Thursday, February 09, 2006

Meeting short take #6: Terra Sigillata comments on the recent saw palmetto trial so I don't have to

Normally, this would be a topic that I'd take on full tilt. Fortunately, Abel Pharmboy explains the recent trial showing no benefit from saw palmetto in prostate hypertrophy. He also brings up a complaint that I've made about the National Center for Complementary and Alternative Medicine, mainly, its lack of scientific rigor and the poor quality of the grants it funds:
Anyone associated with drug discovery and development whether in academia or industry will tell you how extreme the guidelines are for chemical composition and purity of any drug product intended for clinical trials. Yet, NCCAM continues to fund expensive clinical trials of botanical therapies even when the chemicals purported to be responsible for biological activity(ies) are unknown. In the rush to show clinical utility, this funding agency has taken shortcuts on the basic science studies necessary to precede any clinical trial, perhaps hoping that one day they will get a positive result. Instead, they are racking up a series of high-profile failures that cast a broad shadow across all natural products research and creating public relations challenges for otherwise well-meaning herbal education and trade groups.

Only now has NCCAM revealed that they probably should fund investigations of basic science, mechanisms of action, and, be-still-my-heart, phase I pharmacokinetic trials.

Since its inception in 1992 as the NIH Office of Alternative Medicine, NCCAM has been a lightning rod for criticism of how the scientific method has been abandoned in favor of trying to show that ideological therapies work. Basic scientists in pharmacognosy and natural products chemistry were enthusiastic initially that a new funding source would be available to support their work. However, NCCAM was charged with reviewing all types of alternative therapies, from the more legitimate realm of herbal medicine to the implausible, homeopathy, for example. Review panels were stocked with individuals who had never held an NIH grant, much less with experience reviewing grant applications. An unusually high percentage of dietary supplement industry and trade group panelists infiltrated the peer-review system. In 2002, Quackwatch.com reported that just ten individual investigators held more than 20% of the NCCAM budget. I'd encourage Dr. Sampson to conduct another assessment today.
Read the whole thing.

4 example(s) of insolence returned:


At 2/09/2006 11:26 AM, Anonymous Anonymous said...

I think the post is slightly one sided.

Let's say we knew saw palmetto was not harmless in adults at the dosages given; we could deduce that reasonably accurately if it were true, from looking at samples of past users. This isn't a new compound after all.

Let's say we didn't know whether it *worked* (it probably doesn't). And we wanted to know.

Skipping the binding studies and proceeding to a clinical trial could be appropriate in certain, VERY limited, circumstances:

1) We don't know what the compounds ARE which cause the purported good effects (just the main fractionated compound? Or does it work in concert with other compounds which are present? Are any of them precursors?
-We're pretty good at NMR to identify what's in something, but as an ex-researcher I know that identifying what something does, and where it acts, is far harder.

2) You have trouble designing a physical model. I.E. you may not know where to run your binding studies. Or you may have difficulty finding the proper animal for dose/response studies (mice are different from dogs are different from rats are different from guinea pigs are different from primates and so on as I am sure you know). And of course depending on the way you isolate your compounds, and how you dose them (remember the possibility of other trace compounds having an effect) you may fail to find an effect if it exists.

3) You may want to reduce fase negatives. Drug companies like the one where I used to work are used to discarding failed compounds and do so all the time. Nobody develops much of a vested interest in something in the in vitro stage; we failed stuff constantly.

But when doing so, *everyone* knows there's a false negative that can pop up. The many stages of trials are designed to eliminate false positives, but anything which gets eliminated from consideration based on a binding study or a single rodent workup has some chance of being falsely eliminated--maybe it would have worked in humans, given through IV; yadda yadda.

Any you know what? Those false negs are OK. Without them we couldn't do science. They're par for the course.

BUT, with something like saw palmetto, or another supposedly wonderful treatment with constant support, you have to ask more questions:
-What would be the cost to society of a false negative?
-What would be the cost to SCIENCE in terms of its credibility among the altie set, if it was later proven to have given a false negative?

This last point, I fear, is quite compelling to many.

And no, I don't take saw palmetto, homeopathy, etc. Never will. I am not an altie. Hell, I have done years of in vitro and in vivo research at a large drug company. But I think that automatically dismissing all fast track clinical trials is a poor idea as well. There are a VERY VERY few instances where they MIGHT be warranted.

Erik H.

 

At 2/09/2006 11:37 AM, Anonymous Anonymous said...

When I heard this on the radio, I went to find out the citation for the study. Using Google News, I found it and also saw that the Health Fraud Industry is already trying to discredit the study. See http://www.naturalproductsinsider.com/hotnews/62h815837.html for an example. Most of the previous studies they tout were small, short term, and poorly controlled (e.g., the placebo was obvious). To me, those are no better than anecdotes.

 

At 2/09/2006 12:40 PM, Blogger Abel PharmBoy said...

Thanks for the plug, Orac. Having you off at a meeting and giving your own talk is about the only way I can sneak in with something significant before you get to it first!

Erik H.: I greatly appreciate your comments and former pharma background. I encourage you to go back and look at some comments I added this morning. Regardless of whether one agrees that sufficient literature existed to embark on the trial (I actually agree that there was), it's irresponsible to go into clinic with a specific plant extract that hasn't even been characterized by a bioassay for some surrogate endpoint. I support the use of well-qualified, whole herbal products but still hold that a thorough chemical analysis should be required where specific compounds or combinations are quantified and linked in a dose-response fashion to a biochemical or cellular endpoint that would have suggested a high probability for clinical success.

In fact, my argument supports your concerns of this trial being a false negative. I will be very sorry for patients with BPH if the negative outcome seen here was not because saw palmetto doesn't work, but that the extract of saw palmetto used simply lacked the compounds, or a high enoug concentration, necessary to reduce prostatic swelling.

 

At 2/11/2006 9:40 PM, Anonymous John Johnson said...

From my understanding, saw palmetto isn't recommended for the severity of swelling studied.

But who the heck am I to know. While we can probably, as Erik suggested, skip some of the preclin studies, and maybe even PK is hard to do, but what I didn't see was a dose-ranging study. Instead, an NCCAM advisory committee evaluated different products, and the articles I've seen (e.g. the one in Forbes) didn't describe the criteria. They only said that smaller studies had ambiguous results.

So, how hard is it really to adapt some of the earlier phase strategies into a CAM product development. That way, large negative studies such as this saw palmetto one and the echinacaea one have a better chance of being avoided (either by being planned with a dose in a therapeutic range or avoided altogether). Or, if the large, well-controlled and powered study does end up with a negative result, the design can withstand more criticism.

 

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