In 2005, four hundred thirty six "serious adverse event" reports related to Botox had been reported to Allergan, the manufacturer of Botox. Two hundred one of these cases were possibly or probably due to remote spread of the toxin, including 42 cases reported after wrinkle injections. Also in 2005, Allergan had reported to the FDA that they had identified 38 patients -- 20 children, most of them with cerebral palsy, and 18 adults -- who had suffered seizures after Botox injections.
During May 2007, European regulators requested that Allergan and two other toxin competitors add information to their product labels and to warn doctors that the toxin could spread, causing botulism like symptoms (dry mouth, difficulty swallowing, blurred or double vision, drooping eyelids, slurred speech and progressive muscle weakness). In July of that same year a confidential report made to Allergan by a consulting firm showed 207 patients had developed medical problems associated with the spread of toxin, including several deaths. A third of the cases reported occurred in people treated for wrinkles. The rest were treated for muscle spasms, muscle spasticity and eye problems. Proportionately more problems were reported amongst children who had received Botox.
Given those statistics, however, it must be stated that Botox and Botox Cosmetic are extraordinarily safe drugs when used correctly by a qualified physician. Issues occur when medical literature is, at times, totally incorrect and when you have a manufacturer who is unwilling to admit the true number of adverse reactions. The accurate and safe usage of this toxin becomes problematic when a physician's or injector's expertise and knowledge become questionable. Therefore, one must choose their physician carefully.
Recently, the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society stated:
"Botulinum toxin type A was found to be generally safe in children with cerebral palsy. However, the Food and Drug Administration is presently investigating isolated cases of generalized weakness resulting in poor outcomes."
I think that rather than use words like "poor outcomes"; it would be more accurate to use the word "deaths." Indeed, in Orange County, California, there is a trial currently underway concerning the death of a seven-year-old girl after she was treated with Botox--not for cosmetic purposes, but for cerebral palsy. While it is widely known that Botox will reduce the spasticity of the leg and arm muscles in individuals with cerebral palsy, the question that must be answered is "Is it safe?"
How does Allergan educate physicians for the use of this product for cerebral palsy when it is not approved for this indication? Allergan, through its extensive chain of paid consultants, has created a vast array of courses they sponsor through assorted CME (Continuing Medical Education) programs. This is not widely known outside of a select medical community. The FDA has seemingly turned a blind eye toward Allergan's off-label promotion of this drug for a myriad of purposes.
In the deposition for this trial, the treating physician (Dr X) stated that he went to two Allergan-sponsored symposiums to learn how to treat cerebral palsy with Botox. Indeed, Allergan has been known to pay the travel expenses of physicians to attend such meetings. While the physician named in this suit is not a neurologist, he was trained to use Botox in cerebral palsy by a pediatric neurologist. Would you not think training of this type be best left to training other pediatric neurologists? He was taught to use a dose of Botox in treating children which in reality is twice the maximum dose. What makes no sense is that even though sales representatives of Allergan visited the physician's office over 50 times; maximum dosing was never discussed nor was why the patient was hospitalized 10 times for difficulties breathing while undergoing Botox therapy. This is a well known side-effect which occurs with spread of a botulism based toxin. Why was the treating physician unaware of this sign that the toxin had spread? Was he unaware that death can happen as a complication if you have severe problems with swallowing or breathing after treatment?
What is even stranger is that, according to Mitchell Brin, Vice-President of Allergan for Botox/Neurology, the company has never shared its maximum dosage information with physicians due to a federal ban on marketing for non-approved uses. What is meant by maximum dose is even confusing. Some individuals consider the maximum dose in cerebral palsy to be 400 units per visit. However, the child's weight, muscle mass and acute nature of the illness will modify this dose. So the idea of a maximum dose for a specific condition is indeed variable and physicians should be aware that there are no specific rules, but rather the physician must understand the toxin, the disease and various factors that determine the treating dose to be used in a given patient.
So, apparently, Allergan can teach physicians how to treat cerebral palsy with Botox, but not how to treat it safely? Furthermore, there is literature that supports the use of low-dose rather than high-dose toxin in treating cerebral palsy. Was Dr X aware of this or the fact that low volume with precise injections produces the best results? Maybe he believed volume does not matter in that it has been printed in a journal?
Why have there recently been so many more reports of severe adverse reactions and deaths associated with botulinum toxins, which never seem to find their way into public awareness? Certainly, it could be the greater number of physicians using the toxin. But there is a much more serious issue; the current medical literature on Botox should be approached with caution, in that many of the articles are far from accurate. Also, they have not recognized or have even ignored the dangers that accompany the use of this product, even in cosmetic settings.
The following illustrates how physicians and pharmaceutical companies can attempt to compromise the medical literature, the cornerstone of medicine:
A few years ago, the lead consultant for Allergan (who was a foreign doctor and not even licensed to practice in the US) attempted to publish a manuscript that supported the concept that dilution of the agent did not matter, even though it has long been known that large dilutions of the vial of toxin could result in the toxin migrating and reaching unintended muscle areas. Additionally, FDA studies had found that problems with dilution were the greatest cause of adverse reactions with Botox. A review of the submitted paper uncovered serious problems and contradictory data, including graphs which suggested a worsening of wrinkle severity from baseline after the Botox wore off. Additionally, small sample size and adverse events in the larger dilution groups were noted. In light of these concerns, the article was rejected for publication.
The authors then resubmitted this article, choosing to alter the data and remove the results which suggested wrinkles worsened after the toxin wore off. I spoke to the editor of the journal and, once aware, he promised to address the problem with the authors. Two years later, in a special issue of the journal, Dermatologic Surgery, an issue sponsored by Allergan, this article was published with the altered data and the conclusion that "dilution used when administering Botox was unimportant." When I brought this to the attention of David Pyott, Allergan's chief executive, he stated that while they financially supported the issue and this foreign physician who authored the piece (their chief consultant and their aesthetic Czar), they could do nothing about the altered data.
In another article in the same issue of Dermatologic Surgery, this very same foreign physician attempted to include my name on an article regarding the supposed safety of an injectable type B toxin. I demanded that my name be removed. I was then offered $10,000 by Soltace, who manufactured this toxin (Myobloc), to include my name on this paper. This is supposedly the same sum they paid the lead author.
I voiced my concern that this article was incomplete and did not reflect the true toxicity of this agent as had been indicated in other studies, including Japanese studies which have shown this toxin to be much more toxic than originally believed. In clinical use, this toxin had been known to cause distant side effects such as dysphagia (inability to swallow) when it was used in normal doses. My name was removed from the article but the manufacturer refused to include this important safety data. The article concluded that this toxin was both safe and effective. The field of aesthetics has been badly damaged by these acts.
My voicing of serious concerns and having raised questions about the alteration of data published in peer-reviewed journals did not go unnoticed. As a result of trying to inform the medical community of these issues, I was terminated from two manufacturer's advisory boards and from the editorial board of three peer-reviewed publications (Dermatologic Surgery, Journal of the American Society of Dermatology and the Archives of Dermatology).
Interestingly enough, William Coleman, who was editor during the entire altered-literature episode, remains at the helm of Dermatologic Surgery today. Furthermore, due to the power of Allergan and other companies, I am no longer invited to speak at any Dermatologic or Plastic Surgery meetings. Recently, Allergen used a patient of mine in an advertising program. My long-standing patient was told that I could no longer be his treating physician. Is this not illegal?
I have been disinvited from CME meetings, as well as being prevented from using an educational grant they had provided me to teach courses. Finally, Robert Grant, the president of Allergan Medical, called me and stated that even though I was the best injector in the world, my services would no longer be needed.
Having read of the problems in Europe and Canada and being aware of Allergan's tendency not to reveal severe adverse reactions to Botox, the black box warning they received in 2009 from the FDA vindicated me and the allegations I had made against Allergan, according to BNET/money.com. While consultants to Allergan, as well as the company itself, have publicly denied any problems with the cosmetic use of Botox, the previous data indicate fatalities can occur.
Through all the above and despite multiple letters to the FDA, I never have met once or heard from the FDA regarding the information I had provided regarding botulinum.toxin. In that the chief aesthetic czar to Allergan, Alastair Carruthers, is a foreign national not licensed to practice in the US, I would have expected at least a response in that he injected and demonstrated Botox injections throughout the USA without a license in any state.
I also expected to get a response to the information I provided in regard to dilution of toxin wherein the authors suggested it did not matter. Even though I proved the authors had altered their data to reach this conclusion, again I heard nothing.
So while the FDA has seemed disinterested in forged literature and unlicensed physicians injecting Botox, the FDA has changed and there is now new leadership. There may still be hope.
The following is something I hope never comes to be:
Allergan recently filed a lawsuit stating that the ban on off-label marketing of Botox violates its First Amendment rights to free speech. In that a significant portion of their product's $1.3 billion in annual sales comes from off-label prescriptions, to treat everything from migraine headaches to juvenile cerebral palsy, they feel they have the right to sell it for these purposes. Just remember that people have died from wrinkle treatment with this toxin. Do we want to see more children dying when it is used in cerebral palsy? We do not want abuse of this drug, we should want proper use. How can this happen when the studies surrounding approved applications include data that has been forged?
Next week: Cosmeceuticals 2- or where did all my Vitamin D Go?
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