The Scientist : NewsBlog Print: Diet drug duke-out

by James Gormley

[Comment posted 2008-07-08 16:30:12]

Dear Dr. Karpf (or Kapf...your name is is spelled one way in the byline and one way in your listed affiliation slug),
Last time I checked my AP manual, accusing someone of making false statements (falsehoods) is tantamount is calling them liars ... so perhaps you wish to rephrase or retract your statement referring to "outright falsehoods."
As to your comments re GHB, apparently the poster meant to refer to L-tryptophan and that whole debacle that had nothing to do with the supplement industry and had everything to do with one company in Asia cutting corners on a batch of product. Period. Full stop. End of that story.
And you may have failed to note (or at least comment on) my observation regarding the over 1 million adverse events in hospital per year from properly prescribed, FDA pre-approved drugs and over 100,000 deaths from those same drugs as indicative of a system that is associated with a model that, far be it from working, is rife with danger and mortality and is part of a failed, drug em, cut em and forget em paradigm.
As to orlistat and alli, how is it disingenuous to refer to the increased incidence of or risk for pre-cancerous lesions (aberrant crypt foci) associated with this drug. It's a real risk that was dismissed by the FDA as being of no clinical significance; the National Cancer institute (NCI) does not dismiss the importance of these pre-cancerous changes.
Nobody in the world (who is credible or rational) is saying that all supplements are always 100 percent safe and all drugs are always 100 percent dangerous. What is fair to say is that dietary supplements are inherently benign (which is why they are a sub-class of FOODS) and drugs are inherently risky.
To suggest that almost all supplements have no data demonstrating safety or efficacy in controlled trials is so mistaken (and erroneous) and far from the truth as to warrant a citation-laden response that would far exceed the limits
of this blog.
As an endocrinologist, you may appreciate having an opportunity to read the following review I co-published in 2005, Nutritional Supplements Modulating Metabolic Syndrome Risk Factors and the Prevention of Cardiovascular Disease (http://www.bentham.org/cnf/sample/cnf1-1.htm).
As to your post, I would probably suggest you consider including a label along with it entitled Reader Beware.
Sincerely,
James J. Gormley

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comment:

Adding Some Balance

by David Kapf

[Comment posted 2008-07-02 15:31:52]

Anthony Musci makes some valid points; in contrast, both Hunt's and Gormley's posts are rife with outright falsehoods.

Hunt states that GHB "may have the highest margin of safety of any drug known". Nothing could be further from the truth. GHB is a potent anesthetic that produced a number of adverse experiences during studies in the 60's & 70's. More than 16 published studies from 1990-2000 on the widespread public experience with GBH document serious side-effects including profound coma (all the more serious d/t abrupt onset), respiratory acidosis, bradycardia, myoclonus, acute delirium, aspiration, vomiting, excessive salivation, incontinence and death.

Over a 3-year period at SF General Hospital, of 88 GHB ODs 70% were males (not date-rape) and one third took GHB without any co-ingestion, including alcohol. Of 15 ODs over a 6-month period, 73% were male, 33% had no co-ingestion, and 73% had GCS levels of 3 (30% had sig. bradycardia, 13% required intubation, and 7% aspirated). Of note, even with these serious ODs there was a wide range of serum GHB levels, ranging (peak) from 45 to 300 mg/L, attesting to the huge inter-individual variability in drug level from the same dose. Of the 20 of 88 patients who died, blood GH levels varied from 140 to 2900 mg/L! GHB is also addictive, with symptoms of insomnia, extreme anxiety % diaphoresis developing within 1-5 hours of last dose; agitation, dysphoria, delirium, hallucinations, tachycardia & hypertension developing over several days, with symptoms lasting 5-15 days in a series of chronic users aged 23-38 (75%M, 25%F) (Miotto, in press).

What really contradicts the claim of a wide safety margin are the 3 factors of abrupt onset of CNS depression/coma; profound variation in drug levels with the same dose; and substantial variation in patient response to the same drug level. All of these data come from the California Poison Control System-SF.

Gormley cites the black-box warning on Avandia as an indictment of the drug safety review process, indicating that he doesn't understand how the process works. Approval is based on Phase 3 trials that simply cannot be powered to demonstrate rare serious events (less than about 0.5-1% incidence). Post-marketing surveillance is supposed to identify the rare serious events, which is what it did with Plavix (a single case of TP during Phase 3) and Avandia (no imbalance of CV events during Phase 3). Adding a black box to the label actually shows that the system works.

Further, while he is correct that use of orlistat (especially at the Rx dose) can be associated with some unpleasant (& embarrassing) side-effects, none of these are remotely serious. However, it is quite disingenuous to cite ?such serious potential problems as pre-cancerous lesions). The carcinogenicity studies with orlistat were quite clean, as expected for a drug that simply inhibits (partially) an intestinal lipase and which is essentially not absorbed, acting in the GI lumen. There is no suggestion from any nonclinical or certainly human study suggesting any carcinogenic potential for this molecule.

There is simply no basis for the view that all pharmaceuticals are dangerous whereas all ?supplements? or botanicals are safe ? some of the most toxic compounds known are found in plants. While GSK certainly has a very vested interest in trying to put a hurdle in front of unregulated OTC ?herbal? weight loss ?drugs?, the fact remains that with rare exceptions (such as glucosamine/chondroitin for OA), almost all the supplements have no data demonstrating efficacy (or safety) in controlled trials. It is truly ?Buyer Beware?.

David B. Karpf, MD
Adj. Clinical Assoc. Professor of Medicine (Endocrinology)
Stanford Univ. School of Medicine

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comment:

Pollyannas of the supplement world

by Anthony Musci

[Comment posted 2008-07-02 13:28:02]

That the political and economic influences of pharma on the drug market create problems in the proper execution of drug safety monitoring should not detract from the fact that so-called dietary supplements are often either inefficacious, poorly standardized, and at worst hazardous. The supplement industry has their own spin doctors, and talking about the "safety" of dietary supplements relative to pharmaceuticals is ridiculous considering that most of them receive a fraction of the scrutiny of FDA-approved pharmaceuticals.

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At one time I would have supported more FDA involvment. No longer.

by Ellen Hunt

[Comment posted 2008-07-02 13:23:15]

The appeal to science and the public interest in this petition is apparently for the good. But in reality, it is a cynical ploy engineered with intent I think is worse than questionable. In the simplest way of looking at it, this drug raises serious health concerns.

The pharmaceutical industry has become a behemoth dedicated to its own sky-high profits. This has attracted the attention of investors and venture capital with mixed effects. Do we actually have more drugs and vaccines to maintain public health now? Barely for the former, and hardly, for the latter. Instead we have a parade of "latest thing" compounds which are touted through studies that are conducted by science that has become routinely questionable.

On the darker side, there are such matters as the withdrawal of L-tryptophan, a simple amino acid, from the market because of what turned out to be contamination of a batch. Following that was the hue and cry over GHB as a "date rape drug" despite the fact that prescription alternatives such as rohypnol have both escaped scrutiny and continue to be sold on the street. (Don't try to tell me the big pharmaceutical companies don't know where much of their product ends up. They know darn well exactly what happens to all of it.)

For both items, the real problem appears to have been that these simple compounds actually work to induce sleep, are not addictive, and are quite inexpensive. GHB may have the highest margin of safety of any drug known. That it can be mixed safely with alcohol and is not synergistic should be in its favor.

There was a time when the big pharmaceutical companies were truly dedicated to the public interest. But that day is long gone with the 1970's. In today's world, they routinely manipulate the media to get laws that will favor their profits, they routinely fudge or hide bad results. And yes, the big pharmaceutical companies routinely manipulate the legal process surrounding the FDA and influence peddle in order to prop up their products.

Disappointment does not do justice to what I feel about them today. Yes, they provide jobs for a myriad of PhDs coming out of biosciences. But at what cost? Who is trying to save humanity now? Who can even function within the current setup who wants to? I know some people are there, want to, try to.

But, it all boils down to the god of Wall Street in the end. The public good has nothing to do with any of it. To get ahead, to get into a position of making more money in pharma, a person must more than sell out. If they find something that works which isn't patentable, they must bury it as deep in the ground as they can. A publicly acknowledged example of this is Barry Sears finding a non-patentable compound that cured atherosclerosis, administered IV. There are others.

It is a terrible state of affairs really. The people at FDA in the trenches are mostly good folks still I think. I cannot say as much for the appointees. From one administration to the next, democrat or republican, things just trundle on.

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comment:

Trimming the facts?

by James Gormley

[Comment posted 2008-07-01 15:16:15]

The Newark Star-Ledger's June 29th article ("Trimming the competition") was well written yet sadly missed a number of critical facts that would have given it proper balance and perspective.

Firstly, the article---and your post---neglected to note that GSK was joined in this petition by three organizations that GSK supports: the American Dietetic Association, The Obesity Society and Shaping America?s Health. The organizations? signatories included a lobbyist, a person who helped get obesity classified as a disease and a fundraising guru.

If the FDA were to agree with this petition, American consumers would be unarguably cheated out of hundreds of legally and responsibly marketed dietary supplement products. The stage would also be set for challenges to other types of claims and to what would constitute irreparable damage to the dietary supplement industry and irrevocable losses to consumer choice.

Although the article did mention that approval of this petition would eliminate competition from dietary supplements which provide weight-loss or body-composition benefits, the article--and your post--failed to note that, on April 10th, 2006, Public Citizen called on the FDA to not allow GSK's orlistat to be re-classified as an over-the-counter (OTC) weight loss drug, now called alli.

Although the FDA dismissed Public Citizen's well argued request, the group had cited such embarrassing usage problems as anal leakage and such serious potential problems as pre-cancerous lesions.

The article (and your post) did not point out that this product went through both a prescription drug and an albeit cursory OTC safety review process and it still has a number of potential concerns associated with it.

In terms of safety, the article (and your post) also neglected to mention that GSK's prescription diabetes drug, Avandia, had an FDA safety alert issued for it, one which indicated that "there is a potentially significant increase in the risk of heart attack and heart-relate deaths in patients taking Avandia."

Shortly thereafter, the FDA required a black box warning for this drug, one which says: "Warning: Congestive Heart Failure and Myocardial Ischemia." It appears the much-touted drug safety review process didn't work here either.

Given the solid safety record of dietary supplements sold in health food stores---and the incredibly poor safety record of drugs---how could any pharmaceutical company have the gall to ask this country, and its servant the FDA, to ignore the 100,000 plus deaths and over 1 million adverse events every year from properly prescribed FDA pre-approved drugs?

The Star-Ledger and your post do not appear to find a disconnect in the fact that a corporate giant has filed a "citizen" petition. FDA.Citizen petitions, when originally instituted, were supposed to be just that: a formal means for a citizen, or more broadly the public, to contact the FDA and ?seek its action or response on a particular matter.?

The original intent of citizen petitions has been perverted to now facilitate ?citizen? petitions from corporate behemoths that are so removed from anything remotely resembling a citizen, or the public at large, that to continue calling them ?citizen petitions? is an insult to Americans.

Perhaps they should be called ?Big Pharma Petitions? since the ones submitted by actual citizens, citizens groups and the public are the ones which tend to fall into the eternal and stygian FDA backlog?unless, of course, the petition challenges the sacred cow of FDA decision making.

As to the claim by one of the article's interviewees that the petion "simply says 'dietary supplement makers need to be accountable in advance for the science,' " this characterization of the petition is a stalking horse that obscures what is obvious: that this is not about science, or safety or safeguarding consumers.

The petition is about politics and money, power and market provenance (read: control of territory).

The most disappointing omission by both the article and your post is the fact that neither discussed, or even mentioned, the consumer backlash to this petition.

To date there are approximately 700 public comments posted on the petition, most of them in strong opposition to the petition.

Perhaps the article should have been called, "Trimming the facts"?

Respectfully,
James J. Gormley
http://thegormleyfiles.blogspot.com/
work: 201-363-3801 (I work in Leonia)
cell: 914-648-9572

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