By Melinda Young, Author

Gene therapy applications are increasing across the globe due to increases in life-threatening and chronic illnesses and developed nations’ moving to accelerate commercialization of gene therapy.

The market’s growth raises the prospect of IRBs overseeing gene therapy clinical trials. It also means that research organizations, both large and small, should be prepared for such trials and develop or have access to an institutional biosafety committee (IBC).

“A subsection of clinical research specifically defines how clinical research needs to be done when it comes to these molecules,” says Daniel Kavanagh, PhD, senior scientific advisor, gene therapy, at WIRB-Copernicus Group (WCG) of Princeton, NJ.

“Any research that involves National Institutes of Health [NIH] funding or is conducted by people who voluntarily wish to submit to the guidelines must be approved by the IBC if the research involves recombinant DNA or RNA technology,” Kavanagh says.

There are more than 1,000 studies underway that fall under the NIH’s definition of human gene transfer. There are five current products, with more predicted to be on the market within the next few years, he says. The following are the latest gene therapies to receive FDA approval:

• Kymriah: Gene therapy for pediatric and young adult patients with acute lymphoblastic leukemia, approved Aug. 30, 2017 (http://bit.ly/2VkYJVo);

• Yescarta: Gene therapy for treating adult patients with relapsed or refractory large B-cell lymphoma, approved Oct. 18, 2017 (http://bit.ly/2Ei9alG);

• Luxturna: Gene therapy to treat children and adults who have an inherited form of vision loss, approved Dec. 19, 2017. (http://bit.ly/2EDyqEf)

For years, IRBs have reviewed studies using small molecules or biologics that do not contain DNA, he notes.

“But if these become a clinical trial where the investigational product incorporates genetically modified DNA or RNA into the product and it’s introduced into a human subject, then it becomes human gene transfer research and a new set of oversight kicks in,” Kavanagh says.

In most cases, the research institution needs to have an IBC.

“There are 1,300 IBCs registered with the NIH,” he says. “If people don’t comply, the NIH can withdraw their funding and make them ineligible for future funding.”

Even when multisite clinical trials use a central IRB for review, they must each have their own IBC for these studies.

“We’re starting a multicentered trial where there are 50 sites for one trial, and all 50 sites will require their own IBC,” Kavanagh says. “There will be one multicentered trial with a single protocol, but 50 sites and IBCs.”

In August 2018, the NIH released a proposal to amend its guidelines to streamline oversight for human gene transfer clinical research protocols. The change would eliminate recombinant DNA advisory committee (RAC) review and reporting requirements to NIH for human gene transfer protocols and modify the roles and responsibilities of institutions, IBCs, the RAC, and NIH. (Find more information at: http://bit.ly/2BVsCUS.)

The proposed change received dozens of public comments. Commenters included Paul Gelsinger, father of Jesse Gelsinger, who died during a gene therapy trial in 1999. Gelsinger wrote in opposition to the proposed change, stating, “So, if you believe that the system has fixed the financial conflicts of interest issues in clinical research, especially the overhyped gene technologies, think again.” (The comment can be viewed at: http://bit.ly/2T4JnaO.)

The proposed change was not finalized by the end of February 2019.

While the changes, if finalized, would affect some IBC responsibilities, they would not change the IBC structure with regard to including community members and how they are required for each research institution that conducts a gene therapy clinical trial.

Research institutions can start their own IBCs or contract for IBC services. Kavanagh offers the following advice on how to form an IBC:

• Select IBC members. IBCs need a minimum of five members, including science experts, at least two community members, and a chair. If human gene transfer occurs at the institution, the IBC must have a gene transfer expert as a voting or ad hoc member.

IBCs should include, in addition to science and gene therapy experts, members who can represent the community’s interests.

“The NIH is serious about the requirement of community involvement,” Kavanagh says. “The community members on the committee must not be affiliated with the research site.”

Community members could include people who work in the biotech industry, so long as they are not affiliated with the research institution. The goal is to find people who represent the interests and concerns of the community, he adds.

This likely is easy to do in large cities but more challenging in rural states and regions.

“Each IBC can only oversee the interests of the local community for which it is registered; a general standard is within a radius of 50 miles,” Kavanagh says. “So, there have to be a lot of individual IBCs registered across the country.”

One strategy for finding IBC members is to create a professional network that can be accessed when starting an IBC or replacing members on one, he suggests.

“I’m always collecting cards from people around the country at conferences, keeping those networks active,” he says.

“If someone were setting up their own IBC from scratch, they’d have to pick up the phone book and guess who would be interested,” he adds. “The goal is to find members who are competent to advise the institution on safety and community standards.”

• Follow NIH rules. Current guidelines are flexible for IBCs, Kavanagh notes.

“There is a large self-assessment tool that NIH has published, which provides a lot of details and points to the IBC in terms of their operation,” he says. “The real purpose is to make sure the work is done safely.”

The rules also ensure trials follow proper technical equipment training, waste disposal, and NIH requirements.

IBCs must make their meeting minutes available and detailed in how the board made its decisions.

“A typical IBC at a major university meets once or twice a month, while an IBC at a hospital with only one gene therapy clinical trial might meet once a year,” Kavanagh says.

The IBC’s role is to assess the facility in which the work will be performed. It includes a biosafety professional, who is knowledgeable about the various biosafety levels and infectious agents, and the types of protective measures needed for each level.

For example, a biosafety level 4 would be for biodefense and high-security studies that involve toxins or bioagents. Protective measures for these studies would include following best practices in room airflow, biosafety cabinets, wearing personal protective equipment, and other measures, he says.

WCG provides services at biosafety levels 1 or 2, Kavanagh notes.

“We send in consultants to do IBC inspections at the site, which is a big part of the review,” Kavanagh says. “An IBC has these boots on the ground and needs to look at facilities, looking at where the garbage and sharps are disposed, and the personnel training and certification.”

These are very different from the IRB’s review and involvement, he notes.

“It’s a facility-specific review of safety capabilities of the site, and every new protocol has to address the new agent,” he adds. “If I have a recombinant DNA molecule that’s one kind of potential hazard, or if I have live virus, that’s a different hazard, and a different assessment is required.”

• Work with IRBs. “It’s at the discretion of the institution, but it’s certainly useful to have somebody from the IRB attend the IBC meeting,” Kavanagh says. “You want communication between the biosafety, human subjects protection, occupational health, and animal protection committees.”

The institution needs a plan to coordinate between those four branches, he says.

“The IRB is focused on the human subject who is enrolled in the study; the IBC is focused on safety of the subject and the protection of everyone around that person, including the community, family, lab workers, physicians, and others,” he explains. “It’s a complementary set of roles.”

The IRB assesses risks and benefits, and IBCs have experts that can shed light on certain risks. It would help IRBs in making their decisions if members can ask the IBC experts about particular agents and the risks they pose to research participants.

IRB and IBC chairs could hold a monthly meeting to discuss studies.

“The current NIH guidelines require IBCs to review informed consent,” Kavanagh says. “Last year, the NIH director proposed some streamlining, which may — if implemented — remove the requirement for the IBC to review the informed consent form.”

This second review by the IBC is a best practice, he adds.

“It’s up to the institution who reviews the informed consent document first, but my company provides a parallel IRB and IBC review of informed consent,” Kavanagh says.