A mad-as-hell Sid Wolfe of the watchdog group Public Citizen sued FDA about the agency's refusal to ban the highest dose of the Pfizer Alzheimer's drug Aricept--and lost. Studies don't show increased efficacy of the 23-milligram pill compared with the lower doses of 5 and 10 milligrams. However, the higher dose does show increased toxicity, including, Wolfe said, increased mortality.
According to a comprehensive article by reporter Ed Silverman, the director of the FDA’s Division of Neurology Products, Rusty Katz, explained his reasoning for keeping the higher dose by posing a question and then answering it: “Does the absence of a demonstration of any superiority of the 23 milligram dose to the 10 milligram dose on measures of overall functioning, coupled with the increased incidence of potentially significant adverse events, argue against the approval of this product?” The 23 milligram dose is “clearly superior to the 10 milligram dose” on a cognitive measure.* “In my view, this strongly argues for a conclusion that the 23 milligram dose is very likely to also have an effect on overall functioning, despite this not having been demonstrated directly in this study” [emphasis added].
Reporter Ed Silverman also wrote that given the few Alzheimer's treatments available, FDA believes that physicians may decide the added side effects justify the benefits.
Following that logic, FDA, Ampligen's side effects are in most cases, minor or manageable, and given that there are no FDA-approved ME treatments, shouldn't Ampligen be approved? Instead the FDA committee, while endorsing Ampligen's safety, voted that the drug didn't meet FDA's standards for efficacy--though it was "probably effective." Probably effective sounds an awful lot like the "very likely" of two paragraphs up.
Why the double standard, FDA? Could it be FDA is throwing the pharmaceutical giant a big bone because the patents on the lower doses are expiring? Could it be that FDA believes Alzheimer's to be more important than ME? Could it be, as Sid Wolfe suspects, that FDA doesn't want to admit it was wrong in approving the 23 milligram dose in the first place?
Sid Wolfe also testified at the FDA Ampligen hearing on December 20 that Ampligen shouldn't be approved either. (And a patient I talked to at the meeting said she overheard him say that cognitive therapy works.)
Here's Ed Silverman's story, if you want more info.
*In three of the four tests, there was no increase in cognitive function at the higher dose.
*In three of the four tests, there was no increase in cognitive function at the higher dose.
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Glad to see I can access this, Mindy - I always enjoy reading your work. For the last few weeks (?) I kept getting a message that I had to be logged into my blogger account or something (haven't got one) and then to be invited by you to read your blog.
ReplyDeleteGlad that's fixed, whatever that was!
It certainly seems like a double standard to me. Why is it all right to approve a drug with dangerous side affects for Alzheimer's because there are no other effective treatments and it is not all right to approve Ampligen for people with M.E. who have no effective treatments?
ReplyDelete"Could it be that FDA believes Alzheimer's to be more important than ME?"
Yes,it could be; and I think it is. Alzheimer's patients are seen as people with a real illness, and people with M.E. are seen as malingerers.
Indeed a double standard. Having said that, and having seen Aricept 'work' in an elderly relative, I'd argue it's a pretty damn dangerous drug and it's use should be strictly limited. So I have an ambivalent reaction to Sid Wolfe who on the one hand seems to be doing good work in flagging up Aricept as a problem but at the same time not giving Ampligen a fair hearing.
ReplyDeletesaddens me to think we get so little help
ReplyDeleteThe higher dose of Aricept showed better efficiency for one of the four tests. You tried to hide that information in a footnote, but that just shows your bias. It was still better for one measure.
ReplyDeleteAs for Ampligen, it showed efficiency for zero measures: if you looked at all the people there was no improvement at all. If you looked at subgroups, there was non-statistically significant improvement.
But more obviously, the laws in the US have always required two statistically significant studies, large enough to show efficiency and safety. For many drugs this requires 300 person studies. For some drugs, much larger studies are required. For example: for type-1 diabetes, all phase-III studies are approximately 300 people. However, for type-2 diabetes and most heart problems, phase-III studies contain thousands of people.
Ampligen has only one controlled study even close to 300 people. So it should not have any chance of getting approved. It's like letting a high jumper run under the bar, because their country has never won a prize before.
Joshua
You also write this: "Could it be FDA is throwing the pharmaceutical giant a big bone because the patents on the lower doses are expiring?"
ReplyDeleteDrug doses are not patented! Drug doses are approved. Drugs are patented. Once the patent runs out for a drug, it runs out for all doses. The FDA will still need to approve doses ("for marketing") no matter what the patent status of the drug is. So approving a large dose here, helps future drug makers get that same dose approved (once the drug is out of patent), but those other drug makers will still have to get their own approvals.
If anything the FDA's approval will make it easier for future companies to market the larger dose, not harder.
Joshua
Joshua,
ReplyDeleteI didn't hide anything. I put that info at the bottom of the post because it fell within a quote. I even used the same size type at the bottom.
The first double-blind trial for Ampligen did show efficacy. The second was more problematic.
Here are some of the reasons for problems in the trials: One, giving a saline IV to placebo patients isn't placebo--many patients use saline IV or salt tablets to decrease autonomic dysfunction. I don't know how you'd get around that. Second, some of the patients in the second trial didn't have ME--thanks to the definitional problems. Third, exercising patients who are just recovering is going to cause crashing. That is just for starters.
I can tell you that I interviewed more patients than any reporter on the planet, and most of the patients in the first trial did respond. Consider reading my Ampligen article from 1994. If you listened to the FDA patient testimony, you'd see how the drug has helped many people.
As far as drug trials, AZT was approved with ONE double-blind study, because the government recognized the need to help desperately ill and dying patients. Which is what I believe the FDA should do for ME patients.
You wrote: "The first double-blind trial for Ampligen did show efficacy. The second was more problematic."
ReplyDeleteThat's a very strong signal that Ampligen doesn't work. Because science improves over time, latter studies are almost always better than earlier studies. It is almost unheard of for a successful drug to do worse in a follow on study.
Latter studies learn better dosing, they benefit from knowing who is likely to benefit, and they are larger and longer, and so on.
(I'm also a little interested in why you think the first study showed success. I haven't seen any statistical results, that show that if you measure everyone in the study, it was successful. Sure, if you manipulate the data by dropping the 7 bad performers, but in terms of the real analysis: with all the people. The FDA analysis was very specific that they did NOT show statistically significant results.)
You wrote: "Here are some of the reasons for problems in the trials: ..." These are all reasons why studies are not perfect. They apply equally to ALL studies done on Ampligen. If you are going to argue that all studies done on Ampligen are bad, then that is another reason why it should not be approved. But you seem to be very selective. The study that you claim showed success, you don't talk about these problems. The the latter (larger?) study that showed no effect, that one has all these problems?
You wrote: "I can tell you that I interviewed more patients than any reporter on the planet, and most of the patients in the first trial did respond."
I'm sure you did. That is classic "reporting bias". When people say it works, but the statistics say it doesn't, that shows the bias of the people you listen to. The whole point of the FDA process is to prevent "reporting bias" (and other forms of bias) from getting ineffective drugs approved. Let's hope it works here.
Your comments about AZT are true, and they also show your huge bias. AZT was approved on one trial. AZT had statistically very strong results. In the treated group, one person died. In the untreated group 19 people died (this was in a 24 week time period). That's huge! Ampligen has nothing like that.
Joshua
Ampligen works dramatically well for a subset of patients. Just because it doesn't work for everybody, does it mean that nobody should get it?
ReplyDelete