Tuesday, August 27, 2013

Overdiagnosis: A Consequence of Commercial Influence

The phenomenon of overdiagnosis is receiving increasing attention in medicine, and is indeed the subject of an international conference to happen in a couple of weeks at Dartmouth. Last year, Ray Moynihan,. the Australian journalist well known to readers of HOOKED as the author of a great book on “disease mongering,” along with Jenny Doust and David Henry, prepared a nice summary of overdiagnosis for the BMJ in advance of the conference (subscription required).

Overdiagnosis is defined as “when people without symptoms are diagnosed with a disease that ultimately will not cause them to experience symptoms or early death.” I think it important to distinguish overdiagnosis (which most people have never heard of) from false positive test results (which most people have at least some idea about). Let’s take breast cancer as an example. If you have a false positive mammogram, it shows a shadow suggestive of cancer, but when you do a biopsy or more definitive test, they see no cancer cells. But if you have overdiagnosis, the shadow on the mammogram actually has cancer cells when looked at under the microscope. The problem is that some cancer cells never grow very fast or spread, and if you have that form of indolent cancer (these authors call it “pseudocancer”), finding out about it early produces no benefit for you. You’ll have treatments to attack the cancer, and those treatments will cause serious side effects, and you’ll be forever labeled a “cancer patient,” but if the “disease” had simply been left alone, you’d never have known the difference. (Most lay people, I would wager, have no idea that there exists a form of “cancer” that can act like this.)

The authors list a number of causes of overdiagnosis: while one big one is screening tests, others are increasingly sensitive tests that find smaller and smaller abnormalities, and redefinitions of “disease” that include more people with milder cases. The authors mention a study of asthma which found that nearly 30% of people diagnosed as such did not really have asthma after all, and 66% of those diagnosed did not need any medicines for it. (The irony here is that we also know that there are people with true asthma who remain underdiagnosed and untreated, too often fatally so.)

The authors list these conditions as currently subject to overdiagnosis (again, not to deny that at least some people with these conditions are currently underdiagnosed and/or lack access to proper care):

·         Asthma

·         Attention deficit-hyperactivity disorder

·         Breast cancer

·         Chronic kidney disease

·         Pregnancy-related diabetes

·         High blood pressure

·         High cholesterol

·         Lung cancer

·         Osteoporosis

·         Prostate cancer

·         Pulmonary embolism (blood clots in lung)

·         Thyroid cancer

So why does all this happen? Improved technology is one big reason, along with our love affair with screening and “prevention” and our near-religious faith that early diagnosis is always good. But coming right up next on the list is commercial influence, with the companies that make money off the screening tests and the companies that make money off the drugs and devices that are then prescribed when more people are labeled as sick doing everything they can to move the curve in the direction of overdiagnosis. (Indeed, if you look back at Don Light’s and my article on the Inverse Benefit Law:
--and review the forces that produce what we called the “left shift” that categorizes more and more previously healthy people as candidates for drug therapy, you’ll see a lot of overlap with the factors described in this paper.)

Moynihan R, Doust J, Henry D. Preventing overdiagnosis: how to stop harming the healthy. BMJ 2012; 344:e3502.

Monday, August 26, 2013

The Fate of a Scientist Who Reveals Drug-Related Harms? The Bennett Case

Initially, our friend Dr. Roy Poses blogged about this on Health Care Renewal:

I was tempted also to blog about this but held off at the time because I was concerned that the facts were not all available, and it was just possible that I would be defending someone who was, in fact, guilty of fraudulent behavior—a concern Dr. Poses shared because he called for more investigation.

Dr. Poses has meanwhile posted again:

--and in turn referenced an article by Paul Goldberg in The Cancer Letter of Aug. 9:

--which now seem to provide enough factual background to at least raise some serious concerns. Let’s see if I can tell this tale the right way around for our purposes, even though it’s a convoluted story.

Let’s go back to the debate over drugs like epoetin that are used in kidney dialysis and cancer care to treat anemia by stimulating the production of red blood cells:

Companies like Amgen, that manufactured these lucrative drugs, were quite upset when studies began to show that higher doses of the drugs increased blood counts by too much and led to life-threatening clotting complications. The problem was that both cancer docs and dialysis centers were being paid on commission, meaning if they used higher doses, they got more money, and so had a strong financial incentive (which of course also benefited the drug’s manufacturer) to use the higher doses. Dr. Charles Bennett of Northwestern University med school played a role in reporting both on the scientific evidence of harm from too-high doses, and later on the role of the drug firms in trying to hide this information—for example:

Dr. Bennett eventually created a unit at Northwestern, the Research on Adverse Drug Events and Reports project, specifically to study serious adverse drug reactions; and it is not too much of a stretch to suggest that his work helped to create the climate in which Amgen pleaded guilty to charges that it misbranded its epoetin drug Aranesp and paid a settlement of $762M in 2012. When Dr. Bennett left Northwestern in 2009, it was to take the offer of $6M in startup funds to study the safety of drugs in South Carolina.

Now let’s look at issues at Northwestern regarding the administration of research grants.

As Goldberg recounts, Northwestern has previously had problem in this area, and a decade ago had to repay the NIH $5.75M that it obtained through inflated reimbursement for faculty effort. Just recently, Northwestern agreed to pay the Feds a settlement of about $3M due to questionable payments on another grant, in this case one whose principal investigator was Dr. Bennett.

Just before this recent Federal settlement was announced, a former Northwestern employee, Feyifunmi Sangoleye, pleaded guilty in U.S. District Court to embezzling $86,000. She worked in the Northwestern cancer division’s grants administration office and set up a phony account, into which she proceeded to divert grant monies that she eventually used to pay for a wedding in Europe.

The statements issued by the Feds and by Northwestern regarding their recent settlement focus on the allegations that Dr. Bennett used NIH grant funds illegally to pay for consulting jobs for family members and for personal travel unrelated to the grant. The whistleblower credited with exposing this wrongdoing, and who as a result takes home a nearly half-million-dollar share of the award, is Melissa Theis, who was a temp employee at Northwestern in 2007-8. What Goldberg finds intriguing about her role is that she apparently never worked directly in the cancer center, so it’s unclear how she obtained information about Dr. Bennett’s grant.

In the normal course of events (as Dr. Poses stressed) Dr. Bennett could not simply pay himself money out of his grant and do whatever with it. He had to submit the expenses to the administration, and they had to approve that the costs were justified before any payment could be issued. The people who would have had to sign off would have been first, the administrator, the recently convicted felon Sangoleye, and the director of the cancer center, Dr. Steven Rosen. Dr. Rosen was initially listed as a co-defendant but his name was dropped as the Federal settlement proceeded.

Dr. Bennett told Goldberg that he did not do any of the things alleged regarding inappropriate payments, that he noted irregularities in the way Northwestern was handling grant funds, and that he duly reported these concerns to his superiors before leaving Northwestern.

The publicity surrounding the Federal settlement was what first attracted Dr. Poses’ attention. The Chicago newspapers jumped on the charges against Dr. Bennett, but completely ignored the Sangoleye guilty plea. Both Northwestern and the Feds seemed primarily interested in alleging that it was all Dr. Bennett’s fault and specifically in clearing Dr. Rosen of any wrongdoing, even though officially he was the person where the buck stopped in approving payouts from the grants.

Goldberg talked with several colleagues of Dr. Bennett who testified that he was not the sort of person one would expect to commit fraud with grant money, and was in fact a scientist dedicated to sniffing out the truth about adverse drug reactions.

Goldberg hints broadly in the article that Dr. Bennett collected his share of foes due to his work on epoetin drugs and their dangers, and that it would not be that strange if at least some of all this recent scandal reflected an effort to smear his reputation. And given that the administrator who oversaw his grant is now a convicted felon, if anyone played fast and loose with money from his grant, it might well not have been Dr. Bennett. And, finally, if there was lax supervision of grants at Northwestern, it would seem that Dr. Rosen and not Dr. Bennett should be answering for it.
I hope Dr. Bennett will have his day in court and have a chance to defend himself against these charges and that we’ll eventually find out the truth. Meanwhile, as we tally up what happens to scientists’ reputations later in life, it seems much safer to put your name on a ghostwritten article for a drug company, than to earn their ire by exposing the toxic effects of drugs that could be harming patients.

Saturday, August 24, 2013

Oregon DOJ Demands More Transparency of Device Payments to Docs

Nick Budnick of The Oregonian reports:
--that the state Department of Justice has gone out ahead of national trends in demanding that physicians reveal to patients the payments they receive from device manufacturers, that could provide a financial incentive for them to implant more devices.
Two Salem cardiologists were fined $25,000 each in settlements in which they admitted no wrongdoing, for failing to inform their patients of fees they received from Biotronik regarding that company's defibrillators and pacemakers. The physicians were being paid fees of $400 to $1250 per implant when a company trainee was present at the procedure.
Let's look at this practice in more detail. First thing to note is that these extra "training" fees effectively doubled the payments the docs received from insurers for performing these procedures. The two physicians made a total of $97,000 and $131,000 over a several-year period, respectively, from these payments. So it's reasonable to conclude that these amounts were large enough to sway the doc's judgments about when and how many devices to implant. (Court documents revealed that one of the docs once complained to the company that he had to do an implant and there was no trainee available on that day.)
Second point--the official reason for these payments was that the company wanted its employees to know all there was to know about the device and its adjustment and placement, so that they could in turn properly instruct new physicians on their proper use. These experienced physicians were merely serving the company in this legitimate function and thereby earning all the dollars paid to them on the up and up. The problem with this is the long history of device companies pulling every trick in the book to disguise paybacks and bribes to docs, in exchange for greater volume of use of the company's product, as if it was payment for some fully legitimate service. Just how many procedures did employees need to see in order to be "trained"? Just what sort of "training" actually occurred at these sessions ("Okay, I am going to implant this device, you can come and watch")?
There is a third point that is a bit more speculative, but relates to an earlier post on this topic:
I noted previously how, according to an insider who knows the device-implant scene much better than I do, it is not the case that these company employees are being "trained" so that they can help physicians do their jobs better. At least in some instances the company employees are being provided to the docs as free labor. They do the technical adjustments of the device which the physicians are too "busy" to learn how to do, and unwilling to pay their own technician to do for them. Having this free labor provided is of course a huge financial incentive to use that particular company's device.
Reasons to suspect that all is not on the up and up include the report, by Budnick, that Biotronik started off as a relatively small German firm and has rapidly gained U.S. market share in recent years. Reportedly its marketing practices are also under Federal investigation.
It's important to note that Biotronik was not directly a party to the Oregon DOJ action, which focused solely on the physicians' behavior. However, Biotronik did come to the defense of its docs, saying it was unfair to single them out when other drug and device companies have paid so much to so many other Oregon doctors. Somehow that does not strike this "ethicist" as a solid defense.
Another ethicist, however, was more pliant. Budnick quotes an affidavit that Biotronik also helpfully submitted to the Oregon DOJ, from my esteemed colleague Jonathan Moreno of Penn. He argued that there was no legal or ethical basis for a claim that the physicians should have informed patients of the company payments. An obvious question--unanswered in Budnick's coverage--is how much payment Prof. Moreno received for this service to Biotronik. (Another esteemed bioethics colleague, Carl Elliott of Minnesota, who's been quoted here many times before, was cited by Budnick as disagreeing with Prof. Moreno--as I would.)

Tuesday, August 13, 2013

Pfizer Does It Yet Again—More Perpetrator-less Corporate Crime

Once again to defer to Dr. Roy Poses at the Health Care Renewal blog:

--on an issue we also have blogged about in the past:

--it seems that Pfizer has yet again settled with the Feds, in this case actually going so far as to admit guilt, in relation to a $491M claim over illegal marketing of the drug Rapamune. This drug, manufactured by Wyeth, which Pfizer bought out, was approved for use to prevent immune rejection only in kidney transplants, and data show that it causes serious risks when used in other organ transplants. Nevertheless Pfizer now admits that Wyeth illegally marked the drug for different sorts of organ transplants, to the extent that 90% of the firm’s revenue from Rapamune resulted from non-kidney uses. (Sounds like a pretty effective marketing campaign to me, even if illegal.)

Dr. Poses makes the excellent point, even if it’s a broken record that he’s getting tired of playing, that just as we sometimes talk about “victimless crimes,” the drug industry seems to have teamed up with Federal prosecutors to perfect perpetrator-less crime. A firm is caught doing illegal stuff and settles for huge sums of money—but no actual human beings ever seem to be responsible, much less get punished for their misdeeds. Apparently both Wyeth and Pfizer are operated robotically and no actual person ever takes charge of any decisions.

Pfizer, while admitting guilt, acted like all this is water under the bridge anyway because of course, this crime was not committed by sterling and pure Pfizer, it rather was committed by that nasty, evil company Wyeth, which by the way no longer exists as a separate entity. Which leads to the question of what happens when a company like Pfizer decides whether or not to buy a company like Wyeth. I am of course far from being a business tycoon, but in my state of ignorance I imagine it goes something like this. Pfizer looks at Wyeth’s assets and at its liabilities, and decides on a purchase price based on how both balance out. Among the liabilities, the buyer looks at any future legal actions that might be pending or that it can anticipate. It sets the purchase prices such that if it ends up paying out a lot of money in a legal settlement—just say, to take a wild hypothetical example, $491M—it has paid a low enough price for the bought company so that the assets it acquires makes up for whatever it has to pay out in the legal settlement(s). I assume that’s how business is done. So that seems to make Pfizer a full participant in the process. And any claim that it had nothing at all to do with any chicanery sounds pretty hollow.

The other question, of course, is how this fits with any patterns of long-standing behavior on Pfizer’s part. Dr. Poses admits that by now he’s lost count of how many times Pfizer has had to settle with the Feds over alleged or actual wrongdoing. He adopts the term “umpteenth” as the best count he can manage. And of course, each time it happens, Pfizer promises on its grandmother’s grave never to do it again.

Doing Patents the Indian Way

Last week’s New England Journal of Medicine features a “perspectives” by Amy Kapcynski of Yale Law School:

Prof. Kapcynski reports on a ruling by the Supreme Court of India last April that effectively upholds that nation’s Patent Act, against a challenge to a patent ruling by the drug giant Novartis.

Folks in poorer nations have a strong interest in promoting locally made generic drugs and limiting the ability of international firms to extend the patent life of their expensive brand-name drugs. With these concerns in mind, Section 3(d) of the Indian Patent Act was designed to forbid patents of the sort that lead to the most extreme cases of “evergreening” in the U.S. Pharma world (as described in HOOKED). It forbids a company getting a patent on a new, minor chemical variant of a known drug, such as a salt or isomer, unless it has shown that the new form offers a significant advantage in efficacy.

Novartis tried to extend its patent on the cancer drug Gleevec by claiming a patent on the beta-crystalline form of the drug’s active ingredient. The Supreme Court cried foul.

Prof. Kapcynski says that the Indian law and the Court’s ruling have two virtues. First, they keep prices lower for the developing world. But they also do the opposite of what Novartis immediately claimed when the adverse ruling came down—that the Indian law was stifling innovation by reducing the financial rewards to big companies. Prof. Kapcynski argues that the law rather promotes the right sort of innovation. It turns companies’ attention away from silly me-too drugs and forces them actually to innovate—to discover new drugs that work better than existing drugs.

That’s the business and public health end of the equation. What about the legal end? The basic idea behind patent law, those non-lawyers among us are told when we try to study the issue, is that important criteria for deciding whether to issue a patent are novelty and non-obviousness. Now, patenting a minor chemical tweak in an existing drug sounds like a poster child for “obvious” and “not novel.” So why has the U.S. patent office acted like such a wuss and granted patents to drug companies wholesale for these “new” drugs?

Prof. Kapcynski makes the claim that it’s not merely the case that the Indian patent law should be allowed to stand—but that it would be a great model for other countries to emulate. How about the USA?