The unknowns of gene therapy pose challenge

Close monitoring can reduce worries

Gene transfer research offers new hope for people suffering from some rare or deadly diseases, but the research also has suffered major setbacks due to serious adverse events, including subjects’ illnesses and deaths, and this creates a greater burden for IRBs reviewing such protocols, experts say.

"Gene therapy is an evolving area of therapeutics that has been unfortunately associated with adverse events due to studies in Europe involving immunodeficiency," says Bruce Gaynes, OD, PharmD, assistant professor of ophthalmology and pharmacology and IRB committee member at Rush University Medical Center in Chicago.

Although the research also has had some promising outcomes, a chief dilemma for IRBs is that subjects often have unrealistic expectations.

"You can imagine that with gene therapy, because it sounds promising and high tech, that subjects would think they are going to obtain benefit from the study," says Alan Korenblit, MD, CIP, senior attending at Rush University Medical Center and chair of the Rush IRB.

"We’ve been talking about gene therapy for decades, and so there are expectations by the medical community and patient population that deal with these diseases, which in some cases have very little treatment options," he says. "Gene therapy sounds as though it should result in improved quality of life and survival and eventual elimination of their underlying disease."

However, recent examples show that gene therapy sometimes can harm subjects. For instance, gene therapy studies in France involving the congenital disorder of Severe Combined Immunodeficiency Syndrome (SCIDS) patients resulted in some patients developing leukemia that was found to be directly related to their gene therapy treatment, Gaynes notes.

"One of the most important jobs of an IRB is to protect subjects from excessive risk," he says. "An IRB has to look at the risks and benefits of each therapy in patient-specific circumstances and trial-specific circumstances."

The challenge to doing so with gene transfer research is that such studies are few and infrequent, Korenblit says.

Many risks are unknown, and there haven’t been enough studies to provide much data on benefits.

"There were quite a few subjects who did improve with gene therapy, and that was very promising," Gaynes says. "And it’s now being used in a lot of disorders, including cardiac disease — trying to stimulate growth with new blood vessels."

So the fact that gene transfer research has also led to the deaths of subjects should not mean this area of research should be discontinued or considered to be too risky by IRBs, he notes.

"There have been instances where there have been adverse events occurring with other therapeutic agents that were definitely linked to the agent, which in the long term has shown significant promise in treating certain types of cancers," Gaynes says.

Gaynes, Korenblit, and other experts offer these suggestions for IRBs dealing with gene transfer research or with similarly higher-risk protocols:

• Ask the researcher to provide data safety monitoring board (DSMB) information to the IRB. For gene transfer research protocols, some institutions require oversight by a DSMB or data safety monitoring committee (DSMC), says Deborah Barnard, MS, CIP, director of the Office for the Protection of Research Subjects at Dana Farber Cancer Institute in Boston.

"For studies where we’re concerned about safety issues, we’d refer the study to the DSMC," Barnard says. "And by default, some go to it anyway, including gene transfer studies."

The IRB reviews all of the DSMC’s safety management information regarding protocols, Barnard says.

"We had a study where the DSMC noticed something in all of the adverse event reports that hadn’t been picked up by the IRB," Barnard notes. "The DSMC recommended the IRB obtain more information from the investigator and then make recommendations to modify the study for safety concerns."

• Use a serious adverse event committee to screen study adverse events (AEs). At Rush University Medical Center, there’s a separate serious adverse event committee that screens all adverse events and then determines which should be seen by the IRB, says Howard Kravitz, DO, MPH, associate professor of psychiatry and preventive medicine and associate attending in psychiatry. He also is the chair of the IRB 2.

"The IRB still sees its fair burden of adverse events, and we’ve had meetings where half of our work is reviewing adverse events," Kravitz says. "A lot of these are with oncology studies and deaths and determining whether this is the progression of disease or whether the drug has anything to do with the subject’s death."

The serious adverse events committee enters AE information on a database and when studies come up for continuing review, the IRB receives a printout of the AE database for any particular study, he says.

"Then the IRB looks at this in the context of how ill this population is; this includes HIV studies and cancer studies," Kravitz adds. "Subsequently, the real goal is to reduce the potential risks to subjects."

If the IRB, when reviewing the committee’s data, decides the study is posing significant risk, the IRB can close the study or suspend it until further information becomes available, he says.

• Limit gene transfer research and IRB review to institutions that have the necessary expertise. "The difficulty with gene transfer research is there is not much precedence in this type of research, so we don’t have the luxury of large studies with large numbers of subjects," Korenblit says. "It’s a relatively select population with unusual disorders and various medical issues that are not common, and therefore it become difficult to predict what complications, if any, will occur with any of these innovative treatments."

So it’s challenging for IRBs to obtain expertise in this area when they are considering gene transfer protocols, he adds.

"Because of its rarity, you’d potentially want this limited to certain institutions that either have knowledge or expertise in this area," Korenblit says. "The question for an IRB is, How many subjects have undergone a procedure and who is administering the treatment and monitoring the patients?’"

When the answers show that the studies are very small with potentially high risk, then it may be best to limit the research to certain geographic areas where there’s necessary expertise and knowledge, he says. "It allows the IRB in that locale to become more educated regarding that particular topic and to, hopefully, make the best decisions for the protection of subjects."

• Ask for expert consultations when in doubt. IRBs will have to make a reasonable estimate of risks vs. benefits on a case-by-case basis in gene transfer research, and doing so may require consultation with experts in this new area of research, Gaynes says. "If IRB members feel they have questions that need to be resolved, then the IRB is expected to bring in outside sources to act as consultants to inform them."

"As more novel treatments are studied, there is going to be a greater need for expertise and consultations with experts," Kravitz says. "It’s an evolving process, and one way to stay on top of what’s going on in the field is to get help when you need it."

Likewise, a centralized review of gene transfer research protocols would be a way to ensure expertise on the IRBs handling these cases, Korenblit says.

"I would like to see a centralized review of any of these potential studies prior to their being disseminated to the various centers," he says. "However, no group is infallible in its evaluation of the research project, and it’s the responsibility of the local IRB to determine if it’s an acceptable intervention and whether subjects are adequately informed."

• Ask federal officials for guidance in reviewing research involving new treatments and research with large numbers of adverse events. IRBs need to know how gene therapy research reviews are handled at other locations and there’s a need for consistency in dealing with this type of research, Kravitz says. "We’d like to see more guidance on a broader scale.

"What happens is it is handled on an institutional level," Kravitz says. "There are 60 sites involved in a study, and you don’t get deliberation from other sites on how they’re handling it."

So one site may think a particular protocol has potential problems, and another one does not, he says.

"There’s no clear guidance on handling these, so we do the best we can," Kravitz adds.

• Address risks adequately on consent form. With gene therapy research the risks are largely unknown, but they still must be adequately addressed on the consent form, Gaynes notes.

For example, even though a gene transfer research study at one institution may involve an entirely different disease and population than the SCIDS studies conducted overseas, it’s still a good idea to make a mention of those problems during the consent process, Gaynes advises.

"People have to know there have been failures in gene therapy that have led to death and that there are unknowns which must be mentioned in the consent form," he says.

The key is to make certain subjects know that serious problems occurred in another type of gene transfer study, but not in the study for which they are enrolling, Gaynes adds.

• Use IRB auditors to keep fully up to date on higher risk research. Some IRBs are beginning a system of using auditors to check studies where the risks are unknown or considered high, Barnard says.

The auditor will report back to the IRB, which then can make a determination of whether IRB members are comfortable with the study continuing as it has, Barnard says.

The auditor typically is someone in the IRB office who has the skills and ability to check the protocols on a regular basis, Barnard says.

"We have onsite auditors we send out for both random audits and to ensure protocol adherence," Barnard says. "We do for-cause audits, and the IRB can refer a study they have concerns about to the auditing team."