Wednesday, February 08, 2006

Another botanical clinical trial doomed to failure from day 1

You'd think the funding folks would learn at the NIH National Center for Complementary and Alternative Medicine (NCCAM). But, not as evidenced by the report in tomorrow's New England Journal of Medicine detailing the lack of efficacy of saw palmetto (Serenoa repens) extract in the treatment of benign prostatic hypertrophy.

Yet another well-designed double-blind, placebo-controlled trial has been doomed to failure by inadequate chemical characteriztion of the study material. Political pressure to produce a postive clinical result has bypassed the normal path of pre-requisite basic science studies, casting a shadow on what may still be a useful herbal medicine.

About 2.5 million US men use extracts of berries from saw palmetto, a low-lying, scrubby palm native to the coastal southeast from South Carolina to Florida that can also be found in southern California. A couple of small clinical trials, covered in this Cochrane review, had intimated that saw palmetto extracts can improve urinary flow in men with enlarged prostate glands, with efficacy similar to the prescription drug finasteride. Finasteride, sold in the US as Proscar, inhibits an enzyme called 5-alpha-reductase that converts testosterone to its more active form, dihydrotestosterone. As a result, finasteride has been associated with a greater incidence of sexual side effects (mostly ejaculatory disturbances) relative to saw palmetto as detailed in this meta-analysis.

No one knows for sure how saw palmetto is thought to work. Some reports suggest that it too is a 5-alpha-reductase inhibitor, but then wouldn't it be expected to produce the same sexual side effects as finasteride? No evidence exists either to suggest that saw palmetto might act as a alpha-1A adrenergic receptor antagonist, like another prescription drug, tamulosin.

In fact, no one knows the precise chemical compound(s) in saw palmetto extract that reduces prostate swelling. How then could a major US funding agency approve the conduct of a clinical trial when there was no possible way to chemically characterize the study agent? If you don't know what to look for, how do you know it's there?

Well, an advisory panel for NCCAM thinks they know. Cited in the paper was that while there are no widely-accepted guidelines on the content of saw palmetto extracts, a number of authorities have recommended that extract contain 80-95% fatty acids or 85-95% fatty acids and >0.2% sterols. Why no requirements for the presence of specific compounds with real, IUPAC names?...because no one knows the identity of the active components of this herbal extract. Would you be willing to invest what was probably $2-4 million in a clinical trial of this extract?

Not me, and certainly not with US taxpayer's money. The scientific approach would be, minimally, to design an in vitro model for markers of prostatic hypertrophy (not exactly my area of expertise) and then chemically fractionate saw palmetto extracts to find the one, two, or ten chemical compounds that had effects on these endpoints. Then, you might want to try some simple metabolism experiments (and perhaps a phase I clinical trial where these pharmacokinetic parameters are assessed before anyone in their right mind would jump full bore into a phase III efficacy trial) to be sure that any of these compounds might make it to bloodstream and the prostate in concentrations consistent with these effects when patients are given a certain dose. After all, we catabolize fatty acids for energy and the liver's cytochrome P450 drug metabolizing enzymes are likely to have first evolved to destroy plant sterols we encounter in our diet.

Instead, the authors report that NCCAM chartered an "expert advisory committee" who conducted a bidding process to find a company that would provide them with an extract that met the above criteria together with a placebo. One of my herbal industry sources close to such a bidding process for another botanical trial reported that all NCCAM cared about was whether the company would absorb the costs of providing the study material. This all but rules out any small company that might be doing excellent science and favors the herbal big-boys, narrowing the choices to two or three companies. And why worry about saving $100,000-$200,000 at most when a $3 million trial is riding on the quality of the study material?

No offense is intended toward the investigators and authors of this trial. They are all highly-qualified MDs, PhDs, and/or MPHs at one of the premier US academic medical centers and the primary author was a recipient of a highly-competitive physician-scientist career development grant called a K08. However, the investigators relied on their funding agency to procure for them the best product and one that had been well-characterized for chemical composition and biological activity. In this case, the funding agency clearly let down their grantees.

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, reported that just ten individual investigators held more than 20% of the NCCAM budget. I'd encourage Dr. Sampson to conduct another assessment today.

Herbal or botanical medicine holds great historical promise for the prevention and treatment of illness. In the past, we have usually tried to identify the biologically-active compounds present in herbal medicines so that doses could be established for standardized scientific products. (This principle was first recognized and appreciated in the early 1800s when the German pharmacist and chemist Serturner first isolated morphine and codeine from the poppy, Papaver somniferum.).

But, if you jump into a clinical trial without knowing what you're testing, how can you have any confidence that a positive or negative outcome is meaningful? Or reproducible?

Only time will tell if NCCAM's newfound embracing of mechanistic, basic science studies will improve the likelihood of success in clinical botanical trials. I encourage my basic science colleagues to answer the call if they are asked to serve on NCCAM grant review panels.

The only way to be sure that solid science is done is to have solid scientists represented in the review and funding process.


At Wed Feb 08, 01:26:00 PM EST, Blogger Bill Hooker said...

The basic issue, I think, is reproducibility of the extract. Different methods of extraction, seasonal variation in the raw ingredient and a range of other factors will mean that different extracts may contain very different mixtures of compounds.

Fractionation gets around this problem, but creates its own replacement problems: what if the "active ingredient" in the extract is actually several different molecules with complementary effects? If (f'rinstance) one is lipid-soluble and the others water-soluble, most initial fractionation methods are going to separate them. Why split everything up and then run combinatorial screens in vitro, when the claim for efficacy is being made for whole extract in vivo?

You want an in vitro model, but those can be hard to come by and very expensive to establish and maintain in their own right (a single, relatively small mouse colony, for instance, will run you $20-30,000 per month).

I don't think the trial was a complete failure: it showed that the extract they used has no effect. Anyone who wants to further test efficacy has now a standard to compare with, and will want to be using a different extract (with, at best, some rational design behind the difference).

At Thu Feb 09, 12:15:00 PM EST, Blogger Abel PharmBoy said...

Dr Hooker, howdy, mate! I'm honored to have you come over and comment.

I think we agree in principle. In fact, I have been quite vocal prior to starting the blog that negative clinical outcomes in botanical trials refer only to the formulation being tested and NOT all products made from the same herb.

I'm also a fan of whole extract studies since Frank Stermitz's famous demonstration of NorA inhibitors in Berberis spp. that accounted for why whole extracts were superior to pure berberine in killing S. aureus.

Where I object to funding this trial is that more work should've gone into a complete chemical characterization of the fatty acids and sterols. I know of no way to interrogate a complex herbal mixture without having at least 1) a surrogate model system for your desired endpoint and 2) fractions or pure compounds that comprise the entire plant extract. Dr Ed Croom of Indena (who supplied the extract) and the Univ of Miss Ctr for Nat Prod Research is a world-class natural products chemist whose lab could have done this if NCCAM provided the funding. My objection is that the funding agency has been trying to get off on the cheap and bypass the level of rigor that, say, GW Pharmaceuticals has done with their cannabis-based analgesic, Sativex.

What is lacking for a subsequent study is to know whether the entire dose should be increased or whether the specific source of saw palmetto berries used lacked sufficient concentrations of the active principles. "Characterization" by broadly defining the extract as X% total fatty acids and X% total sterols may miss crucial individual compounds whose concentrations may be too low at these doses to have a clinical effect.

Bottom line: By herbal standards, there was a very reasonable amount of evidence to put saw palmetto in the queue for a good clinical trial. But, now, before starting another trial, I'd encourage funding of a couple of very rigorous chemical studies of various saw palmetto cultivars to identify specific compounds, alone or in combination, that would reduce BPH biochemical surrogates in culture and/or in vivo rodent models (if one exists - as I said, I'm not a BPH expert, but I'm told I will be in about 10 or 15 yrs!)


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