The SUPPORT Trial: Good intentions in medical research are not enough--especially when lives are at stake--you also need to avoid hurting patients and to use a design that will yield useful info

Medical research is necessary:  there are innumerable unanswered questions about how to best treat patients.  When lives are at stake, answering the questions is very important.  Modern medicine was built on the back of medical research, built on clinical research that must rely on the goodwill of human volunteers.

Volunteers participate as research subjects under the expectation that they will not be placed at greater risk of harm by volunteering than they would be otherwise.  Their willingness to volunteer comes from the expectation that the research is being conducted intelligently, and ethically, in order to move medical care forward, and not for other reasons.

Furthermore, federal regulations regarding human research require that volunteers be fully informed about the risks and benefits of the research in which they will participate.

When the research involves children, the regulations are even stricter, since children cannot give informed consent and are considered a vulnerable group.

Now to the SUPPORT trial.  Tiny, premature newborn babies were the subjects of experiments the were meant to answer questions about the ideal amount of oxygen to be given, the use of surfactant in premature lungs, and how oxygen should be administered.  Good questions.

But the trial design and the way the trial was conducted failed to meet current legal and ethical standards.  And therefore it has been investigated by the Office for Human Research Protection in the office of the HHS Secretary.  (OHRP moved out of NIH in 2000; I thought it was still under NIH when I first wrote this.) In response, the medical research and bioethics communities are beginning to link arms to defend the sanctity of this medical research, and scream loudly about those who dare to question the research and researchers.

This makes sense when you realize that Bioethics as an academic 'discipline' has become (mostly) a group of apologists for whoever is paying the bills:  the pharmaceutical industry, research universities, the federal government, etc.  And medical researchers understandably feel the need to prevent too much questioning and investigation of what they do.

In the case of the SUPPORT trial, the apologists have tried to shift the terms of the debate.  Normally, this is a very effective strategy.  But this is what you need to know, which the apologists are doing quite a dance to obscure, and will never discuss:

1.  Some or most mothers of preemies were asked to provide "informed consent" -- while they were in labor!  How can you possibly give thoughtful consideration to subjecting your about-to-be-born, very premature baby to medical research while you are in the midst of trying to deliver that baby?  Clearly there was no true informed consent under these circumstances.  Have the bioethicists, and researchers who came up with this plan, ever experienced labor?

Another major issue wrt informed consent was that the trial objectives and strategies were not accurately explained in the consent document.  Here is the consent form.

2.  The design of the trial was bizarre.  The "pulse oximeter" that is used to continuously record blood oxygen levels was redesigned to provide inaccurate values for blood oxygen levels in the babies.  The result was that treating physicians were given false values of oxygen saturation in the babies.  Clearly, this might and probably did interfere with babies receiving optimal, individualized adjustments of oxygen delivery.  Would you want doctors in an intensive care unit treating you to get altered, inaccurate test results?

3.  Since the treating doctors were given incorrect information, the trial results are based on abnormal circumstances and altered physician responses, which throws into question whether the results are of any value at improving clinical practice.

Why didn't the participating physicians, institutional review boards and medical centers notice these failings?  Because that is how things are, with no one really responsible for getting it right, despite the fact that it is humans who offer themselves and their children up to the research enterprise.

Thank Public Citizen and AHRP for calling attention to these serious lapses in medical research on critically ill, newborn humans.

Time to learn what is in the vaccines you receive

Two years ago a bill was brought to the Maine legislature asking for a list of ingredients to be provided to parents with each childhood vaccination.  I wrote in support of it then.

A similar bill was again presented in the legislature, and I have written again in its support.  I also enclosed a copy of the very popular CDC list of vaccine ingredients, annotated by me to identify the presence of animal or fetal-derived cells in vaccine production.  Here is the letter:

Meryl Nass, MD

Board Certified in Internal Medicine

5 Alexandra Rd.

Southwest Harbor, Maine 04679

207 522-5229 C   207 244-9165 W

May 4, 2013

Dear Maine HHS Committee Member:

I wanted to comment on LD 754, a bill that would require that a list of vaccine ingredients be provided to parents when their children are vaccinated.  I practice medicine in Maine and am an expert on anthrax vaccine. An abbreviated CV is attached.

It is important that both recipients and medical providers be well-educated regarding vaccines, in order to make wise vaccine recommendations.  I was a licensed physician for 17 years before I learned anything about the composition, testing and licensing of vaccines.  I had, at most, a one hour lecture on vaccines in medical school.  I wonder how many other doctors are equally ill-informed?

1.  Medical providers are required by federal law to give parents or recipients a Vaccine Information Statement (VIS), a 2 page informational sheet prepared by CDC, with each of the following vaccines administered:

Ø     DTaP (includes DT)

Ø     Td/Tdap

Ø     Hib

Ø     hepatitis A

Ø     hepatitis B

Ø     HPV

Ø     influenza (inactivated and live vaccines)

Ø     MMR and MMRV

Ø     meningococcal

Ø     pneumococcal conjugate

Ø     polio

Ø     rotavirus

Ø     varicella 

The VIS mentions some, but not all, risks related to vaccines.  For example, the VIS for Hepatitis B vaccine mentions a potential allergy problem due to the presence of yeast in the vaccine, but does not mention that soy is also present, and it too is a common allergen.

Some vaccines contain eggs, which occasionally cause serious allergic reactions.  Some vaccines contain gelatin (prohibited for kosher Jews); others are made in [aborted] fetal cells or their derivatives, and some people may choose to avoid a vaccine for that reason.

Listing vaccine ingredients may not be necessary all the time.  But remember that FDA considers it important enough to require food manufacturers to list all ingredients on their packaging.  This enables consumers to choose which ingredients to avoid, whether due to allergy, a religious dictate or for any other reason.

2.  Hundreds of vaccines are in development, and they contain an array of new ingredients to stimulate increased immunity.  These ingredients do not have to be tested for their "stand-alone" toxicity:  their only required testing occurs during a clinical trial of the complete vaccine.  Most human vaccine studies

last only one month.  If no serious side effects are identified within that period, the candidate vaccine may be licensed.

However, this testing is insufficient to identify whether the vaccine or its components may cause or promote cancers.  (Many vaccines have never been tested for carcinogenicity, for example, although many contain formaldehyde, a known carcinogen.)  

Vaccine testing can miss birth defects that might be related to vaccination.  This is because pregnant women are not included in vaccine trials.  The HPV vaccine Gardasil was approved after a six-month, "fast-track" review by FDA.  Merck, the manufacturer, was asked by FDA to collect information on possible birth defects after approval.  The VIS for Gardasil vaccine says,

"Any woman who learns she was pregnant when she got this HPV vaccine is encouraged to contact the manufacturer’s HPV-in-pregnancy registry at 800-986-8999. This will help us learn more about how pregnant women respond to the vaccine."

3.  In 2009-10, swine flu vaccines were made with and without novel adjuvants (new additives used to enhance the immune response), using abbreviated testing.  Novel adjuvants had not been used in previously licensed US vaccines.

Here is an important example of how an ingredient list would be beneficial to vaccine recipients:

The 2009 Pandemrix swine flu vaccine caused narcolepsy (at a rate 12 times greater than expected) in hundreds of children and young adults, and some other swine flu vaccines caused seizures.  Their use in children was stopped in some countries (Finland, Ireland and Australia).

Pandemrix used a novel adjuvant (named ASO3) to increase the vaccine's effectiveness.  ASO3 had not been used in children before, nor had it ever been used in the US.  It probably contributed to narcolepsy. A vaccine containing ASO3 is under consideration now by FDA for avian flu. I think it is very important that parents be informed when a vaccine that will be given to their child contains ASO3.

 

4.  Consider the difference between ingesting food and injecting vaccines.  Food has to pass through the gastrointestinal tract, which acts as a barrier against noxious substances entering the body, protecting us from harm.

Injections bypass all skin and mucosal barriers, overriding important protective mechanisms.  Substances injected into us therefore need even more careful vetting than is given to foods. Vaccines should be at least as safe as foods, and their components should be equally transparent.

5. Providing a list of ingredients at the time of inoculation will not add a large burden to medical providers or manufacturers.  The Vaccine Information Statement is already given out with most inoculations. An ingredient list is part of the vaccine package insert, which is included with each bottle of vaccine sold. This package insert or the list of vaccine ingredients it contains could easily be included along with the Vaccine Information Statement, when vaccinations are administered. 

Thank you for the opportunity to comment on this piece of legislation.

Sincerely,

Meryl Nass, M.D.

Medical Research: An Ethical Breakdown / NYT Editorial

From today's NY Times on yet another medical research project (performed at 23 top academic medical centers) that was done sloppily, missing a standard-care arm, and failed to provide truly informed consent... performed on unconsenting very low birthweight newborns, who were at extremely high risk of a bad outcome, but who might also lead a normal life:

Despite reforms to protect patients from being harmed by medical research in recent decades, 23 academic institutions authorized a research project that failed to meet the most basic standard: providing an informed consent document to parents that accurately described the risks and benefits of the research to be conducted on extremely premature babies. 

This failure was startling, and deplorable. Federal officials have rightly demanded that the University of Alabama at Birmingham, the lead institution, and Stanford, Duke and Yale, among others, take corrective action to prevent a recurrence. Such actions, which must be approved by federal officials, could include requiring investigators to undergo additional training in the ethical conduct of research, enhancing oversight by institutional boards that monitor research and notifying parents of the ethical breach. 

The study involved more than 1,300 premature babies, born between 24 weeks and 27 weeks of gestation. The underdeveloped lungs in such babies are often unable to extract enough oxygen from the air to nourish the brain, so doctors often supply extra oxygen. 

The danger is that too much oxygen can cause severe eye damage and blindness, whereas too little can lead to brain damage and death. The current standard of care calls for the blood to be saturated with 85 percent to 95 percent oxygen, but the researchers sought to pinpoint a more exact range that would minimize eye damage without increasing the risk of death. 

The study, financed by the National Institutes of Health, was conducted between 2004 and 2009 and published in 2010. The researchers randomly divided the 1,300 babies into two groups; one got oxygen at the low end of the range, while the other got oxygen at the high end of the range. The parents were asked to sign consent forms that had been approved at all 23 medical centers by the institutional review boards that are supposed to ensure ethical conduct of federally supported research. 

But, in this case, the federal Office for Human Research Protections concluded that the consent forms failed to reveal that there was a greater risk of dying in the low-oxygen group and a greater risk of severe eye damage in the high oxygen group. The form also stated that, because both groups would receive oxygen within the standard of care, there would be no predictable increase in risk no matter which group a baby was in. 

But the federal agency found that many infants could have faced greater risks by participating. For example, if a baby whose clinical needs might ordinarily have led doctors to deliver a relatively high level of oxygen was enrolled in the study, the infant might be randomly assigned to receive lower levels of oxygen. The Department of Health and Human Services needs to investigate how this breakdown occurred. And if the institutions do not offer strong reforms, the agency can suspend their ability to conduct federally financed research on human subjects.

Rights Groups, in Letter to Obama, Question Legality and Secrecy of Drone Killings/ NYT

Finally, human rights advocates are asking the US government on what legal basis it can choose to assassinate people, and by the way, what is the process for choosing who gets offed and another thing, what's up with the drones?!  The usual administration response is just too precious: “Our approach is marked by scrupulous adherence to the rule of law.”

Scott Shane of the NYT reports on a letter sent by NGOs and some at the NYU and Columbia law schools:

In a letter sent to President Obama this week, the nation’s leading human rights organizations questioned the legal basis for targeted killing and called for an end to the secrecy surrounding the use of drones.The “statement of shared concern” said the administration should “publicly disclose key targeted killing standards and criteria; ensure that U.S. lethal force operations abroad comply with international law; enable meaningful Congressional oversight and judicial review; and ensure effective investigations, tracking and response to civilian harm.”The nine-page letter, signed by the American Civil Liberties Union, Amnesty International, the Center for Constitutional Rights, Human Rights First, Human Rights Watch, the Open Society Foundations and several other groups, is the most significant critique to date by advocacy groups of what has become the centerpiece of the United States’ counterterrorism efforts.While not directly calling the strikes illegal under international law, the letter lists what it calls troubling reports of the criteria used by the Central Intelligence Agency and the Pentagon’s Joint Special Operations Command to select targets and assess results. The reported policies raise “serious questions about whether the U.S. is operating in accordance with international law,” the letter says. It is also signed by the Center for Civilians in Conflict and units of the New York University and Columbia Law Schools.The letter comes as American strikes in Pakistan, Yemen and Somalia, and the example the United States has set for the world, are drawing intense scrutiny. United Nations human rights investigators are reviewing the American record, and Congress has shown a new willingness to discuss the classified program in public, with a House subcommittee hearing on the constitutional and counterterrorism implications of targeted killing set for April 23. That hearing was postponed for a week in an effort to persuade the administration to send an official to testify, a committee aide said.Caitlin Hayden, a spokeswoman for the National Security Council, said the administration was “committed to institutionalizing and explaining to the Congress and the public as much as possible about our drone policies, including the process for making strike decisions.” She added: “Our approach is marked by scrupulous adherence to the rule of law.”By the count of the New America Foundation, a research group that tries to track targeted killing, the United States has carried out 422 strikes in Pakistan and Yemen, 373 of them since Mr. Obama took office in 2009, in addition to a handful in Somalia. The foundation estimates the number of deaths resulting from the strikes to be between 2,426 and 3,969, of which about 10 percent were of civilians and nearly as many of which were identified as “unknown.” An overwhelming majority of the strikes have been carried out by unmanned drone aircraft, though cruise missiles, fighter jets and helicopter gunships have also been used.Agreeing to the degree of openness sought by the human rights groups would mean a sea change for the Obama administration. Though officials have given a series of careful speeches on the administration’s legal reasoning, the Justice Department’s classified legal opinions on the subject have been shared only recently, even with the Senate and House Intelligence Committees, and the government has asserted in battling Freedom of Information Act lawsuits that the Pakistan strikes are too politically delicate even to be officially acknowledged.Gabor Rona, the international legal director of Human Rights First, said that the letter to Mr. Obama reflected increasing concern that government secrecy has hidden grave legal and practical problems with the strikes.“The more the administration is rightly forced to disclose about who it is killing and why,” he said, “the more obvious it becomes that the practice is growing, is illegal in its scope, is causing large-scale civilian casualties and is a slow-moving train wreck with serious blowback consequences to U.S. national security.”In pushing for greater candor, both the human rights groups and Congress are responding to Mr. Obama’s own stated goal. In his State of the Union address in January, the president said: “In our democracy, no one should just take my word that we’re doing things the right way. So, in the months ahead, I will continue to engage with Congress to ensure not only that our targeting, detention and prosecution of terrorists remains consistent with our laws and system of checks and balances, but that our efforts are even more transparent to the American people and to the world.”No action has followed so far. In announcing his plans for a Judiciary Committee hearing, Senator Richard J. Durbin, the Senate’s second-ranking Democrat, noted that Mr. Obama “has made it clear he wants to work with Congress to establish ‘a legal architecture’ for drone strikes to prevent abuses.” Mr. Durbin said the hearing would “begin this important constitutional debate.”The Obama administration has been asked to provide a witness to discuss its position on the drone strikes, but the administration has so far not agreed to provide one, according to the committee’s staff. Similarly, efforts on Thursday by Representative Jan Schakowsky, Democrat of Illinois, to get John O. Brennan, formerly the president’s counterterrorism adviser and now the C.I.A. director, to discuss strike policies during a hearing of the House Intelligence Committee went nowhere.“I would say right now that I am at the helm of the C.I.A. and will carry out policy guidance as directed by the administration,” Mr. Brennan said.Ms. Schakowsky was prompted to question Mr. Brennan in part by an article this week by McClatchy News Service reporting that it had obtained classified government documents showing that the drone strikes had killed hundreds of low-level suspected militants whose identities were not known. The article suggested that the documents undercut assertions by Mr. Obama and his aides.“There are a lot of things that are printed in the press that are inaccurate, in my mind, and misrepresent the facts,” Mr. Brennan said. When Ms. Schakowsky pressed the point, he said, “I’m not going to engage in any type of discussion on that here today, congresswoman."

Association between Guillain-Barré syndrome and influenza A (H1N1) 2009 monovalent inactivated vaccines in the USA: a meta-analysis/ Lancet

A US government-Harvard-Hopkins study confirmed what was obvious from many prior, similar studies:  flu shots cause occasional cases of paralytic Guillain Barre Syndrome, with or without adjuvants.  In this case, about 1.6 additional GBS cases per million vaccinations, or approximately double the baseline risk in the six weeks following the vaccination.  From the Lancet:

Dr Daniel A Salmon PhD a c , Michael Proschan PhD d, Richard Forshee PhD e, Paul Gargiullo PhD f, William Bleser MSPH a,Dale R Burwen MD e, Francesca Cunningham PharmD g, Patrick Garman PhD h, Sharon K Greene PhD i, Grace M Lee MD i, Claudia Vellozzi MD f, W Katherine Yih PhD i, Bruce Gellin MD a, Nicole Lurie MD b, the H1N1 GBS Meta-Analysis Working Group†

The influenza A (H1N1) 2009 monovalent vaccination programme was the largest mass vaccination initiative in recent US history. Commensurate with the size and scope of the vaccination programme, a project to monitor vaccine adverse events was undertaken, the most comprehensive safety surveillance agenda in the USA to date. The adverse event monitoring project identified an increased risk of Guillain-Barré syndrome after vaccination; however, some individual variability in results was noted. Guillain-Barré syndrome is a rare but serious health disorder in which a person's own immune system damages their nerve cells, causing muscle weakness, sometimes paralysis, and infrequently death. We did a meta-analysis of data from the adverse event monitoring project to ascertain whether influenza A (H1N1) 2009 monovalent inactivated vaccines used in the USA increased the risk of Guillain-Barré syndrome.MethodsData were obtained from six adverse event monitoring systems. About 23 million vaccinated people were included in the analysis. The primary analysis entailed calculation of incidence rate ratios and attributable risks of excess cases of Guillain-Barré syndrome per million vaccinations. We used a self-controlled risk-interval design.FindingsInfluenza A (H1N1) 2009 monovalent inactivated vaccines were associated with a small increased risk of Guillain-Barré syndrome (incidence rate ratio 2·35, 95% CI 1·42—4·01, p=0·0003). This finding translated to about 1·6 excess cases of Guillain-Barré syndrome per million people vaccinated.InterpretationThe modest risk of Guillain-Barré syndrome attributed to vaccination is consistent with previous estimates of the disorder after seasonal influenza vaccination. A risk of this small magnitude would be difficult to capture during routine seasonal influenza vaccine programmes, which have extensive, but comparatively less, safety monitoring. In view of the morbidity and mortality caused by 2009 H1N1 influenza and the effectiveness of the vaccine, clinicians, policy makers, and those eligible for vaccination should be assured that the benefits of inactivated pandemic vaccines greatly outweigh the risks.FundingUS Federal Government.

Boiling down the Presidential Commission Recommendations on Testing Anthrax Vaccine in Children

Here’s the verbatim recommendation (from the Commission press release) about testing anthrax vaccine in kids:

"Recommends that multiple steps must be taken before ethical pediatric anthrax vaccine trials can be considered by the U.S. government…

In keeping with its recommendation of a strict risk limit in pre-event pediatric MCM research, the Bioethics Commission called for completing all prior ethically sound testing – for example, modeling, testing in animals, and testing in the youngest adults – to assess the level of risk likely posed by pre-event pediatric MCM research. If the risk level for the oldest group of children is determined to be minimal, then progressive testing with younger and younger children should be employed, beginning with the oldest children in order to provide additional protection to younger children. This approach—called age de-escalation—would help to ensure that data from an older age group inform the research design and risk level for the next younger age group. For example, an intervention shown to be minimal risk in the youngest adults – adults 18 years of age –may make it possible to infer that a study with the oldest children of 16 and 17 years of age would present only minimal risk."

Sounds good. But let’s carefully examine the “multiple steps” and the process laid out by the Commission.  Here's the meat:

1. Complete all prior ethically sound testing: for example, modeling, testing in animals, and testing in the youngest adults, to assess the level of risk.
2. If the risk level, based on this testing, is determined to be minimal, start testing in children in a stepwise manner, starting with the oldest children and going stepwise down the ages in younger and younger groups, while assessing safety for each group before enrolling the next younger group.

This method assumes that the risk of the test may be greater for younger children, and you therefore establish a new risk level with each group you test, thereby reducing risk for the youngest children.

The method further assumes that the risk currently is unknown, and needs to be established by modeling, animal tests and testing in young adults.

But each of these assumptions is simply wrong:

• Risk has already been established in thousands of young adults, as made clear in the label and extensive vaccine literature, and this is a dangerous vaccine
• Risk might be highest in the older children, for whom pregnancy (FDA Risk Category D--evidence of fetal harm, according to the vaccine label) is a big risk, indicating the theory that age de-escalation will reduce risk  to child subjects does not stand up
• Modeling, not further defined or explained by the Commission, is not a standard or approved method for assessing risk in humans from vaccine research
• Animal testing is of little value, and only used for pre-clinical research.  Given the extensive human testing already completed, it adds nothing.

Don't you think that FDA might have an established way to assess risk in vaccine research?  Isn't it presumptuous for a Commission of bioethics people to claim their theory for evaluating drug safety in children should take precedence over FDA's standards?  

The Presidential Commission for the Study of Bioethical Issues was desperate to give its parent agency what it wanted:  a green light to test a dangerous anthrax vaccine in children, and a second green light to test other "countermeasures" in children, to circumvent existing FDA standards.  How do I know?

Because earlier this month the Pandemic and All Hazards Preparedness Reauthorization Act was passed by Congress and signed into law.  The bill transfers authority for certain aspects of the evaluation of medical countermeasures from FDA to the office of the Assistant Secretary for Preparedness, Nicole Lurie MD, who also had the bright idea to test anthrax vaccine in children.  Like the Commission members, she has no expertise in drug evaluation, but that didn't stop her attempt to weaken existing federal standards for their use.

Now you understand what this whole charade was really about: lowering the safety standards for using medical countermeasures in humans, including children.

FYI, here is how the FDA evaluates drug safety, according to Congressional testimony by the then-head of the FDA’s Center for Biologics in 2007: 

“From a regulatory perspective, there are four major stages in vaccine development.  These stages include:

The preclinical stage which consists of the development and testing of the product prior to the product being tested in humans.  Early in the product development process, sponsors test candidate vaccines in-vitro (e.g., in laboratory assays, studies in cell lines, etc) and in animals.  These early nonclinical studies give an indication of whether studies would be reasonably safe to proceed in humans and may also provide information regarding the potential effectiveness of the product.

• The Investigational New Drug (IND) stage consisting of multiple phases where the investigational product is studied in human subjects under well-defined conditions and with careful monitoring. In certain cases where studies to demonstrate efficacy in humans are not ethical or feasible, sponsors may conduct studies to demonstrate efficacy of the product in appropriate animal models.

• The license application stage is when manufacturers submit data and information regarding the results of the clinical and nonclinical studies, as well as complete information regarding the product and its manufacturing process to FDA for a complete review of product manufacturing, safety and effectiveness in support of licensure.

• Finally, for products that are approved, FDA continues its oversight during the post licensure stage to include review of post-marketing safety information from adverse event reports, periodic reports, post-marketing studies, review of lot release information and testing, and inspections of manufacturing facilities.

• FDA often provides guidance to sponsors, even prior to submission of an IND, in regard to both the types of preclinical studies needed and the design of the clinical trials needed to assess the intended use(s) of the product.  FDA’s guidance is intended both to help protect human subjects and to assure that the studies performed are designed in such a manner that the study results are likely to provide sufficient information to allow a determination of the product’s safety and efficacy…

• FDA strives to develop processes that facilitate product development to meet emerging public health needs, such as protection from terrorist agents and prevention of pandemic influenza and other emerging threats.  The regulation known as the “Animal Rule” provides a mechanism for FDA to approve medical treatments based on effectiveness data from animal studies when human efficacy studies are unethical and/or not feasible. Under the “Animal Rule,” effectiveness would be evaluated in adequate and well-controlled animal studies that establish that the product is reasonably likely to produce clinical benefit in humans. Such approvals also require the demonstration of safety in humans.   These safety studies may be conducted concurrently with the animal studies. 

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.

Schizophrenic Report on Testing Anthrax Vaccine and other Medical Countermeasures in Children is Issued: Where it is good it is very, very good, but where it is bad, it is horrid!

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.