Wednesday, March 20, 2013

Tower of Babel as Reporters Try to Decipher Bioethics Commission Report

Reading 26 media reports describing the Presidential Commission for the Study of Bioethical Issues' report on testing anthrax vaccine and other countermeasures in children, one learns very little:
  • This was a really hard job for the Commission. 
  • They had to get it precisely right. 
  • The safety of kids is our most important priority.  
  • The tests were approved.  
  • The tests weren't approved.  
WC Fields understood this process perfectly:  "If you can't dazzle them with brilliance, baffle them with bullshit."  It isn't the media that have gone mad: instead, the text of the report the journalists are trying to understand is contradictory and confusing.

Important Point 1:  The Bioethics report confabulates regarding the degree of risk children would experience in an anthrax trial.

The NBSB (the first federal advisory committee tasked to evaluate an anthrax vaccine trial in children) report on giving children anthrax vaccine didn't waffle about the risk of the experiment.  That is why they only approved the trial with the proviso that a federal ethics panel approve it:

"Generally, the administration of experimental drugs or biological products is neither normal nor routine, and therefore not minimal risk, and thus such an intervention could not be approved by an IRB under 21 CFR 50.51."
On page 88, the Bioethics Commission Report acknowledges this critical fact:
The National Biodefense Science Board (NBSB) stated that, given the lack of data about AVA use by children, pre-event AVA research with children currently would “present more than a minor increase over minimal risk.”216 Accordingly, pre-event AVA research with children as envisioned by NBSB would not be appropriate for national-level review or approvable under section 407 because this lack of data sets the level of risk beyond the acceptable threshold of a minor increase over minimal. 
But then the report says that by using its "age de-escalation strategy" one might get around this problem and could conduct "minimal risk" research.

Anthrax vaccine is considerably more dangerous than the vaccines routinely given to children, as my last post showed.  The Bioethics Commission, however, used questionable citations selectively to claim the vaccine was perfectly safe:
"AVA safety has been evaluated in adults through both active and passive surveillance studies, and its safety is comparable to other vaccines regularly administered during routine medical appointments.129 Data in adults indicate that the mild and moderate adverse events associated with AVA are no worse than for other vaccines...130
Systemic events—such as fever, malaise, and myalgia—although associated with receipt of AVA, are much less common than injection site reactions, and are similar in both rate and type to events observed following receipt of other vaccines that are routinely administered.133 Accordingly, it might be possible to conclude that the administration of AVA in adults is minimal risk because “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered ... during the performance of routine physical ... examinations or tests.”134
One article cited is by Sever et al, which actually showed that reports of Gulf War Syndrome-like symptoms were about 3 times more common after anthrax vaccine than expected by chance.  The article by Manette Niu had so many gross errors I told her it could be considered scientific misconduct, and she published an erratum to correct several of the errors... the Commission failed to cite the erratum.

The important anthrax vaccine safety data, such as that from the IOM, GAO and CDC trial, were ignored by the Commission, although these data carry the most weight.

Instead of discussing the vaccine label, the Commission cited the CDC Vaccine Information Statement, which is an unsigned piece of PR that diverges greatly from the carefully written vaccine label, which must be based on actual data.

Important Point 2:  The Bioethics report is completely contradictory about vaccine efficacy.  The truth is that efficacy is unknown.

First the report admits that vaccine efficacy is an issue:

the immune response it elicits is not as well characterized as its safety. While the mechanism of immunogenicity is understood and has been qualitatively observed, the quantitative relationship, or the precise level of antibody that confers protection against anthrax, is not known.135
But the report then implies the animal models (rabbits and rhesus monkeys) are reliable, when they are not.  And it wanders into the Twilight Zone with the following statement:
These studies have shown that AVA is most effective against anthrax when combined with antibiotics and given before the onset of clinical illness.
As Vera and I pointed out to the Commission, and confirmed by CDC's Advisory Committee on Immunization Practices, after the anthrax letters between 10 and 30 thousand people potentially exposed to anthrax spores took antibiotics.  Not a single one developed anthrax.  One hundred ninety-eight also took vaccine.  They failed to get anthrax.  Does vaccine improve the effect of antibiotics?  It is impossible to improve on 100% protection, though the Commission would like us to forget this  human efficacy experiment. If you give the vaccine with something that is highly (100%) protective, the vaccine will naturally appear to be "most effective" under those  circumstances.

The report's final unjustified statement on efficacy:  "Observational data in humans also provide evidence of efficacy in adults.139"  

Since the only observational studies of inhaled anthrax were of Fort Detrick workers (at least one of whom died from anthrax) and the people exposed to the anthrax letters, it is difficult to know what this could possibly refer to.  CDC researchers Marano and Lingappa said in 2001 that "medical studies to date have elicited some understanding of the anthrax vaccine, but there remain many unknowns. Among them is how many shots are really required to achieve protection against anthrax, and how long that protection lasts." That is a clear statement on the lack of efficacy data, and we are no farther along today.

Again, I must ask:  what were those Commissioners smoking?

Important Point 3:  Ignoring the NBSB conclusion on risk, the data on safety and the fact that it is unethical to perform an experiment on human subjects that can't yield the data you supposedly seek, the Commission set out to craft a "minimal risk" anthrax experiment in children.

Their implicit assumption was that the vaccine is perfectly safe in adults.  So all you have to do is show this in a small trial of 18 to 20 year olds, and if you find no major problem, start testing in younger and younger children.

Before moving from adult AVA trials to pediatric trials, data characterizing adverse reactions of AVA for persons 18 years of age are required. Researchers should begin with a thorough examination of adverse event data in the youngest adult AVA recipients before they can infer that an AVA trial with the oldest children (e.g., adolescents ages 16 and 17) poses a minimal level of risk. Additional dosing studies in the youngest group of adults must also be completed. Specifically, studies evaluating the adequacy of different dosing strategies in adults are required before pediatric studies may be conducted.142
Then the report repeats its trick of acknowledging an important truth, while confusing the meaning of the truth:
The U.S. Centers for Disease Control and Prevention (CDC) and the Institute of Medicine also have recommended additional investigation into long-term side effects, alternative dosing methods, and quantitative determination of correlates of immunity in animal models.143 
Obviously, the CDC and IOM recommended investigation of long term side effects because there were safety issues, and the safety of the vaccine has failed to be established in adults.  This should make the trial impossible to do in kids.  And the phrase about correlates of immunity acknowledges the lack of a reliable animal model, which should again prohibit such a trial in children.  But the report fails to acknowledge these crucial issues and their implications for a pediatric trial.

Important Point 4:  After saying in the early part of the report that no research involving more risk than "a minor increase over minimal risk" can be performed in children who receive no personal benefit, the Commission weasels out of this principled (and legal) stand.

The report states on page 60:  ...While the Bioethics Commission did not rule out the possibility that other sorts of extraordinary circumstances might warrant exposing children to slightly more than a minor increase over minimal risk in research from which they do not have any reasonable expecta- tions of benefit...

Important Point 5:  The Report acknowledges that countermeasures research can only be done in children if of vital importance to addressing a serious problem--but fails to acknowledge that the proposed trial will be too small for meaningful safety data to be derived, and without an animal model, the immunogenicity data cannot be used to assess efficacy or dosing.

On page 66 the report states:

In addition to being of vital importance to addressing a serious problem, the proposed MCM research must present a “reasonable opportunity” to further the understanding, prevention, or alleviation of that serious problem.154 Although various natural and manufactured threats can present a serious problem, the gravity of the problem alone is not enough to justify the research if the research itself does not present a reasonable opportunity to learn something significant to developing or deploying an MCM.
and on page 70:
Scientific validity is required for ethical human subjects research. In pediatric MCM research, each study should be well designed to answer a specific question of importance to the protection of children; studies should be adequately powered, rigorous in data collection, and feasible.161 The research plan should be peer-reviewed and approved as scientifically valid before moving forward with participant recruitment. 
The Report ignores the admission by its witness Major General John Parker, MD (retired), who said the reason for the trial was to reassure parents the vaccine had already been tested in children.  It fails to admit that the lack of an animal model precludes deriving meaningful dosing and efficacy data from a pediatric trial.

Important Point 6:  Were the contradictory and conflicting statements that pepper this report designed to allow its interpretation in a variety of ways?

Gentle readers, I know you won't be dazzled by brilliance, but be sure you are not baffled by the bullshit, couched in confusing language, to be found within this Bioethics Commission Report.

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