational review board (IRB) referral process for pediatric studies.

In a May 25 determination letter, FDA concluded that totally implantable central venous access devices (TICVAD), or ports, may be used in the ESSENCE trial of two exon-skipping compounds to aid the weekly infusion process.

FDA’s decision directs Sarepta to obtain documentation from the local investigator about the expertise of the consulting surgeon in the placement of the port. The company also must incorporate monitoring of the safety and use of the port into the study protocol.

Sarepta must obtain documentation from the local investigator about the expertise of the consulting surgeon in the placement of the port and incorporate monitoring of the safety and use of the port into the study protocol.

The determination came a mere seven days after FDA’s Pediatric Advisory Committee and its Pediatric Ethics Subcommittee unanimously concluded there are circumstances in which an in-dwelling central venous access device should be allowed in ESSENCE. (Also see "Sarepta’s ESSENCE Trial Gets FDA Panel Nod For Protocol Changes" - Pink Sheet, 18 May, 2017.)

FDA’s decision came in the form of a recommendation from the Office of Pediatric Therapeutics that was approved by Rachel Sherman, deputy commissioner for medical products and tobacco.

Newly installed FDA Commissioner Scott Gottlieb delegated the decision to Sherman, an action that may have helped expedite the decision-making.

The decision has the potential not only to help speed enrollment of, and reduce dropouts from, the 99-patient ESSENCE trial, but it also could make other placebo-controlled studies in DMD easier to conduct. (Also see "Sarepta Protocol Changes Could Impact Future Duchenne Trials" - Pink Sheet, 21 May, 2017.) ESSENCE is approximately one-third enrolled.

Protocol Changes Reflect AdComm Views

ESSENCE is a 96-week, double-blind, placebo-controlled study of two compounds, SRP-4045 and SRP-4053, in DMD patients with out-of-frame deletion mutations amenable to skipping exon 45 and 53, respectively.

When FDA reviewed the original protocol in 2015, the study plan allowed for use of a venous access port at the investigator’s discretion. However, the agency concluded that implantation of a port in a patient randomized to the placebo arm exceeded a minor increase over minimal risk, offered no prospect of direct benefit, and was not approvable under federal regulations governing safeguards for children.

Consequently, the current ESSENCE protocol for US study sites allows only for use of a peripheral intravenous line for weekly infusions.

The University of California at Los Angeles (UCLA) IRB requested a protocol change due to difficulties with peripheral venous access experienced by study subjects at the site.

In March, the IRB decided to refer a proposed protocol change allowing the use of ports to FDA under 21 CFR 50.54. Under this regulation, a pediatric study protocol may proceed even when it fails to satisfy additional safeguards intended to protect children if the FDA commissioner determines, after consulting a panel of experts, that it meets certain criteria. (Also see "Eteplirsen Revisited? FDA Panel To Weigh Protocol Changes For Two Sarepta Drugs" - Pink Sheet, 24 Apr, 2017.)

At the advisory committee meeting, DMD patients and their families testified to the pain, stress and anxiety created by numerous failed attempts to achieve peripheral venous access each week. The chairman of UCLA’s IRB also raised concerns about the potential for study dropouts due to the need for multiple needle sticks and the inability to achieve peripheral access in some patients.

The advisory committees voted 14-0 in support of allowing an in-dwelling central venous access device. Committee members declined to place restrictive criteria on whom should receive such devices or when they should be implanted, concluding only that the decision should be at the discretion of the study site investigator in consultation with the family and patient.

Although panelists favored the use of ports because they can remain in place for years and are less prone to infection risk than other central venous access devices, they nevertheless left the door open to use of other methods.

FDA’s decision on the protocol amendment mirrors the committee’s recommendation. (See box) “The revised protocol may provide for the use of alternative methods of central venous access, such as a percutaneously inserted or tunneled central venous catheter, as long as the patient has a documented contraindication in the opinion of the consulting surgeon for the placement of a TICVAD,” the decision memo states.

The local or country-specific regulatory body for each study site may consider further requirements for use of ports, such as criteria for difficulty with peripheral venous access. “While permissible, under FDA’s regulations these local requirements may be considered site-specific amendments, and would not require a modification of the protocol nor notification, review and approval at other study sites,” the agency said.

Will Referrals Become More Common?

The protocol change is positive news for DMD advocacy groups who sought to ease the burden on patients participating in clinical trials and their families, and for Sarepta, which is conducting the first long-term, placebo-controlled study in DMD with the ESSENCE trial.

The study design was informed by learnings from trials of other exon-skipping compounds, including the troubled development program for Sarepta’s Exondys 51 (eteplirsen).

Sarepta President and CEO Edward Kaye said the company was pleased with the agency’s decision. “This is a prime example of the agency, advocacy community and industry collaborating to find solutions that best serve patients.”

The Jett Foundation, a DMD patient advocacy group, welcomed the advisory committee and FDA’s conclusions that the decision to place central venous access catheters should reside with physicians and the families that are affected.

Jett Foundation’s McSherry said she hopes that the ESSENCE protocol amendment will empower other IRBs that may be struggling with ethical issues in pediatric studies to similarly reach out to FDA and its external experts under the referral process.

“The Jett Foundation believes that patients and families who undergo the hardship of having these types of rare diseases need options,” said Christine McSherry, the group’s founder. “It comes down to having an option to get a medication in a less traditional way.”

McSherry said she hopes that the ESSENCE protocol amendment will empower other IRBs that may be struggling with ethical issues in pediatric studies to similarly reach out to FDA and its external experts under the referral process.

Robert “Skip” Nelson, deputy director of FDA’s pediatric therapeutics office and senior pediatric ethicist, has said the rarely used referral process is viewed as cumbersome, and IRBs are often hesitant to engage with FDA. He plans to ask the agency’s Office of Chief Counsel whether FDA could initiate the public review process for a protocol under 21 CFR 50.54, rather than waiting for an IRB referral.