Generics not the same? Oh dear me..

Any sort of even minor groundswell against generics could lead to a catastrophic disintegration of the global healthcare system. Generics are cheaper, not just a little, but A LOT cheaper, like 90% or more than the branded versions, and their existence lies at the very core of the modern capitalist-patent innovation system.

We (society) agree not to copy a pharmaceutical company's innovations for a specified period of time (the length of a patent), as long as the details of said invention are published and made openly available after the end of the patent. In the meantime, the innovator enjoys a monopoly on his/her invention and can therefore price and market it at will, thus enabling the innovator to recoup their capital, and society to enjoy the innovation's benefits during the length of the patent. Obviously a key element of generics, once the expiry of the patent, is to exactly copy the original drug. Specifications are of course provided in the original patent, in addition to the fact that most small-molecule drugs can rather easily be reverse-engineered.

Well, this smoothly running deal between society and innovators that underpins the entire innovation paradigm of modern healthcare, while providing the obvious answer to future concerns over skyrocketing drug costs, is being called into question. Apparently, generic versions of GSK's Wellbutrin (bupropion, see label here) have been called into question.

New test findings by ConsumerLab.com that were released to MSNBC.com showed that one of a few generic versions of Wellbutrin XL 300 mg, sold as Budeprion XL 300 mg, didn't perform the same as the brand-name pill in the lab...

...For the testing, ConsumerLab.com purchased both the original Wellbutrin XL
300 mg sold by GlaxoSmithKline and the generic version sold by Teva, the same
one that Douglas took and that many other readers complained about, and had six
samples of each drug analyzed. While both drugs contained the stated amount of
the active ingredient, bupropion, "dissolution testing" showed that the generic
drug, which has a different time-release mechanism, released the active
ingredient into a solution at a quicker rate. "The Teva product released
nearly half of its ingredients in the first four hours," says Cooperman. "The
original Wellbutrin released 25 percent." Within the first two hours, 8
percent of the original Wellbutrin had dissolved, compared with 34 percent of
the Teva product, according to Cooperman. By 16 hours, both drugs had released
all the medicine.

WOW. A few quick-hit thoughts:

1. Teva isn't just some fly-by-night sketchy generics operator, it's one of the world's premier generics manufacturers (in fact, it even has one or two of its own branded drugs, like the oral MS drug Copaxone).

2. The MSNBC article, and none of the other articles I've seen, make any mention of the potentially enormous economic and social ramifications of loss of patient faith in generic drugs.

3. While the article notes it briefly, the test done by consumerlabs.com is highly suspect, in that it was an in vitro test ('in glass' i.e. in a test tube) and thus is not as rigorous as FDA testing. The FDA tests 'bioequivalence' which measures the actual drug biology in healthy volunteers, and is thus far more realistic than some test tube. Nonetheless, the words of this pharmacist stick in my head:

"the combination of anecdotal evidence and the conclusions of the in vitro study
would lead one to believe that patients might receive a different therapeutic
outcome from the two medications."

Alcohol as a therapeutic?

From Australia (where else?) comes this gem of a story about alcohol being used therapeutically:

DOCTORS used a case of vodka to help save an Italian tourist being treated for poisoning in a Queensland hospital. And hospital authorities later proved very understanding about the booze bill. The 24-year-old man was brought to Mackay Base Hospital, in north Queensland, two months ago after he had ingested a large amount of the poisonous substance ethylene glycol, found in antifreeze, which can cause renal failure and is often fatal.

Well I got curious, of course, as to how exactly it was possible for alcohol to be GOOD for you (asides from red wine, but then its not the booze in red wine that's helping you, but some of the other stuff). I also got curious, however, because this story directly relates to the Chinese Poison Toothpaste Fiasco that has been leading headlines this year (you may recall, ethylene glycol is similar to glycerine and was substituted in toothpastes made in China).

Luckily, the beauty of the modern 'radiated library' known as the internet has merged with the 1980s/90s 'evidence-based medicine' movement to let average Joes like me access lots of free medical information. Here, you can find "Methanol and ethylene glycol poisoning: a case study and review of the literature" which neatly summarizes (in fairly penetratable medspeak) exactly what happens with ethylene glycol poisoning.


Essentially, ethylene glycol and alcohol go through the same metabolic pathways in the body, and thus are broken down by the same compounds. Ethylene glycol itself is not poisonous, it is its after-molecules that cause trouble. Oxalate acid in particular has a tendancy to build up in certain bodily tissues, especially the kidneys. This 'oxalate crystal deposition' is a primary mechanism of ethylene glycol's toxicity, and leads to kidney failure (and potentially death). This is ethylene glycol's metabolic pathway:

Treating ethylene glycol poisoning is really easy, you first have to block the molecule's metabolic pathways, to prevent further harm. This is usually accomplished with IV ethanol (alcohol) or fomepizole, and seeks to block the action of ADH in metabolizing the compound. Fomepizole simply inhibits the ability of ADH to do its work, while ethanol 'competes' with ethylene glycol for ADH floating around in your system. It turns out that booze is 100 TIMES more able to soak up ADH than ethylene glycol, so putting just a little bit of alcohol into your system quickly takes up all the available ADH, simply preventing ethylene glycol from breaking down while you are drunk. In the meantime, while ADH is being blocked, ethylene glycol is simply floating around, not dangerous, but not going away. Simple hemodialysis (filtering of the blood through an external machine) can accomplish the task of scrubbing your blood of the ethylene glycol.

This is why the docs gave the guy 3 drinks an hour for 3 days, because they essentially needed to keep him long-term buzzed , to prevent his kidneys from failing, while they scrubbed his blood. I guess he took so much, that it took them a while. HAH.

Also check out wikipedia.

FDA shuts down company for illegally marketing their product as a drug....nice

Well, this is exactly what it is designed to do, grats to the FDA. From here:

The U.S. Food and Drug Administration (FDA) has issued a Warning Letter to Brian Manookian, owner of Melanocorp, Inc. in Hendersonville, Tenn. for the illegal sale and marketing of the product Melanotan II, which is not FDA-approved, on Melanocorp's Web site.

The website www.melanocorp.com is currently a blank page. Luckily we have the internet wayback machine.

The FDA letter is here. A great read. Essentially, they got nailed for saying their product was a drug, but more than that, by saying it was a NEW drug. Looking through the archive above, you can see they claimed it worked when it was "not generally recognized as safe and effective for its labeled uses"(fda words, great phrase).
But the FDA letter is worth a read more because it is so harsh, and they clearly dont believe the company have any valid claims, and have any chance of recovering.

Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps you have taken to correct violations . Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction. If you no longer manufacture or market Melanotan II, your response should so indicate, including the reasons, and the date on which you ceased production.

That bold part is my favorite. they're saying, "If this letter caused you to shut down, let us know". The height of FDA bureaucratic arrogance, however, and frankly hilarious to me, is the very last paragraph in the letter, which I feel is kind of like "ok buddy, nice try. If you want to make a real drug, you can learn all about that online at this website or write to these kind folks and they'll answer your questions":

A description of the new drug approval process can be found on FDA's internet website at http://www.fda . ,gov/cder/rep-ulatory/anplications/default htm . Any questions you may have regarding this process should be directed to the Food and Drug Administration, Division of Drug Information (HFD-240), Center for Drug Evaluation and Research, 5600 Fishers Lane, Rockville, Maryland 20857 .

More on healthcare issues

So I wrote about the incredible burden of complex bureaucracies on the US healthcare system here, well, here's a really cool piece from Slate about same-day appointments at family doctor practices, something called an 'open access' model. There are huge difficulties in setting up such a system, not the least of which is the process of actually switching over from your appointment system. Another big issue:

Doctors also have to make sure their practices don't take on more patients than they can handle. The total number of patients in a practice, called the panel size, is crucial because it determines the demand for service on a typical day. Obviously, the larger the panel, the higher the number of expected daily appointments, and if demand outstrips supply, waits are inevitable. Yet many doctors have no idea whether their panel size is too large. They track only the patients they see, not the patients who wanted an appointment but didn't get one. That's a formula for underestimating actual demand for service.

Sound like we need more business and economics in medical schools.?..come on people!! Every time I mention this to someone in healthcare, or med school, they tend to enthusiastically agree. Anyway, luckily (or not) some academics are on the case!

Taking into account the total number of appointment requests is the first step to open access, but it doesn't do the trick on its own. It seems like common sense to balance the number of daily appointment slots with the average daily number of appointment requests. But a mathematical model built by operations researchers at Columbia University shows this intuition to be wrong.

Interesting. So I checked out the article, it's published online because they want to make the results as freely available as possible. In fact, they even have a spreadsheet where docs can enter variables about their practice size to get assistance on operating an open access practice. They summarize the above situation in a different way, and I think a little better:

A fundamental feature of patient demand for primary care
is its random nature: the actual number of patients
requesting care on any particular day will vary around the
average daily value, sometimes substantially. It is this
inherent randomness that makes it difficult to determine
the answers to questions such as: “How large a panel size
can be served by a given physician practice?” If not for this
variability in demand, the answer would be obvious—the
panel size would be the one that made the daily demand
for care equal to the daily number of physician appointment
slots available. However, with this variability, making supply and demand equal on average would create chronic backlogs for care and waits for appointments that would likely get longer and longer.

Really, really interesting. I'm looking for a doctor, I need to find me an open access doc, that would be awesome.

Lies everywhere

I ran across two completely unrelated, yet seemingly identical instances of data manipulation recently that I thought I would call out.

The first, from the NYT, suggests that the Pentagon and Bush Administration revised upwards the casualty totals from last winter, to retrospectively show a decline in violence during the much ballyhooed Surge-that-will-win-the-war (who the f calls a military strategy a surge? Eisenhower or Roosevelt would've laughed in his face).

"There were significant revisions to the way the Pentagon’s reports measure sectarian violence between its March 2007 report and its June 2007 report. The original data for the five months before the surge began (September 2006 through January 2007) indicated approximately 5,500 sectarian killings. In the revised data in the June 2007 report, those numbers had been adjusted to roughly 7,400 killings – a 25% increase. These discrepancies have the impact of making the sectarian violence appear significantly worse during the fall and winter of 2006 before the President’s “surge” began."

Another example comes from the publicly reported filings of Overstock.com, which have been analyzed by Sam Antar, reformed white-collar criminal. Overstock has been engaging in similarly sketchy machinations, this time with its inventory. In accounting, you track the value of your inventory-on-hand by estimating the lower of two numbers: either its cost, or its current market value. IF you don't sell your inventory, and it sits around and becomes unfashionable etc., then your inventory reduces in value. Typically companies will institute 'inventory reserves'. I'm going to use Sam's example:

In the first quarter, a company buys merchandise for $120, its books and records will reflect $120 of inventory.

In the second quarter, the company, under GAAP, reduces the value of its merchandise by increasing inventory reserves by $50 to reflect diminished future demand and market conditions. Therefore, in the second quarter, the company reduces its gross margins by $50. The net inventory book value on its balance sheet is reduced to $70 (original cost $120 less $50 inventory reserves).

In the third quarter, the company sells the merchandise for $90. Since the net value book value of the merchandise was previously reduced to $70, (as a result of taking a $50 reserve against its original purchase price of $120 in a previous quarter), the company recognizes gross margins of $20 (Sales $90 minus net book value $70).

The company, under GAAP, had gross margins of $20 in third quarter after selling the previously written down inventory. It would seem on its face to be an improvement over the reduction of gross margins by $50 in the second quarter resulting from the inventory write down. However, in reality the company lost $30 on its merchandise. The original cost of the merchandise was $120 and they sold it for $90.

Therefore, taking inventory reserves increases future gross margins.

Sam has put together a 3-part post (warning, pretty technical part 1, part 2, part 3) on the sleight-of-hand being done by the company behinds the scenes. In recent conference calls, the Overstock.com company executives have been touting their recently high margins. Well, as is convincingly demonstrated by Sam, overstock.com cooked the books by taking too many inventory reserves in previous quarters, which reflects positively on margins when they actually sell the inventory in later quarters, but is still a net loss for the company. Sound familiar? Like...maybe what the Bush Administration just did?