October's Rant

I wasn't even sure I would even have much to rant about for October, but then I got yesterday's Wall Street Journal. A disturbing new article was published on the front page of yesterday's (October 26, 2005) edition of The Wall Street Journal. (see: http://online.wsj.com/article/SB113028992607079538.html to read the full article). Basically, the article highlighted a rogue FDA drug reviewer, Dr. Robert Misbin, and his efforts to see that Symlin did not get FDA approval, and his subsequent efforts to try and bypass his own boss and the agency's approval of Symlin by making an issue of hypoglycemia, an adverse effect that is only caused by insulin, not by Symlin alone. Dr. Misbin even went so far as to send a letter to Mothers Against Drunk Driving, urging the group to post the Symlin warning label on the MADD web site. In his letter to MADD, Dr. Misbin said the FDA removed him from the Symlin review "after I expressed concern that this drug might increase the risk of motor vehicle accidents."

Make no mistake, I think it is entirely appropriate to raise red flags on flaws in the FDA approval process, especially given the recent problems with approvals for such drugs as Vioxx which was associated with cardiovascular problems, but Dr. Misbin's actions do not seem justified, and there is a body of published data to support Symlin. The FDA is working just fine, which is why his efforts failed to derail Symlin's approval. Most alarmingly, there is no comparison between biomedicines and chemical drugs, even as far as adverse effects are concerned. In most cases, the dosage of a biopharmaceutical can be adjusted, and the side effects are then mitigated. The same cannot be said for chemical drugs. Yet Dr. Misbin makes direct comparisons between Symlin (a biopharmaceutical analog of the human hormone amylin) and the chemical drug known as Rezulin was developed as a treatment for Type 2 diabetes. Rezulin was always a foreign, chemical substance which did not exist anywhere in nature, unlike amylin.

It is worth noting that the "adverse effect" Dr. Misbin is apparently so concerned about is hypoglycemia, ironically, something which Symlin by itself does not cause. Only insulin (either with or without Symlin) causes hypoglycemia, and Dr. Misbin has made no effort to address this issue, not even with warnings on the MADD website addressing the risks of hypoglycemia associated with insulin alone. In fact, amylin (along with several other elements, such as c-peptide) are suspected to be missing pieces to the metabolic puzzle that have plagued doctors since insulin was discovered in the early 1920's. A well-written, peer-reviewed article on amylin was published in the respected diabetes journal "Clinical Diabetes" back in 2002 (see
http://clinical.diabetesjournals.org/cgi/content/full/20/3/137 to read the article) suggesting that the idea of insulin alone to effectively treat diabetes may be flawed. Ironically, Dr. Misbin seems to disagree. In fact, in written remarks presented to a July 2001 meeting of an FDA advisory committee, Dr. Misbin called the safety findings for Symlin "alarming" and the drug's long-term benefits "trivial." Diabetics would do just as well sticking to insulin alone, he wrote.

But other diabetes clinicians did not share his perspective. Notably, Dr. Steven Edelman, assistant professor of medicine at the University of California San Diego School of Medicine, wrote to the FDA in 2003 in support of Symlin, "Our country has tunnel vision in that a drug is judged on its ability to drop the A1c and is blinded to the many other important aspects that a therapeutic agent for diabetes can offer."

It is a known fact that amylin is a missing hormone in all patients with Type 1 diabetes, and I think its clear that this hormone plays some role in metabolism, or it wouldn't be there in the first place. Why, then, does Dr. Misbin, seem so hell-bent on derailing Symlin, which The Wall Street Journal acknowledges is the first new treatment for Type 1 diabetes since the discovery of insulin? The presentation Aymlin Pharmaceuticals made to the FDA regarding Symlin was apparently sufficient to obtain the agency's approval (see http://www.fda.gov/ohrms/dockets/ac/01/slides/3761s1_01_amylin.ppt for more detail).


I believe the FDA is working fine, and Symlin's approval is a testament to this fact. If Dr. Misbin is really concerned about safety, then he should be pushing to address the nasty side effects of exogenous insulin use by making sure that innovative new treatments, such as Smart Cells, Inc.'s "Smart Insulin", which will not cause hypoglycemia, gets fast-track approval. Smart Cells, Inc. (http://www.smartinsulin.com/), if it continues along its so-far successful path, will likely clean up with its nanotech insulin solution, and while it may be a few years away, to date, the company has experienced pre-clinical success in animal models, namely with the nonobese diabetic (NOD) mouse, which is the most widely used animal model for Type 1 diabetes today. I believe Dr. Misbin, however, has stepped over the line of appropriate behavior and should probably lose his job at the FDA. His concern is flawed and frankly, I do not believe it is genuine. Insulin is the "drug" he should be fighting, not Symlin. The FDA presentation made by Amylin Pharmaceuticals shows that with Symlin, insulin use is reduced and weight loss is a common benefit in many patients.

If Dr. Misbin is really so concerned about the adverse effect, namely hypoglycemia, then why not address the cause of hypoglycemia itself - insulin, not Symlin, which does not cause hypoglycemia. I suspect the reason is because any attack on insulin would be seen as career suicide for Dr. Misbin, and furthermore, it would challenge the status quo of nearly 100 years of insulin usage (including the nasty side effect of hypoglycemia), an issue that the medical profession rarely acknowledges, and routinely practice a game of blame transference to the patients with diabetes along the lines of "you wouldn't have hypos if you counted carbohydrates correctly." Really? Why is it that dosing insulin continues to be more of an art than a science? The answer is because insulin alone is not all that is missing. Even Eliott Joslin agreed with this assessment over 80 years ago, yet some like Dr. Misbin, fail to acknowledge this. Fortunately, the FDA seems to be working just fine, in spite of efforts from rogue doctors like Dr. Misbin. Apparently, the FDA declined to comment about Dr. Misbin's recent activities. Amylin said it wasn't aware of them. MADD hasn't posted a warning on its site. A spokeswoman for MADD said via e-mail that the organization focuses on drunk driving and can't address all the substances that might impair someone behind the wheel. Good Riddance!