Reports of botulism poisoning resulting from a wrinkle-flattening injection may have made patients - and some physicians - a little jittery about the safety of botulinum toxin type A (Botox).
In early December, newspapers around the country reported that four people had been paralyzed by a single injection of the wrinkle smoother.
But as federal and state investigators dug deeper into the case, the focus turned from a product approved by the Food and Drug Administration (FDA) to a knock-off that was being marketed to physicians as a less expensive substitute.
Now, one month after the events that landed four people in hospitals in New Jersey and Florida, officials think they understand how it all happened.
The evidence suggests that a suspended physician unknowingly injected himself and three others with massive doses of botulinum toxin that had been purchased from a company that had been illegally marketing research grade toxin as a cheap stand-in for botulinum toxin type A.
At first, physicians with years of experience using botulinum toxin type A dismissed any connection between the poisonings and the FDA-approved drug. Steven Frucht, MD, said he was immediately suspicious about any link to botulinum toxin type A. My colleagues and I have done many injections over the years, said Dr. Frucht, Assistant Professor of Neurology at the Columbia University Medical Center in New York City. One never sees these sorts of catastrophic events when the product is used appropriately - that was the first tip-off that something was not right about those four cases.
The FDA has approved botulinum toxin type A for several indications beyond the therapy for smoothing out wrinkles. It is also used in the treatment of cervical dystonia in adults and in the treatment of strabismus and blepharospasm.
PATIENTS GET SICK
State and federal officials became aware that there might be a problem with certain wrinkle-smoothing treatments when the four patients turned up at hospitals in Bayonne, NJ, and Palm Beach, FL, in late November.
Investigators were originally told that Bach McComb, DO, had injected himself and the three others - co-worker Alma Hall and patients Eric and Bonnie Kaplan - with botulinum toxin type A.
But records from Dr. McComb's clinic and Allergan, Inc., the manufacturer of botulinum toxin type A, suggested a different scenario. The clinic had, indeed bought two vials of botulinum toxin type A in 2004.
We determined that the clinic had bought two vials of botulinum toxin type A earlier in the year, said Caroline Van Hove, Senior Manager for Corporate Communications at Allergan. So we were able, through tracking, to confirm that, and we did a quality check on the batches and confirmed that there was nothing wrong with them.
But, records show that those two vials had been used in treatments for other patients at Advanced Integrated, according to the affidavit of FDA Special Agent Susan J. Leeds. Ms. Leeds' affidavit was filed in US District Court of Northern California to support an application for a search warrant of a facility thought to be selling unapproved botulinum toxin to physicians.
SOURCE FOR BOGUS PRODUCT
After interviewing several witnesses, Ms. Leeds and her colleagues figured out where the bogus botulinum toxin type A came from and why it had such devastating consequences.
The Kaplans' son told investigators that he watched as Dr. McComb injected his parents with the botulinum toxin on November 24. He also told investigators that Dr. McComb told his parents that the botulinum toxin being injected was left over from a batch that Dr. McComb had used on himself and the Halls.
Thomas P. Toia, an employee at the clinic, told investigators that the botulinum toxin used by Dr. McComb was bought from a California company called List Biological Laboratory, which has been marketing botulinum toxin in conjunction with a Tucson, AZ, company called Toxin Research International (TRI).
Mr. Toia, whose father owns Advanced Integrated, was working as an assistant at the clinic.
When the FDA searched TRI's offices in early December, they found not only a large quantity of botulinum toxin, but also numerous marketing materials advertising seminars that talked about ways that unapproved botulinum toxin could be used in treatments for humans.
The FDA search also turned up a printout of a testimonial from TRI's Web site by Robert Baker, MD, which included TRI's posted prices of the botulinum toxin type A; specifically one vial for $1,250 and two vials for $1,000. Handwritten notes on this printout state: 'Botox for your wrinkles.'
Mr. Toia admitted that he had ordered one vial of botulinum neurotoxin type A, 100 micrograms from List. He also told Ms. Leeds that that he watched as Dr. McComb prepared to reconstitute the toxin with 10 milliliters of saline - the same amount he would have used with a standard 100 unit vial of botulinum toxin type A.
Figure. Dr. Steven F...Image Tools
But, Mr. Toia said, by his calculation, the 100 microgram vial of botulinum toxin from List was equivalent to 20,000 international units of botulinum toxin A. Mr. Toia said he warned Dr. McComb that the mixture would be too strong. He said he suggested that the Florida osteopath use 100 milliliters of saline to approximate the dosage normally used in a botulinum toxin A injection.
But Dr. McComb insisted he was right and stuck with the 10 milliliters, according to Mr. Toia. As it turns out, even Mr. Toia's calculations may have been an underestimate, Ms. Van Hove said.
Our own calculations indicate the vial may have contained as much as 10 million units, she added. For comparison purposes, one vial of botulinum toxin is only 100 units.
RECOVERY COULD BE SLOW
By the time the Kaplans showed up at the Palm Beach Gardens Medical Center, they were very ill, according to the FDA affidavit. Their symptoms included: immobility of the extremities, respiratory difficulty, double vision and other vision problems, and inability to swallow, Ms. Leeds reported.
Meanwhile, in Bayonne, NJ, Dr. Mc-Comb and Ms. Hall were admitted to a hospital with symptoms similar to those of the Kaplans, according to the affidavit.
All four patients are still in the hospital, according to Lindsay Hodges, a spokeswoman for the Florida Department of Health. The South Florida Sun-Sentinel reports that the four are in critical but stable condition. And it's not clear exactly when they will be well enough to go home.
Ms. Leeds noted that according to the CDC, botulism is a muscle-paralyzing disease caused by a toxin made by Clostridium botulinum. Once in the body, the toxin binds to nerve endings at the neuromuscular junction, causing weakness and paralysis that may include breathing. Recovery can be extremely slow. Assuming the patient receives proper care to support breathing, recovery occurs only when the affected nerves grow new endings, a process that can take several months, although the time varies from case to case, Ms. Leeds noted.
PRODUCT EASILY ACCESSIBLE
One particularly distressing fact turned up by the FDA investigation was the ease with which botulinum toxin can be acquired. While Allergan sells only to licensed health care professionals and to specific hospital pharmacies, the rules at List were apparently a lot looser.
Mr. Toia said he called the phone number provided on the List Laboratory Web site and ordered one vial of botulinum neurotoxin type A. Mr. Toia told Ms. Leeds that List did not request any information from him other than his name, address, and billing information.
Mr. Toia backed up at least part of his story with a copy of the charge on the clinic's Visa card.
How can physicians and patients be sure they have the real thing? The product can be identified by a state-of-the-art holographic film, which appears on each vial, Ms. Van Hove said. As an added protection for patients, Allergan keeps a list of physicians who are trained and qualified to use Botox on its Web site, Ms. Van Hove said.
The good news is that the four cases appear to be isolated, Ms. Hodges said. After the first report of possible botulism cases, the Department of Health in conjunction with Poison Control and the Centers for Disease Control and Prevention sent out alerts to all hospitals and physicians asking them to consider botulism as a diagnosis in cases of paralysis, Ms. Hodges said. But there have been none.
In mid December, the Department of Health again suspended Dr. McComb's medical license as well as the licenses of three others affiliated with the clinic. According to the affidavit, the FDA has not received any reports of botulism caused by actual botulinum toxin injections.
This is not a surprise to Dr. Frucht. My feeling and that of my colleagues is that the chance that these events had anything to do with the actual product approved by the FDA was virtually zero, he said. It was just not physiologically possible.
MORE LEGAL ACTION TO COME
As it turns out, the Florida case may not be the last word on bogus botulinum toxin type A. In late December, a federal judge in Florida issued a temporary restraining order against two individuals - Chad Livdah, ND, and Zarah Karim, ND, of Toxin Research International - and four companies - Toxin Research International, Powderz, Inc., The Cosmetic Pharmacy, Inc., and Z Spa, Inc. - involved in making or marketing botulinum toxin. They were also restrained from marketing or promoting botulinum toxin for the treatment of wrinkles in humans.
At press time, there was a hearing scheduled to decide if the restraining order is to be made permanent, set aside, or modified. Clearly, List Laboratories was not listed in the restraining order. When asked whether the FDA or the Justice Department is pursuing List or any other companies, Carlos B. Castille, Special Counsel for Public Affairs at the US District Attorney's Office in Florida, had no comment.
In January, the FDA posted this alert on its Web site: Unlicensed botulinum toxin has been imported into the United States via international express mail services without proper declaration of contents by the sender. These shipments are small and are generally shipped cooled using a cold pack. Several foreign pharmacies have sent unlicensed product directly to physicians.
ARTICLE IN BRIEF
✓ Four people were hospitalized after using bogus botulinum toxin A. Temporary restraining orders have been brought against some of the individuals and companies responsible.
© 2005 AAN Enterprises, Inc.