Monday, January 28, 2013

Amgen's Latest Escapades

I wouldn't want any of you to think writing this blog is easy. Among the things I sweat bullets over is whether to include posts about bad behavior of a drug company when it does not directly address the main theme of this blog, which is the ethics of the relationship between the pharmaceutical industry and the medical profession. When a drug firm does dirty without involving the medical profession in its nefarious deeds, then it seems like unfair piling on to make a big deal of it here. At the same time, if you don't know some of this background, it's hard to make sense of some of the other aspects of drug industry behavior that do impact more directly on medicine.

As often is the case, I'll refer you over to our friends at Health Care Renewal blog for the main details--
--as well as to a recent newspaper editorial:

What's at issue here is two actions involving the drug firm Amgen. First, as we noted in a recent post:
--Amgen settled with the Feds for a $762M fine for illegal marketing of Aranesp, a drug for cancer and kidney disease patients that's dangerous in higher doses. Second, lobbyists for Amgen managed to sneak into the fiscal cliff legislation a special provision that favors another Amgen drug, Sensipar, by postponing for 2 years Medicare price controls for the drug. This will probably cost taxpayers an extra $500M, which by coincidence almost pays for Amgen's fines in the first case. Amgen won this special treatment in Congress thanks to its cozy relationships with, and generous donations to, Sens. Orrin Hatch, Mitch McConnell, and Max Baucus.

Here's the critical summation from HC Renewal: "In summary, Amgen seems to have leveraged its use of former legislative aides affiliated with both political parties as lobbyists, and its presumed influence over former employees who are currently legislative aides, that is, to people who have transited revolving doors in both directions, to influence policy in its corporate favor.  It has also leveraged its contributions directly to politicians, to political action committees (PACs), and to non-profit advocacy groups to influence policy in its direction for this purpose.  All this leverage apparently resulted in continuing government favoritism to a company the government had just convicted of a crime, and to a company whose actions likely led to sick and dead patients.  Furthermore, legislators who publicly deplore excess government spending and enlarging government deficits supported spending more taxpayer money to favor a particular company that they ought to have shunned."

The Sacramento Bee's editorial concludes, "At the end of last week, a bipartisan group in the House introduced a bill to repeal the Sensipar provision. Given Amgen's clout, chances are slim the House bill will pass. But it's a good fight to fight." Seems like folks who care  more about patients' health than about corporate profits do a lot of that--fighting the good fight against heavy odds.

Friday, January 25, 2013

More on Ghostwriting

As promised in a recent post--
--I'm returning to summarize the main message of a 3-part blog post by Drs. Jonathan Leo and Jeffrey Lacasse, of which the 3rd part has just appeared:

Drs. Leo and Lacasse take aim especially at academic institutions and organizations and ask how serious they are about eliminating ghostwriting. Not very serious, they conclude, if they cannot even agree on when ghostwriting occurs.

They go on to say that the basic question is: did people make substantial contributions to writing the paper and yet are not listed in the authors' byline? If so the paper is ghostwritten. That is, the named authors did not actually do the work that the paper's byline suggests that they did; and the source of the ideas contained in the paper may be very different from what the readers are led to think.

They then proceed to look at some recent cases where ghostwriting was alleged and various institutions defended the purported authors, denying that ghostwriting occurred. The reasons for the denial include:
  • the named authors signed off on the final draft
  • the facts contained in the paper are accurate
  • there's nothing wrong with employing a skilled medical writer to help make a paper more readable
  • at the time a certain paper was written there were no policies in place regarding ghostwriting
Drs. Leo and Lacasse reply that all these might be good things to know, but none of them address the basic issue of whether the paper was ghostwritten.

Perhaps the most important point they make is that by saying that look, why worry, experts say the facts in thuis paper are accurate, or something like that, these supposedly academic institutions that supposedly stand for the integrity of scholarship seem to be saying to readers, just trust us, it does not matter who actually wrote the paper. If that's their position, then why bother to list authors on the byline at all; just write "trust us, it's all true." Which of course is ridiculous. Which of course means that what's really going on is academic institutions refusing to take seriously that one of their own faculty, who's a local star for bringing big bucks from industry into the university, may have misbehaved. And so long as that remains the prevailing attitude, nothing seriously will be done about ghostwriting.  My own previous question remains on the table--show me when faculty who allow their name to be put on ghostwritten papers actually suffer in the advancement of their academic careers, and I'll show you a time when maybe ghostwriting will start to go away. (For one of the rare cases in which such consequences appear to have occurred, see:

Thursday, January 24, 2013

Using the Medical Record to Advertise Drugs to Doctors: Thank the Cloud

At various times in the past I've taken a break from discussing medicine and Pharma to talk a little about health information technology and the electronic record, another area where commercial influence seems to be corrupting good medicine and the public's health (most recently:)
Today however I can talk about information technology with no apologies about deviating from the major theme of this blog. As Pamela Dolan writes in American Medical News:
--some makers of electronic medical records for doctors' offices are exploring how to embed drug ads in the record, in such a way that when the doctor is seeing a patient with a certain disease, an ad for a drug for that disease pops up at just the strategic moment.

To do this the record must be "cloud" based (I am still too much of a Luddite to feel sure that I know what "cloud" means in this context)-- a record that's based on a hard drive in the office cannot do the work required to select the right ads at the right time. The attraction for docs is that if the HIT company is making big bucks off selling ads, they can offer the record to the doc at a deeply discounted rate. Since electronic records are very expensive as an up-front cost--and as the promised back-end savings from the supposedly more efficient records have generally not materialized--this is a big deal for an office practice.  One of the scariest aspects of the article from the standpoint of medical professionalism is that one company, Practice Fusion, offers docs a choice. They can pay a monthly fee to get an ad-free electronic record; or they can get a free or much cheaper version with the ads. Only 1% of docs cough up the money to buy the ad-free version.

The article also makes clear that this is one element of what happened to Pharma with their 2009 "code of conduct" in which they agreed to give up a lot of the old-fashioned freebies for docs like the once-ubiquitous drug pens. I have yet to read a scholarly study of drug advertising expenditures to see if marketing costs actually went down at all but I would guess they didn't as the industry simply refocused its spending on new areas, the Internet being a high priority. And the electronic record is obnviously a very attractive portion of the Internet for drug firms.

The whole matter of electronic records (and the medical record more generally as some of this has little to do with whether it's electronic or paper) needs a lot more discussion to investigate the gradual erosion of this important aspect of professionalism in medicine, the historic concern for the record as ideally a tool of patient care. Physicians have been bought off by promises of higher reimbursements and have gradually allowed the record to become a tool for every imaginable administrative and bureaucratic function, to the point where one has to sort through pages and pages of idiocy in order to find one thing that tells you what's going on with a sick person. These data-loaded but real-information-poor records have become a positive threat to the patient's health instead of a tool for better quality care. To tell us now that by the way, they are going to be a vehicle for drug ads too, is the last straw--and a group of independent merchant-contractors who allow this to happen no longer deserve the title of "professionals."

(Hat tip to my esteemed colleague Dr. Scott Monteith for suggesting the Dolan article.)

A Really Bad Ghostwriting Joke

We previously heard from our pals Jonathan Leo and Jeff Lacasse on the issue of ghostwriting:

They are in the process of doing a 3-part blog posting on ghostwriting and I had planned to read all three parts and maybe summarize any new points. But their Part 2 so grabbed me--
--that I decided to link to it right away, because it contains what would be considered a really bad joke about ghostwriting.  Trouble is, no one was trying to be funny.

The issue is Medronic's InFuse-- see:

I commented on the Senate Finance Committee report in that previous post but need to mention what Drs Leo and Lacasse pulled out of it. The basic point is that Medtronic, and communication companies hired by Medtronic, are writing drafts of papers, sending them to their orthopedic surgeon "key opinion leaders," rewriting parts of the papers to spiff up InFuse's image (mostly by denying any adverse effects), and then having the surgeons send the papers to journals as if they wrote them themselves, with no mention of the company input. The surgeons were paid hefty consulting fees for their work--Leo and Lacasse report a total of $210M changing hands with one prominent surgeon getting $34M all on his lonesome.

As Drs. Leo and Lacasse recount the record, in 2004 a paper appeared in the journal Spine co-authored by Dr. J. Kenneth Burkus, one of the KOLs. The Senate committee uncovered internal company e-mails showing that Medtronic did not like the part of an early draft that said "this review of the results...are [sic] encouraging." So a Medtronic exec, Rick Treharne, sent Dr. Burkus a revised draft in which he had inserted several new paragraphs, which began, "In conclusion, this detailed, independent review of the results..." and went on in that vein extolling the wonders of InFuse. And that was the version that Dr. Burkus and his colleagues submitted to the journal, with their names on the byline, and with no mention anywhere of Treharne or anyone at Medtronic being an author or contributing to the writing of the paper.

Well, the reviewers for the journal, bless them, didn't like the new conclusion. They actually thought it sounded, well, biased. (Who would have guessed?) So Dr. Burkus decided to defend the draft by sending the journal a letter in response to the reviewer's comments, to reassure the editors that the paper was truly an independent work by unbiased scientists. But Dr. Burkus did not write the letter himself. He turned instead back to Mr. Treharne, and Mr. Treharne and another Medtronic executive wrote the letter to the editor to explain why the article was in fact independent and unbiased. And of course when the letter arrived at the editor's desk, it was not signed by Treharne or anyone at Medtronic; it was signed by one of the (purported) physician-authors of the study.

Now, if I told you a joke about a college student who downloaded a class paper off the Internet, turned it in as his own work, and was accused by his prof of plagiariam, and defended himself to the prof with a letter that he also downloaded off the Internet and signed as his own work, you'd think I was telling a bad joke.

And Drs. Leo and Lacasse report that despite all this record being laid on the table by the Senate committee, both Medtronic and the University where one of the key "authors" works stoutly deny that any ghostwriting occurred at all.

Haid RW, Branch CL, Alexander JT, Burkus JK. Posterior lumbar interbody fusion using recomlinant human bone morphogenetic protein type 2 with cylindrical interbody cages. The Spine Journal 4:527-38, 2004.

Thursday, January 10, 2013

Appeals Court Throws Monkey Wrench into FDA Regulatory Authority

For background see:

Readers of HOOKED and this blog have seen this general scenario repeated more times than I can count:
  1. A drug firm markets a drug aggressively for ineffective or unsafe uses.
  2. A whistleblower within the company alerts the Feds.
  3. The Feds begin investigating the company with an eye toward prosecution for legal violations.
  4. As part of the investigation the Feds force the company to cough up internal documents. These documents provide folks like us with our only glimpse of what Pharma is really up to, as normally all that is buried deep as proprietary information.
  5. In the end, the Feds reach a settlement with the company, which pays a fine of lots of bucks, which is often only a pittance compared to the revenues received from sales of the drug--so that the company then does it all over again with the next drug.
Now notice that for this process to work (Step #3), there has to be a legal violation that the Feds could find the company guilty of. The standard up till now has been off-label marketing--the company promoting the drug for uses that are not included in the official label. It is not that the off-label marketing aspect of the promotion of the drug is really what is most egregious, necessarily--it just turns out that that's often the handiest legal peg on which to hang the case. Bottom line--if the FDA lost its ability to prosecute companies for off-label marketing, the even-now-super wimpy degree of control that the FDA exercises over drug promotion gets wimpier still.

This is precisely what's threatened by the case of U.S. v. Caronia as decided by a 3-judge panel of the U.S. Second Court of Appeals for New York in December. Caronia was a drug detail rep who was working with a doc (one of those "key opionion leaders" aka shills) who was giving industry sponsored speeches recommending sodium oxybate (Xyrem, Orphan Medical/Jazz Pharmaceuticals) for off-label uses (it is only approved for catalepsy and narcolepsy in adults). The DOJ heard about this and conducted a sting, recorded both the rep and the doc, and then arrested them. The trial court convicted, and dismissed Caronia's defense that the conviction violated his first-amendment free speech rights.

The panel of the Appeals Court, by a 2-1 vote, overturned the conviction, ruling that  limiting Caronia's rights as a detail rep to recommend the drug for off-label uses, which are legal for docs to prescribe for, is an inappropriate limitation of his first amendment rights as he claimed, unless the Feds could show that the off-label promotion was itself false or misleading. The one dissenting judge mentioned the "well,duh" point that if reps had the first-amendment right to say whatever they wanted to docs, then that totally throws any powers of the FDA to regulate drug marketing out the window.

To unpack that concern just a bit, what's the rationale for the FDA's prerogative to regulate off-label marketing of drugs, even if docs can freely prescribe the drugs for those uses? If the company cannot market for off-label uses, then they have an incentive to apply for label changes to extend use of the drug when they discover possible new uses. They thus have an incentive to submit data to the FDA to prove safety and effectiveness when the drug is used in those ways. If companies can market off-label with impunity, their incentives change--they have an incentive to seek the narrowest possible label at first, spending the minimum on studies to prove safety and efficacy, and then they can market the drug for any old thing without having to prove that the drug is safe and effective over that much wider range of use. Hence--establishing marketing off-label as a free speech right basically eviscerates FDA regulatory powers.

The two-judge majority of the panel did not see it that way, and stated that if the goal of the FDA is to limit off-label prescribing, they could do so just as well by imposing ceilings or caps on off-label prescriptions without interfering with commercial speech. The dissenting judge, no fool, was not buying that. She pointed out that ceilings or caps could require incredible record-keeping burdens and also result in some patients being denied a useful drug while others were prescribed a dangerous drug. To which I might add: the whole reason for the FDA regs as they now stand is that they presumably can regulate drug manufacture and marketing, but the FDA has no remit (as they say across the pond) to regulate medical practice. Setting ceilings on off-label prescribing sounds to me like trying to regulate medical practice.

What the various authors linked to above seem to disagree about is how big a deal this decision is. The New England Journal prespective by Marcia Boumil appears to see the matter as relatively dire--this case is sure to be appealed up to the Supreme Court, where the conservative majority is very likely to extend the first-amendment rights of "commercial speech." By contrast, Kate Greenwood at Seton Hall Law School's health blog seems a bit less concerned. She notes that the government has up its sleeve a number of arguments to defend FDA powers, including for instance the interpretation that what was effectively appealed in this case was a set of erroneous instructions to the trial court jury, and not the principle of free speech vs. drug regulation, severely limiting the scope of any unfavorable ruling.

Also, it's my understanding that before the case goes up to the Supreme Court it may be appealed to the entire Second Appeals Court bench, beyond just the 3 judges who initially ruled. I have no idea about the political makeup of that bench as to whether that would likely change the outcome.

I don't, as a non-lawyer, know what to make of the eventual implicatons except for two things:
  • From an ethical and common-sense point of view the two-judge panel decision sounds like idiocy.
  • If the prerogative of the FDA to limit off-label marketing is seriously restricted (and it has already been chipped away to a large degree), then expect to have even more problem in the future ever discovering what the drug industry is really up to--let alone seeing anyone held accountable for marketing unsafe drugs.  

Wednesday, January 9, 2013

Why We Need Independent Drug Research

History quiz--in what year was this statement made in Congress as a reason to propose new legislation on standards for drug approval?

As the law reads at present, the FDA determines the safety and efficacy of a drug solely on the basis of information supplied by the drug company making the application. The dangers involved in the dependence on drug firms to perform, direct, or arrange for the testing of drugs in which they have a financial interest is obvious..... [T]here is an inevitable tendency--no matter how conscientious the firm--to emphasize the positive features and deemphasize the negative. Many of the people they engage to do their testing are equally anxious to secure additional contracts for drug testing... A physician who turns in unfavorable reports on the drug he is testing may not have his contract renewed... [S]ome firms have been guilty of misrepresenting, distorting, and even withholding information developed in their testing of drugs which might in any way retard or prevent an approval to market. Injury and death have resulted from such actions.

Testing of drugs should be done by specialists who have no direct relationship with the manufacturer, who cannot benefit financially from the results, who are not motivated even subconsciously by the desire to get anything but the truth. We must remove the responsibility for testing drugs from the applicant who has a financial interest in the drug.

Answer: 1971 (Sen. Gaylord Nelson)

I blogged previously about Marc Rodwin's important book on conflicts of interest and drug development:
Professor Rodwin (of Suffolk U. Law School in Boston) has now written a law review paper--
--recommending that we reinvigorate this longstanding quest for a financially independent way to do clinical research on drugs, and to eliminate the corrupt influence of industry money on the present pharmaceutical research enterprise.

As the introductory quotation indicates, Prof. Rodwin is big on history and carefully reviews both the story of the FDA and its enabling legislation, and four different Senate hearing cycles (by Senators Kefauver, Humphrey, Nelson, and Kennedy) between 1960 and 1980, before which evidence was repeatedly presented to show the failure of current efforts to regulate drug research successfully so long as the financial incentives continued as they were. He concludes with an argument to move toward some form of government-overseen, independent method for conducting the research needed for new drug approvals, and a reply to criticisms of such proposals.

Prof. Rodwin frames his argument by noting the possible spectrum ranging from total manufacturer control to total government control over clinical trials of drugs:
  1. Drug firms conduct their own trials; minimal regulation
  2. FDA oversees drug-firm-sponsored trials
  3. Only government-certified researchers allowed to do trials
  4. Government promotes transparency by requiring registration of trials, disclosure of data, etc.
  5. Government selects independent researchers to conduct trials
  6. Government agency conducts all trials
To date we have relied mostly on #2 with some elements of #4. Rodwin argues that this has been shown extensively to have failed and we should be moving toward #5 or #6.

Rodwin cites extensive past work arguing for this same conclusion (as I reviewed in HOOKED where I made basically the same recommendation). Now all we need is the political will to actually do something. Rodwin is largely silent on where that is going to come from-- he assumes that further scandals will eventually turn the tide. One can read HOOKED and this blog and wonder if past scandals have not moved the needle any farther than they have, what exactly it would take to light a fire under us.