Saturday, June 29, 2013

Correcting the Medical Literature: It's Not Just About the Future

A couple of important papers have recently appeared in the BMJ:

These have to do with an initiative called RIAT, for "restoring invisible and abandoned trials." A flaw in past work addressing commercial influence on medical research, leading to failure to publish or to distort important scientific findings, has been the focus on how to change things for the future so that these abuses no longer occur. That ignores the fact that the existing scientific literature, which continues to be the basis upon which decisions are made about treatment as well as about future research priorities, remains tainted so long as it's uncorrected for past abuses.

The authors, who have been involved in a variety of actions involving the pharmaceutical industry that gained them access to unpublished studies, provide a table of more than 100 studies known to them, which were either never published or were published only in distorted form. The authors refer to a type of document most physicians have never seen--a clinical study report. This document is the internal report of a research trial compiled for use by a pharmaceutical company, and adheres to fairly strict standards for inclusion and organization. They typically run hundrerds or even thousands of pages (for a study that when published in a journal would ordinarily occupy 10-15 pages). It is the clinical study report that the company typically submits to the FDA to support a request for new drug approval, though the FDA treats these as proprietary and refuses to release them publicly. The European Medicines Agency has inaugurated new public access policies that now make materials available that previously were kept secret.

The authors propose a detailed and well-thought-out plan for first allowing the original investigators of all these trials to proceed to publish them in a responsible and accurate way. If the original investigators refuse or decline, the clinical studies reports would next be made available for new authors to review and report on, following established protocols to assure quality and accuracy (along the lines of the current Cochrane Collaboration systematic reviews). The goal is to fill as quickly as possible as many of the known gaps in the scientific literature as possible.

The authors' main point seems to be that so long as these clinical studies reports exist (and there are no doubt hundreds more beyond what these authors personally have copies of), there exists a mechanism to correct the scientific literature and to fill in these gaps. Not to take advantage of that fact would be irresponsible.

The accompanying editorial by Drs Loder, Godlee, and others states the issue succinctly:

"Nothing better underscores the urgency and importance of the RIAT proposal than the list of abandoned trials that accompanies it. Read it and weep: on the list are clinical trials for drugs used by millions of people, including zanamivir, atorvastatin, gabapentin, and paroxetine. The number and variety of drugs on the list show clearly that incomplete reporting of clinical trial results is not an isolated occurrence, confined to a few drugs. Rather, it is an entrenched and widespread problem. Secrecy and selective reporting were an integral part of the system. Reforms such as trial registration and mandatory results reporting will improve things in the future but can do nothing about the flawed evidence of the past....

"The results of clinical trials are a public, not a private, good. The public interest requires that we have a complete view of previously conducted trials and a mechanism to correct the record for inaccurately or unreported trials. If we do not act on this opportunity to refurbish and restore abandoned trials, the medical research community will be failing its moral pact with research participants, patients, and the public. It is time to move from whether to how, and from words to action."

The Pharmapologists' Ballad: Same Song, Second Verse

In the immediately last post, I noted the staying power of the old rationalizations repeated by clinicians found with their hands in the Pharma till, that of course those big bucks for speakers' fees, etc. could not possibly influence their prescribing habits. The subject of this post is how the same old dirge, in the version trotted out by defenders of the status quo relationships between academic medicine and industry, continues to get sung even in the face of massive contrary evidence.

Our pal Dr. Roy Poses at Health Care Renewal blog called attention to a set of papers in the latest JAMA Internal Medicine that included a viewpoint by Dr. Susan Desmond-Hellman, chancellor of the UC-San Francisco health science campus. The paper is worth walking through point by point because it illustrates so many of the old canards that still afflict our thinking about relationships between medicine and industry.

Before I do the walk-through, let me get to the bottom line. Dr. Desmond-Hellman apparently wishes to have robust, positive relationships between academic medicine and the pharmaceutical and biotech industries. I want exactly the same thing, as I have stressed in earlier posts. No one imagines that somehow, academic medicine can simply proceed on its own and ignore the essential role of industry in making new drugs available to patients. No one imagines that either side can do its best work if deprived of the insights and ideas that could come from a productive exchange with the other. What's left to argue about, therefore, is the ground rules by which such a positive relationship for the future could be created. We pharmascolds say that the current system is broken, and only by frankly admitting this could we then go forward and create something that really works for the benefit of patients and the public health. The pharmapologists insists that everything is just peachy as it is, and the best move forward would be for us pharmascolds simply to shut up.

So now for the walk-through. First step: who is this person anyway? For background on Dr. Desmond-Hellman we go back to an earlier Health Care Renewal post:
This post makes two points. First, while the present viewpoint refers modestly to the author's "16 years of employment in the pharmaceutical and biotechnology sector (at Bristol-Myers Squibb and Genentech) prior to returning to academia," it fails to note that during her time at Genentech, she held a president's role that paid somewhere between $7M and $11M annually. So this is not exactly a mere employee of the industry. Second, by the usual measures of such things, her background in academic medicine is notably skimpy--her number of papers reportedly published, for example, would ordinarily not earn a junior faculty promotion from assistant to associate professor. So her being hired as Chancellor (i.e., big boss) at UCSF was hardly an example of a solid academic physician coming home to her roots; it was more a matter of, "Let's see if we can attract a really high roller in industry to come run our shop, and see if we can't get our hands on some of those big industry bucks."

Next step: denounce the pharmascold "pundits." While admitting coyly that this places her in a bit of an awkward position as a would-be pundit herself, Dr. Desmond-Hellman begins by attacking the "pundits" who suggest that the industry may not have the purest or noblest motives. Interestingly she picks on one particular pundit, Dr. Ben Goldacre of the UK, whose book, Bad Pharma, I recently reviewed here:

Now Dr. Goldacre is an interesting "pundit" to target, especially coming from a person who holds an MPH degree and so who supposedly knows something about epidemiology and research methods. You can kick about a lot of what he write in his book, but one thing you can't kick about is his evidence base--he seeks out the most careful, systematic reviews available in the literature to support every point he makes, and when he can find no such studies, he tells you. By contrast, Dr. Desmond-Hellman's viewpoint consists of one unsupported anecdote after another, basically saying: I have spent a lot of years working with industry; the people I worked with are really fine people; where's the beef?

Next step: appear even-handed. Dr. Desmond-Hellman now has to defend her bona fides and so proclaims, "I readily appreciate both the opportunities and the threats to private-public partnerships with industry." Great--she is going to admit that it's not all roses and there are thorns here as well. Except she doesn't. It turns out that all the threats, as we'll see in a minute, are on the academic side, and she makes abundantly clear her immediate conclusion that "I strongly believe that the benefits--the enhanced ability to ameliorate disease, extend life, and improve health--outweigh the risks." It's typical of her strategy that she explicitly lists the benefits, even as mom-and-apple-pie generalities, but says nothing about what the "risks" might be--when push comes to shove, she apparently cannot think of any.

Next step: attack bias in research. Next we encounter an argumentative strategy that we've looked at in the past in considerable detail, for example:
Briefly, this refrain in the chorus goes: Investigator bias is a ubiquitous problem in research; financial conflicts of interest with industry are merely one of many forms of investigator bias; therefore financial COI fades into insignificance as a concern about academic-industry partnerships. Let's study this for a minute (besides referring to all the refutations of this flawed line of argument from the previous posts).

As an individual academic-medicine investigator, I may have a strongly held belief that the earth is flat. This gives me a strong and pervasive bias. When I do a study, I will selectively seek out evidence showing that the earth is flat and tend to dismiss data showing that it isn't. Given a choice of things to study, my interests will gravitate toward flat-earth issues. My published papers, if the editors allow it to get through, will contain a variety of statements tending in a flat-earth direction. And so on.

There are also many things that won't happen. I cannot assure anyone will give me funding for flat-earth research. I cannot assure that if I get funding, I won't be the only one; there will be a whole stable of investigators all studying flat-earth matters. I cannot hire expert science writers to draft all of my published papers for me to aid them through the editorial review process and to assure that things about flat-earth are slipped in at every possible point in the manuscript. I cannot afford to buy tens of thousands of dollars of reprints of my published articles, making it more likely that journal editors will be swayed to print them. I cannot afford to hold international "consensus" conferences at glitzy five-star hotels, in which all the high rollers in the field are paid big bucks to come and proclaim how flat-earth thinking is the new best thing in medicine. I cannot donate millions fo dollars to medical specialty societies to assure that when they write their guidelines on a clinical subject, they'll be sure that paid consultants to flat-earth thinking dominate the panel and write flat-earth-friendly clinical practice guidelines, which will then be imposed on practitioners as "evidence-based." And so on and so on.

There is a big difference, in short, between investigator bias, and well-funded investigator bias.

Final step: call for more transparency and reduced bias across the board. Since according to this chorus, financial COI is just one of many forms of investigator bias, the solution is better quality research across the board; no reason to single out industry funding as in any way more problematic. Plus of course do a bit of hand-waving toward improving matters: "In addition, we must ensure that communication of research findings is robust and clear."

The answer to this canard is well provided in an accompanying editorial by Drs Robert Steinbrook and Rita F. Redberg:
Drs. Steinbrook and Redberg do what Dr. Desmond-Hellman ought to have done at the get-go if she wanted to be taken seriously-- they note the existing problems: "But in our view, any path forward must include the urgent restoration of trust in industry-funded research. On Wikipedia, there is a remarkable list of the 20 largest legal settlements reached between the US Department of Justice and pharmaceutical companies..."

A common theme is these largest legal settlements, many of which we've reviewed in this blog, is the systematic and deliberate failure of the drug industry to communicate research findings in a "robust and clear" way, so long as obfuscating produces higher profits. Anyone who imagines that we don't have to recognize this sorry track record, and start off any proposal for improved academic-medicine/industry relations by indicating precisely how we are going to avoid these pitfalls in the future, has a lot of explaining to do. Singing the same old song won't cut it.

Wednesday, June 26, 2013

Bribery Still Works: The Case of Bystolic

A lot of catching up to do with recent news that happened while I was off on vacation; but for now, here's the latest from our friends at ProPublica, home of the important Dollars for Docs campaign:

Charles Ornstein, Tracy Weber, and Jennifer LaFleur told NPR:
--about the findings of a comparison between Medicare prescribing data and drug company payments to physicians. They focused especially on Bystolic (nebivolol), a beta-blocker anti-hypertensive manufactured by Forest Labs.

There are two schools of thought in the comments quoted in the report. One is that Bystolic is indeed a unique drug, that justifies its higher-cost as a brand-name drug despite so many tried and true beta blockers being available as generics. Supposedly its side effects are less, especially interference with breathing, for example.

The other is that there is simply no scientific evidence that nevibolol is anything other than a classic "me too" drug, and that so far as we know there is no reason to prescribe it given its higher price.

Guess which point of view is expressed by docs paid as speakers for Forest Labs. Guess which point of view is expressed by national experts in cardiology that have no such conflicts of interest.

What is especially instructive from the interviews is how the old, old, tired rationalizations still have staying power: "I have never felt that there were any expectations or pressure on the part of the company that I would prescribe it more or at all," ... said [Dr. Gary Reznik, Los Angeles cardiologist and top US prescriber of Bystolic, who was paid $3750 by Forest to give talks in 2012].

Here's a special gem:
"Another top prescriber, internist Mark Barats, of West Hollywood, Calif., said he uses smaller doses of Bystolic to achieve the same effects as higher doses of generic medications. 'It has much less side effects, particularly much less side effects on the respiratory system,' he said.
"'I've never seen anything that contradicts what Forest said about Bystolic,' said Barats, who was paid $3,750 to speak for Forest in 2012."

OK, let's see if I get this. It is not the job of Forest Labs to prove a scientific basis for their claims about Bystolic. Rather, if somebody thinks those claims are wrong, it is up to those other dudes to do a study and contradict Forest. Until that time, we should all believe 100 percent whatever the Forest reps tell us. A whole new approach to evidence-based medicine...

Anecdotes aside, what about the policy implications? ProPublica quotes several drug companies as explicitly denying that prescribing levels have anything to do with which docs are offered positions on their speakers' bureaus. As is standard, they insist that they use only the physician's expertise and credentials in making such decisions.

So ProPublica found that among those paid to give company talks are 17 of the top 20 Medicare prescribers for Bystolic; 9 of the top 10 prescribers of Novartis's Alzheimer drug Exelon; and 7 of the 10 top prescribers for GlaxoSmithKline's asthma drug Advair Diskus.

Could it be that we are seeing a pattern here?

As I have said before:
--the available evidence from the inside has shown that drug companies hire rotten speakers who prescibe a lot of their drug, and fire excellent speakers who don't prescribe a lot of their drug. As I have also said before:
--it seems that the drug companies would be quite happy to have their paid speakers give talks for rooms of cardboard cut-out people if it came to that, because the real issue was bribing the speakers to continue to be high prescribers, and not to "influence" anyone else. But of course you can never say that out loud, so the industry charade demands that you stoke the doc's ego and tell them how influential they are in the community and that's the only reason you are hiring them, cross your heart and hope to die.

Memo to 3 out of 20 top Bystolic prescribers, 1 out of 10 top Exelon prescribers, and 3 out of 10 top Advair prescribers: you all need a new agent. How come you're not getting your cut?

Thursday, June 6, 2013

Finally, the Sunshine Act: Commentary in NEJM

Last week's New England Journal of Medicine (you can see I'm a bit behind in my journal reading) featured three "perspectives" on the Sunshine Act that became law as part of the Affordable Care Act of 2010:

The third piece, coming from the Center for Medicare and Medicaid Services (CMS) that's responsible for administering the law, is just an overview of what the law requires, and the timeline for implementation. The second article, by Meredith Rosenthal and Michelle Mello, notes that the reason for the sudden interest is that after a delay of about 15 months occasioned (they said) by public comment:
--CMS finally issued its final regulations for implementing the Sunshine Act in February. Data collection (says CMS) is to begin in August and the first public release of data is scheduled for September 2014.

The first piece, by Dr. Aaron S. Kesselheim of the pharmacoepidemiology-pharmacoeconomics program at Harvard, is a summary of what they have learned by studying an earlier example of a state-level Sunshine law, in Massachusetts. Of the various tidbits of information they provide, perhaps the most fascinating is the breakdown of how much money physicians in various specialties rake in in different categories of industry payment. Go to their link and then click on the Figure (B). You'll see that all categories including food, CME conference support, research grants, and education or training are shown as extremely thin slices at the top of the bars in the graph for all specialties, and the vast majority of funds, usually in excess of 90 percent, consists of one category: consulting fees.

Now, according to the official designation, consulting fees mean that these physicians provided a "bona fide service" for the company and the company paid them a reasonable and justified fee for those services. As we have had numerous occasions to note in this blog, it is really hard to swallow that all these physicians provided all these incredibly valuable services for these companies and according earned these fees legitimately. Pharmascolds like me will persist in suspecting that these are thinly disguised bribes to win the loyalties of these docs to the brand in question.

Anyway, Dr. Kesselheim's piece is a reminder of one important value of sunshine legislation. Maybe no patient will ever log onto the website and decide which doc to go to based on which have their hands in the Pharma till. But the few, smart investigators who have the wherewithal to analyze these data can tell the rest of us things about trends in the industry-medicine interface that we'd otherwise never find out. In previous posts we've seen how shrewd investigative reporters have mined these sunshine reports for significant insights--see for example:

This is basically the point made by Meredith and Mello in their commentary. It's unlikely that directly releasing these data to the public at large will change anything. But what our lawyer friends like to call "learned intermediaries" can process these data and take significant actions to limit undue industry influence. They note that insurers in particular may look askance on docs who seem too eager to feed at the industry trough.

One point about the Kesselheim study-- for a while, Massachusetts had a ban on significant gifts from industry, including most meals. The Pharma lobby and the restaurant lobby combined to get this ban repealed:

Since some of the data was gathered while this ban was in effect, it could be that the mammoth consulting fees paid were due to the industry reinvesting what they would have spent on food in other forms of influence; and that if we went back to check today we'd see a lot more spent on food instead. At least the Massachusetts restaurant lobby hopes so.