Tuesday, January 8, 2013

MISUNDERESTIMATED: Anthrax Vaccine's New Label Misses Most Adverse Events

The May 2012 updated anthrax vaccine package insert (a.k.a. label) provides cause for concern.  Would you give this vaccine to your dog, let alone your child?  Next week the Presidential Commission for the Study of Bioethical Issues will have their final meeting to discuss giving anthrax vaccine to children.  Whose children would be sacrificed?

1.  An arithmetic error reduced the rate of serious adverse events (SAEs) by a factor of ten.  
"The percent of serious adverse events was similar between the BioThrax combined groups (193/1303 or 1.5%) and the placebo group (38/260 or 1.5%)."  page 6
These fractions correspond to 14.8% in the study group and 14.6% in the placebo group, not 1.5%.  However, these numbers may not be correct.  The 2008 JAMA paper on the same trial indicated that about 40 subjects had multiple SAEs.  Whether the numerators correspond to the total number of SAEs or the number of people with SAEs is uncertain.  Of more importance is a breakdown of what symptom(s) each SAE represented clinically, its duration and whether it resolved.  This is missing from both the text and tables.  

According to CDC's P.I. for this trial, Jennifer Wright (slides 26-27) and FDA, a Serious Adverse Event is defined as "one that results in death, is life-threatening, leads to or prolongs hospitalization, results in persistent/ significant disability or congenital abnormality."  229 events fell into this category during the trial.  What were they?

Dr. Wright also notes that the trial analyses were completed in mid 2009 and a final report sent to FDA then.  The trial results have not been made public.

2.  Table 2 (pages 7 and 8 of the label) is a breakdown of local and systemic adverse events in trial participants.  However, half the subjects in the CDC trial are not included.  The number of subjects in Table 2 totals only 775, while there were 1563 trial subjects.  The adverse events for 788 anthrax-vaccinated subjects are missing.  The number of "moderate/severe systemic adverse reactions" in Table 2 totals 65. There were 127 "moderate/severe local adverse reactions".  Yet the 2008 JAMA paper reported 229 serious adverse events for which VAERS were filed.

3.  The vaccine is dangerous in pregnancy.  (Pregnancy Category D*)
"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."  page 3 of the package insert
Yet during the CDC clinical trial, 
"Of women who received vaccine within 90 days of the estimated date of conception (n = 14), 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. "  page 6
Fifty-one pregnancies occurred during the trial (or 48 according to CDC's PI powerpoint presentation).  Why weren't women evaluated for pregnancy before receiving each vaccine dose, given the vaccine's known teratogenicity, and the trial protocol, which required subjects to use a birth control method and be non-pregnant?  Exclusion criteria for the trial included: 
"Pregnancy or plans to become pregnant for the duration of the study and/or not agreeing to exercise adequate birth control from the time of the screening procedures to one month after the last vaccination."  
The package insert tells practitioners, "Advise women of the potential risk to the fetus."  page 15                       
4.  The abbreviated CDC Gulf War Syndrome definition remains a reported adverse event in the package insert:
"Infrequent reports were also received of multisystem disorders defined as chronic symptoms involving at least two of the following three categories: fatigue, mood-cognition, and musculoskeletal system." page 9
5.  The vaccine hurts more than other vaccines.  
"Up to 11% of subjects rated the brief pain or burning they experienced immediately after vaccine injection as 8 out of 10 or greater." page 5
6.  Women have significantly more local and systemic adverse events than men.  No numbers are given.  page 5

7.  The "Information for Patients" states on page 16:
What are the possible or reasonably likely side effects of BioThrax? 

  • Pain, tenderness, redness, bruising, or problems moving the arm in which you got the shot   
  • Muscle aches  
  • Headaches  
  • Fatigue  
  • Fainting

"There is positive evidence of human fetal risk based on adversereaction data from investigational or marketing experience or studiesin humans, but potential benefits may warrant use of the drug inpregnant women despite potential risks"

In terms of giving this vaccine to children and teens, potential harms that can reasonably be anticipated include syncope and risk to the fetus if a young recipient becomes pregnant.  Fifteen percent of subjects might experience a severe adverse event "that results in death, is life-threatening, leads to or prolongs hospitalization, results in persistent/significant disability or congenital abnormality."

Can such anticipated adverse events be justified in a pediatric trial for a condition that does not exist in children at this time, and probably never will?

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