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:
http://brodyhooked.blogspot.com/2012/10/against-capitalism.html

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.

New Report: Harder for Drug Reps to See Doctors

Katie Thomas reports in the New York Times:
http://www.nytimes.com/2013/05/17/business/a-data-trove-now-guides-drug-company-pitches.html?hp&_r=0
--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.)

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:
http://features.blogs.fortune.cnn.com/2013/05/15/ranbaxy-fraud-lipitor/
--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.

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:
http://www.nytimes.com/2013/05/07/health/psychiatrys-new-guide-falls-short-experts-say.html?_r=1&

(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:
http://brodyhooked.blogspot.com/2010/03/nimh-director-on-industry-influence.html
--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.

Two New Books Take Aim at DSM-5

I have blogged often about the American Psychiatric Association's forthcoming DSM-5, most recently:
http://brodyhooked.blogspot.com/2013/03/more-on-dsm-5-irrelevant-and-perhaps.html

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:
http://www.nytimes.com/2013/05/02/books/greenbergs-book-of-woe-and-francess-saving-normal.html?emc=eta1&_r=0

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.

More Smoke and Mirrors on Statins, Brought to You by Pfizer

An esteemed colleague called my attention to:
http://content.healthaffairs.org/content/31/10/2276.full
--in which a team of authors, who either work for Pfizer or who mostly have extensive financial relationships with the drug industry, explain to us that prescribing statin drugs is a huge economic plus for society. According to their calculations, prescribing statins aggressively even for people at low risk for cardiovascular disease costs the US each year about $305B and yields health benefits worth $1.25T. So naturally they recommend revising guidelines to recommend statins for more people and in even higher doses, and more vigorous use of pay-for-performance incentives for docs to get on the ball and prescribe more statins.

Sounds like a no-brainer, right?

Of course in this blog I've been harping on all the accumulated evidence that statins have been way overhyped and are probably of little use in all groups except those with already-diagnosed cardiovascular disease. So what's the deal?

It turns out that a careful reading of the article shows that Exhibit A for the huge success of statins, according to which the authors then calculated their economic benefits, was the CTT meta-analysis which I have previously alluded to: http://brodyhooked.blogspot.com/2012/05/statins-in-water-supply-continued-why.html

In that earlier post I took advantage of the expertise of David Newman to explain why the CTT analysis basically answered the wrong question--not, what happens if you put people in various risk categories on different doses of statins; but what happens if you prescribe statins and the result is that a patient's LDL level drops by a certain number of points. If you do an analysis the latter way, then statins appear to be marvelously useful, but as explained in the earlier post, that doesn't answer the doc's question about whether it's good to start the statin in the first place. If you answer the question in the former manner you get the more pessimistic numbers that show no real benefit except in the highest-risk groups.

Here's the other kicker in the more recent economic analysis, this amazingly bald statement near the begimnning of the article: "Importantly, we do not account for possible side effects in our social value calculations below." Come again? If statins make half the people who take them sicker than dogs, that doesn't count as a social cost--so your number-crunching simply assumes that statins are completely free of side effects?

The authors try to finesse this by noting that statins cause low levels of adverse reactions in many of the large-scale studies of efficacy--studies for the most part sponsored by the drug industry. This ignores the accumulating evidence of serious adverse reactions, even though most of them are not deadly, thank goodness. Consider for example a research letter by Golomb and colleagues (subscription required), noting from randomized trial data that as many as 4 in 10 patients might have worsening of fatigue and energy loss when taking statins; or other recent evidence raising the question of memory impairment as a consequence of statin use.

So what are we to conclude? First, this recent economic "analysis" is incomplete for omitting adverse reactions, and is probably deeply flawed by being based on a flawed meta-analysis of trial data that asks the wrong question. Second, this is how industry marketing works. First, get a study that's methodologically weak, but that contains the message your marketers wish to convey, out there in a prestigious journal (in the case of CTT, The Lancet). Second, keep churning out more and more articles conveying the same marketing message, referring back in each case to the first article, and hope that the journal's prestige will prevent any readers from questioning the methodology closely. Third, you can prove anything you wish in a cost-benefit analysis, just be sure to make the assumptions that tip the scale your way.

Golomb BA, Evans MA, Dimsdale JE, White HL. Effects of statins on energy and fatigue with exertion: results from a randomized controlled trial. Archives of Internal Medicine 172:1180-82, August 13/27, 2012.

The Price of Leukemia Drugs: 100 Doctors Protest

I generally try to avoid posting on the price of drugs, as I see that as less directly related to the ethical issues at the interface of medicine and the pharmaceutical industry. However, to the extent that physicians interpret their medical professionalism as requiring patient advocacy, and drug prices prevent patients' access to needed drugs, then the issue moves front and center. And when prominent physicians push back against the drug industry, that's also news.

So:
http://bloodjournal.hematologylibrary.org/content/early/2013/04/23/blood-2013-03-490003
--we have a statement in the journal Blood, the organ of the American Society of Hematology, signed by 100 prominent physicians from around the world who all treat leukemia, objecting to the price of newer drugs for that disease.

In HOOKED, I wanted to start the book with a couple of narratives about drugs, one showing the pharmaceutical industry as knight in shining armor, the other showing the dark underbelly of drug marketing--just to try to set a tone of even-handedness at the get-go. I selected the drug Gleevic as my Exhibit A for Pharma good behavior. In order to do that I had to soft-pedal one of the problems with that drug for chronic myelogenous leukemia (CML)--the way Novartis set its price, guaranteeing a very high profit margin and exceeding considerably (as it turned out) their investment in research. (One of the signatories to the new statement is Brian Druker, whom I discussd in HOOKED as an early advcate for the drug and who tried to push Novartis to do clinical trials in early days when the company was reluctant.)

Since Gleevic entered the market, a number of related compounds, all in the class of tyrosine kinase inhibitors, have come on line, and are priced even higher--in excess of $100,000 per year. (Gleevic came on the market in 2001 at a price of about $30,000 annually and has now risen to $92,000.) These drugs are the nearest thing to the proverbial magic bullet in cancer treatment--they are highly effective at suppressing cancer cells but cause very few side effects. When I wrote HOOKED, the long-term story of CML therapy with these drugs was unknown--would they keep working year after year? Could a patient stop taking them and be cured, or would the patient need routine maintenance, maybe for life? As things have worked out, as best as I can tell from the Blood paper, it's the drug industry's dream come true--the drugs keep working but the patients have to keep taking them forever. So those big bucks just keep rolling in--if the patients can afford to pay.

The 100 leukemia physicians object to these prices preventing many patients, especially in poorer nations, ever having access to these drugs, and they protest that there's no justification for the high prices based on the true costs of R&D.

The article begins by referring to the concept of the "just price." This, the authors explain, is based on "moral necessity" where "price must reflect worth." The cynic would wonder what planet these folks live on. Everyone knows that on this planet, prices reflect one thing and one thing only--what the market will bear, and morality be damned. If the drug industry actually started thinking like these physicians recommend, one shudders at the consequences.