MERCKANTILISM

Merck was once an honored name. The Merck Manual was relied on by every
doctor, the Merck Index by every chemist. The Merck image was precision and
exactitude. Today Merck means Vioxx and spin.

Merck was spending $8.5 million a month advertising Vioxx, until the CEO
announced a "voluntary recall" in late September. Merck's prescription
painkiller was peddled so persistently on TV that "It's a beautiful
morning" must have been lilting into the ears of at least a few arthritis
sufferers as their Vioxx-induced heart attacks and strokes onset. Maybe
some were even humming along: "It's a beautiful morn-AAARGH."

I know it's not funny, it's a form of assault, even murder. More than two
million Americans had been taking Vioxx, and thousands of users may have a
heart attack, stroke or serious blood clotting as result. In 2003 Merck
sold $2.5 billion worth of Vioxx, accounting for 11% of their worldwide sales.

This is a drug for which there was only a trumped-up need, and for which
there would have been no need whatsoever if the DEA allowed U.S. doctors to
prescribe codeine readily - not to mention cannabis.

"Safety" was the rationale for developing Vioxx (and Celebrex, now made by
Pfizer but developed by G.D. Searle, a Monsanto subsidiary). Aspirin and
other non-steroidal inflammatories such as ibuprofen (Motrin, Advil) and
naproxen (Aleve) are effective, but large doses can cause gastrointestinal
bleeding and peptic ulcers in some people. (Tylenol isn't anti-inflammatory
at all. It reduces pain and fever while damaging the liver.) So the drug
companies saw an "easier-on-the-stomach" marketing niche that, given the
prevalence of arthritis and chronic pain -and the rationing of codeine and
prohibition of cannabis- could prove lucrative.

Aspirin and the other NSAIDs work by inhibiting an enzyme called
cyclooxygenase (Cox), that helps make compounds called prostaglandins that
facilitate the inflammatory response and have other important functions,
including protecting the stomach lining and maintaining kidney
function. In the 1980s a team led by Searle researcher Philip Needleman
found that there are two forms of cyclooxygenase (Cox-1 and Cox-2). Because
the NSAIDS inhibited Cox-1 more than Cox-2, and because Cox-2 was more
prevalent in damaged tissues associated with arthritis, it was hoped that a
drug that inhibited only Cox-2 production would reduce inflammation without
gastric side effects.

So, billions were invested in research and development, and the Cox-2
inhibitors were pushed towards the market. One of Merck's early studies
showed that patients on Vioxx suffered more heart attacks than patients on
naproxen, but the company claimed, without evidence, that this was due to
some protective effect of naproxen, and the FDA bought it. (Aspirin reduces
heart attacks; naproxen doesn't.) People with heart problems were excluded
from subsequent clinical trials of Vioxx. The goal of the large-scale study
that revealed a 200% increase in heart attacks and strokes was to show that
Vioxx reduced polyps in the colon! Merck was looking for an additional
marketing niche, not trying to answer ominous questions about the safety
profile of its #3 bestseller.

According to Marcia Angell, MD, former editor of the New England Journal of
Medicine, "It is likely that many more people had heart attacks and strokes
from Vioxx than were saved from bleeding ulcers, given the high prevalence
of heart disease in the population that uses Vioxx and the deliberate
exclusion of those people in the trial... Cox 2 inhibitors like Vioxx are
no better than over-the-counter drugs for relieving arthritis symptoms
(they do not enable you to skate like Dorothy Hamill), far more expensive
and of only limited effectiveness in preventing gastrointestinal
complications."

Marcia hasn't always been an angel when it comes to full and frank
criticism of the medical establishment. As editor of the NEJM she ardently
vouched for the safety of silicon breast implants on behalf of the
manufacturers. But now she's calling on the FDA to require long-term trials
of Celebrex and other Cox-2 inhibitors. (Celebrex is currently being tested
as an anti-polyp drug in two clinical trials and to slow the progression of
Alzheimer's disease in another. Pfizer will report any safety problems.)

U.S. drug companies spent $3.8 billion last year on advertising aimed
directly at consumers -a practice that was illegal until the mid-1990s but
now is upheld as some sacred "consumers' right to know." Kerry and Edwards
have mentioned that direct-to consumer advertising of pharmaceuticals
drives up health-care costs, but don't expect the corporate media, with so
much revenue at stake, to publicize the issue.

CEO Raymond Gilmartin was twitching (probably due to a cannabinoid
deficiency) when he announced Merck's "voluntary" recall of Vioxx, but he
managed to take credit for conscientious corporate behavior -and the media
played along. The struggle is now on for the hearts and minds of jurors
who will decide what Merck owes to thousands of victims. The company has
begun the search for Gilmartin's successor by auditioning several
headhunter firms. Could you design a system more irrational, wasteful,
corrupt, unfair, and inefficient than capitalism in this late, degenerate
stage?

In a related story, the British equivalent of our FDA, the Medicines and
Healthcare products Regulatory Agency, has closed the factory in Liverpool
where Chiron was making 48 million doses of flu vaccine for the U.S. market
The MHRA impounded all the vaccine (while Chiron execs whined to the FDA
that only a small percentage was contaminated). Chiron is a biotech company
based in Emeryville, California, whose scientists have no experience
producing flu vaccine by the current method (injecting viruses into the
embryos of eggs that get incubated, hatched, and processed). Chiron has a
longterm plan to manufacture vaccines by a yet-to-be-perfected cell-culture
technique. To gain entree to the flu-vaccine market, they bought the
Liverpool egg-embryo-culturing facility in early 2003 and assumed
responsibility for providing half the U.S. supply. But they basically
didn't know what they were doing.

In the summer of 2003 U.S. FDA inspectors found "deviations" from good
manufacturing procedures at the Liverpool facility -equipment that wasn't
sterilied, variations in potency and stablility, and high levels of
bacteria in some unfinished batches of vaccine. According to the Wall St.
Journal, "John Taylor, the FDA's associate commissioner for regulatory
affairs, said 'systemic quality-control issues' led inspectors to conclude
that Chiron wouldn't necessarily be able to discover problems, identify the
root cause and take steps to prevent similar issues from arising again."
But the FDA wasn't moved to intervene, even after Chiron reported in August
of this year that finished batches of vaccine at the Liverpool plant were
contaminated with serratia, a bacteria that can cause bloodstream
infections. Good thing the MHRA was on the case.

APPROVAL AS A 'BOTANICAL'

We asked a source at the FDA what it would take for cannabis to get
approved as a "botanical" rather than a pharmaceutical drug. He replied:

"I've never heard anyone at a drug company or FDA talk about medical
marijuana, but there's a lot of useful experience with other botanicals.

"The first step in qualifying a product for medicinal purposes, here or in
any other developed country, is to have a well-defined product, and this is
where most botanicals have difficulty. Even a botanical with a strong
claim for homogeneity (e.g., one made in huge, well-mixed batches, with
some sort of convincing standards to control batch-to-batch variation)
would be suspect; it must contain many chemical species, and it's unlikely
that all are useful or even benign. Why not hold out for a better-defined
preparation? Opium and digitalis leaf were both important, but regulators
and clinicians feel that they are on firmer ground with morphine, codeine,
digoxin, or digitoxin. It might have turned out that morphine works only
in the presence of codeine, and so on, but I don't know of any example
where anything like that is the case.

"There is no legal basis for FDA recognition of the differential cost of
one medication over another, so moderate difficulty in separating the
components of a botanical does not elicit any bankable official sympathy.

"On the other hand, many so-called pure substances are in fact racemic
mixtures, and there is only tepid interest in specificity at the enantiomer
level. Even returning to botanicals, the heterogeneity issue would be
tractable if there were solid proof of safety and efficacy, and if
separation of the active components appeared to be extraordinarily
difficult. Suppose that a sponsor presented data to that effect to FDA.

"That's the point at which the FDA would start to hear from outsiders in
the Administration and in drug companies. The Administration would be able
to weigh in first because an application before FDA is not publicly
discussed until an (optional) Advisory-Committee meeting, late in the
course of review. Before then, the Administration could quietly arrange
that the application be rejected. I would have regarded this possibility
as far-fetched until this year, but all things are possible with Bush.

"The drug companies might chime in at an Advisory-Committee meeting, but
it's hard to imagine a scenario in which things got that far. If it were
agreed that some easy-to-produce version of medical marijuana could be
considered by FDA, then its sponsor would face two problems, one much more
serious than the other. The easy problem would be opposition from drug
companies with competing products, but aspirin has always held its own
against the brand-name NSAIDs, and even within the aspirin business, Bayer
has made no serious attempt to drive the cheaper brands from the field.

"The more serious problem is that if marijuana were approved, then the
original sponsor would have no effective way of making any money from it.
This is the reason why newer uses of aspirin are rarely studied."

We also asked if there were any significant differences between the FDA and
the UK's Medicines and Healthcare products Regulatory Agency.

"The main difference is that the FDA is much bigger, so FDA is the only
drug-regulating agency in the world able to look at raw data instead of
working from the summaries provided by academic experts. Also, there are
at least a few deep thinkers at FDA, but in my experience I came across
only one at any other drug-regulating agency, and she was from the German
agency, not the UK.

"Some other agencies (notably that of Australia) have arms that look at
cost-effectiveness, unlike FDA. Some (notably that of Germany) have arms
that look at various folk medicines (homeopathy, etc.) by different
standards."

We've got the deep thinkers, all right. We're number one. Maybe not in
literacy, or longevity, or men's basketball, but deep thinkers.