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:
http://brodyhooked.blogspot.com/2013/12/more-on-cholesterol-guidelines-cochrane.html
--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—

http://www.nejm.org/doi/full/10.1056/NEJMe1401508--
--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:

http://www.nejm.org/doi/full/10.1056/NEJMp1400488

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:

http://www.nejm.org/doi/full/10.1056/NEJMp1400104

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.

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:

http://brodyhooked.blogspot.com/2009/12/bmj-medical-research-is-broken.html
http://brodyhooked.blogspot.com/2012/09/more-on-tamiflu-challenges-of-getting.html

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:

http://www.bmj.com/content/348/bmj.g2630
http://www.bmj.com/content/348/bmj.g2548?ijkey=ded5662cf46f75236fb45a9cda0bb2a671ec0e98&keytype2=tf_ipsecsha&linkType=FULL&journalCode=bmj&resid=348/apr09_2/g2548&atom=/bmj/348/bmj.g2630.atom

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?

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):
http://hcrenewal.blogspot.com/2014/04/finally-article-in-large-circulation.html

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.

Pharma Lobbyists Have Their Way: FDA “Breakthough-Drug” Policy

A group from the excellent Pharmacoepidemiology-Pharmacoeconomics center at Harvard, a.k.a. Dr. Jerry Avorn and friends, wrote this commentary in the current New England Journal:
http://www.nejm.org/doi/full/10.1056/NEJMhle1311493

If you skip to the very end to see their conclusion: “In the next few years, evidence will accumulate to indicate how well the new breakthrough-therapy designation improves the options of patients with serious and intractable diseases and to what extent it facilitates the market entry of treatments that promise more than they can deliver.”—then you’d guess that they are pretty wishy-washy about the new category of “breakthrough therapy” that Congress enacted in 2012. A close reading shows that you’d be wrong; if you check out all the fine print you’ll see that the authors are very negative about this new FDA category aimed at hastening new drug approval.

Why the negativity? The points they make are:

• There’s really no good evidence that currently, patients suffer as a result of slow FDA approvals. FDA approval times are steadily decreasing.
• There’s some evidence at least that unsafe drugs are getting onto the market because of current FDA approval practices. The authors mention among other examples the leukemia drug, ponatinib, approved on an accelerated basis in 2012, then temporarily suspended in 2013 when it was shown that nearly half of patients on the drug followed for 2.7 years developed serious blood-clotting events like heart attacks and strokes.
• Before Congress enacted this new “breakthrough” category, there were already several pathways for “fast track” approvals.
• In the first year after the “breakthrough” category was approved, the FDA received 92 new drug applications for this designation. As I noted in HOOKED and previously on this blog, in recent years, sober appraisals of new drugs have shown repeatedly that no more than a small percentage of new drugs qualify as significant advances over existing therapies. If this many drugs are seeking approval under the new designation, it is certainly being used for drugs that aren’t “breakthroughs” in any meaningful sense of the term. (The FDA approved only 27 of those applications.)
• We’ve seen many times here how a good way to approve a useless or a harmful drug is to look only at surrogate endpoints and not at meaningful patient outcomes. Under previous rules, a drug had to show activity first against a “well-established surrogate endpoint,” and then later, it was all right to address a “less-than-well-established surrogate endpoint,” whatever that is. Apparently even that was not loosey-goosey enough for Pharma, so this “breakthrough” category allows approval based on “an effect on a pharmacodynamic biomarker(s) that does not meet criteria for an acceptable surrogate endpoint, but strongly suggests the potential for a clinically meaningful effect on the underlying disease.” (And here I would have thought that would be the definition for an “acceptable surrogate endpoint”—shows how much I know.)

The bottom line seems to be that the drug industry lobby continues to have its way in Congress and can get most any legislation passed they want. I suppose the next thing is that they will decide that even with this new category, drugs are not being approved fast enough, and so they will come up with a new category that requires that the FDA approve a drug if the company promises (cross its heart and hope to die) that the drug will do something to an almost-acceptable sort-of-surrogate endpoint, sometime in the next 5 years.

When the industry lobbies for a slicker greased pathway through FDA approval, it never comes to Congress by itself; it always comes along with “consumer” lobbyists supposedly representing patients desperate for cures. We’ve also seen numerous times how often those “consumer” groups are actually bankrolled by Pharma, so that pretty much disposes of that argument—but Congress laps it up nonetheless.

I explained in HOOKED how back around 1972, some brilliant Pharma lackey invented the “drug lag,” the claim that people were dying like flies in the U.S. because wonder drugs approved years ago in Europe were being held up by a stodgy, unresponsive FDA. I there compared the “drug lag” to John F. Kennedy’s famous “missile gap.” There are two analogies. One, the “lag” and the “gap” both turned out on investigation to be purely mythical. Two, once given voice, they refused to die, no matter how much proof was amassed on the other side. And so today we still operate under the myth that the FDA is too slow to approve marvelous new wonder drugs and somehow we have to speed up the process. Or at least Congress operates under that myth when huge piles of Pharma lobbying cash are spread around along with it.

Over-Enthusiasm in Research Results: How Pharma Finds a Seam

Every so often I comment on a research study that has nothing directly to do with pharmaceutical matters, but which illustrates some basic points about the medical literature and how apparently authoritative studies can be misleading. As is often the case, I am prompted here by Rick Bukata and Jerry Hoffman in their monthly Primary Care Medical Abstracts. Here I'll rely especially on Jerry's commentary on this paper, utilizing his skills as an evidence-based medicine mayvin.

The paper is:
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)60852-1/fulltext

The study was funded by NIH and the authors declare no conflicts of interest, so at first blush this would appear to be a poster child for reliable, unbiased research.

The research question is: If you take a group of folks who have had a stroke of one specific type (lacunar strokes, located in the lower portion of the brain and comprising about a quarter of all strokes caused by blood clots), will they do better in the future if you set a lower (less than 130) rather than a higher (130-149) target for controlling their blood pressure? To study this the research group enrolled about 1900 folks at 81 sites in North America, Latin America, and Spain and followed them for nearly 4 years. The local physicians used whatever medicines they wanted to try to reach the blood pressure goals; and the lower-pressure group did in fact achieve a lower blood pressure overall than the higher-target group (11 points difference).

If you listen to the authors of the paper, they'll tell you:

• While none of the results of the study were statistically significant, the so-called "trends" were in the direction of fewer strokes of all sorts, and fewer bad vascular events, in the lower-pressure-target group.
• The lower-pressure target group did not seem to have any more serious side effects from treatment.
• Other previous studies have tended to show benefits from lower blood pressure in similar populations
• Therefore, we should recommend setting the blood pressure targets lower for patients who have had a lacunar stroke.

If on the other hand you listen to Dr. Jerry Hoffman's critique (subscription required), he'll tell you:

• Since no results were statistically significant, that means the study failed to show any real benefit from the lower blood pressure target in these patients.
• Let's for a minute pretend that all the so-called "trends" were in fact statistically significant. We'd still have to ask how large the resulting differences were. It turns out that the differences are really tiny anyway--often in the fractions of a percentage point.
• If you are going to look at slight, nonsignificant trends, how about the slightly higher overall mortality rate in the lower blood pressure target arm of the study? Funny how the authors get so excited about "trends" that confirm their hypothesis, and yet ignore similar "trends" that go the wrong way.

So what's going on here? A large group of enthusiastic and dedicated investigators spent years and tons of NIH money at 81 different sites all over the world. You can't blame them if they were desperate to rescue something of value from  their disappointing numbers. Sadly, that doesn't make it good science.

If good scientists like this can publish results that are so little supported by their data, and a supposedly excellent journal lets them get away with it-- then what happens when to the natural enthusiasm of the research team, we add the incentives as well as the incredible monetary resources of the drug industry? You start to get a sense of how much misleading information can appear on the pages of the "best" medical journals, and how long it could take us to sort through it all and decide what's really best for patients.

Pharma Slashes Budgets for Physician Speakers--Why?

The nice folks over at ProPublica:
http://www.propublica.org/article/as-full-disclosure-nears-doctors-pay-for-drug-talks-plummets
--who gave us their Dollars for Docs web tool to track drug company payments to individual physicians, now report major drops in recently reported expenditures for promotional speakers. For example:

• Eli Lilly, from $47.9M in 2011 to $21.6M in 2012
• Pfizer, $22M in 2011, $8.3M in 2012
• Novartis, $24.8M in 2010-11, $14.8M the following year
• GlaxoSmithKline, $24M in 2011, $9.3M in 2012 (and announced last December it would stop using physicians as paid speakers entirely)

This was not true of all companies; AstraZeneca stayed flat (though they had declined sharply the previous year) and Johnson & Johnson posted a 17% increase. One company only began reporting figures in the past year, Forest Labs, and this relatively small company, interestingly, topped all the giants by spending $40M on physician speakers.

A brief reminder: Dollars for Docs became possible after several drug companies, either voluntarily or as a result of legal settlements for marketing infractions, began to make public their payments to physicians, which ProPublica then kindly gathered into one central location. The Physician Payment Sunshine Act, a part of the Affordable Care Act of 2010, does not kick in till later this year, after which all companies will be required to report.

So--why these steep cuts? One possibility, apparently favored by the ProPublica reporters, is the Sunshine Act looming, and the increasing degree of suspicion attached to payments to physicians from Pharma. But another possibility they outline is simply the dropoff in major drugs protected by patent--and the increasing tendency of the newer generations of brand-name drugs to be highly specialized drugs used by only a small number of docs, such as a new treatment for Hepatitis C. It may take fewer paid speakers to market these newer drugs, or else companies may be finding new ways to market via the Web that bypasses paid speakers altogether.

What about other types of marketing payments? More recently, ProPublica provided us with a clickable graph:
http://projects.propublica.org/graphics/d4d-slopegraph
This graph enables us to track company by company how spending for meals for docs declined by 20%, for "gifts" by 47%, for travel by 29%, and for consulting by 18.7% (among the companies reporting). That raises the interesting question of whether, for the first time in recent history, we may be seeing an actual fall-off in the total amount Pharma spends on marketing--or whether it's the proverbial balloon that if you push in one end it simply bulges out the other. Only just now no one seems clear on where the other end of the balloon might be. As I described in HOOKED, the companies themselves are quite secretive about the actual amounts they spend on marketing.