Wednesday, November 19, 2008

More on Pharma Intimidation of Doctors

Both in HOOKED and previously on this blog, I have mentioned examples of physicians who attempt to raise warnings about serious adverse reactions from popular drugs, and who are then subject to intimidation by the manufacturer. A recent story by Alicia Mundy in the Wall Street Journal (subscription required for on-line access) shows how far down the food chain this activity extends.

Mundy recounts the case of Dr. Mary Money, an internist in Hagerstown, MD. She and a colleague started noticing diabetics taking Avandia (rosiglitazone) who developed severe cases of congestive heart failure, which often reversed soon after the drug was stopped. Soon after the drug was introduced in 1999-2000, they looked at 85 patients and noted that more than half had developed significant fluid retention, a precursor of congestive heart failure. She alerted the maker of the drug (SmithKline Beecham, which later merged to form GlaxoSmithKline) and tried also to notify the FDA.

She and her colleague got only form letters from the FDA, but received a delegation of SmithKline folks at their local hospital, Washington County Hospital. They soon found that the delegation had no interest in hearing their evidence and had come solely to chew them out for saying incorrect things about their great drug. A consultant who attended by phone accused them of being unable to interpret the echocardiograms that formed part of their diagnostic workup of the patients.

Later, SmithKline executives contacted Washington County's chief of staff and demanded that he make Dr. Money hush up and stop saying bad things about Avandia. (He claims that he refused to go along.)

Subsequently, as evidence mounted that Avandia patients were at increased risk of heart failure, the company was forced to add more stringent warnings to the label, and the WSJ notes that Avandia sales have been falling since a major article on its risks appeared in the New England Journal.

Two things seem instructive about this case. The first is that, no offense to Dr. Money, but she really seems like small potatoes. One does not usually expect a private-practice internist in Hagerstown to sway medical opinion all that much on her lonesome. The fact that the drug company went to all this effort to discredit and intimidate her seems impressive.

The other instructive thing is that GlaxoSmithKline even today is willing to defend its actions. The company told Mundy that they felt completely justified in "correcting" the "inaccuracies" contained in Dr. Money's claims. When a commercial company cannot tell the difference between a scientific exchange of ideas, or a physician's or scientist's rights of free speech for that matter, and its own marketing and sales agenda, we see why medical professionalism requires that physicians put as much open space as possible between themselves and the drug industry.

Public Announcement Regarding New Documentary Produced by Scientology-Related Group

Some time ago I was asked by a group doing a documentary about problems with psychiatric drugs to do a filmed interview about my research into the drug industry, as summarized in HOOKED.

I was assured at that time that this was an independent project, despite the fact that the documentary group had ties to the Church of Scientology.

I subsequently became better educated about the many underhanded and dishonest methods used by Scientology to attack the practice of psychiatry and the use of psychotropic medications. Readers of this blog will be aware that I have many issues with how psychiatry is often practiced today, but I cannot endorse across-the-board condemnations and certainly cannot endorse positions that are ideologically motivated and not well grounded in medical evidence.

I then contacted the producers of the documentary and asked that my segment be deleted and notified them that I was withdrawing my consent to participate. They refused to accommodate this request.

I am now advised that the documentary, Making a Killing, is being circulated, though I have not seen a copy of it and cannot judge whether any remarks I am quoted as making are accurate or not or are in context or not. The fact that I was included in the film after specifically objecting, and was given no opportunity to fact-check my segment, would seem to indicate that the tactics used by Scientologists in their anti-psychiatry campaign are indeed as dishonest and underhanded as their critics charge.

I regret very much allowing myself to have become involved in this project and would like it to be known that I disown and disapprove of the final product and the way that it has been disseminated.

Federal Appeals Court Upholds NH Anti-Data-Mining Law

Stephanie Saul of the New York Times writes--

--that a Federal appeals court 3-judge panel in Boston overturned a ruling of a lower court and upheld the law passed by New Hampshire, forbidding the sale of data on prescriptions written by individual doctors for use by drug reps.

The data-mining giants, IMS Health and Verispan, had brought suit to challenge the law, and efforts to pass similar laws in other states were largely on hold awaiting the outcome of this action.

The data-mining companies had basically two arguments. First, they claimed that the data had other valuable uses such as health services research, apart from their use by drug reps. Second, they claimed a first amendment right of free commercial speech.

The appeals court panel ruled that the state had made its case that there was a direct public benefit of prohibiting the sale of such data. The judges were persuaded by the evidence that these practices led to "the overzealous prescription of more costly brand-name drugs regardless of both the public health consequences and the probable outcome of a sensible cost/benefit analysis." They thus concluded that there was a substantial state interest in prohibiting the sale of data, and no overriding basic right of the companies to sell the data.

The companies are mulling their next legal challenges to the law, and meanwhile, especially with a more friendly administration about to take office in Washington, states considering the passage of such laws will probably be encouraged to do so.

Monday, November 17, 2008

Plague on Both Houses? Biopure vs. Natanson

Nature, in its November 13 issue, reported on the lawsuit filed by the firm Biopure against Charles Natanson, an NIH scientist and author of a study published in JAMA that questioned the safety of one of the firm's products.

At issue is the blood substitute Hemopure, a hemoglobin-based blood substitute. Natanson and colleagues looked at clinical trials of five blood substitutes, one of which was Hemopure. They claimed that these products were associated with a 30 percent increase in death, primarily due to heart attack risk. Biopure then sued, claiming that Natanson had made "false and defamatory statements" about Hemopure both in the JAMA article and also in letters he then sent to health officials in the United Kingdom, Greece, and South Africa (countries in which some of the blood substitutes had been approved for sale). Hemopure was initially approved only in South Africa, where the HIV epidemic has seriously restricted the human blood supply; subsequent to the controversy, South Africa withdrew its approval.

In an editorial, Nature attacked Biopure for this attempt to conduct "science by litigation," and noted that however unlikely the suit was to succeed in court, the clear intention was to intimidate scientists from speaking out against commercial products. (As explained in HOOKED, such a suit is sometimes termed a SLAPP suit, designed to have a chilling effect even it it never goes to court at all--in part because of the disparity in financial power between a large firm that can keep a bevy of lawyers on retainer, and the individual scientist who can barely afford legal counsel if named in such a suit.)

And, as the news account in Nature explained, if you want to measure corporate behavior on the Sleaz-o-meter, Biopure wins hands down. Its previous achievements include: the FDA halting a human trial of Hemopure because of safety concerns; three of its executives and the company sued by the US Securities and Exchange Commission for misrepresenting Hemopure's FDA status to investors; and criminal indictment of the company's former head of regulatory affairs for lying about his own health to avoid testifying before the grand jury.

But the main point that I want to make here is that Natanson, very sadly, appears to have invited some of this treatment through his own conflicts of interest. Natanson (who refused requests to be interviewed by the Nature reporter) failed to disclose that he was involved in a provisional patent application for a new technique to make hemoglobin-based blood substitutes safer. He has since amended his conflict-of-interest statement and has withdrawn his name from the final patent application. But one could not blame Biopure if they saw him more as a business competitor and less as a disinterested NIH scientist. Based on the old adage "it takes one to know one," they might well have concluded that Natanson's research methodology in his meta-analysis in JAMA was just as unreliable as their reports of their own research.

So, while I completely concur with Nature's condemnation of Biopure's resorting to a lawsuit to settle what ought to be a scientific question of drug safety, I must also note that scientists need to cleanse themselves of financial conflicts of interest if they wish their findings to be taken seriously.

Ledford H. Company sues researcher over unfavourable review. Nature doi: 10.1038/news.2008.1219

Science by litigation [editorial]. Nature 456:142, 13 November 2008.

Natanson C, Kern SJ, Lurie P, et al. Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis. JAMA 299:2304-12, May 21, 2008.

Saturday, November 15, 2008

By JUPITER, Part II--A More Skeptical View

When I did my initial post on the JUPITER study (immediately preceding this post), I had not had the benefit of first talking with a true evidence-based-medicine mayvin. I have now just gotten off the phone with Jerry Hoffman of UCLA, who reviewed my post and the attached comments. I thought I had better hurry up and do a new post before my addled brain forgot all of his observations.

Jerry first of all defended Merrill Goozner against some of my skeptical comments about his blog post. Next, Jerry agreed with me that the basic result of JUPITER is to cast more doubt on the "lipid hypothesis" of how statins help in heart disease, and certainly undermine a strategy of widespread testing of cholesterol and trying to achieve a target level of cholesterol by adjusting statin dose.

Jerry concluded by saying that he put JUPITER together with earlier studies in this way. We know that there are basically three groups of folks--high, medium, and low risk for vascular disease. The really high risk people have already had a stroke or heart attack. For them it seems pretty clear that statins help, and that the number needed to treat (NNT), while still on the high side, at least seems to justify the three costs of statin therapy. (These costs are: the monetary cost of these pricey drugs; the known side effects of statins; and the as-yet-unknown side effects among people who may be on the drug for 30-40 years. One reason that the cost-benefit ratio is favorable in the high risk group is that if you already have had a stroke or heart attack, the chances of your hanging around long enough to develop those possible long term side effects becomes quite low.)

Then we have the low-risk people. For them, the NNT is extremely high. It seems hard to show that the costs, in their case, would be low enough to justify these slight benefits.

Finally we come to the moderate-risk group. JUPITER identified a bunch of these folks, who had the elevated C-reactive protein and also were on the older side. Surprise--their NNT turned out to be intermediate between the highest and lowest risk groups. So the question, first, is: does the intermediate NNT justify the still-substantial costs of statin therapy? (This was Goozner's main point.) If this was explained adequately to patients, some might say yes and others would say no.

The second question is trickier and ignoring it was the main defect in my first post. It is true that if you just looked at the people known to have a high CRP test, the NNT is 95 for 2 years. But that is not the best way to look at the data. If a patient comes to you, the doctor, you have a choice of two strategies. You can look at their existing risk factors, place them in a high-or low-risk category, and advise statins or not depending on that risk assessment, using if you want a tool like the Framingham score. Alternatively, you can order a CRP test and then alter your advice to the patient based on whether it is high or normal.

When you consider the true NNT, you cannot just look at those who are already known to have a high CRP. You have to look at the initial population and factor in the uncertainties associated with the test (such as false positives and negatives, etc.) The NNT for the entire strategy (first test, then treat if high) is going to be a higher number than 95 for 2 years to prevent one bad outcome. Jerry's final question is--how much extra value is added by doing the CRP test, compared to just using other knowledge of risk as we would do today? JUPITER did not give us enough data to answer this question. Specifically, it did not tell us how many patients might have been placed on statins anyway due to other risk factors even had the CRP not been done; nor did it tell us how many patients who did not have another reason to be on statins had to be screened with the CRP in order to yield the relatively small percentage of all comers who ended up in the trial.

I will turn Jerry's good observations into a hypothetical patient coming in the door who is perhaps moderate risk for heart disease, and wants to know if he should take a statin and if he should have that new blood test that he heard about on the news. It seems prudent to offer at least three options:
  • Stay off statins and focus on lifestyle interventions to prevent heart disease--especially exercise--which for all we know have a lower (more favorable) NNT than statins do
  • Don't do a CRP and prescribe statins, or not, based on other risk variables precisely as one would if the CRP did not exist
  • Do the CRP and be guided by the results as to whether to give a statin, the cheapest possible one in the lowest reasonable dose (a modified JUPITER protocol)
My point is that all three options make sense to offer the patient. Jerry would add, that if the patient asked which one Jerry would recommend, he's not sure he'd recommend either statin option based on the totality of today's evidence, including JUPITER.

Finally, you might ask--as this blog is not about statins or heart disease prevention, but the pharmaceutical industry and its relationship with medicine, why have I gone off on this long JUPITER tangent? I might reply that we were forced onto this tangent because a major study that got a lot of media play was hampered by obvious conflicts of interest in its sponsorship and authorship (as again, Goozner accurately noted). This is at least the length that one needs to go to, in today's environment, to decide what to believe of what is published, so as to assure that drug company spin does not trump science. The mere fact that the study was discussed at the meeting of the American Heart Association, and published in the New England Journal, is a completely inadequate assurance of scientific reliability, as multiple examples provided in HOOKED attest.

Thursday, November 13, 2008

By JUPITER: Slick Drug Marketing, Great Science, or Both?

The JUPITER study, which you have heard about on the news unless you have been in a deep coma this past week, is the sort of thing us Pharma skeptics would love to find fault with. My fellow blogger Merrill Goozner noted its two sins--first, the study was funded by AstraZeneca, maker of the study drug, rosuvastatin (Crestor); second, the first author, Paul Ridker of Harvard, owns a patent on the high-sensitivity test for C-reactive protein, the test that would be widely used if the study results are accepted. This led Goozner to twist himself into pretzels trying to find flaws in the study:

I studied JUPITER and the accompanying editorial in some detail and (while awaiting a better assessment from my friends who know study design and biostatistics better than I do) would offer the view that our pal Gooz went a bit overboard. Still, there is an important lesson here and it is not what the media claimed.

Basically, JUPITER screened about 89,000 patients and found 17,802 of them who met three major inclusion criteria--they had no existing heart disease; they had a normal cholesterol level; and they had an elevated high-sensitivity C-reactive protein test, a test for general bodily inflammation. The subjects were then randomized to the statin drug or a placebo daily. They were supposed to be followed for 4 years but the data monitoring board recommended cessation of the study after 1.9 years because of a significantly lower rate of all major outcomes (heart attack, stroke, unstable angina, need for coronary artery surgery) in the group that got the statin drug.

One point to note is that the JUPITER population was a relatively high-risk because older population, with the median age in each group being 66.

On one point, Gooz got it exactly right. The news media wildly reported that these bad outcomes had been "cut in half" by the statin. In actual fact, while the rate of bad stuff was generally half as much in the statin as in the placebo group, the more accurate statistic, absolute instead of relative risk reduction, was far less impressive. For example, if you added up all the bad outcomes as a composite endpoint, there would be 1.36 bad outcomes per 100 person-years of follow-up in the placebo group and 0.77 per 100 person-years in the statin group. This translates into a number needed to treat (NNT) of 95 over 2 years (that is, you would need to treat 95 patients for 2 years with statins to prevent one bad outcome). It is worth noting that this NNT is quite a bit more favorable than in most previous trials of primary prevention with statins, where it is not unusual to see NNT's in the range of 300 to 400. (A low NNT is good, a high one is bad.)

Another score for JUPITER--the death rate was reduced by statins but not by as much as the other bad outcomes. (There was only about a 20 percent relative risk reduction in deaths vs. the nearly 50 percent relative risk reduction for the other outcomes.) Still, this is very impressive because in many earlier primary prevention trials, while statins reduced the number of heart attacks or strokes, they could not be shown to reduce the overall death rate one bit. (This is partly what has led some to fear that statins increase the risk of other deadly diseases such as cancer at the same time that they reduce cardiac or vascular risks. In JUPITER there was no increase in cancers among the statin group, through the follow-up period was of course very short.)

There was also a very limited downside to taking statins for the duration of the study. The only adverse event that happened more often in the statin group was a new diagnosis of diabetes, and this was only a slight difference (3.0 vs. 2.4 percent). A lot of these subjects were diagnosed at the start with metabolic syndrome so their baseline risk of diabetes was very high.

So, bottom line-- it seem hard to argue that this study is a winner for using statins for primary prevention (before any vascular disease has arisen) in one high-risk population, those with elevated c-reactive protein; and that in turn implies the value of using the CRP test as a routine screening test. The NNT of 95 is quite respectable among primary prevention trials.

The JUPITER authors seem to have been fully aware of the skepticism that would greet their paper due to the obvious conflicts of interest. They went to great lengths to note that AstraZeneca did not even see the unblinded trial data until after the manuscript was submitted for publication. Two committees were said to be completely independent of both the company and the principal investigators--an endpoint adjudication committee and a data monitoring and safety committee. In short, if these statements are all true, the study was squeaky clean despite the commercial sponsorship.

Now I come to the point that the media seems completely to have missed. Skeptics of the widespread use of statins (like yours truly) have for a long time insisted that the bulk of the research literature to date does not support the "lipid hypothesis"--that statins work by lowering "bad cholesterol" levels; and that it is critically important to screen patients by testing their cholesterol, and then doing repeated tests to be sure that the response to statin treatment is a low enough level. We have insisted instead that the research indicates that whether or not statins are good for you depends almost completely on whether you have certain risk factors. The biggest risk factor, and the groups where statins have been shown most clearly to work, is already existing vascular disease (that is, secondary prevention). By contrast, very little benefit from statins has been seen in most primary prevention trials, except in men at high risk in the roughly 40-65 age group, and even there with a very high NNT. Since you don't need a cholesterol test to know if you have those risk factors, we have argued that the massive use of cholesterol screening leads to the inappropriate overuse of statins. Moreover, there is no evidence that hitting a lower target cholesterol level by increasing the statin dose lowers your risk to any significant degree.

One way to summarize all these data is to suggest that it is quite possible that statins prevent heart attacks and strokes, but not by lowering cholesterol. They are known to have an anti-inflammatory effect, and it is thought that inflammation plays a role in turning arterial plaque into a major blockage of a vessel that leads to bad disease. It may be their anti-inflammatory effect and not the lipid-lowering effect that explains why they work in the highest-risk groups.

Well, if this hypothesis was worthy of consideration yesterday, it has now received a huge boost with JUPITER. Based on lipid screening, these subjects did not need any statin. Yet they did better on a statin for primary prevention. They were a very high risk group (mainly due to age) and also had signs suggestive of an inflammatory process.

The media never picked up on this. All the coverage I heard simply took for granted that it was wise to treat elevated cholesterol with statins, so now we had yet another huge group of patients who needed a statin in addition to those with high cholesterol. On NPR (of all places) this morning, I heard a physician quoted that JUPITER showed that we need to reduce levels of cholesterol much lower than anyone had previously realized--when the real message is to test CRP and forget all about cholesterol. Even if the lipid hypothesis of statin treatment is all wet, we still seem completely hooked on it.

Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New Engl J Med 359:2195-2207, Nov. 20, 2008.

Hlatky MA. Expanding the orbit of primary prevention--moving beyond JUPITER [editorial]. New Engl J Med 359:2280-2282, Nov. 20, 2008.