The pharmaceutical industry is plagued by the same problem as the entertainment industries: their business models are too reliant on blockbusters.  I’m certainly not the first person to notice that — even drug company CEOs have openly fretted about it — but the problem persists and grows each year. As the pharmaceutical consulting company L.E.K. pointed out a few months ago, “Blockbusters have become the centerpiece of the biopharma industry, growing from 16% of global drug revenue in 1995 to 35% in 2010.”

In the entertainment industry, the consequences of that reliance on blockbusters is merely a string of bad sequels to every hit movie and some unfortunate shark-jumping on television.  In the world of drug sales, though, it usually means a lot of people get hurt when a company fails to take a dangerous blockbuster drug off the market or update it with appropriate warnings.

Consider Propecia. Propecia is a 1 mg dose of finasteride, a drug originally used for the treatment of symptomatic benign prostate enlargement in 5 mg doses and marketed by Merck as Proscar. Finasteride, in turn, is a type II 5-Alpha reductase inhibitor that prevents the conversion of androgen testosterone to dihydrotestosterone (DHT).

In many ways, the mechanism of finasteride is quite simple: it inhibits the production of testosterone, a male sex hormone, and so it decreases the problems of high testosterone or testosterone sensitivity (male pattern baldness, prostate enlargement) while creating the same problems as if a man had low testosterone (decreased muscle mass and sexual function, impotence). The FDA-approved label for Propecia warns:

What are the possible side effects of PROPECIA?

Like all prescription products, PROPECIA may cause side effects. In clinical studies, side effects from PROPECIA were uncommon and did not affect most men. A small number of men experienced certain sexual side effects. These men reported one or more of the following: less desire for sex; difficulty in achieving an erection; and, a decrease in the amount of semen. Each of these side effects occurred in less than 2% of men. These side effects went away in men who stopped taking PROPECIA. They also disappeared in most men who continued taking PROPECIA.

Most of that is known and to some extent foreseeable by Propecia users.  It’s similar to the symptoms of low testosterone because that’s pretty much what Propecia does: inhibit androgen conversion to testosterone.

But hormones are funny things.  The endocrine system is as complicated as the immune system, with the added complication of all the hormones working together in concert, and many of the glands responding to any changes in the system.  Tampering with the system often results in mild improvement in symptoms and then some drastic side effect. We saw that with estrogen plus progestin hormone replacement therapy: HRT was conventional wisdom in the medical industry throughout the late 1990s — due in no small part to Wyeth and Pfizer marketed the heck out of Prempro — until the Women’s Health Initiative trials in 2002 revealed a substantial increase in breast cancer, prompting a complete about-face in treatment for post-menopausal women.

Coming back to Propecia, the warning label in the United States didn’t mention until June of this year, but the warning labels in the United Kingdom have said for some time:

In addition, the following have been reported in postmarketing use: persistence of erectile dysfunction after discontinuation of treatment with PROPECIA; male breast cancer (see 4.4 Special warnings and precautions for use)

Propecia in Sweden and Italy has similar warnings. The big problem there — the persistence of sexual problems, even after stopping the medicine — has been known for years. The Wessells et al. study (“Incidence and severity of sexual adverse experiences in finasteride and placebo-treated men with benign prostatic hyperplasia“) found that 15% of finasteride-treated patients (more than double the placebo patients) had sexual adverse experiences arising from Proscar use, and that half of those had problems continuing even after they stopped taking Proscar.

Over time, others have followed up. Earlier this year, the Irwig et al. study confirmed (“Persistent Sexual Side Effects of Finasteride for Male Pattern Hair Loss“) what the Traish et al. study (“Adverse side effects of 5α-reductase inhibitors therapy: persistent diminished libido and erectile dysfunction and depression in a subset of patients“) had suggested: use of finasteride at their the Propecia or Proscar doses results in persistent sexual problems for a number of patients.

Merck responded in June of this year, by adding a new warning, the type of language by-of-and-for the drug manufacturer’s lawyers that I like to refer to as a “wink, nudge” warning:

In general use, the following have been reported: breast tenderness and enlargement; depression; allergic reactions including rash, itching, hives and swelling of the lips and face; problems with ejaculation; testicular pain; difficulty in achieving an erection that continued after stopping the medication; and, in rare cases, male breast cancer. You should promptly report to your doctor any changes in your breasts such as lumps, pain or nipple discharge. Tell your doctor promptly about these or any other unusual side effects.

The language used is, of course, designed to make doctors and consumers ignore the warning. “The following have been reported” indicates Merck doesn’t really believe Propecia causes any of them. Just in case consumers didn’t get that wink, nudge message, it’s emphasized again that these are all “unusual” side effects, not the side effects attributed to the drugs.

So, what gives? Why didn’t Merck update its U.S. labels back in, say, 2008, when it updated the Swedish warning? Why does the Propecia label still claim all instances of erectile dysfunction and decreased libido “went away in men who stopped taking PROPECIA?” Nobody these days thinks drug companies exist for the benefit of mankind — they’re all just profit-seeking enterprises that spend more on advertising than research — but many assume the companies at least worry about getting sued. 

Merck, however, sells almost half a billion dollars worth of Propecia every year, and the bulk of Merck’s patents on Propecia don’t expire until October 2013. Merck’s shareholder filings with the SEC report Propecia is one of its “Diversified Brands,” which are drugs “approaching the expiration of their marketing exclusivity or are no longer protected by patents in developed markets, but continue to be a core part of the Company’s offering in other markets around the world.”

There’s money to be made. Lots of it. Merck knows that leaving persistent erectile dysfunction of the list of true side effects exposes them to civil liability, but they don’t care. Merck’s just doing the Ford Pinto calculation, re-introduced to a new generation as the Fight Club new car recall formula:

A new car built by my company leaves somewhere traveling at 60 mph. The rear differential locks up. The car crashes and burns with everyone trapped inside. Now, should we initiate a recall? Take the number of vehicles in the field, A, multiply by the probable rate of failure, B, multiply by the average out-of-court settlement, C. A times B times C equals X. If X is less than the cost of a recall, we don’t do one.

As I’ve written many times before on this blog, lawsuits against drug manufacturers are hard to win. Courts have precluded the use of class actions against drug makers in most cases (see, e.g., Valentino v. Carter-Wallace, Inc., 97 F.3d 1227, 1230-1234 (9th Cir. 1996)), making it much harder to level the playing field. You can’t even sue a drug maker for intentionally violating federal law by encouraging illegal off-label marketing. Big pharmaceutical companies have wiped out most of the potential claims against them except for the “failure to warn,” and that’s a particularly tricky claim. It doesn’t matter if the maker of the drug was negligent, or if they intentionally or recklessly sold a dangerous product.  The patient can’t show just that and win — the patient also has to show that the drug maker failed to adequately warn the patient that their own drug was unsafe.

As I’ve said before, it’s like if we said you can’t sue someone for driving recklessly, you can only sue them for not giving you enough warning that they were driving recklessly. It’s unreasonable and unfair, but we don’t make the rules, the legislators elected and manipulated through aggressive and expensive lobbying efforts do. Merck knows the deck in court is stacked in their favor, so they’ll play the odds, with your health and safety.