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.

  • Guest

    Lots of people argue that drug companies need these protections from liability in order to encourage research and development. It’s such bullshit. Would companies really cease pursuing a profit-making endeavor simply because their profit is a little less than it otherwise could be? In many cases, there’s still money to be made, even if corporations are forced to value the health and safety of human beings more highly than they do right now. We need better legislators, better laws, and better judges who protect people instead of corporations.

  • Martini

    “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…”

    That is incorrect. Finasteride does not decrease the production of testosterone. Quite the opposite:

    • That study is more than 10 years old and is not, to my knowledge, consistent with the current understanding. A more recent study sums it up: “Finasteride, an inhibitor of 5α-reductase (type II), lowers intraprostatic dihydrotestosterone (DHT), which is reflected in serum as reduced 5α-androstane-3α,17β-diol glucuronide (3α-dG).”

      The Propecia label itself describe the drug as “a 5α-reductase inhibitor.” That label further notes, “Because of the ability of Type II 5α-reductase inhibitors to inhibit the conversion of testosterone to 5α-dihydrotestosterone (DHT), finasteride may cause abnormalities of the external genitalia of a male fetus of a pregnant woman who receives finasteride.”
      In sum, Propecia reduces serum testosterone levels.

      • Martini

        You pasted the part of the study you linked to that says that DHT is lowered. We all know that already. I’m talking about the claim that testosterone is reduced. Part of the first study you linked to that you should have pasted:

        “It also modestly increases serum testosterone”

        I don’t know where you’re getting, “In sum, Propecia reduces serum testosterone levels.” Nothing you pasted from your study concludes that and as I’ve shown you, testosterone levels are increased, not decreased.

        • What I wrote in my post is: “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 …”
          You agree with the first but not the second, because you are divorcing testosterone from DHT. In a very narrow sense, this is chemically correct, but it’s misleading for purposes of our discussion, given how testosterone and DHT relate to each other and how they actually work in the body, with DHT being far more potent. The decease in DHT is extreme while the increase in testosterone is mild — meaning, on the whole, suppressed action of what the vast majority of people would simply call “testosterone.” It’s like losing a bunch of $20s in your wallet while gaining some extra $1s.

        • Martini

          You’re not making any sense. I started by telling you that you are incorrectly claiming that Finasteride inhibits the production of testosterone and posted a study showing it does the opposite. You in turn claimed my study was old and not consistent with the current understanding. What was wrong with the study I posted? You then posted a study that made the exact same claim! I’m very curious what you think in the study I posted was inconsistent with the current understanding.

          No, nothing I wrote is misleading for purposes of our discussion. It is exactly what I have been claiming since my first post! DHT being more potent is a meaningless claim as it’s more potent than testosterone in some regards and less in others.

          The vast majority call DHT, testosterone? Not in my experience, including how YOU differentiate the two in the article you wrote.

          Please tell me what was not consistent with the current understanding in the study I linked to and what you believe about the study that you linked to shows evidence for it.

        • What is your understanding of the relationship between DHT and testosterone?

        • TD

          Hey Martini, you are the one that is wrong. It destroys T. I am a victim and in my 20’s my T levels dropped to nothing and never recovered. its been about 15 years and no recovery. Enjoy your job at Merck.