Friday, April 25, 2014

UCLA Whistle-blower Suit: Does Industry Money Corrupt Academic Medicine?

According to the story in the L.A. Times:,0,3924175.story#axzz2zwLITYhU
--there are two versions of what happened; so to be as fair as possible I'll first give UCLA's version.

Dr. Robert Pedowitz became chair of the orthopedic surgery department at the medical school in 2009. After voicing his concerns to higher officials about how many of his colleagues were taking industry money, in a manner he described as negatively affecting patient care, he stepped down in 2010. In 2012 he sued UCLA and some of his colleagues, charging retaliation for his speaking out, in the form of interfering with his getting research grants and patient referrals.

UCLA investigated the charges Dr. Pedowitz had brought and found a few irregularities, but mostly that no laws or university rules had been violated, and patients had not been compromised. Despite this clean bill of health, the UC regents have now decided to settle with the doctor to the tune of $10M, not because they're admitting any wrongdoing, but to "avoid the 'substantial expense and inconvenience' of further litigation."

Now for the other side of the story. Dr. Pedowitz (noting that the problems he faced are rife among academic medical cents and hardly are unique to UCLA) found when he came on board that one surgeon in his department was being paid $250,000 by the device maker Medtronic for consulting work. That same physician was trying to enroll patients in a research project involving Medtronic products. Sen. Charles Grassley (R-IA) had previously spotlighted a UCLA spine surgeon who had accepted $460,000 from Medtronic and other companies but had somehow failed to disclose these payments. UCLA, Pedowitz and his attorney charge, was too interested in the money to be made by these surgeons and by their potential commercial discoveries to rein in these practices.

I won't say who's right in this dispute, except to note that last time I checked, you could buy an awful lot of legal expense and inconvenience for $10M; so you can draw your own conclusions of which side the UC regents thought was going to win had the case gone all the way through the court.

Friday, April 18, 2014

“Breakthrough Cures”? Reasons for Skepticism

Earlier this week I posted about the current issue of the New England Journal, and mentioned in passing the appearance of antiviral drugs for hepatitis C that are being touted as new miracle cures. My focus in that post—
--was how our so-called free market fails to protect the public interest, so I looked only at the outrageous cost of the hepatitis C drugs and gave a free pass, more or less, to the “cure” claims.

In doing so I overlooked an older and a more recent blog post by our good pal Dr. Roy Poses at Health Care Renewal:

Dr. Poses takes care to show the extraordinarily flimsy evidence on which these new drugs are being ballyhooed. He says a number of things about study design and so on, all of which seem pertinent. But if we try to get a sense of the big picture, all I think we need to know is the natural history of hepatitis C. As Dr. Poses reviews for us, hepatitis C can be a very bad disease leading to liver failure and death. But the total number of folks with the virus who end up with this extreme version of the disease is not that large. A goodly number of people who carry the hepatitis C virus never develop any obvious disease at all. Another good chuck of them develop some liver inflammation, but it never develops into the extreme life-threatening forms.

So before one can get all that excited about a new treatment for hepatitis C, insofar as actual patient-centered outcomes are concerned, we’d need a large-scale follow-up study that showed that people getting the new drugs actually had improved health over the long haul. That would in turn depend on showing that the apparently decent (but hardly perfect) side effect profile of the new drugs is maintained long-term, else the chance of having a bad side effect might be as great as the chance one would have had the bad kind of rapidly-advancing hepatitis C infection with liver damage.

According to Dr. Poses who’s checked out the literature much more carefully than I have, what we know so far is that the new drugs do a pretty good job of clearing the hepatitis C virus from the bloodstreams of patients when followed for a period of up to 24 weeks.

It may well be that a drug that does this good a job of clearing the virus in the short term does an equally good job of saving the patient from long-term, serious consequences of having the virus. Or that may not be the case—we’ve seen many, many instances of initially promising treatments that ultimately fail to pass that test. (This may also be a good time here to remind ourselves of Dr. John Ioannidis’s warning:
--about how it’s a mathematical near-certainty that the first reports about any new drug will give an unduly rosy picture of its effectiveness.)

Now, let’s be fair to the advocates for the new drug. It will take years, to say nothing of tons of money, to do the studies needed to show the real effectiveness of these new hepatitis C drugs. So in the meantime, the data we have so far is probably what’s to be expected at this stage. And so far, the drug is performing more or less as one would expect if indeed it is going to turn out to be a breakthrough drug.

OK, I’ll buy all that. So how about some recognition of the actual limitations of what we know, when this drug is being talked about? Why should supposedly scientifically-aware advocates for the drug feel a need to talk like used car salesmen? (Unless, in fact, their ultimate goal is to sell us a clunker?)

So mea culpa for my earlier post, if I inadvertently added to the hype around these new drugs, instead of joining Dr. Poses in raising the appropriate skeptical concerns. One can hope that the drugs turn out to be what they are hoped to be; and one can also hope that somehow, if that’s the case, people who need them will be able to afford them.

The History of US Drug Policy Since the Cold War

One theme in HOOKED is the need to see today’s relationship between the medical profession and the pharmaceutical industry in proper historical context. When HOOKED was written, I had to struggle, as a non-historian, to try to put together an adequate historical background picture. Since then, useful books have appeared that make that task easier.

Prof. Dominique Tobbell of the University of Minnesota has contributed Pills, Power, and Policy: The Struggle for Drug Reform in Cold War America and Its Consequences. She makes two basic points about our struggle today to reform drug policy, in a direction that brings pharmaceutical manufacture, research, and marketing better into line with public health and public interest. The first point is that this struggle is not new; basically the same issues have recurred ever since the end of World War II. The second point is that the pharmaceutical industry has never waged this battle against what it considers burdensome government regulation on its own; it has always had allies among medical organizations and academic physicians who had a strong interest in defending the status quo.

Prof. Tobbell points out that by the mid-1960s, the drug industry had achieved an impressive enough record in fighting off government regulation that the tobacco industry turned to Pharma for advice and help. During all those years, medical practitioners were primed by the AMA to fear the bogeyman of socialized medicine, and academic physicians worried about excessive federal influence over research policies. It was easy to get these fellow travelers on board when Pharma wrapped itself in the mantle of “free enterprise” and presented a less-regulated industry to Congress and to the American public as a bulwark against communism.

In the heady postwar days, when everyone was thrilled with the tremendous advances in antibiotic, hormonal, and psychiatric therapy, the climate of ethical thought was quite different from what reigns today. For example, Prof. Tobbell describes the efforts at the University of Pennsylvania to create a training program in clinical pharmacology in 1955: “Norman Topping, the university’s vice-president in charge of medical affairs, sought to create an institutional structure that would ensure the program could be responsive to the industry’s needs. Indeed, Topping believed the new program should function, essentially, as a service unit for the drug industry.”While today such a stance would at least raise some eyebrows, apparently no one gave it a second glance in the 1950s.

Similarly, when the National Academy of Sciences formed the Drug Research Board in 1963, to help conduct the massive amount of research required to implement the new FDA amendments Congress had just passed to require that drugs be shown to be effective as well as safe, some in Congress looked askance at the inclusion of scientists with strong industry ties. The Board basically pooh-poohed any such concerns, insisting that it was a great advantage to have these scientists as part of the effort because of their inside knowledge and policy smarts. Conflict of interest—who, us?

One theme that I have addressed at some length in earlier posts—most recently:
--is the impact of the ideology that I prefer to call economism and others call neoliberalism on today’s Pharma policy. Prof. Tobbell was kind enough to respond to an e-mail query, since I noted that the word “neoliberalism” is virtually absent from her volume. Consistent with her thesis, she states that the anti-government-regulation, pro-free-market stance that the drug industry has adopted was present all through the 1950s and 1960s. When neoliberalism/economism entered the US political discourse in a big way in the middle to late 1970s, Pharma was happy to hitch its wagon to that rising star, just as it was happy to jump on the anticommunist bandwagon in earlier decades; but one cannot say that neoliberalism played a major formative role in Pharma’s policy or strategic thinking.

Dominique A. Tobbell, Pills, Power, and Policy: The Struggle for Drug Reform in Cold War America and Its Consequences. Berkeley, CA: University of California Press/Milbank Books on Health and the Public, 2012.

Thursday, April 17, 2014

Yet More on Statins and the Recent Guidelines

Not to make this blog the “Statins Blog” or anything, but since I have been on a tear regarding the unfortunate ACC/AHA guidelines on cholesterol:
--and since my pals at Primary Care Medical Abstracts keep feeding me more ammunition, I wanted briefly to mention two more commentaries that take aim at the guidelines (subscriptions probably required to access).

First, John Abramson, who’s been mentioned here numerous times, and his colleagues wrote in BMJ about the CTT meta-analysis, on which the new guidelines heavily relied. They challenged the rosy picture painted by the CTT by drilling down and recalculating the CTT’s own numbers. The CTT, recall, claimed that if one carefully summed the data from numerous previous clinical trials (none of which showed any reduction in all-cause mortality from taking statins for primary prevention), you could see that statins in low-risk patients save lives and prevent strokes and heart attacks.

So when Abramson’s team went back and crunched the numbers themselves they found, for the populations included in these studies:

  • No significant difference in all-cause mortality
  • You’d have to treat 140 low risk patients for 5 years to prevent one heart attack or stroke
  • The studies overall either fail to report any adverse reactions to statins, or else report adverse reactions at a much lower rate than has been shown in independent (non-manufacturer-sponsored) studies. If the rates of adverse reactions in the independent studies are valid, it is very likely that the chance of suffering an adverse reaction from a statin is notably greater than the chance of preventing a bad outcome.
Skip now to another old acquaintance, John Ioannidis, commenting more recently in JAMA. Ioannidis addresses the new guidelines head-on and is more interested in two issues. One is the total global impact—he calculates as his title suggests that if applied across the world, the “statinization” of humankind would result in at least 1 billion folks being told they needed statins, which would be a huge impact on the health systems of those nations and would conceivably shift resources away from much more desperately needed stuff. The main issue Ioannidis focuses on is the risk calculator employed by the guideline—a calculator that’s new, and that was shown right from the get-go to have significant weaknesses, that have been since confirmed. He gives us the math to show why it’s not very reliable.

Ioannidis takes a step back then and asks the question—we’ve been in the business of trying to calculate risk of coronary artery disease for more than 30 years; so how come we still can’t get it right? He also notes that the decision on the part of the guideline writers that a 10 year risk of developing cardiovascular disease of 7.5% ought to be the cutoff for recommending statins is a completely arbitrary number, unsupported by any empirical evidence—the “right” number could be 2% or 20% for all we know.

What these commentaries have in common is that both point out how messed up the basic data are due to all the major studies being supported by the drug industry, and how serious conflicts of interest contaminate this entire enterprise.

Abramson JD, Rosenberg HG, Jewell N, Wright JM. “Should People at Low Risk for Cardiovascular Disease Take a Statin?” BMJ 347:f6123, 2013.

Ioannidis JPA. “More Than a Billion People Taking Statins? Potential Implications of the New Cardiovascular Guidelines.” JAMA 311:463-464, Feb. 5, 2014.

Summarizing the “Market Failure” Special Issue of the New England Journal

Three articles in this week’s New England Journal of Medicine all combine to illustrate “market failure” in the pharmaceutical industry. As you can guess, the editors of NEJM didn’t adopt my suggested title for their issue. (See the end if you want more explanation as to why I’m calling it that.)

First is the editorial by Drs. Hoofnagle and Sherker—
--that talks about what would ordinarily be considered unalloyed good news elsewhere in the issue. Hepatitis C, which up till now has been quite resistant to treatment, appears to be well controlled by a new family of antiviral medications, with a minimum of side effects. This indeed appears to be one of those all-too-rare-today “breakthroughs” in drug treatment.

So what’s not to like? As the editorialists explain, the price tag. A complete course of one of the drugs comes in at $84,000, which works out to $1000 per tablet. The authors note a collision course between newly expanded public health efforts to do a better job of detecting the additional 1.6 million Americans who have Hep C and don’t know it, so that they can get this wonderful new treatment, which then many of them will not be able to afford—or if we could provide it for them, would break the bank of what the authors delicately call an “already overburdened medical care system.” The authors work for the NIH and as dutiful government employees are apparently discouraged from saying anything bad about the pharmaceutical industry, so they offer no ideas on what might be done about this problem.

Now jump to two “Perspectives” pieces in the same issue. One is from our good friends at the Harvard-Brigham and Women’s program in Pharmacoepidemiology and Pharmacoeconomics, including Dr. Jerry Avorn:

The P&P gang describes what has happened under a program begun by the FDA in 2007, the Risk Evaluation and Mitigation Strategy. The idea when this passed Congress was to speed the entry onto the market of useful new medications that also posed safety issues. If the company could come up with a special plan to limit the use of the drug in such a way as to lower the risk of adverse reactions, then the drug could go on the market. But the proviso added on was that this plan ought not be used as a way to stop generic products from entering the market later.

Unfortunately the amendments that passed Congress also included a monkey wrench that was virtually guaranteed to undermine this intent (assuming that Congress intended what they said, and that Pharma lobbyists did not rewrite the law in the back room). The company that developed this special safety plan for the new drug could also patent the plan.

So Dr. Avorn and colleagues list several cases where the drug company has sued generic competitors claiming patent infringement if the generic guys use the same safety plan, and also filing suit to stop any generic that uses a different safety plan as raising the risk level for the public unacceptably. The only sensible way to fix this problem, say the Harvard guys, is to use the same safety plan for all versions of the drug regardless of manufacturer, but to make this happen Congress would probably have to amend the 2007 act. Bottom line—a policy that was intended to allow patients access to drugs while assuring safety, that was not supposed to interfere with generics entering the market, is being used by Pharma precisely as an “evergreening” tool to prevent generic competition.

Now we come to another Perspectives article authored by Drs. Sham Mailankody and Vinay Prasad:

They also address the cost of new drugs, in this instance for cancer. Their basic point is—there are newly developed drugs for cancer treatment that provide small but apparently real benefits, such as an average extension of life by a few months. These drugs work by mechanisms very similar to old, generic drugs. (They give the example of the new drug abiraterone, which works in much the same way as an old anti-fungal antibiotic, ketoconazole.) So the ideal scientific question now to be asked is how well these same cancer patients would do if instead of getting the very expensive new drug, they got the very cheap old drug, ketoconazole. They might do just as well, or it might be that the new drug has some advantage—until we did the study we wouldn’t know.

The kicker that Mailankody and Prasad now note is—how would this new study be paid for? No way that the drug company that’s making a mint off abiraterone is going to bankroll a study that might pull the rug out from under its golden goose. So suppose some neutral investigators try to organize the study? Well, assuming that for the very same reasons, the manufacturer won’t just give away abiraterone for free (especially knowing for what purpose it’s going to be used), the investigators would have to pay market price and buy the drug. And the authors calculate that for a study large enough to answer the question of non-inferiority of ketoconazole, the cost of the drug alone—forget the rest of the cost of the study—would be about $69 million. In other words, no study of this sort will ever be done.

These authors also work for the NIH, and so are also apparently leery of saying anything controversial, and so don’t offer any proposals for a solution to this problem.
OK, so we have three articles in the same issue of NEJM, all of which have the same basic theme—in the name of profits, the drug industry is working contrary to the public health and the advancement of science. This is what old-time economist Kenneth Arrow famously called the market failure of health care—it simply does not follow the laws of supply and demand. Those who continue to extol the supposedly “free” market as the right way to manage all of our affairs, pharmaceuticals and health included, have to stick their heads in the sand and pretend that market failure never happens. As this blog has shown extensively, it happens all the time.

Thursday, April 10, 2014

More on Flu Drugs and the Broken Drug Research System

We’ve discussed the debate over oseltamivir (Tamiflu) and the problems in determining whether it offers advantages to flu patients, given how hard reviewers had to search to get all the data:

The story led the editor of BMJ back in 2009 to proclaim about the scientific evaluation of drugs, The current system isn’t working. Worse than that, it gives a false sense of security.”

The latest BMJ readdresses the oseltamivir story, and if the system was broken in 2009, it has not gotten fixed since. The summaries of what they have to say can be found in two editorials:

In the previous blog posts, I reviewed how difficult it was for the authors of a Cochrane review of neuroaminidase inhibitors for influenza (the class of drugs to which oseltamivir belongs) to get their hands on all the relevant data from unpublished studies conducted by the manufacturer. Once they did get a reasonable amount of data, they found the data so voluminous that it took several person-years of labor to sort through it all. But they persevered, and what we now know is that drugs like oseltamivir may shorten your bout of flu, if you start taking the drug within the first two days of symptoms, by half a day. It may cause a number of worrisome side effects. And we have no reason to believe that the drug will prevent the bad complications of influenza requiring hospitalization and admission to an ICU (which is the anticipated benefit that led the WHO to champion the drug and many nations to spend billions of dollars stockpiling the drug as a public health precaution).

We also know that the published studies on these drugs, virtually all of which were conducted by the manufacturers, overstated the benefits and understated the adverse reactions. In short, if you went to legitimate, prestigious medical journals for information, as all us docs were taught to do in med school, you’d be mostly clueless.

The editors of BMJ gamely propose a list of reforms. But I believe that two conclusions are inescapable. First, if it took this much time and effort to get the goods on oseltamivir—and we still don’t know what the drug is really good for, if anything, since the really important studies of its potential value have not yet been conducted—then what about the hundreds of other drugs that have been introduced with great fanfare in the last few decades, and none of which have been subjected to anything like this degree of inquiry and investigation? Second, on what basis can we claim any longer that we should have any faith at all in drug research sponsored by manufacturers?

Tuesday, April 8, 2014

AMC Leaders on Corporate Boards—A Modest Proposal

Dr. Roy Poses over at Health Care Renewal has for some time been speaking out about conflicts of interest posed by leaders of academic medicine and supposedly “not-for-profit” health systems who also rake in big bucks for sitting on the boards of large corporations such as drug companies and other firms that often do business with those same health centers. He most recently called attention to a research letter in JAMA that provides some of the first data on the frequency of these ties (see link in blog post):

Dr. Poses notes a number of serious ethical concerns that result from these board relationships. He is most worried about the way that a small group of very wealthy corporate insiders seem to have formed an old-boys-and-girls club that runs not only the corporate sphere but increasingly the world of health care as well, and how in the process the interests of ordinary folk get left behind. There is also the narrower question of the role of these people on those corporate boards which forms a sort of Catch-22. These corporations, as we have detailed ad nauseam in this blog, often take actions that go against the public interest. If (say) a university president is a member of the board of directors, then the prez presumably should speak up and demand that the corporation cease and desist all such behaviors. If the prez says that really, don’t blame him, he has no control over that behavior, then he is admitting that he’s failed in his role as a corporate overseer, which is what legally the board of directors is supposed to be about.

In the middle of this debate I have one of my occasional modest proposals. It does not address the deeper issues, which would entail leaders of academic medical and health centers not being on those corporate boards at all--but see my Modest Prediction at the end.

Whenever do-gooders like us complain about these conflicts of interest, apologists for the One Percent crowd claim that after all, these board relationships are very valuable for the university or the AMC or the health system. They expose the board to the presumably enlightened views of academic and health care leaders. They expose the leaders to important information about what’s happening on the corporate side, thereby stimulating productive university-industry partnerships for the future. So how could anyone be so narrow-minded as to object to these relationships?

Hence my modest proposal—demand that any academic or health care leader who serves on a corporate board do so without pay and at his/her own expense for travel and lodging. If their being on the board is so all-fired valuable to the academic or health institution, then let that board service be a part of the CEO’s job at that institution. Last I heard, none of these high rollers were being underpaid for their leadership roles. They have funds to cover their activities if they travel on university or hospital business, so why not regard board service under that category?

I would along with the modest proposal make a modest prediction. If you ceased paying these CEOs personally for their board service, commonly nowadays in the six-figure-per-year range, suddenly none of these CEOs would want to be on corporate boards any more. So much, if so, for all the wonderful intellectual advantages of board service and industry relationships.