Meanwhile, back at the ranch…
Over at his “Human Exceptionalism” blog, Wesley Smith is appalled that the Presidential Commission on the Study of Bioethical Issues (PCSBI) has done something that President George W. Bush’s Bioethics Commission would never have “countenanced;” viz., the PCSBI has “given conditional approval to test anthrax vaccine on children!” (The exclamation point is his.)
This is a reminder to me to keep an eye on what the PCSBI is up to. I have not had a chance to review their report, which was just issued today. I’ve only been able to read the executive summary. What the PCSBI was considering, at the request of HHS Secretary Sebelius, was the ethics of “pre-event” testing, in children, of medical countermeasures intended to treat people in the event of a terrorist attack like an anthrax release, or a big radiation exposure. The anthrax vaccine was the test case-in-point. It has been tested in adults, with some side effects, mostly mild but a couple more serious. For brevity’s sake, no more about that at the moment. But what about testing in normal kids, before an attack? Why not do such a study now? The reason to do it would be mainly to get the dose right—but the dose could be different for 17 year-olds than for babies, because the immune system develops along with the entire individual. Goodness, are we talking about exposing babies to the risks of anthrax vaccine?
My first reaction was to be as aghast as Smith. I can scarcely imagine a scenario in which I, were I sitting on an IRB reviewing a proposal, could approve of testing anthrax vaccine on normal, unexposed children. My second reaction, after reading the PCSBI’s executive summary, is that we should not rush out to lynch them.
Some background: The current regulations protecting children in biomedical research are, of course, patterned on Belmont principalism, and while found in more than one place, are principally given in 45 CFR 46, Subpart D. I don’t think, today, that I can improve on them; maybe other readers of this blog are willing to take that task on. But they are the common reference point in the U.S., anyway, for questions like this. Briefly, with few exceptions, biomedical research on children must expose them to no more than minimal risk, which means “that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.” Also, any research involving children as subjects must provide for parental informed consent and age-appropriate assent of the child.
What are the exceptions to the minimal risk standard? They are:
a) Research that offers the prospect of direct benefit to the participating child and poses more than minimal risk may be acceptable if the prospect of benefit outweighs the risks (in the IRB’s judgment); or
b) Research that offers no prospect of direct benefit, but is likely to yield generalizable knowledge about disorders or conditions affecting the participating child, may be acceptable if the risks posed are “a minor increase over minimal risk;” or
c) Research not otherwise approvable, but which “presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health and welfare of children” may be acceptable if it passes IRB muster AND the Secretary of HHS, “after consultation with a panel of experts in pertinent disciplines…and following opportunity for public review and comment,” finds the research passes ethical muster.
What did the PCSBI recommend? Rather than enumerate the recommendations, I’ll paraphrase. It helps to go in somewhat reverse order. The Commission ended by saying that “post-event” studies (i.e., testing AFTER an attack had been launched) in kids would be an ethical responsibility, and such studies should be designed now, in the awful event that an attack occurred. (Can’t we imagine the clamor for an experimental vaccine for our kids in such a case?) Such testing should be done under existing regulations for an “IND,” an exemption (from the requirement for drug approval) for testing of an investigational new drug—the drill that every new drug in development goes through. No argument there.
Beyond that, while some might think that the Commission opened the door for testing anthrax vaccine in children, in advance of an attack, I don’t see the door ajar yet. It seems to me that the PCSBI was describing the shape of the lock. From their cover letter to the Secretary:
“The Bioethics Commission concluded that in the case of pre-event pediatric MCM research, absent exceptional circumstances, all research must be designed to pose only minimal risk to child participants. When pre-event pediatric MCM research cannot be conducted as a minimal risk study, only research that poses no more than a minor increase over minimal risk—a level that is still very limited and poses no substantial risk to health or well-being—should proceed to national-level ethical review under current regulations (45 C.F.R. § 46.407/21 C.F.R. § 50.54). The Bioethics Commission proposed an ethical framework to ensure the thoroughness and ethical rigor of such national-level review. Regardless of whether pre-event research is conducted, post-event pediatric MCM research should be planned in advance and conducted when MCMs are administered to children in an emergency. When untested MCMs are made available to children in an emergency, research protections should be in place.
“In addition to generally reviewing the ethical considerations of MCM research, Secretary Sebelius requested that the Bioethics Commission specifically address the ethical considerations of pediatric testing of AVA. (The Bioethics Commission has not been provided a protocol to review, nor is it within the purview of the Bioethics Commission to sit as an institutional review review board or a national-level review panel under 45 C.F.R. § 46.407/21 C.F.R. § 50.54.) The Bioethics Commission concluded that before ethical pre-event pediatric AVA trials can be considered, further steps must be taken, including additional minimal risk research with adult participants, in order to determine whether the research risks to children—who do not stand to benefit directly from it—can be reduced to a level that poses no substantial risk to their health or well-being.” (Emphases mine.)
In other words, heaven forbid we might ever really want to consider this, and if we do, we would not even let an IRB review it unless a lot more information and justification were made available, and the study were designed in certain ways to ensure as close to minimal risk as possible. But given the awful nature of the potential threat, the Commission refused to say “we shall not.”
I will say that, from my brief initial review, it sounds like the Commission may have been conflating exceptions b) and c) from my list above. (BTW, 45 CFR 46.407 is “exception c” above.) Clearly, “pre-event” research would fit criterion c), because healthy children would not have a “condition” like being exposed to anthrax. Yet, the Commission appears to be applying the more rigorous standard of exception b), above. Then again, depending on how much one trusts our appointed officials (and, pointedly, our HHS Secretary), the process of review for c) maybe doesn’t inspire as much trust as the authors of the regulations hoped. Frankly, I prefer the insistence on the “minor increase” over minimal risk limit.
So, at this juncture, I’m not willing to rush to condemn the Commission, but I also think the bar is about as high as the moon for this kind of research. I think I’d want to see a nearly adverse-event-free vaccine in adults and a threat sufficiently imminent to have the CDC wanting to vaccinate the adult population widely. Smith suggests that the first kids volunteered for these “pre-event” studies should be the children and grandchildren of Commission members. That’s a little rough, but unless I was convinced there was a meaningful threat (and risk thereof), I would actively try to keep my grandkids OFF such studies.
This is not a simple case, and I’ve glossed over a lot here, blog space and my energies being limited. What do others of you think?