[Ip-health] Forget Vioxx! Its worse than that... Former FDA Reviewer Speaks Out About Intimidation, Retaliation and Marginalizing of Safety

Riaz K Tayob riaz.tayob at gmail.com
Mon Jul 30 00:39:47 PDT 2012


[So is Health Imperialism (abroad) possible with health tyranny @ home? 
WHO was hot off the button for "counterfeits"... will they act on this 
and other dangerous drugs or are they too well paid to bother?]


    Former FDA Reviewer Speaks Out About Intimidation, Retaliation and
    Marginalizing of Safety

Sunday, 29 July 2012 08:37 By Martha Rosenberg 
<http://truth-out.org/news/item/index.php?option=com_k2&view=itemlist&task=user&id=46519&Itemid=252>, 
Truthout <http://truth-out.org> |

Red pill in hand(Photo: ThomasThomas 
<http://www.flickr.com/photos/thomasthomas/268846488/>)The Food and Drug 
Administration (FDA) is often accused of serving industry at the expense 
of consumers. But even FDA defenders are shocked by reports 
<http://truth-out.org/news/item/10342-in-vast-effort-fda-spied-on-e-mails-of-its-own-scientists>this 
week of an institutionalized FDA spying program on its own scientists, 
lawmakers, reporters and academics that included an enemies list of 
"actors" and collaborators.

The paranoid and retaliatory email monitoring program, which sought to 
suppress the safety opinions of those hired to /give their safety 
opinions/, has provoked swift action from Capitol Hill. "I am writing to 
express my disappointment and disbelief with the way the Food and Drug 
Administration (FDA) has retaliated against whistleblowers who expressed 
concern to Members of Congress and the Office of Special Counsel (OSC) 
regarding safety concerns about medical products," wrote 
<http://freepdfhosting.com/4577fcb522.pdf> Sen. Charles E. Grassley 
(R-Iowa), ranking member on the Judiciary Committee, to FDA Commissioner 
Margaret A. Hamburg, the day after the breadth of the surveillance was 
reported in The New York Times.

Government agencies cannot discourage whistleblowing and reporting of 
wrongdoing by monitoring employees, echoed a White House memo 
<http://www.nytimes.com/2012/07/17/us/politics/inquiry-sought-of-extensive-fda-surveillance.html> 
sent to all government agencies about the FDA spy program.

*"Devicegate" dates back at least to January 2009 
<http://archive.truthout.org/010909A>when scientists in the FDA's Center 
for Devices and Radiological Health wrote President Obama that top FDA 
managers "committed the most outrageous misconduct by ordering, coercing 
and intimidating FDA physicians and scientists to recommend approval, 
and then retaliating when the physicians and scientists refused to go 
along." Review procedures at the agency (which approves stents, breast 
implants, MRIs, and other devices and machinery) were so faulty that 
unsafe devices - including those that emit excessive radiation - were 
approved, charged the scientists, provoking an OSC investigation 
<http://www.nytimes.com/2012/07/15/us/fda-surveillance-of-scientists-spread-to-outside-critics.html?_r=4&;pagewanted=all>.*

For reporting the safety risks, the scientists became targets of the 
now-disclosed spy program and some lost their jobs 
<http://www.nytimes.com/2012/07/15/us/fda-surveillance-of-scientists-spread-to-outside-critics.html?_r=2&;pagewanted=all>. 
"It has been brought to our attention that FDA management may have just 
recently ordered the FDA Office of Criminal Investigations (OCI) to 
investigate us, rather than the managers who have engaged in 
wrongdoing!" wrote the FDA scientists in a follow-up letter 
<http://freepdfhosting.com/02b725af30.pdf> a few weeks later to 
President Obama. "It is an outrage that our own Agency would step up the 
retaliation to such a level because we have reported their wrongdoing to 
the United States Congress."

During the same time period, Ronald Kavanagh B.S.Pharm., Pharm.D, Ph.D., 
an FDA drug reviewer in the Center for Drug Evaluation and Research, 
encountered similar intimidation and suppression of safety research. 
Truthout met with Dr. Kavanagh on several occasions to learn about his 
FDA whistleblowing experiences.

*Martha Rosenberg for Truthout: You were an FDA drug reviewer from 1998 
to 2008, working on well-known drugs like Cymbalta, Zyprexa, Concerta, 
Invega, Provigil and Saphris, and encountered the same kind of coercive 
working environment as the device reviewers.*

*Ronald Kavanagh:* That's correct. In the Center for Drugs [Center for 
Drug Evaluation and Research or CDER], as in the Center for Devices, the 
honest employee fears the dishonest employee. There is also irrefutable 
evidence that managers at CDER have placed the nation at risk by 
corrupting the evaluation of drugs and by interfering with our ability 
to ensure the safety and efficacy of drugs. *While I was at FDA, drug 
reviewers were clearly told not to question drug companies and that our 
job was to approve drugs*. We were prevented, except in rare instances, 
from presenting findings at advisory committees. In 2007, formal 
policies were instituted so that speaking in any way that could reflect 
poorly on the agency could result in termination. If we asked questions 
that could delay or prevent a drug's approval - which of course was our 
job as drug reviewers - management would reprimand us, reassign us, hold 
secret meetings about us, and worse. Obviously in such an environment, 
people will self-censor.

*MR: What are some of the ways in which safety risks were minimized in 
drug evaluation and review?*

*RK:* *Well, first of all I think most people would be shocked at how 
malleable safety data is. Human studies are usually too short and the 
number of subjects in them too small to adequately characterize the most 
dangerous risks. That's why even a single case has to be taken 
seriously. A safety signal from any study - and not just safety data 
from short term efficacy and safety studies (used for labeling) - needs 
to be evaluated. This means data from long term safety studies needs to 
be evaluated as well as the data from even longer, ongoing safety 
studies and from clinical pharmacology studies. Some of this information 
also needs to be examined during development of a drug. Yet I have seen 
new drug reviews where none of this was done by the medical safety 
reviewer.*

*MR: Would you give an example?*

**RK:* For example, human clinical pharmacology trials are typically 
done in Europe, yet clinical pharmacology reviewers at FDA have been 
barred from analyzing this information prior to studies being conducted 
in the US. Without being able to do this, we are unable to detect 
evidence of risks early and cannot provide guidance that would help with 
the development of the drug in terms not only of safety and proving 
efficacy, but also with the efficiency and cost effectiveness of the 
drug's development. New labeling policies can also mask risks as they 
exclude the labeling of adverse events if they are under a certain 
percentage and/or not double the rate found with a placebo. By this 
rule, certain serious and potentially lethal adverse events that 
eventually resulted in a drug being withdrawn from the market would not 
have had any mention of the adverse events made in the labeling at all. 
On top of that, I frequently found companies submitting certain data to 
one place and other data to another place and safety information 
elsewhere so it could not all be pulled together and then coming in for 
a meeting to obtain an agreement and proposing that the safety issue is 
negligible and does not need further evaluation.*

*MR: Like they are trying to pull the wool over the FDA's eyes?*

*RK:* During development, if reviewers say things that companies don't 
like, they will complain about the reviewer or they will call upper 
management and have the reviewer removed or overruled. On one occasion, 
the company even told me they were going to call upper management to get 
a clear requirement for approval that they did not want to fulfill 
eliminated, which I then saw happen. *On another occasion a company 
clearly stated in a meeting that they had "paid for an approval."*

*MR: That is shocking. Wouldn't the FDA managers want safety risks 
investigated?*

*RK:* Just the opposite. Sometimes we were literally instructed to only 
read a 100-150 page summary and to accept drug company claims without 
examining the actual data, which on multiple occasions I found directly 
contradicted the summary document. Other times I was ordered not to 
review certain sections of the submission, but invariably that's where 
the safety issues would be. This could only occur if FDA management was 
told about issues in the submission before it had even been reviewed. In 
addition, management would overload us with huge amounts of material 
that could not possibly be read by a given deadline and would withhold 
assistance. When you are able to dig in, if you found issues that would 
make you turn down a drug, you could be pressured to reverse your 
decision or the review would then be handed off to someone who would 
simply copy and paste whatever claims the company made in the summary 
document.

*MR: You have recounted that this is what happened to you with the nerve 
gas drug pyridostigmine.*

**RK:* Yes, pyridostigmine is intended to be given preventatively in 
case of a nerve gas attack with the nerve agent Soman and it was used 
experimentally on Gulf War troops. After the first Gulf War, there were 
concerns it was linked to Gulf War Illness. Then, prior to Operation 
Iraqi Freedom, the Defense Department (DoD) tried to have President Bush 
waive informed consent for pyridostigmine, even though it was still an 
investigational drug.*

*MR: Why?*

*RK:* Possibly because there is less hassle medicating troops if no 
informed consent is required. When President Bush refused to waive 
informed consent, the FDA approved pyridostigmine using the "Animal 
Rule" which allows the approval of drugs for human use based on animal 
data. It was employed because it was unethical to dose humans with the 
nerve agent Soman to see if pyridostigmine would actually prevent death. 
However, the way the drugs were used in the animal studies didn't 
reflect how they would be used in humans and resulted in misleading 
conclusions.

*MR: Another FDA reviewer turned down pyridostigmine before you?*

*RK:* Yes. I was assigned to re-review his conclusions regarding 
pyridostigmine and even before I began my review I was pressured to 
approve it and this pressure continued through nearly two dozen meetings 
with FDA management. After it became clear that I would not be pressured 
into an approval and it became apparent that it would be approved 
according to the animal rule in spite of the science, I raised an even 
stronger objection: not only did it not work against nerve agents other 
than Soman, but /pyridostigmine actually increased lethality in the 
presence of other nerve agents and we knew that Saddam Hussein was not 
using Soman and was instead using these other nerve agents./

*MR: So, you were just stating what should have been obvious?*

*RK:* This information was not secret - both FDA and DoD public 
documents acknowledge increased lethality with other nerve agents such 
as Sarin, and DoD and other government documents that are public also 
document that Saddam Hussein was not using Soman and was instead using 
these other nerve agents exclusively. Yet because I raised this as an 
objection, I was immediately replaced as the primary reviewer so that I 
could not document my concerns and so that pyridostigmine could be 
approved. It's since been proposed that if we ever face the prospect of 
nerve agents in the future, that this approval will be used as a 
justification to convince the President at that time to waive informed 
consent without presenting a full picture. Even though using 
pyridostigmine would likely only invite the use of nerve agents.

*MR: Why would the FDA and DoD allow troops to be put in this kind of 
harm's way?*

**RK:* I don't know and don't want to speculate. However senior managers 
made statements indicating knowledge that the approval was illegal. In 
any case, it was clear and known that use of pyridostigmine would 
interfere with the operation of our troops.*

*MR: Your training as a pediatric clinical pharmacologist has made you 
especially sensitive to drug risks for children. What are some of the 
unique drug risks children face?*

*RK:* *Pediatric approvals are based on the assumption that children 
will respond similarly to similar exposures. Yet dosages that are used 
for studies in children are often based on approved adult dosages rather 
than a scientific determination of whether children achieve the same or 
higher exposures than adults.* This is because companies don't want to 
develop lower dosages for children if they don't have to. Thus exposure 
studies in children are done after the efficacy studies have been begun 
instead of before when it's needed. The exposure studies then may also 
use overweight children as well as too few children. Since no allowance 
is made for race, age, puberty, or actual weight and since there are 
differences in children's clearance of drugs, there are often higher 
exposures to active and toxic metabolites in children compared to 
adults. Thus there are often unnecessary risks with the doses that are 
approved.

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

**RK:* 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 in children exposed during the pregnancy. Not 
only does the labeling suggest possible use during pregnancy, the 
labeling recommends a higher dose during pregnancy. All the while, it 
appears that the company was aware of the formation of a metabolite that 
likely affects brain development from well before the drug was ever 
submitted to the FDA.*

*MR: Are the risks just ignored?*

*RK:*_*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.

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

*RK:* 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, Blephamide. 
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.**

*MR: 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.*

**RK:* Yes. Largely because of my presentation, the advisory committee 
voted 12-1 against approval, but Cephalon claimed in the press that the 
rash was viral and was not from the drug. The next year, armodafinil, a 
related drug, was approved with a contraindication for children with a 
contraindication following three months later for modafinil. 
Contemporaneously, Cephalon agreed to pay $425 million for off-label 
marketing of modafinil. That means that for 18 months, the FDA kept 
quiet about the issue of SJS in children, while Cephalon continued 
off-label marketing at full steam. Later, I found that the FDA had 
internal documents that had the same conclusion as my analysis but they 
had been withheld from the advisory committee.*

All drugs have dangers including death, and psychiatric drugs tend to be 
particularly dangerous, but as long as we make reasonable attempts to 
minimize risks, and provide adequate information for prescribers and 
patients, I am not opposed to them. On multiple occasions I have stood 
up for smaller drug companies against FDA management.

*MR: The recent revelations of reprisals against FDA device reviewers 
must not have surprised you at all.*

**RK:* No they didn't. After FDA management learned I had gone to 
Congress about certain issues, I found my office had been entered and my 
computer physically tampered with. I saw strange cursor movements on my 
computer when I was just sitting at my desk reading that I suspected was 
evidence of spying. After I gave Representative Waxman's (D-CA) office a 
USB drive with evidence, FDA staff was admonished that it was prohibited 
to download information to USB drives. Then, after I openly reported 
irregularities in an antipsychotic drug review and FDA financial 
collusion with outsiders to Senator Grassley's office and the House 
Committee on Oversight and Government Reform, I was threatened with 
prison if I should release trade secret information to Congress.*

*MR: That is similar to the FDA's claim with the device reviewers. Why 
do efforts to silence free speech always seem to be couched as "trade 
secrets"?*

*RK:* Because much of the information we receive are trade secrets and 
companies explicitly label everything they provide the FDA as such and 
explicitly prohibit their dissemination. In spite of this, the Food Drug 
and Cosmetics Act explicitly allows communication of trade secrets by 
FDA employees to Congress, but since most people are unaware of this, 
FDA management can use the threat of jail for violation of the Trade 
Secrets Act, not only to discourage reviewers, but in my case they got 
Senator Grassley's staff to destroy the evidence I provided them. The 
threats, however, can be much worse than prison. One manager threatened 
my children - who had just turned 4 and 7 years old - and in one large 
staff meeting, I was referred to as a "saboteur." Based on other things 
that happened and were said, I was afraid that I could be killed for 
talking to Congress and criminal investigators.

*MR: Still, the FDA transparency meeting transcripts indicate you not 
only went to members of Congress, you appealed to the Health and Human 
Services inspector general.*

*RK:* Congress did put me in contact with the Justice Department, 
however, I don't believe my complaints were taken seriously by the FBI 
or investigated. I believe that actual felonies may well have occurred. 
For example, I found evidence of insider trading of drug company stocks 
reflecting knowledge that likely only FDA management would have known. I 
believe I also have documentation of falsification of documents, fraud, 
perjury, and widespread racketeering, including witnesses tampering and 
witness retaliation.

*MR: And in addition to this alleged wrongdoing, the public is at risk 
from unsafe drugs that were approved?*

*RK:* Yes. In fact, thanks in part to the Prescription Drug User Fee 
Act, [in which drug companies pay for expedited reviews] thalidomide 
could not be stopped today.

This article is a Truthout original. <javascript:return 
addthis_sendto('email');>


    Martha Rosenberg <http://truth-out.org/author/itemlist/user/46519>

Martha Rosenberg is an investigative health reporter. Her first book, 
"Born With a Junk Food Deficiency 
<http://www.barnesandnoble.com/w/born-with-a-junk-food-deficiency-martha-rosenberg/1106752596>," 
has just been released by Prometheus books.




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