The Presidential Bioethics Commission Report on testing anthrax vaccine and other countermeasures on children was issued today, March 19, 2013. It was accompanied by a press release , an article in the NEJM , and a conference call with the press yesterday. The result is many news articles, but there is confusion about what the report actually recommended. Reporters disagreed about whether testing anthrax vaccine in children would now proceed.
The USA Today headline said, "Panel urges limited tests of anthrax vaccine in kids" and Reuters said "Test of anthrax vaccine in children gets tentative okay." BBC agreed that the report opened the door to testing.
But the AP headline said "Panel: Thumbs down on anthrax vaccine test in kids"and the Washington Post wrote "Ethics panel sets high bar for anthrax vaccine research in children."
I suspect the confusion was deliberate. DHHS and the Bioethics Commission appear to have wanted a few things emphasized, around which they created some buzz, and hoped the rest would be missed and forgotten. Au contraire, let's get down in the weeds and study the report in more depth than the media mentioned above were able to do.
Here it goes: the good, bad, and the ugly. First, the good.
The Commission paid close attention (finally) to the existing ethical and legal standards for performing pediatric research under US law. [Vera Sharav and I emphasized them in our Feb 18 letter to Amy Gutmann , Commission Chair. This is, after all, the law of the land.] The Commission correctly concluded that children cannot be subjected to research that entails more than minimal risk (defined by DHHS as the level of risk experienced in everyday life) without jumping through major hoops.
For research that is just a wee bit riskier (defined by the Commission as equal to getting a chest Xray or skin biopsy), and written in law as "a minor increase over minimal risk," the research would have to follow the requirements of 45 CFR 46.407 , which includes a public review by FDA and a federal IRB, and it is tough to gain their approval for research that puts healthy, nonconsenting children at even a low risk of injury.
The Commission made explicit that research that was any riskier than this would not be permitted, period, unless a child had a preexisting medical condition to which the research was directed... and none have preexisting anthrax. This was a very strong, clear statement about what is legally approvable pediatric research, and what is not. But the Commission did not develop this standard: they only noted that this is the existing legal standard, and it cannot be breached. All good so far.
Now, the bad.
After demonstrating a detailed understanding of the 1977 National Commission report * and the laws it generated to protect human subjects of research, the Bioethics Commission Report followed with a series of mistakes and omissions.
For example, federal law requires that for research involving human subjects, the research must be done to obtain legitimate scientific knowledge. Although Vera and I told the Commission this, they ignored it, saving face for DHHS, the manufacturer, the National Biodefense Science Board (NBSB), which had already approved the research, and themselves.
Our detailed February 18, 2013 letter to the Bioethics Commission Chair pointed out that the proposed pediatric research was actually a bad joke: it was intended for public relations purposes, not for answering scientific questions, as acknowledged during questioning by General John Parker , the chair of the National Biodefense Science Board . That is not a legally acceptable reason to do research on people. This alone should prohibit any anthrax research in humans (allegedly for efficacy and dosing) from taking place. Funny, the Bioethics Commission failed to notice this red flag, though Vera and I waved it in their face.
The inconvenient truth is that there is no acceptable animal model for anthrax, which means that none of the animal experiments done to study anthrax vaccine can be scientifically extrapolated to humans. Thus scientists still do not know how effective the anthrax vaccine is in humans (in both adults and children), nor do they know how to determine an optimal vaccine dose and schedule of inoculations. Even the anthrax vaccine manufacturer acknowledged the need for a usable animal model , as recently as January 2013. Without an animal model, the only way to test the vaccine's effectiveness is to vaccinate humans, then expose them to anthrax: which thankfully has not been proposed.
When the vaccine was licensed in 1970, the Michigan Department of Public Health, which manufactured the vaccine before 1998, was asked by the federal government to provide human efficacy data for the vaccine- -but they never did. No one else has, either. So the vaccine's effectiveness in humans has never been established for inhalation anthrax. The human vaccine protects well in some animal species, and very poorly in others. Its effectiveness in monkeys is not very good.
Did you know the FDA has not approved the vaccine for post-exposure use? It is for this very reason: there is no evidence it will work. According to the vaccine label , "The safety and efficacy of BioThrax in a post-exposure setting have not been established. "
Despite citing some anthrax literature, the Bioethics Commission fails to acknowledge this critical fact, which I and the AHRP informed them of on 4 separate occasions, starting 13 months ago , even sending full text articles and over a dozen citations in order to make this critical problem clear to the Commission members and staff. If you can't test effectiveness, you also can't test dosing. So why do this trial on children, as you can't obtain the information that is said to be the reason for the trial?
This takes us from the merely bad to the ugly. In order to give DHHS a method to test the vaccine on kids, the Commission studiously ignored all literature demonstrating that the vaccine is unsafe. The Commission suggested instead that by testing in a small group of 18 to 20 year olds, the research can be turned into "minimal risk" research.
How do you turn an extremely dangerous experiment into one that involves no more risk than daily life? You cherry pick the data you cite, and you ignore obvious problems, like the fact the federal advisory committee (the NBSB) that called for your Commission to review the research was BECAUSE THEY SAID IT INVOLVED MORE THAN A MINOR INCREASE OVER MINIMAL RISK.
How do I know the vaccine is unsafe? For starters, according to FDA it causes birth defects. Per the label , "BioThrax can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus." [This implies the mother may want to consider an abortion.]
During the 2002-7 CDC trial of anthrax vaccine, there were 51 pregnancies in about 780 female subjects aged 18 to 61, even though the trial protocol warned women of the pregnancy risk and only enrolled women who promised to use birth control and not get pregnant. Most of the safety data from this trial have never been published or released. And the Commission never asked for the safety data, though the trial was considered the most carefully done study of anthrax vaccine ever performed.
Of 14 women in the CDC trial who received anthrax vaccine within 3 months of conception, " 2 spontaneous abortions and a first trimester intra-utero fetal death were reported, along with one report of a healthy term infant with mild right clubbed foot abnormality. "
If you enroll teenage girls in an anthrax vaccine trial, or 18-20 year old girls, you will invariably have girls becoming pregnant and you will almost certainly see miscarriages and birth defects. How did the Commission miss this? How did they consider this no more risky than everyday life?
Vera Sharav and I informed the Bioethics Commission about the safety issues , but our information fell on deaf ears. I explained that the current vaccine label underestimated the number of serious adverse events in the CDC trial by a factor of ten, due to an arithmetic error. Instead of 1.5% of subjects with serious adverse events, the true number was 12-15%. We told the Commission the GAO in 2007 said that experts from CDC and the Vaccine Healthcare Centers acknowledged that 1-2% of vaccine recipients developed illnesses that could result in permanent disability or death.
After the anthrax attacks, CNN reported that Bill Frist, M.D., bioterrorism expert and Senate Majority Leader pointed out :
"The vaccine is a dated vaccine, it's an old vaccine. There are very real and potentially serious side effects from the vaccine and anyone who elects to receive the vaccine needs to be made aware of that. I do not recommend widespread inoculation for people with the vaccine in the Hart Building. There are too many side effects and if there is limited chance of exposure the side effects would far outweigh any potential advantage."The Institute of Medicine in 2002 revealed that data from the military showed that rates of many illnesses increased after anthrax vaccinations. See the five Tables from Appendix G in the IOM report , on pages 246-252. The data were generated by about 500,000 soldiers who received anthrax vaccine between 1998 and 2000.
Reviewing the IOM report data (from the military's Defense Medical Surveillance System) reveals that after receiving anthrax vaccine, women were 5.14 times as likely to be hospitalized for carcinoma in situ of the breast and/or genitourinary system, compared to the rate before they began the vaccinations. Soldiers were 3.46 times as likely to be hospitalized with diabetes, and about 3 times as likely to be hospitalized for thyroid cancer. Hospitalizations for psychoses were 1.5-3 times as common. To my knowledge, these worrisome numbers have not been updated with the additional 2.5 million soldiers vaccinated since 2000, and vaccine causality has never been proven nor disproven. Have a look at the Tables. There are also more fractures because the vaccinations are given to soldiers on deployment, who are more prone to injury than if they remained stateside.
To recapitulate: the Commission report properly says kids can't be subjected to research that involves more risk than a chest Xray or skin biopsy would entail. But it would potentially be okay to test anthrax vaccine on them, which can kill or maim adults, nonetheless. What were those Commissioners smoking?
The only way the Commission could perform this sleight of hand (claiming that a very dangerous vaccine was actually a safe vaccine) was by failing to have a single anthrax vaccine expert testify before them, and by selective use of the literature. Not only did every Commission member have an MD, PhD or both (except one with an MBA), seven Commission staffers had PhDs and seven were lawyers. I don't think we can give this highly educated Commission a pass for missing the critical safety and efficacy issues that were put right in front of their eyes.
Tomorrow, I will discuss additional problems with the Commission Report.
* The National Commission for the Protection of Human Subjects of Biomedical and Behavioral
Research was established in 1974 under Public Law 93-348. The Commission’s reports and
recommendations laid the ethical and legal foundation for human subject research in the US. The
Commission’s Report and Recommendations: Research Involving Children, 35 (1977) provides the
most authoritative ethical framework for evaluating the permissibility of research involving children.