Tuesday, May 28, 2013

The Corporate Shell Game: Crimes that No One Is Guilty Of

Once again I get to put up my feet and let my friends over at Health Care Renewal write this blog for me:

Today's sermon is about a drug company called ISTA which makes a drug called Xibrom, which reduces pain and inflammation in the eyes after cataract surgery. ISTA, it seems just pleaded guilty in Federal court to a scheme to use kickbacks to get doctors to prescribe Xibrom off-label for other eye conditions.

As Phil Fairbanks writes in the Buffalo News:
--the evidence against the company was pretty overwhelming, explaining why they took the unusual step of actually pleading guilty in a criminal case. Prosecutors showed that docs were recruited ostensibly for speaking and consulting engagements to market the drug off-label, but in fact just as much to bribe them to prescribe the drug themselves. Company reps were directed not to leave written materials behind at the doc's office or to make records of their visits for fear of leaving evidence. (Eventually a couple of company employees blew the whistle.)

OK, so these guys broke the law, and ISTA had to pay a total fine of $33M (chickenfeed of course in big Pharma circles, and not such a big bite even for ISTA whose annual sales are $160M). So somebody must be guilty, right?

That's where Health Care Renewal jumps in. It seems that somewhere along the line, after the Federal investigation had begun but before final judgment, ISTA was bought out by the big eye product firm, Bausch & Lomb. B&L was shocked, shocked to find out what horrible things its new company had done in the past, but of course that was all in the past and there's no way that innocent B&L could be blamed for those old incidents, right? Now, despite the fact that B&L has no guilt, they are allowed as part of the ISTA sale to buy out Xibrom and rights to all future sales of the drug.

As part of the Federal case against ISTA and the guilty plea, ISTA suffered what is supposed to be the equivalent of capital punishment in the Pharma world--it's now banned from doing any business with Medicare or Medicaid. But the ISTA that's subject to this extreme penalty no longer exists. In capital punishment terms, it's sort of like digging up a corpse and sending it to be hanged. B&L does exist and it can sell Xibrom merrily as long as it wishes, but it's not guilty and so it can do as much business with Medicare and Medicaid as it wants.

So when corporations can play this now-you-see-it, now-you don't shell game, it's pretty obvious that any penalty visited by the Feds is pretty much a charade. The worst joke was said in the Buffalo federal courtroom, according to Fairbanks:

 "[U.S. District Judge Richard J.] Arcara also wanted to know if the $33 million settlement was large enough to serve as a deterrent for a company that generated $160 million in sales in 2011.

“'This will have national consequences in the pharmaceutical industry,' [Assistant U.S. Attorney Mary Ellen] Kresse assured him."

Yeah, right. It's interesting, in today's wonderful world of corporate law, how corporations are people when it suits them to be--for example, when corporations are suddenly discovered to have first-amendment rights so that it's unconstitutional to limit their political donations. But if I commit a crime, and the investigation is ongoing to see whether or not I am guilty, I am not allowed to announce at the time I'm found guilty that I have morphed into a completely different person and so it's the old, no-longer existing dude that's guilty, and I should be allowed to go scot-free. Only corporations, it seems, are allowed to play that shell game.

Saturday, May 25, 2013

Is FDA Covering Its Fanny on Avandia?

Dr. Steven Nissen, head of cardiovascular medicine at the Cleveland Clinic and a central figure in the debate over the diabetes drug rosiglitazone (Avandia), has a hard-hitting commentary at the Forbes blog:

Dr. Nissen published a meta-analysis in the New England Journal in 2007 claiming that rosiglitazone increased the risk of having a heart attack by 43%. It later turned out that the drug maker, GlaxoSmithKline, had done its own in-house analysis that more or less confirmed these figures. At first GSK sat on the data but eventually they did notify the FDA's Center for Drug Evaluation and Research. As FDA critics have long noted, the CDER has a sort of structural conflict of interest, being responsible both for approving new drugs and then for assessing the safety of drugs on the market. If they later find a drug unsafe and having to be restricted or removed from the market, they are basically admitting that they blew it the first time around when they approved the drug.

Dr. Nissen says: "Initially, GSK withheld the internal analysis from the FDA, but in 2006, the company informed CDER of the findings. FDA statisticians confirmed the risks, but, incredibly, CDER and GSK agreed privately to conceal this hazard from patients and practitioners....[After Nissen published his analysis in NEJM] The leadership of CDER was intensely embarrassed by these revelations and furious with us for publicly challenging the safety of Avandia (and indirectly the competence and integrity of CDER). The FDA appeared incredibly insensitive to the welfare of patients. GSK knew, FDA knew, but patients and physician were not warned."

Later, GSK came forth with data from a new trial called RECORD, which they claimed absolved rosiglitazone from charges of causing excess heart disease. CDER latched onto RECORD and hoped to use these findings to claim that they had not done anything wrong in concealing the risks of the drug. As Dr. Nissen recounts the story, this all backfired when FDA's own internal analysis of RECORD showed that the trial was so flawed as to be unreliable. As I commented in an earlier post on the Nissen case:
--it appeared that GSK itself invalidated RECORD by inappropriately breaking the blind early, trying to mine the RECORD data for early signs that Nissen's meta-analysis was off base. In the end the FDA's own statisticians agreed with Nissen and dismissed RECORD.

Despite all this, CDER has announced a new round of advisory hearings on rosiglitazone, despite the fact that after all the negative publicity only a handful of patients are still taking the drug. The hearings basically exclude anyone who might say critical things about the RECORD trial or the drug. Dr. Nissen's charge: none of this has anything to do with protecting the public health, but it has everything to do with a small, entrenched group of careerists within CDER leadership protecting their supposed reputations by insisting they did nothing wrong back in 2006.

He concludes: "We have endured a series of drug and device safety disasters (Vioxx, Avandia, Ketek, defective defibrillator leads, and recently, compounding pharmacy oversight, and the list goes on) that have harmed many of our fellow citizens. In each case, the permanent FDA bureaucracy has sought to deny responsibility and often failed to learn the appropriate lessons necessary to prevent future catastrophes. In the middle of the sequester, CDER is willing to spend a large sum of taxpayer dollars to conduct a 2-day advisory meeting on a drug nobody uses, for the sole purpose of absolving its own bureaucracy of responsibility for a terrible drug safety tragedy. The current Director of CDER, Janet Woodcock, has directed this division for nearly 20 years, increasingly insulated from the Agency’s true constituency, the American public. If CDER is allowed to re-write the history of Avandia, this vital FDA Center will continue to function as an unsupervised, self-regulating bureaucracy, accountable to no one. That’s just unacceptable when the public health is at stake."

Hat tip to Marilyn Mann for sending along this link.

Friday, May 24, 2013

Running a Pharm-Free Office: One Group's Story

Recently I posted on a report suggesting that drug reps were having a harder time getting in to see docs:

For background on why this is so, in at least one family practice in Oregon, we can turn to an article by Dr. David Evans and colleagues:

Dr. Evans describes how a 7-person practice (6 physicians and a PA) started in 2005 to make the transition to pharm-free. At the start, providers were divided on the wisdom of such a move and stafff complained that they'd miss the free lunches, samples, and free office items that the reps provided.

The practice began by quantifying the current level of influence of reps on the practice. They noted an average of 33 visits per month and 2.3 lunches per month. They also checked out the sample cupboard and noted hardly any first-line drugs for treating any common condition; instead they found drugs that would cost an average of $90/mo while the ideal generic substitute would have cost an average of $22/mo. These figures helped persaude the resistant members of the group on the value of making the transition away from reps (the new pharm-free policy went into effect in 2006).

The group next addressed the absence of the reps' talks for drug updates. They developed a process for holding staff meetings with evidence-based assessments of new pharmaceuticals. They also invested in regular staff lunches so that the social activities were not curtailed.

Finally the practice announced its new policy to the local media, garnering favorable publicity. No patients complained of the new policy and the community response was generally laudatory.

Dr. Evans and co-authors noted the general absence of similar accounts in the literature applicable to rural primary care practices, and offer their experience as one possible template for implementing change.

I would add that while the Oregon group did not mention it, a practice that wished to take the same steps might be helped by the materials provided by the National Physicians Alliance's Unbranded Doctor campaign: http://npalliance.org/action/the-unbranded-doctor/

Saturday, May 18, 2013

Catching Up: Dr. Ben Goldacre's Bad Pharma

I recently noticed that I had only mentioned Dr. Ben Goldacre's book Bad Pharma in one previous post:

In that post I was perhaps unduly dismissive. Since I only recently got around to reading his book, I wanted to update the record with a few observations.

The book, Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients, was published last year in the UK by Fourth Estate and in the US this year by Faber & Faber. Dr. Oldacre trained as a psychiatrist and is presently a research fellow in epidemiology. He is author of a popular "Bad Science" column in The Guardian, and Bad Science was the title of his earlier book.

My initial assessment of his book, that it would provide little that is new to any regular reader of this blog, is more or less correct. I also admit to being miffed that (as far as I can see) it fails to cite HOOKED, which naturally raises questions about how thorough a literature search the author did. But there are definitely some unique strengths to the book that deserve notice.

  • Dr. Goldacre's main thrust is the quality of the medical data, as befits a researcher in epidemiology. He's as concerned about the data he uses to make his case as well as about the data that medicine has at its disposal to make decisions about patient care. In general he does a very good job of presenting an evidence-based assessment; where his evidence is weak, he says so. That means that whenever he addresses a topic, such as for instance the impact of drug ads in medical journals on physicians' prescribing, he seeks out the most recent systematic review of the literature as his ideal source. That means that this book is a good compendium of those reviews. (It also indicates why he might not cite HOOKED, as he's more interested in the original data and in systematic reviews than in commentaries by other authors.)
  • Dr. Goldacre obviously practices in Britain and so his view is a British perspective. This adds punch to a number of things he says, since, for instance, when drug companies mislead doctors, they waste British taxpayers' money. He has harsh criticisms for the way the UK and Europe regulate the drug industry, especially their penchant for keeping all their activities secret; and it's a tiny bit reassuring that he sees some US practices (like the Sunshine Law) as ahead of Europe.
  • Being worried about missing data hidden by drug firms and the way this has systematically distorted the medical literature means that Dr. Goldacre has some recommendations that are stronger than those we often hear. For example, most critics of industry practices of burying unfavorable trial results and of sponsoring ghostwritten articles would be quite happy if Pharma agreed that as of now, they would stop doing these things, and then somehow demonstrated to us they had kept their promise.  Goldacre would not be satisfied, though, until we had fixed the problem retroactively--publishing all previous trial data now hidden, wherever the data are currently stashed away, and accounting for all past ghostwritten papers and revealing their true authors. Only in that way could future systematic reviews of the literature be reasonably sure of getting the right answer, he says reasonably.
  • Dr. Goldacre makes one recommendation that simply seems impractical, calling for a pledge that any clinical trial results will be published within one year of completion of the trial. In principle this sounds fine. I am author of many papers that have not been published as of one year after the completion of the project, and none of those are complex clinical trials that require a lot of work to sift through all the data and decide how to present them meaningfully. The way the medical journal business works means that no author can be held responsible if any paper, let alone a trial, is not published after a set time has passed. Maybe what Goldacre really has in mind is that medical journals should no longer publish trial data, and all of these should be freely available on an open access website. If that's what he has in mind he should say so.
  • The title would suggest that Dr. Goldacre is following in the footsteps of the US's Dr. Marcia Angell in her The Truth about the Drug Companies (2004), blaming the big bad drug industry for all wrongdoing and absolving physicians as innocent victims. Never fear; he's as critical of physician and professional society misbehavior as he is of industry's.
One thing Dr. Goldacre said raised my ethicist hackles. He describes a promising project in the UK where GP practices are fully computerized and some geeks have figured out a way to run comparative effectiveness trials as a smooth, routine part of everyday office practice. A physician, instead of prescribing a drug, could be presented with a pop-up box on the computer screen saying that right now we don't know which of two drugs is better for this problem, so if she just clicks on one button, the patient will automatically be enrolled in a controlled trial and assigned one or the other drug randomly. He's quite enraged at the research ethics review boards who won't let his group do this without a detailed informed consent process.

What Dr. Goldacre proposes has a lot of advantages, and if he goes to the British public, and they endorse his scheme, and change the rules in the UK to permit this type of research, and individual patients are notified and can opt out if they wish, I'd be all in favor. But in the absence of public dialogue and democratically voted approval, I can't agree that the convenience and ease of doing trials this way simply trumps patients' rights. Goldacre focuses on the physical harm of taking a medicine in a trial setting and notes that there can be no increased harm if the two medicines being compared are both in common use by GPs. But that's not the issue. The issue that once your physician stops treating you and starts doing research on you, then the relationship fundamentally changes, and patients need to be made fully aware if what that means. As clunky as the informed consent process is (and I agree that 20-page forms are much less useful than a 1-page form would be), it's the way we now try to signal to patients that this basic change in relationship has occurred.

Bottom line: Dr. Ben Goldacre's Bad Pharma has a number of positive features to recommend it.

Thursday, May 16, 2013

New Report: Harder for Drug Reps to See Doctors

Katie Thomas reports in the New York Times:
--about how the firms that sell data to drug companies are getting smarter and smarter at tracking more and more data about patients so as to fine-tune what the industry knows about each individual physician's prescribing patterns. They manage to do this without (supposedly) stepping over the line to identify any patient by name.

I didn't see any real news flashes here about how the firms mine data; most of this more or less confirms what we've long known. I was a little bit more impressed with some side comments about why companies are finding it worthwhile to invest funds in these more detailed data-mining techniques. Here is Thomas's account:

"Companies are refining their pitches to doctors in part because it is getting harder to market to them. Studies show physicians are less willing to speak to sales representatives, either because they are opposed to such pitches, or because they are under pressure to see more patients. At the same time, the industry has laid off thousands of sales representatives in an effort to save money as once best-selling drugs have lost their patent protection.

“'The industry is now having a harder time getting direct access to physicians,' said Edward Rhoads, a managing partner and principal at the New England Consulting Group. As a result, he said, drug companies are asking, 'How can we get the information into the community in a different way?...'"

As I have reported both in HOOKED and later in this blog, the era 2006-2009 (roughly) saw something of a sea change in drug marketing. Before that, Pharma seemed to have its own way and all the complaints of pharmascolds like me and many others fell on deaf ears. Suddenly it seemed that all the mounting criticisms had taken hold and that the landscape was rapidly shifting. I have still not seen reliable studies in academic journals to document just what changed, how much, and how quickly; so anecdotal reports like this may be the best we have to go on for the present. (And what I hear from my medical students who go out into the community to spend time with practitioners seems to suggest that the beaming drug rep who rolls into the office bearing lunch for the entire staff is still a staple of medical practice.)

Wednesday, May 15, 2013

Fraud at Ranbaxy: David's Sleazy Behavior

I have not blooged much about the Indian generic drug company, Ranbaxy (one previous post: http://brodyhooked.blogspot.com/2011/12/time-out-for-some-drug-pricing-issues.html
--was really mostly about Pfizer and how they planned to protect their profits when Lipitor went generic). However, in the various reading I had done in the past as research about the drug industry, Ranbaxy was usually featured as a sort of David fighting the Goliath of the huge Western band-name drug makers. For example, Ranbaxy was praised when it dared to oppose the brand-name monopoly of expensive anti-AIDS drugs and produced generic versions that could be sold in Africa at affordable prices, presumably saving thousands of lives.

Unfortunately, according to recent investigative reporting for Fortune magazine by Katherine Eban:
--this particular David was guilty of some extremely sleazy behavior. (My Bible knowledge is a bit rusty but as best as I can recollect, the original David had some ethical problems too.)

Ranbaxy, which is now majority-owned by the Japanese drug firm Daiichi Sankyo, pleaded guilty on May 13 to 7 counts of selling adulterated drugs with intent to defraud, in response to charges brought by the U.S. government regarding drugs intended for American sale. The company agreed to pay $500M in fines, the largest penalty ever assessed against a generic company; but as will seem amazing in a minute, no execs were charged with any criminal wrongdoing.

What Eban's long piece reveals, based on now-released company documents and interviews with former employees turned whistleblowers, is that there was a pervasive and consistent culture of fraud at Ranbaxy through most of the decade of the 2000s at least. They gained regulatory approval for their generic drugs all around the world simply by making up the data.  In some cases they secretly substituted samples of the original brand-name drug for their generic and then showed (no surprise) that their drug was just as good as the brand-name. But much of the time they did not even bother to go to that much trouble and just made up numbers. This fraud was well known at the highest levels of the company and winked at.

Eban is particularly concerned for where the FDA was during all this. Her key whistleblower-informant, who in the end became the main figure in the federal fraud case, told the FDA in 2005 about the company's pattern of falsification of data. But for the remainder of the decade the FDA continued to approve new generic drug applications for Ranbaxy, including its biggest potential moneymaker, generic atorvastatin (Lipitor), even as its inspectors were looking into the company's Indian plants and unearthing massive problems and coverups. One FDA official who was communicating regularly with the whistleblower admitted at one point that the FDA was under a lot of pressure to approve these drugs and not to be too hard on Ranbaxy. Where Eban's investigations fall a bit short is not explaining to us where this pressure came from.

Just who was after the FDA to get it to go easy on an Indian (later Japanese-owned) company, even if it had an American subsidiary? One way to give this picture a bit of a rosier glow is to note that nearly all the events that Eban recounts took place during the George W. Bush administration, when we know that the FDA was under orders from higher up the executive branch to view its role as being as friendly to industry as possible. If that's a possible interpretation, we have to ask how confident we can be that the FDA has actually changed enough since those years so as not to be repeating this same pattern nowadays.

Saturday, May 11, 2013

Another County Heard From: NIMH Boss Takes Aim at DSM-5

I have been becoming a bore in this blog in my ongoing criticisms of DSM-5, the new "bible" of psychiatric diagnosis, most recently in the post immediately preceding this one. So now, here's apparent help from another quarter, as nicely reported by Pam Belluck and Bernedict Carey in the NY Times:

(Sorry if the link above does not work; if so you may have to manually type in the "&" at the end)

The rest of this post is a further development of the word "apparent" in the above comment.

Dr. Thomas Insel, the controversial figure we've met before:
--advises his colleagues in psychiatric research to ignore the DSM-5 categories and work harder to discover the biological basis for mental disease. He's quoted: “As long as the research community takes the D.S.M. to be a bible, we’ll never make progress ... People think that everything has to match D.S.M. criteria, but you know what? Biology never read that book.”

Such an observation from arguably the top person in psychiatric research in the US is very important in bursting one bubble of the DSM-5. When DSM undergoes one of its periodic major revisions, in this case the first since 1994, one hopes that the impetus for this is a significant change in the basic science of mental disorders, so that we can better bring clinical practice into line with the new science. Critics of DSM-5 have charged among other things that we don't really have the scientific advances to justify a brand new edition in the first place, and accordingly, the new DSM-5 cannot claim to be based on science to the extent that its advocates claim. As Belluck and Carey nicely summarize, most of the important brain science since 1994 has gone to remind us of how much we don't yet know--and hence, the (apparent) justification of President Obama's recent call for mapping the human brain as the next huge scientific frontier after the human genome (the genome thus far having proved largely a psychiatric bust).

But at the same time that Dr. Insel bursts one DSM bubble, he reinforces the use of DSM that has most worried critics like me: "Dr. Insel said in the interview that his motivation was not to disparage the D.S.M. as a clinical tool..." Well, sorry, disparaging the DSM-5 as a clinical tool is highly appropriate when, based on bad or incomplete science, the American Psychiatyric Association assembled panels of "experts" riddled with industry conflicts of interest, and allowed them to construct psychiatric diagnoses that will end up labeling millions more people as mentally ill and appropriate for drug therapy. 

Now whether Dr. Insel is right in calling for the program of psychiatric research that he favors is another question entirely, and goes well beyond my competence. I will simply note as an interested observer (and philosopher of medicine by training) that psychiatry seems to tack back and forth over the decades between biological psychiatry, that all mental illness results from measureable chemical lesions in the brain, and a more holistic psychiatry that takes things like early life experiences and other environmental factors more into account. Dr. Insel, if I understand, seems to be calling for a deeper turn toward the biological. An appropriate model would in any case include the biological component; the only querstion is whether research into links between biology and environment will be pursued adequately, or whether only biologically-restricted studies will be funded by NIMH. But as I say this is above my pay grade--I hope some real experts will comment.

So Dr. Insel is no doubt right in saying that future psychiatric research should not be guided by DSM-5. He's dead wrong in saying that DSM-5 works as a clinical practice "bible." He may or may not be right in what sort of improved psychiatric research program he's calling for.

Wednesday, May 8, 2013

Two New Books Take Aim at DSM-5

I have blogged often about the American Psychiatric Association's forthcoming DSM-5, most recently:

To summarize, my main concern has been evidence of serious conflicts of interest among the "scientific" panels writing the new handbook of psychiatric diagnosis, resulting in a formula for millions more people to be diagnosed with a psychiatric disorder and (potentially) to be treated with drugs.

Now two new books each attack the DSM-5 content and process:

Gary Greenberg is a counselor and Dr. Allen Frances is the former chair of the committee that produced DSM-IV. They therefore have somewhat different perspectives but converge on criticisms of the new manual and how it was produced.

I reiterate my personal view that I hope other medical specialties will refuse to recognize DSM-5 and encourage their members not to utilize those diagnostic categories. The American Psychiatric Association may, if they wish, go back to the drawing board and produce a diagnostic manual that sticks to science and is not commercially biased.

Hat tip to Dr. Bernard Carroll for recommending this book review.