Taking Trust With a Grain of Sodium

I was rather intrigued when a drug company representative showed up at my institution with some literature on a medication called Vaprisol manufactured by Astellas Pharma. This drug is one of a class of drugs called vasopressin receptor antagonists (VRA's) and is used to treat low blood sodium levels (also called hyponatremia).

I may be the worst philistine in academia but to me, Vaprisol is a so-so solution in search of a problem. Hyponatremia is typically treated by first identifying its underlying cause. Once that cause is determined, treating it generally makes the hyponatremia go away or at least improve. And guess what? Even if the problem can't be cured, the chronically low sodium that results rarely causes serious problems by itself.

That said, I can imagine rare scenarios whereby drugs such as Vaprisol may be useful. Obviously, attempting to be helpful, the rep left a reprint of a paper from the reputable American Journal of Medicine. It summarized some expert panel recommendations regarding the diagnosis and treatment of this condition.

I was surprised however to find that of the articles eight pages of text regarding the actual treatment of hyponatremia, half were devoted to VRA's. This may have been appropriate for a review of developments in the field but this was ostensibly a guideline for current management practice.

I encounter hyponatremia frequently but I've never seen nor known of a physician using this drug or any drugs in its class. I hardly think that the use of VRA's is generally accepted by the medical community. Which brings me to the title of my reportage. Are the recommendations of this guideline really trustworthy? Curious, I immediately flipped through the reprint to find the authors' financial relationships disclosure which had been dutifully reported.

I wasn't the least bit surprised that of the five authors, all five had financial ties to one or more of the companies selling VRA's:

Joseph G. Verbalis, MD, has served as a consultant and member of advisory boards and Speakers’ Bureau for Astellas Pharma US, Inc.; as a consultant and member of advisory boards for sanofi-aventis, and as a consultant to Otsuka.

Stephen R. Goldsmith, MD, has served as a consultant and member of advisory boards for Astellas Pharma US, Inc.

Arthur Greenberg, MD, has served as a member of advisory boards and Speakers’ Bureau for Astellas Pharma US, Inc., and as a consultant to sanofi-aventis.

Robert W. Schrier, MD, has served as a consultant to Otsuka.

Richard H. Sterns, MD, has served as a member of advisory boards and Speakers’ Bureau for Astellas Pharma US, Inc.

Now don't get me wrong. I myself haven't done an exhaustive search of the literature to determine whether or not these drugs are in fact any good. For all I know, they're magic bullets that should be put in the water supply to treat and prevent all current and future cases of hyponatremia.

But that's not my point. The problem is that even before checking out this particular drug's usefulness, I'm already starting from a position of mistrust. With such an undeniable "appearance of impropriety" how can I truly rely on these experts to give me the unvarnished truth? It's one thing to report hard facts. It's something entirely different to render an opinion which is what a guideline is.

Surveys of physicians have shown that most believe that the clinical judgment of other physicians can be influenced by financial encumbrances. However, those same doctors also believe that they themselves wouldn't be. What does this tell us?

Should any of us in medicine have unerring faith in the fairness and objectivity of our profession's opinion leaders and can we as patients trust that our doctors have access to the best information available? Perhaps we all need to read Dr. Daniel Carlat's 2007 New York Times article on his transformation from honest clinician to drug company shill (and back again).

It seems to me that we're getting to the point where we have to get away from the very concept of having clinical guidelines (not to mention FDA Advisory Committee reports) formulated by opinion leaders altogether. It may be far better to simply convene skilled but generic clinicians, epidemiologists, and statisticians with no ties to the pharmaceutical industry to create recommendations based only on a nonbiased, critical reading of the existing medical literature.

As drug reps are being increasingly isolated from prescribing physicians due to practice group and academic institution policies, pharmaceutical companies are shifting more of their advertising budgets towards cultivating (financial) relationships with academia's clinical gurus. No one can deny the moral hazard associated with this trend.

Understand that I am not impugning the integrity of the authors of the above-mentioned guideline but truthfully, I have no a priori reason to trust them either.

More "What Drug Reps Think of Us"

CafePharma is a website for drug reps. that I've written about before. The best part are the message boards. In fact, I have posted a link to them on my blogroll because they are fascinating to read. While I can't say whether those that post there are truly representative of all drug reps, reading them is an eye opener. It is amazing how deeply some of them loathe physicians.

Recently, a psychiatrist named Daniel Carlat wrote a stunning mea culpa piece in the NYT Magazine. In it, he documents his less than savory "career" pushing the drug Effexor for Wyeth Pharmaceuticals. Read the article to get your bearings then read some of threads in the Wyeth board and see what the reps say about him and doctors in general. Another approach to finding choice quotes about him would be to google Carlat or his piece within the website like this.

Lovely.

Drug Companies and Their Big Marketing Budgets

A recent post of mine was pretty down on the drug companies (or at least GlaxoSmithKline). Now I'm back to defending them.

Amy Tenderich, was diagnosed with Type I diabetes several years ago and was galvanized to start my favorite patient blog, Diabetes Mine. She recently blogged about the big marketing budgets of pharmaceutical companies and the relative paucity of money they spend on R & D. As usual, I have some thoughts on this.

Click here for more.A recent post of mine was pretty down on the drug companies (or at least GlaxoSmithKline). Now I'm back to defending them.

But first, a disclaimer. The subject is an extremely complex one and an attempt to arrive at a truly informed opinion would require a great deal of time which given my regular gig, hanging with the wife and kid, and watching old Picket Fences reruns is in precious short supply. But ignorance won't stop me from pontificating on this topic because I believe it is important and engaging. The bottom line is, if you've got a more solid viewpoint than mine, I'm happy to be educated!

Amy Tenderich, was diagnosed with Type I diabetes several years ago and was galvanized to start my favorite patient blog, Diabetes Mine. Her writing is passionate, engaging, and represents the informed work of an advocate seeking to better both her life and the lives of others affected by this disease.

She blogged recently about an article in Newsweek decrying the lack of progress the drug companies are making at bringing new and innovative products to market. In the article she cites, ex-Intel CEO Andrew S. Grove skewers the industry. Grove has Parkinsons disease and is understandably upset at the lack of progress being made by pharma as is Tenderich for diabetes.

He notes the incredible progress the computer industry has made compared with that of the drug trade. In the years he worked at Intel, integrated circuits went from 1,000 transistors per chip to 10 billion transistors per chip. For the treatment of Parkinson's in that same period, "we have gone from levodopa to levodopa" (not entirely true but a not unreasonable first approximation).

Tenderich too is concerned about the same thing. She points out that the drug industry spends a third of its revenues on marketing but only a fifth on R & D. I assume she pointed out this lack of priority as a reason for why the pharmaceutical industry lags the computer industry.

Well guess what. I looked up Intel's 2006 financials (see page 33). With revenues of $35 billion, they spent $6 billion on R & D which comes to only 17%. This is less than Pharma. I can't calculate the percent spent on marketing because Intel doesn't break their expenses down that way (it will certainly be less than a third though because marketing, general, and administrative were lumped together and were around $6 billion as well).

Let's assume for argument's sake that Intel is representative of its industry as a whole. We then note three things:

1. The semiconductor industry spends the same (or even a lower) percentage of revenues on R & D than pharma.
   
   
2. The semiconductor industry seems to be accomplishing far more with its research dollars than pharma.
   
   
3. Pharma probably spends a higher percentage on marketing

Taken together, these facts raise several questions. First of all, why is the semiconductor/computer industry progressing in leaps and bounds while pharma is languishing in the doldrums?

Truthfully, there is an implicit assumption that hasn't been proven and is likely unprovable, namely that the progress made in medical interventions isn't as extraordinary as that made in computer science.

Sure, we can measure the strides made in IC chip technology with CPU cycle times and transistor densities. However, medical science doesn't lend itself to such simple benchmarks. Ask yourself: does the 10 million-fold increase in transistor density described above really outstrip say the dramatic reduction in mortality in AIDS or in some cancers? Who can say?

If age-specific breast cancer mortality rates have fallen by only a percentage point or two, that doesn't sound nearly as sexy as the strides companies like Intel can boast. Let me remind you however that the former corresponds to a few thousand lives saved each year. These patients and their family members are probably more impressed with that than with having fancier Gameboys.

So just because the semiconductor industry can cite some cute statistics doesn't mean we should discount medical advances over the same period.

I'd also like to point out as though we really need to be reminded of this: human biochemisty, physiology, and pathology is almost unimaginably complex. Diseases such as Parkinson's and diabetes are tough nuts to crack. Getting to the moon was comparatively easy and was accomplished back in the sixties with computers less powerful than the one driving your $10 throw-away watch. Don't downplay either the complexity of these or other diseases nor the vast array of factors that have to be taken into account to ensure drug efficacy and safety.

The second question that I would raise is why aren't drug company R & D budgets significantly bigger than their marketing budgets? This is equivalent to asking why pharma doesn't shift more of its revenue from marketing towards R & D. I think the reason is straightforward and has to do with risk.

R & D money by definition is money spent on speculation. Marketing money is "safe". As the venture in question becomes more risky, the safer thing is to partition capital towards marketing (safe) and away from R & D (risky). The fact of the matter is that there are few high-stake risks more threatening than those assumed by drug companies.

Consider that it costs over $800 million dollars to bring a new drug to market (in 2000 dollars). This number includes the presumably less risky "me too" drugs that are relatively simple modifications of existing drugs. One can only imagine the cost of bringing a completely novel drug class to market.

Then one must figure in the post-market risks. Pfizer just took a $2.8 billion write-off for their inhaled insulin technology, Exubera. It was a lousy performer in the marketplace. Merck is going to spend untold billions settling their Vioxx lawsuits.

And there's something else that drug companies are having to deal with that's relatively new. This is something that can dramatically increase the risk of development thus causing CEO's to flee even further in the direction of marketing and away from R & D: evidence-based access.

It used to be that to get your drug covered by a health plan all you needed was to show that it was incrementally better than the old drug. If your new drug only needs to be taken once a day rather than twice like the old drug, that was enough for it to be added to the authorized formulary of the insurance companies. No more.

With evidence-based access, not only does your drug have to be better, it has to be demonstrably better at improving outcomes. It may get past the FDA but if you want your drug to get on the insurance companies' formularies, you have to also show an economic advantage. For example, if your antibiotic can be taken just once a day compared to twice a day, will patient compliance be better with demonstrably better outcomes (i.e. eradication of infections)? Obviously this is much harder to prove and this increases the risk of bringing that drug to market. So you can see, many factors and many risks are involved in the drug industry that make comparisons with companies like Intel unfair.

In the best of all worlds, companies developing medical technologies would spend the bulk of their non-operational costs on R & D and none on marketing. If the technologies they produce are so great, shouldn't they just sell themselves? Unfortunately that's not how the world works. You can bet that your competitors are investing in marketing like crazy. It would be corporate malpractice for a CEO to not do the same thing.

In the final analysis, it's the competition between companies for increased market share that drives American pharmaceutical companies to be the most innovative and productive in the world. Not that either Grove or Tenderich were advocating this, but government regulation of R & D budgets or in some other way interfering with managements' drive to maximizing shareholder return will surely cause us to lose that edge.

Of course for those with serious medical conditions such as Parkinson's or diabetes, this is small consolation. What is really necessary is for advocates like Grove and Tenderich to continue to speak out as they are doing. If the drug companies can be convinced that there's a big enough market from a demanding enough constituency, they will seek to fill that vacuum.

Is GlaxoSmithKline Engaged in Extortion?

This is truly pathetic. Professor John Buse was apparently "intimidated" by GlaxoSmithKline (GSK), the drug company that produces Avandia (generic name rosiglitazone). Dr. Buse was one of the earliest researchers to speculate publicly on the possibility that this drug causes increased adverse cardiovascular events.

This charge, and it is stunning, was raised in a report by the U.S. Senate Committee on Finance. I would urge interested readers to take a look at it as it is quite eye-opening. The report stated, "The effect of silencing this criticism is, in our opinion, extremely serious."

GSK sent emails to Buse's superiors complaining about him and threatening a lawsuit. Subsequently, Buse was made to sign a letter drafted by GSK stating he was no longer worried about cardiovascular risks associated with Avandia. The report documents Buse's regret at caving in to GSK's intimidation.

As one who often defends drug companies for the good they do for society, I find this maddening. Attempting to silence a scientist for expressing a scientific viewpoint is an abomination. This is especially true when the public safety is involved.

I personally feel that the question of whether Avandia does or doesn't increase the risk of heart attack or stroke is still up in the air. The principal data used to support this hypothesis is a meta-analysis that has important methodological problems. But to stifle the discussion is wrong. Whether GSK's tactics are illegal is something that's beyond my pay grade, but in my mind, this constitutes extortion. There's no question that they're immoral They make a mockery of the concept of academic freedom and of John Stuart Mills' notion of the greatest good for the greatest number.

Their actions are a slap in the face to anyone such as myself who would defend pharmaceutical companies' right to maximize shareholder return (to make a profit). When a company such as GSK violates basic standards of morality and decency, it doesn't deserve my support.

Rather, its reprehensible behavior should be proclaimed loudly and widely.