The FDA recently issued multiple draft guideline documents on the fast-emerging field of gene therapy, including guidance on specific diseases like hemophilia and the need to follow some research subjects long-term to assess delayed adverse events.

Much of the FDA gene therapy guidance addresses stakeholders in the research and development industry. However, IRBs will be involved in establishing the risk-benefit of gene therapy and ensuring research subjects are followed for adverse effects that may appear years later.

“IRBs assess whether the risks are reasonable in anticipation of the intended benefits to the subjects and the importance of the knowledge to society,” says Currien MacDonald, MD, CIP, IRB chair at the WIRB-Copernicus Group (WCG). “There are a lot implications for study design and monitoring of subjects for safety, both routinely and for unexpected adverse event reporting.”

Three different FDA guidance documents address human gene therapy for hemophilia,1 retinal disorders,2 and rare diseases.3 The long-term follow-up guidance4 addresses the risks of gene therapy in general, as adverse consequences may arise that are not initially apparent. These FDA guidance documents and two others are available for comment through Oct. 10, 2018.

“The main implication I see from this is the attention and detail that the FDA has obviously put into the oversight of these products,” MacDonald said. “I expect to see an increase in the amount of information and specifics for gene transfer studies that will come out of this. From the other side, the IRB’s role hasn’t changed. This guidance makes it clear that there is an increase in the knowledge base required to be current and compliant, and adequately protect the rights and welfare of human subjects.”

While opening a path for a dynamic research platform, the FDA is to some extent trying to stay abreast of the rapid advancement in gene therapy science.

“The guidance is about as current as the FDA can be in keeping up with a rapidly advancing field,” he says. “We are definitely seeing some of these issues and sponsors starting to struggle with them. The FDA is very timely in putting out this guidance.”

Risk and Reward

In announcing a total of six draft guidelines now open to comment, FDA Commissioner Scott Gottlieb, MD, emphasized that gene therapy research carries an implicit risk.

“We still have much to learn about how these products work, how to administer them safely, and whether they will continue to work properly in the body without causing adverse side effects over long periods of time,” he said in a statement.

Indeed, the follow-up guidance is necessary because gene therapy is not without a variety of risks inherent in, for example, inserting a virus in cells to target certain diseases. Thus, gene transfer into human research subjects must be approved by institutional biosafety committees (IBCs).

“For example, if you are producing a virus that is intended to transmit a therapeutic gene, you need to make sure that nothing else in there is infectious — nothing other than the product that you want to transfer,” says Daniel Kavanagh, PhD, senior scientific advisor, gene therapy at WIRB-Copernicus Group. “That is part of the federal guidance and that is also part of the domain of IBC review.”

The draft guidelines contain a lot of information about best practices that could be generally applied to drug development and clinical trials, he says. The IBC will “look at risks to the study participants, the clinical staff, and the general public related to the recombinant nature of gene therapy products,” he adds.

In that regard, IBCs can be a source of information for IRBs trying to better understand FDA guidance that goes into “nitty-gritty detail about how the products should be manufactured and tested,” Kavanagh says.

“The typical roster of an IBC includes molecular biologists and microbiologists — people who came up through their careers handling these kinds of products,” he says. “So a well-constituted IBC can be a really valuable addition to the IRB in terms of the specialized knowledge. Beyond that, the IBC checks that the waste handling is appropriate, the injections are done safely, and that the material is handled correctly.”

Gene therapies are being studied in many areas, including genetic disorders, autoimmune diseases, heart disease, cancer, and HIV/AIDS, Gottlieb noted. The three disease conditions for which FDA guidance was issued — hemophilia, retinal disorders, and rare diseases — account for a lot of current gene therapy research, Kavanagh says.

“Depending on how you define gene therapy, most therapeutic modalities and clinical trials are going to fall under one of those three guidances,” he says. “Certainly, a large swath of the work that we do is going to be effected by this guidance.”

Hemophilia gene therapies are currently developed as single-dose treatments to trigger long-term production of the missing or abnormal coagulation factor. This may reduce or eliminate the need for coagulation factor replacement, the FDA states. Gene therapy for retinal disorders includes a wide variety of conditions affecting both adult and pediatric patients. Moreover, there are some 7,000 rare diseases, defined as afflicting fewer than 200,000 people in the United States.

“Since most rare diseases are pediatric diseases or have onset of manifestations in childhood, pediatric studies are a critical part of drug development,” according to the FDA guidance. “However, treatment in pediatric patients cannot proceed without addressing ethical considerations for conducting investigations in vulnerable populations.”

As many of these conditions are marked by few treatment options, the risk-reward ratio of gene therapy comes down to manipulating biological material in way that it fights a disease without causing additional harm.

“The risks of most gene therapy products include the possibility of unintended effects that may be permanent, along with adverse effects due to invasive procedures that may be necessary for product administration,” the FDA notes. “Because of these risks, it is generally not acceptable to enroll normal, healthy volunteers into GT studies.”

Informed Consent

Given such risks, informed consent in trials involving long-term follow-up must include a description of any reasonably foreseeable risks from participating in the research, the FDA advises.

“The informed consent document must describe, among other things, the purposes of the research, the expected duration of the subject’s participation, and the procedures to be followed,” the FDA states. “Accordingly, the informed consent document must explain the purpose and duration of [long-term] observations, the time intervals, and the locations at which you plan to request the subjects to have scheduled study visits or be contacted by other means, and details as to what those contacts will involve.”

Informed consent also should convey that an autopsy may be requested to test vector persistence and other adverse effects if the subject dies during follow-up.

“Sponsors must ensure that investigators submit the informed consent documents for institutional review board approval,” the FDA states.

In addition, some of the elements the FDA recommends for long-term follow-up protocols include patient visit schedules, specimen sampling plan, and the methods of monitoring tests and clinical events of interest.

“The investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each subject administered the investigational drug or employed as a control in the investigation,” the FDA states in the guidance. “These records would include a baseline history prior to exposure to the investigational product in which all diseases, conditions, and physical abnormalities are recorded.”


1. FDA. Human Gene Therapy for Hemophilia. Draft Guidance for Industry. July 2018. Available at:

2. FDA. Human Gene Therapy for Retinal Disorders. Draft Guidance for Industry. July 2018. Available at:

3. FDA. Human Gene Therapy for Rare Diseases. Draft Guidance for Industry. July 2018. Available at:

4. FDA. Long-Term Follow-Up After Administration of Human Gene Therapy Products. Draft Guidance for Industry. July 2018. Available at: