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Former FDA Reviewer Reveals Shocking Intimidation and Retaliation Within Agency



Rosenberg: Are there other risks with one-size-fits-all doses?


Kavanagh: There are racial differences in drug metabolism that are not taken into consideration. For example, one anticancer drug breaks down faster in African Americans so patients don't get sufficient exposure to the drug to kill tumors. Yet African Americans were not included in the safety and efficacy studies. When drugs break down faster by one particular pathway, the patients will also sustain greater toxicity and even death from the toxic metabolite that is formed. This is especially true when the company subsequently recommends higher doses to overcome the lower exposure due to faster metabolism. In one case, this occurred with a drug used in pregnant women, where hormonal changes during pregnancy cause a greater breakdown to a metabolite that is suspected to cause mental retardation and other birth defects in children exposed during the pregnancy. Not only did the drug receive a supplemental approval for use in pregnant women, the company later changed the labeling to recommend a higher dose during pregnancy. All the while it appears that the company was aware of the increased formation of a potentially tetratogenic metabolite before the drug was ever submitted to the FDA.


Rosenberg: Are the risks just ignored?


Kavanagh: FDA's response to most expected risks is to deny them and wait until there is irrefutable evidence postmarketing, and then simply add a watered down warning in the labeling. In fact, when patients exhibit drug toxicity it is usually attributed to an underlying condition which we know is likely to make the drug toxicity worse. This also allows the toxicity to be dismissed as being unrelated to the drug in any way. Consequently, toxicities are only attributed to the drug when the evidence is irrefutable. Thus the majority of cases where there is a contributing factor are simply dismissed. When you do raise potential safety issues the refrain that I heard repeatedly from upper management was‚"where are the dead bodies in the street?" Which I took to mean that we only do something if the press is making an issue of it.


Rosenberg: You have also spoken about the dangers of certain ADHD drugs and presented some damning data about Cephalon's stimulant Provigil.


Kavanagh: In 2006, a medical reviewer found several cases of what he thought might be Stevens Johnson Syndrome (SJS) in children who took Provigil or modafinil. SJS and the related conditions erythema multiforme and toxic epidermal necrolysis (TEN) are life-threatening skin conditions where huge swathes of skin covering large sections of the body die and slough off and the mucus membranes are also affected. The diseases are incredibly painful and kill 10 and 40 percent respectively of the people who develop them. The reviewer believed he was going to be overruled and asked me for help. We were able to get an advisory committee meeting in which I was allowed to present slides of the data that supported a diagnosis of SJS in a child in the study. I also showed that a metabolite of modafinil was 16 times higher in children than in adults and similar to the worst drug that exists for causing SJS, belphamide. The drug company doctors were unprepared for my presentation and claimed they had no information on the child, including no photos and that they had lost contact.


Rosenberg: One of the pharma doctors actually tried to downplay SJS with modafinil, saying a child was hospitalized but was not in the "burn unit," according to the transcript.

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