SACHRP chair updates IRB Advisor on IRB regulations

Ernest Prentice gives Q&A interview

[Editor's note: In this question-and-answer interview, Ernest Prentice, PhD, associate vice chancellor for academic affairs at the University of Nebraska Medical Center in Omaha, NE, and the chair of the Secretary's Advisory Committee on Human Research Protections (SACHRP) for the U.S. Department of Health and Human Services (HHS) discusses with IRB Advisor SACHRP's work through mid-July, 2006, and what is expected later this year.]

IRB Advisor: What are some the latest issues and things discussed and decided by SACHRP?

Prentice: The subcommittee of research involving children has been meeting continuously since we began our deliberations. And they have produced a series of reports.

They've had all of their recommendations to date accepted by the [HHS] Secretary. One set of recommendations has already been implemented by OHRP, and the other recommendations are waiting, so we have a complete set which will occur hopefully at our August meeting, where we're going to be able to provide a complete set of recommendations about how Subpart D should be interpreted and applied by IRBs so we have what we refer to as consistent protection of children involved in research, so that we neither unduly prohibit their participation, nor do we exploit them in any way.

We're very concerned about having appropriate, additional protections in place. So that subcommittee will complete its work as of the August SACHRP meeting.

IRB Advisor: What are some of the recommendations that will be considered and probably will end up in the document?

Prentice: One subcommittee is looking at the issue of additional protections for children. The problem with additional protections for children is that there are a whole lot of terms in there that IRB's have never understood before, things like what are the definitions of minimal risk. Should minimal risk be tied to the daily life the individual research subject, which is called a relative standard, or should it be tied to the daily life of healthy children? All of the protections built into subpart D rest upon that definition, as to whether or not there is the prospect of direct subject benefit. So that's a threshold level of risk that determines what additional protections should be in place. So it's extremely important that IRBs have an appropriate way to interpret minimal risk and apply minimal risk. So we have advocated the utilization of what we call a uniform standard that is tied to the daily life of a healthy child living in a safe environment, as an example. We also look at other terms in subpart D which were problematic for IRBs to interpret over the years. And "a minor increase over minimal risk." No one ever knew what that meant. "Disorder or condition." That was very confusing to IRBs. There's a requirement that research be of vital importance when it's to understand or amelioration of subject's disorder or condition when the subject is greater than minimal risk and there is no prospect of direct subject benefit. Well, nobody really understood what "vitally important" meant. So we spent days and days and days with a group of very brilliant people who were experts in the field, basically discussing how to interpret these terms that were included in subpart D.

IRB Advisor: Will you publish your recommendations?

Prentice: Everything we do is public. It's all published on the Web site. We don't publish the letter, but the recommendations that are passed at the meeting are a public transcript, available to the public.

The fourth subcommittee, which is ongoing, is what we call our subpart A subcommittee. The subpart A subcommittee is looking all aspects of subpart A, and they're trying to determine how best to interpret some of the terms, including "minimal risk." How should minimal risk be interpreted for research involving adults? Should it be tied also to the healthy person standard? This is our newest subcommittee, so we have not generated any letters to the Secretary.

The subcommittee also is looking at expedited review: Should the list be expanded? Should it be clarified? We're looking at continuing review: should continuing review be required to be performed no less often than annually? Or should you have a longer interval for minimal risk research? We're looking at concepts like when does a study actually end; that seems to be unclear as to when continuing end should be able to cease. Do you continue to perform continuing review as long as subjects are in follow-up? Do you perform continuing review as long as the data is in the analysis phase? So we're looking at things of that nature.

One of the problems with the current guidance issued by OHRP and FDA is that if an investigator fails to get their continuing review application to the IRB and it's not re-reviewed and re-approved by the IRB approval expiration date, all research activities have to halt unless it's in the best interest of the research subjects to continue, in which case the IRB can make an exception. One of our problems is investigators sometimes wait until the last minute, and if you are reviewing a continuing review application at an IRB meeting, and you have any questions or require even minor clarifications and you're up against that IRB approval date, you have to stop the research.

So we're recommending that if the continuing review is already underway by the IRB and there are no significant problems that are identified then we feel as though there ought to be a 30-day window. Have the IRB expiration date when the IRB can complete its review without halting the research. So these are some of the issues that the subpart A subcommittee is grappling with and, again, these are not recommendations passed by SACHRP, these are issues considered by the subpart A, subcommittee which will eventually result in recommendations produced by SACHRP, which will go on to the Secretary.

We're also going to look at, on the subpart A subcommittee, IRB membership requirements. You've often heard that other committees have looked at this and there are people who suggested various percentages of non-affiliated members, we'll we're going to take a look at that and make some recommendations of what IRB membership should look like.

Another activity is that we have had a panel for some time on IRB review models. This panel discussed various models of IRB review, such as the traditional institutional review board, which is located at the institution that does the research, to the independent IRBs, otherwise known as the commercial IRBs. And there are maybe between 35 and 40 now. We've looked at central IRBs and community-based IRBs.

There will be a conference held Nov. 20-21 in Washington, DC, where we're going to continue our examination of IRB review models to try to provide guidance to institutions contemplating developing a relationship with an independent IRB. How should that partnership look like? How should the responsibilities be divided up? What about liability issues and that entire sort of thing.

IRB Advisor: So you are going to come up with a model that IRBs can follow?

Prentice: That's the idea.

IRB Advisor: And that would include a change in recommendations on the breakdown of the members' expertise and things like that?

Prentice: Probably. The agenda's not set. What we want to do is have all of the stakeholders involved in this. We want representation from the independent IRB world, the academic IRB world, the central IRB world. We want to have general counsels from various institutions, who are worried about liability. We want them to be at the table, so all of the stakeholders can be at the table so we can discuss all of the issues. Get them all out at the table and figure out what kind of a system should a given institution adopt in consideration of one, obviously the need to protect the rights and welfare of human subjects, but also the fact that it's important that we foster research for the benefit of human society. Also, if you look at a typical multi-center clinical trial, which may involve 100 sites, to go through 100 IRBs just is not cost effective. So we've got to get a better handle on what is the best mechanism to review multi-center clinical trials, where you have an academic institution participating as one of the sites. Or where you have 50 academic institutions participating as sites, and you've got another 50 who are community hospitals that may not have an IRB, or individual doctor's offices or clinics who don't have IRBs. Is it really cost effective to have 50-60 IRBs reviewing one single clinical trial where you can't change the design of the trial; the only thing you can do is revise the consent form. These are some of the issues that we want to examine.