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You can’t do emergency research in a vacuum
Community education a prerequisite
Emergency research may raise a number of issues for IRBs that either review such protocols or are asked to assess criteria for emergency room use of an investigational drug or device, experts say.
"Emergency research still is an area of confusion at times," says Paul W. Goebel Jr., CIP, vice president of the Chesapeake Research Review Inc. of Columbia, MD.
"The biggest issue has to do with obtaining consent and the competency of the potential subject to give that consent," says Karl M. Nelson, PhD, director of research at Aultman Health Foundation in Canton, OH.
"Emergency patients are either unconscious, or the last thing they want to think about are the risks, benefits, and etc. of participating in a research project," he adds.
"Emergency research is a very specialized area, and the regulation 21 CFR 50.24 is very specific," Goebel notes.
For instance, the sponsor must submit an investigational device exemption (IDE) or investigational new drug (IND) to the FDA, and a separate IND needs to be requested for life-threatening emergency situations, he explains.
In these type of situations only, an investigator will not be required to obtain informed consent from subjects, but this is not meant to be a loophole.
"This can’t be something we think is not convenient to obtain an informed consent; it has to be something where the use can’t wait for informed consent," Goebel says. "There has to be, of course, IRB review, but the two most onerous provisions are community consultation and public disclosure."
Investigators as well as IRB members need to know the difference between emergency research and compassionate use of an investigational product, notes Joseph Breault, MD, SCD, CIM, CIP, IRB chair at Ochsner Clinic Foundation in New Orleans.
"If somebody has a life-threatening emergency and needs to use an IND product outside of what the trial will allow, then usually the sponsor or the FDA is likely to approve that in an emergency setting," he says.
And if it’s used for treatment and not research, then the IRB does not need to approve its use prospectively, Breault notes. "IRBs cannot give retrospective approval, so all they do is acknowledge the use after the fact and the investigator has to notify the IRB within five days."
Compassionate use’ goes outside the box
The term "compassionate use" is not a regulatory term, although the FDA’s guidance indicates that this is when someone who is likely to benefit from a research product that’s not yet marketed may be given the product, even if the person will not become a participant in a clinical trial, he explains.
From an IRB’s perspective, the compassionate use is meaningless because it is not research that needs IRB approval; however, if an investigator plans to study the patients with whom the investigational product is used, then IRB approval would be required, Breault adds.
IRBs need to consider whether it will possible for investigators to obtain informed consent under the emergency research situations that will arise, and then determine how best to do so.
For instance, can the investigator ask the potential subject questions, and will the potential subject understand what is going on? Nelson asks.
"Can they repeat, These are the risks; these are the benefits?’" he adds. "And if they can’t, then ask about legally authorized representatives and durable powers of attorney and state laws that pertain to those situations."
IRBs will need to see an informed consent document and approve its use prior to the beginning of an emergency research trial, Goebel says.
"Some people won’t be able to give consent, but there could be a legally authorized representative available, and then consent would not be waived and there would be informed consent," he adds.
In some cases, subjects who were enrolled in an emergency research trial and who were unable to provide consent later will be able to provide consent for their continued involvement, Goebel says. "You can’t go back and get approval for what has already happened, but for their continued involvement you want their consent."
For trials where it’s likely there will not be time for individual informed consent, the IRB will need to be actively involved in the community consultation part of the regulations, Goebel points out.
"It’s a lot of work and it’s expensive for IRBs to do this, and it’s expensive for sites and sponsors — there’s no question about it," he says.
The emergency research Polyheme clinical trial and its extensive public education efforts demonstrate how carefully IRBs must pay attention to the public disclosure provision.
The Polyheme trial will study patients in hemorrhagic shock, giving the control group standard care of salt water, and the study group will receive Polyheme, an oxygen-carrying blood substitute made from human blood.
Before the Polyheme study was granted an exception from informed consent, under 21 CFR 50.24, investigators developed a public education campaign that included notices in newspapers, coverage on local television stations, and advertising in English and Spanish. They also provide "no participation" study bracelets to anyone who requests one.
"We conducted several community meetings in which we provided a PowerPoint presentation detailing the product, previous clinical trials, and the design of the current study, with emphasis on the exception from informed consent," recalls Jeffrey S. Long, RRT, clinical research specialist in the department of surgery at Denver Health Medical Center.
"We handed out surveys at the end of the meetings, which we provided to our IRB along with minutes and an overall impression of the meeting," he says. "Additionally, we placed advertisements in several local publications, some with details about the study and dates/times of upcoming meetings, and others just to announce meetings."
The trial received some local news coverage from print and broadcast outlets through interviews and basic news stories, Long reports.
"Finally, we directed the community to our web site, or directly to the principal investigator or to myself for questions and comments," he adds.
"Community consultation is a requirement that either the IRB or clinical investigators or someone has a local consultation with leaders of the community about this planned use of the treatment without obtaining informed consent," Goebel says. "They have to inform the public at large that if they go to such and such emergency room with loss of blood or a heart attack or whatever, then they are likely to be entered into a research that study, and there has to be public awareness of this."
The FDA decided that public disclosure is not satisfactorily achieved by merely placing a legal notice in the town’s newspaper, he notes.
"What does work are notices or stories in mainstream publications, notices or stories on the radio, and the big gorilla in the room is television," Goebel says. "So you’d be hard-pressed to say we disclosed this to the public if it has not appeared on television."
It’s expensive to buy a television ad, so the best way to obtain this coverage is through a free public interest story, he suggests.
"The surgeon who’s doing the research can be interviewed, and you can obtain public disclosure this way," Goebel says.
Investigators also might visit churches, schools, or other community venues to explain the research, and this part is left to the discretion of the IRB, whose members know the community, he adds.
"It’s not that each of these is extraordinarily difficult, but there are a lot of decisions that an IRB and team have to make, and it takes a lot of time and effort for the IRB to sort through this," Goebel says.
Another requirement is that when the research is concluded, there must be a notification of the results of the research, and this may include publishing an article in a professional journal, Goebel notes.
Responding to sponsors
One other issue that IRBs sometimes face is a request by a sponsor asking for acknowledgement or approval for an investigator/clinician to use a particular IDE or IND in emergency situations, Breault and Nelson say.
"Usually the principal investigator will call and say, The sponsor says I can have it under emergency use, but they want a letter from you saying it’s approved,’" Breault says. "I say, I am aware of this and it appears to fit the emergency use provision, but this is not officially an IRB approval, which can only be done by the IRB’s full panel."
This situation is different from a planned research protocol in the emergency room because it may be a situation in which Dr. X knows about a device that Dr. Y has been using, but Dr. X hasn’t brought this to the attention of the IRB although he’d like to have the option of using the device under certain emergency circumstances, Nelson explains.
The sponsor of that particular device will write the IRB requesting a letter that addresses the situation, he adds.
In response, the IRB may write something like this: "We’re aware of the situation, and we feel those criteria for those regulations have been met," Nelson suggests.