TABLE  OF  CONTENTS

 


ANIMAL CLINICAL TRIALS are perhaps the most important aspect of this website because the most dangerous of all drug actions for Aldara and imiquimod (IQ) are described and found sprinkled throughout the animal trial data.   Much of this data was quickly pulled from the public domain shortly after I filed suit against 3M for my injuries.   As I proceed to go through this section with you, it will require me connecting a few dots for you  so you get the most detailed understanding of how each listing of the data connects to some of our most serious side effects and injuries.  More importantly, I am anxious to show you how 3M used and misused the data to reach the desired conclusions necessary for advancing to the human clinical trials.  So, let's get on with it....

Some Animal Clinical Trials of course predate Gerster's patent on IQ placing the first trials conducted in the early 1980's.  However, additional animal trials were performed by 3M after they acquired the patent rights and Riker.  So let's start the discussion about the time 3M purchased Riker and Gerster's patent rights on IQ. 

 

THE ANIMAL TRIALS REVEALED:

The animal trials on imiquimod began in the early 1980's and ran through most of the 1990's.  Riker Industries conducted some of the first trials on animals but shortly after 3M bought out Riker and imiquimod inventor Gerster joined the 3M research team, animal trials really kicked off.  Remember, the purpose for running animal trials is to determine the projected efficacy and safety profiles that justify going forward in conducting human clinical trials Phase I.  Let's see if 3M was able to demonstrate a safety profile in the animal trials that warranted going on to conduct Phase I human trials.  

I want to show you one example of how 3M spins the data to their best interest.  This will not take but a few minutes to lay out for you.  It is so important I wanted to make it the first example revealed.  Below are excerpts from a 3M animal trial:

Despite imiquimod's ability to induce IFN, (interferon), in virtually every (animal) species tested thus far, it did not induce IFN in rabbits. Reference: IMIQUIMOD     by: Gary A. Richwald


 

Imiquimod applied topically, a novel immune response

modifier and new class of drug

R. L. Miller, J. F. Gerster, M. L. Owens, H. B. Slade, M. A. Tomai

3M Pharmaceuticals, St.  Paul, Minnesota, U.S.A.

Received 29 May 1998 and accepted 31 July 1998

Finally, in a rabbit papillomavirus infection model in rabbits,  topically applied imiquimod was ineffective, which is likely due to the drug's inability to induce IFN and possibly other cytokines in this species.  All of the authors of this clinical trial document are top 3M researchers and Slade is the Director of the 3M Pharmaceutical Division.  So, virtually everyone at 3M knew the rabbit did not respond to Aldara.  And remember too that animal trials took place first putting the date of these 3M executives having knowledge of rabbit data prior to FDA Approval.


 

IT DID NOT INDUCE INTERFERON IN RABBITS.........This is a statement that I literally rammed down 3M's throat and I did manage to get 3M to drop its reference to the rabbit data from their literature written after 2004, as I will show you later on.  First, let's see why this rabbit business is so reflective of 3M's mindset and willingness to knowingly put fraudulent data into their literature just to achieve FDA Approval for Aldara.  And, they do this over and over in the approval data with the total disregard for human health and safety.   By the time we get through with this page you might think 3M is only interested in making money.   Do you think that's possible with  

Ok, here is the story on the Rabbit......

The FDA requires all animal trials to be conducted utilizing "only" those species of animal subjects that respond to the drug under investigation.  The animal must be able to react to the drug's pharmacological mechanism or any data generated by that non-responding species would be irrelevant and would disqualify it for participating in the trials, period.  That is not hard to understand, is it.  The animal, for what ever the reason, is incapable of being stimulated by the drug under investigation so why use it, right?  Well, there is a very good reason to use it if you are 3M and needing to get returns on your investment in Aldara to the tune of $500-million, as was the picture in 1996 when they applied for FDA Approval. 

All that was standing  between them and the multi-billion dollar market was this last, final step, FDA Approval.  So here is what 3M did.

If you remember from past pages, interferon alpha is considered by 3M to be the most prevalent and most desired cytokine induced by Aldara's drug mechanism.  Without it, Aldara could not function.  So, there you are; we just answered the question about the rabbit in one simple two line paragraph.  

By 3M's own admission, in many different places in print, the rabbit "is the only species" that cannot and does not, for whatever the reason, produce heightened levels of interferon when stimulated by Aldara.  You can literally cover the animal in Aldara and there will be no drug induced interferon.

This is the absolute definition of the FDA's statement which excludes all "irrelevant species" from participating in drug related animal trials.   Now look at the volume of rabbit related data 3M included in their FDA Approval package back in 1996.  Folks, this is pure and simple fraud on the FDA because all of this data was known by 3M to be just that fraudulent.  Yet they used the rabbit data to project the entire "safety statement" for Aldara in the FDA Approval process and the FDA never had the data nor the knowledge this fraud existed.

Safety statement for Aldara, 1997 date of approval:

OVERDOSAGE

Overdosage of Aldara 5% cream in humans is unlikely due to minimal percutaneous absorption.

Animal studies reveal a rabbit dermal lethal imiquimod dose of greater than 1600 mg/m2. Persistent topical overdosing of Aldara 5% cream could result in severe local skin reactions. The most clinically serious adverse event reported following multiple oral imiquimod doses of >200 mg was hypotension which resolved following oral or intravenous fluid administration. 

 

REVISED   Safety statement for Aldara, 2009

OVERDOSAGE

Topical overdosing of Aldara Cream could result in an increased incidence of severe local skin reactions and may increase the risk for systemic reactions.

The most clinically serious adverse event reported following multiple oral imiquimod doses of >200 mg (equivalent to imiquimod content of >16 packets) was hypotension, which resolved following oral or intravenous fluid administration.

As you can see, the subject of percutaneous absorption, which I get into later and the rabbit statement have both been dropped.   Not only that, the present safety statement, which is what this OVERDOSAGE statement is, contains no Lethal Dose Limit for Aldara nor is there any mention of a definition of what OVERDOSAGE actually means in the context of safety information for the treating physician and patient. 

The Lethal Dose Limit or LDL is the amount of topical Aldara it takes to kill any given animal during clinical trials.  It is a safety statement for the drug.  It demonstrates to a treating physician how safe the drug is, in this case Aldara.  Simply stated, the higher LDL for Aldara the safer it appears to be, the lower the LDL the less safe it is because it takes less drug to kill the animal.   The LDL was quite low for the monkey and a bit higher for the rat but neither of these species survived the LDL for Aldara.  The question presented to Dr. Jim Lee of 3M in Federal Deposition Testimony is as follows:

Q.  You tested Imiquimod on all kinds of different animals, correct?

A.  That's correct.

Q.  You gave it to them orally, you put it on them, you did all kinds of things to them,  

      correct?

A.  That's correct.

Q.  One of the animals that you gave Imiquimod to was rabbits, correct?

A.  That's correct.

Q.  Do rabbits produce cytokines and interferon?

A.  Well, yes, they do produce cytokines and interferon's.  I'm sure they do.

Q.  Does their system operate differently than humans in that regard?

A.  No. They're _ they are slightly different than humans.

Q.  Are they_how are they different?

A.  Well, in reference to their response to the imiquimod, they don't seem to have as strong a  

      response as humans.

Q.  Do rabbits produce interferon?

A.  I'm _ I don't know.  I'm sure they do.

Q.  Okay.  The rabbits were given large doses of the medication orally and they _ before they

      died,  correct?

A.  Correct.

Q.  They are able to take more of it than some of the other animals before they died, correct?

A.  Yes.

Q.  For instance, the monkey in your study died sooner than the rabbit did?

A.  That's correct.

Q.  Do you know why that is?

A.  The monkey seemed more sensitive to the effects of the Imiquimod.

Q.  Was the rabbit the least sensitive of all the animals to the Imiquimod from what your

      studies  referenced?

A.  Of all the animal species?

Q.  Right.

A.  That's correct.

Q.  Do you know why that is?

A.  I do not.

Q.  Why did 3M make the decision to reference only the rabbit in its labeling as opposed to

      the other  animals?

A.  I don't know the specific reason.  I believe it was an FDA requirement.

Q.  To reference a rabbit?

A.  Correct.

Q.  Okay.  You think the FDA requires rabbits be referenced?

A.  They require two species.

Q.  They don't specifically say rabbit though, do they?

A.  That's correct.

Q.  Why did 3M make a decision to reference a rabbit versus a monkey or some other more

      sensitive  animal in its packaging?

A.  I don't _ I don't know.

Q.  Who made that decision?

A.  I don't know.

Q.  Do you know who in this company would know the answer to that?  If I'm going to say,

      Dr. Lee, go find out the answer to that question, who are you going to go ask?

A.  I would ask someone in the toxicology area  or someone in the regulatory affairs.

A.  Regulatory affairs.

Q.  The packaging states that animal studies reveal a rabbit dermal lethal Imiquimod dose of

     greater  than 1600 milligrams.  What does that mean?

A.  The _ the amount of Imiquimod to _ to induce death in a rabbit _ was it 1600 milligrams,

     you said?

Q.  Yes.

A.  That's what that means.

Q.  What does that _ what does dermal lethal Imiquimod dose dermal?

A.  When the _ basically, the amount of Imiquimod applied dermally.

Q.  On the skin?

A.  To induce the death in the rabbit.

Q.  So, it took 1600 milligrams on a rabbit to keep giving it to them?

A.  That's correct.

Q.  And you're aware that the studies referenced that the other animals it took less than that

     to kill  them?

A.  That's correct.

Ok, so the top ranking officials at 3M have now admitted that Aldara has no affect on the rabbit insofar as it inducing cytokine activity, the primary drug action for IQ.  I will be posting the complete original FDA Approval Package on this website and I want you to find anywhere in it where 3M disclosed this fact that the rabbit is an irrelevant species in the context of Aldara.  It's not there, believe me.

We also learned from Dr. Lee's testimony that he only studied a limited number of the clinical trial data yet he is the director of Adverse Event Reporting and FDA Relations for 3M.  I find this to be strange for someone in that position not willing to take the time to fully understand the safety data for Aldara. 

All throughout the testimony, Dr. Lee talks about deaths that occurred to rabbits during their animal clinical trials.  In fact, no deaths were ever reported for the rabbit.  Not one.

Dr. Lee stated that the rabbit was killed by a dermal dose of 1600 milligrams of IQ.  The data actually states that the rabbit LDL is "greater than" 1600 milligrams of IQ dermal dosage.  In fact, one 3M trial applied 5000 milligrams of IQ to the rabbit and it still did not die.

The European Agency for the Evaluation of Medicinal Products

18 September 1998 CPMP/1176/98 COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS  EUROPEAN PUBLIC ASSESSMENT REPORT (EPAR)

Toxicology

Single dose toxicity of imiquimod was studied in mice, rats and monkeys. These studies indicated a high degree of safety. Adverse effects were limited to the central nervous system resulting in a number of clinical signs, usually convulsions, prior to death.

In two dermal toxicity studies in rabbits with doses of 2000 and 5000 mg/kg under occlusion there were no deaths and no signs of toxicity other than mild transient erythema at the application site.

So, I think this describes fairly well the fact that 3M used fraud at the highest level when they "knowingly" used safety data they knew to be from an irrelevant species, the rabbit.   The FDA relied upon this fraudulent rabbit data as demonstrating a high degree of safety for Aldara and it was this data that the FDA used in part to grant 3M approval to market Aldara.  A safety statement for Aldara that was completely based upon an irrelevant species which the FDA itself strictly prohibits. 

 

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

C. Animal Species/Model Selection (3.3)

 Safety evaluation programs should include the use of relevant species.    A relevant species is one in which the test material is pharmacologically active due to the expression of the receptor or an epitope (in the case of monoclonal antibodies).    A variety of techniques (e.g., immunochemical or functional tests) can be used to identify a relevant species.

 

Today, there remains no Lethal Dose Limit statement in the safety statement for Aldara.  

Is this one fraudulent event , out of a dozen, responsible for Aldara making it to the market?  Of course not!  But if your treating physician is trying to decide whether or not to prescribe Aldara for you he or she will likely read this OVERDOSE statement in his PDR at some point and the rabbit data will clearly indicate an exaggerated high profile of false safety for Aldara.  And, to see nothing at all describing the LDL for Aldara makes matters even worse by having a decision made by your physician for your use of Aldara based upon incomplete information at the hands of 3M .

The next page will show 3M using the rabbit to demonstrate even higher degrees of fraudulent safety features for Aldara. 

 

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