Matt Herper over at Forbes has a very cogent perspective piece up today on FDA's so-called "black box process" for unapproved drugs -- it has this to say about Schering's sugammadex: 
. . . .[T]he U.S. Food and Drug Administration shocked investors on Aug. 1 by rejecting sugammadex. Schering relayed the news in a 447-word press release, explaining that the FDA's concerns were "primarily related to hypersensitivity/allergic reactions," a known and rare side effect of the drug.
Those six words are all that investors and concerned anesthesiologists are likely to get in the way of explanation for the surprise rejection. As a matter of law, the FDA must keep communications about unapproved drugs confidential.
That silence reflects larger ways in which the agency is having trouble adapting to a world of super-sudden stock movements, Internet-speed rumors and an unrelenting 24-hour news cycle.
"One thing I've said now for several years is, if a company is telling you about the letter, I would ask to see the letter, because that's the only way to know what the FDA said," says John Jenkins, director of the FDA's Office of New Drugs. . . .
That is very-solid advice, Mr. Jenkins -- but what are we to think about the case where a company (think Schering, here) simply declines to provide the letter? Said another way, is it time to rethink the FDA's letter policies/right of public access rules? Perhaps.
More to come, later. . . .
5 comments:
Based on contacts within FDA there's a lot of people within FDA who would like to see this become public information also.
However, personally I don't think Dr. Jenkins is one of them.
Salmon
Aug 13 Evening
I just saw an article on the TheStreet.com about Sugammadex.
There was only one case of “anaphylactic” reaction.
"subject 008" suffered some troubling complications. As doctors administered the drug, the patient began exhibiting a number of symptoms -- including rash, nausea and flushing -- that could signal a serious "anaphylactic" reaction. Once doctors halted infusion of the drug, however, the patient recovered without any further treatment at all.
Actually this sounds more like histamine release to me and not an anaphylactic reaction. It occurs with IV infusions of a number of drugs e.g. vancomycin and you can simply infuse it slower or give an antihistamine or a steroid with it.
The article goes on.
“But Schering-Plough itself spotted no further problems during its expanded review. However, since the company supplied its new results to FDA experts at the last minute, the agency decided to take a closer look on its own.”
(i.e. more safety data from ongoing trials that the FDA reviewer probably asked for because they were suspicious of something)
“After scouring the databases from late-stage trials, which are designed to measure efficacy rather than risks, the FDA came up with four more cases of potential hypersensitivity to the drug.
“In every one of those cases, however, the patients appeared to suffer primarily from stomach problems -- such as nausea and vomiting -- that often follow surgery regardless of the anesthesia drug involved. Moreover, in at least two of those cases, the nausea surfaced a full day after the operations had taken place and continued long after the reversal agent would have seemingly worn off. “
ooohh scouring!
Sounds like that pesky reviewer was really looking to get something on SP and turned over ever possible stone until they found something.
What!! Stomach problems a full day later. What kind of stomach problems? What were the symptoms? Where were they located?
Considering it’s a full day later and considering the structure of sugammadex I would worry about how sugammadex is being eliminated. For example uptake and clearance by bile transporters in the liver.
Maybe somebody’s concerned about hepatotoxicity? Maybe even in a subgroup where the anethestic is released in the liver or maybe in a different subpopulation that’s deficient in an producting a transporter. So it builds up in the liver. That sure wouldn't show up in animal studies.
Don’t worry about the advisory committee. AC meetings are set up so far in advance for a first in class like this that they’re usually held before the review is even complete, and if SP suspected a problem. I would bet they didn’t provide the safety update in time for it to be reviewed prior to the AC meeting.
This is all speculation, but I’ve said it before these letters are usually written in such a way in order to give the company a way to spin it away from the real reason for the turndown, and the “anaphylactic reaction” sure doesn’t pass the sniff test in my opinion.
Salmon
P.S. No wonder John Jenkins (Head of the Office of New Drugs) said that the letter should be released.
The street is notorious within FDA for twisting things in favor of drug companies.
With what they wrote this "anaphylactic" reaction looks like a pretty lame excuse to turn down a drug.
But 4 cases of hepatoxicity or say symptoms associated with ischemic bowel disease or even pancreatitis that occur 24 hours later would be a whole nother ball of wax.
When are you going to recommend to Congress that all safety and efficacy information and all reviews are made public John.
Salmon
A few more comments on the article from "The Street"
The Street reported the following:
"Ultimately, FDA advisors saw no real cause for alarm.
"The various patients that (the FDA) found, vs. the ones that the company is reporting, need to be resolved," John Farrar, chairman of the FDA advisory panel, agreed back in March. "But given the fact that every drug has the potential for a person having an immune response ... it would be surprising if this drug didn't have at least one or two patients who showed up with some response that was unexpected." "
WHAT!!! Is Farrar joking! You never see anaphylactic reactions in this few people in drug development. Plus anaphylactic reactions need a prior exposure and these patients had none.
The Street goes on:
"Even Natixis Bleichroeder analyst Jon LeCroy -- an M.D. who reviewed Sugammadex's trial results at length -- felt reassured.
All told, LeCroy calculated, more than 2,000 patients received Sugammadex during clinical trials of the drug. Based on the FDA's own review, he noted, no more than eight of those patients -- or 0.03% of the total -- displayed any signs of sensitivity. Of those eight possible reactions, he continued, only three could have possibly been caused by the drug itself. Moreover, he concluded, not one of those reactions proved to be severe."
N.B. An analyst said this I'm sure he has no ulterior motives.
Plus 0.03% is 1 in 333. Remember Lotronex from about 8-9 years ago. It also caused stomach pain in 1 in 300 people in the clinical trials. Well that was ischemic bowel disease which normally is about 1 in 1,000,000 and causes your bowels to perforate and if you don't do emergency surgury it's a death sentence. That probably paralyzed the intestinal nerves or blood flow in the intestines.
Now here we have a drug that sequesters drugs that paralyze muscle if this localizes and or releases the paralytic agent in the intestine we've got troubles.
Like I said before when I proposed potential hepatotoxicity. At this point we don't know. Neither SP nor the FDA is releasing sufficient details. However we know SP is going to spin it, FDA can't release info, and something has got even upper management at FDA scared enough that they'll actually put their signatures on an NO when there are powerful and connected financial interests at stake.
Salmon
By the way Lotronex was eventually pulled from the market. There were Congressional Hearings and it turned out that there were secret phone calls between FDA and Glaxo. The division director got canned over this even though apparently phone calls were made at higher levels.
Salmon
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