Friday, July 31, 2009
The decks were somewhat stacked with those opposing industry funding. The redoubtable Dr. Thomas Stossel of Harvard and ACRE (see previous posts too numerous to list) was on hand to offer the non sequitur, that because scientific advances in medicine over the past 40 years had helped people, and for the past 40 years we have permitted industry funding of CME, we need to continue the latter or we risk losing the former. Al Franken, making his Senate debut following his long-disputed election in MN, offered the comment that he did not see any logic in Stossel's reasoning. I suppose Franken, as a former comedy writer, is especially qualified to understand the reasonings of Dr. Stossel and colleagues. (Sorry, couldn't resist that.)
All that is bye the bye, as I think the most important exchange by far at the hearings was the indirect exchange between Dr. Steve Nissen of Cleveland Clinic, and Murray Kopelow, head of the Accreditation Council for Continuing Medical Education (ACCME), the outfit that is supposed to monitor all US CME activity. Kopelow offered what to our commentators appeared to be pretty wimpy testimony. Prescription Project summarized it as: "[A]fter mulling a stop to accredited industry-supported programs in 2008, the [ACCME] 'would not be taking any action to end the commercial support of accredited [CME],' and defended its continued efforts to clarify independence criteria and firewalls." The basic message appeared to be: trust us, we're taking care of everything, just leave it to us.
By contrast, Steve Nissen came out swinging. Again, per Prescription Project, Nissen "called the [ACCME] 'uninterested or incapable' of enforcing its own rules, and called for its end. 'Whatever ACCME is doing is ineffective,' said Dr. Nissen. 'We need ACCME to go away and we need to replace it with something else.' He said that third-party companies called medical education communication companies are very much behind the wheel of CME programs that claim support from 'unrestricted educational grants,' and that based on the selected topics and speakers, he can nearly always guess the sponsoring company." To which Danny Carlat added the anecdote that he knows that at least on some occasions, ACCME slaps the wrist of a CME sponsor that allows undue commercial bias, because they issued such a letter after he once complained. Only ACCME took two years to do it, and Danny cannot tell us any details because ACCME also put a gag order on him.
Now, if you go back and look at some of my earlier posts on this blog as well as in HOOKED, I think in hindsight I was overly deferential to ACCME and took them more at their word, that they were working diligently to create firewalls and police commercial bias, than should have been the case. I have certainly heard comments from CME coordinators to the effect that what the CME rules are supposed to be, and how people behave in real life, are often two different things.
Danny Carlat, who blogged the hearings live, also offered later reflections as follows (http://carlatpsychiatry.blogspot.com/2009/07/senate-cme-hearing-impressions-more.html):
Senator Mel Martinez, a republican from Florida, summed up the mood best with his perplexed question (I'm paraphrasing here): "Wouldn't it just be better if doctors paid for their own continuing medical education?" As a lawyer, he said, he always paid for his own CLE (continuing legal education) and he was never paid to give CLE lectures.To those of us who have lived and breathed this issue for years, his question came across as innocent, but in fact it hit the obvious point, and surely summarized the view of most Americans.
Tuesday, July 28, 2009
Somehow this book escaped my attention when it was first published and I noticed it only lately. Of the books I relied on when I was researching HOOKED, its closest analog is Sheldon Krimsky's Science in the Private Interest.
Greenberg, an experienced journalist covering science and policy matters, begins by offering us two "grand narratives" to chew over:
- Since the Bayh-Dole Act of 1980 opened up academic research to patents, licenses, and royalties, we have arrived in a promised land of win-win. The campus benefits from income from its scientific discoveries, and the new entrepreneurial spirit that now pervades campus science assures that a steady stream of new discoveries will improve the lives of all.
- Bayh-Dole began a race to the bottom in which commercial behavior and values have steadily eaten away at the fabric of scientific integrity. We no longer have science for the sake of truth and the public good; we have science for the sake of the dollar, leading to widespread fraud and the manipulation of data for marketing purposes.
Having presented to us his (two-sided) review of the broad scene of academic science today, Greenberg then focuses on interviews with individuals in different places within the academic science establishment, devoting a chapter to each interview. These I found generally to be tedious because Greenberg seems to feel the need to include every word with hardly any editing. The exception was an excellent interview with Drummond Rennie, which I found compelling mainly because Rennie has been such an important figure in the debate over pharmaceuticals and medical journals.
In the end, when Greenberg finally has to come clean on what he thinks, he adopts a position not much different from what I have been advocating in this blog. On the one hand he resists the Chicken Little view that science's sky is falling. Most scientists still do very good, honest science. Most universities have not auctioned off their departments to commercial companies. Commercial sponsorship still accounts for a very small percentage of on-campus research. Bahy-Dole is not going away and we might as well figure out how to live with it.
On the other hand, Greenberg finds credible most of the concerns raised by the negative impact of commercialization on the world of science, and agrees that steps must be taken to ward off the dangers. He is reasonably skeptical when the foxes try to write the new ethical code for the henhouse. He is alert to the dangers that patents have become a barrier rather than a facilitator to future discovery.
One theme that I addressed very briefly in HOOKED, that Greenberg picks up on, is the power shame. Suppose that we were to tell a university scientist, "We can tell you your future with confidence, if you continue your present behavior of pursuing lucrative research grants, consulting contracts, and speakers' fees with commercial industry. We can guarantee that your scientific work will continue to go well in the lab, and also that you'll increasingly live a life of material pleasure and plenty. There will be only one penalty that you'll have to pay. Whenever you encounter one of your fellow scientists, you'll feel as if you wish you had a paper bag over your head." Greenberg argues that a substantial number, perhaps the vast majority, of scientists would foreswear commercial relationships if they could be told this and believe it. Being ashamed in the face of your fellow scientists is, he asserts, a very powerful force for maintaining scientific integrity, one that ought perhaps to be exploited more by those seeking reform.
Saturday, July 25, 2009
Perhaps easy to miss in Danny's run-down is a possible positive role for ACRE, if you happen to look at them from the vantage point of us "Pharmascolds" who believe that conflicts of interest are a serious matter at the medicine-Pharma interface. Let me reflect first on why a positive role may be possible, and then describe what it would be. (I trust from previous posts that it's very clear what their negative role is--to continue to rationalize the status quo in which physicians line their pockets with Pharma money and continue to trash professionalism and public trust in medicine and medical science.)
Danny offered us a personal glimpse of Dr. Tom Stossel, ACRE's chief mover and shaker. From a distance he's an in-your-face blowhard with nothing to offer in a serious debate over COI except soundbytes. Danny insists that up close and personal, he's really a pretty nice guy, and the positions he argues for are much more moderate than his public persona would suggest.
That bit caught my attention because I was tempted to say the same thing about my colleague here at the University of Texas Medical Branch, Avi Markowitz. Danny does not know him and described him as one of the more extreme, take-no-prisoners speakers at the ACRE meeting--and also the one who has the longest list of financial relationships with Pharma. I do know him a bit and would describe him in the same way as Danny describes Stossel--when you get him aside and talk one on one, he is quite reasonable about most of the issues.
So these glimpses of the real people behind all the anger and angst that Danny described at the ACRE meeting raise the question of when they are all done with their hissy fit, can they contribute? And Danny sort of hinted at how that could happen.
I have for all of my professional-academic career been a great believer in Epstein's Law: If you think the problem is bad now, just wait till you've solved it. If we ever have truly meaningful health reform in the US, it will without doubt lead to major problems. Now, I personally would much prefer to discover and then to deal with those new problems, than to keep on dealing with 45 million uninsured, 75 million underinsured, and the incredible, crazy bureaucracy of the present-day nonsystem. But I'd be an utter fool if I claimed that the new, reformed system would be problem-free and would work like a charm from the get-go.
Now the same must be true of the new relationship that we Pharmascolds would like to see created between the pharmaceutical industry and the medical profession. I personally welcome a world in which no patient will ever have to wonder whether their doctor prescribed a certain drug for them because the drug rep gave her a neat pen or took him out for a nie dinner--or whether an academic physician in the pay of the drug company helped to cook the books when the research trial was being done. But for sure that new world will have its own set of problems and we will have to deal with them.
To any Pharmascold who has followed this debate for any period of time, ACRE's claim--that the pendulum has now swung too far in the direction of those imposing tight COI restrictions, and the crazy and useless restrictions are seriously hampering the progress of medical science--is simply a hoot. Period. But even if so far, the pendulum has come nowhere near a swing to the opposite side, it is nevertheless true that in the past couple of years, particularly, the pendulum has shifted noticeably in that direction. And so, if present trends continue, in another couple of years, perhaps, there might be a serious danger of overreaction and excess in the way we deal with COI.
My case study, to date, is the somewhat clumsy but well-intentioned effort at NIH to impose strict COI guidelines in the face of news reports that senior NIH officials had for years been flaunting the existing rules and pocketing, in some cases, six figures' worth of drug company consulting fees in ways that directly conflicted with their NIH research. At one point, the new draft NIH rules said that if you were a scientist there, your secretary could not own stock in a drug company. I agree--give me a break. Both NIH employees who seriously agreed with the intent of the new rules but thought them overkill, as well as many employees looking for a handy stick to beat the new rules with, pounced on this particular provision. So I agree--the next time a Pharmascold comes up with a rule as wild as that one, somebody needs to call a time-out.
If a group like ACRE would grant the fundamental premise, that today and in the past, COI is a serious problem, and the way Pharma has spent its money on medical science has threatened to undermine rather than to advance that science, then we could imagine them serving a very useful watchdog function in the future, reining in the inevitable excesses of us do-gooders. But at present, that appears to be a very big if.
Friday, July 24, 2009
- While PhRMA is by itself a big spender, the real issue is the combined spending of all the drug companies put together, plus their umbrella organization--$40 million over a 3 month period, which is huge.
- The $40M bought them the services of 29 individual lobbyists and 45 lobbying firms. That means that many more people are lobbying Congress, on behalf of the drug industry alone, than there are Congresspersons serving on the committees that are working on health reform legislation.
- Dr. Jerry Avorn of Harvard noted what you can expect to see--or, more accurately, not see-- as a result of how that money is spent. Issues simply disappear off the table and are never discussed again. As examples he cites: saving money by reimporting drugs from Canada, and by allowing the government to use its bulk purchasing power. Without any fanfare, those issues simply went away.
Our friends over at the Prescription Project were able to attend ACRE's meeting and issued a report: http://blog.prescriptionproject.org/?p=733.
The group beat up its various villains--interestingly, the media was high on the list; apparently if you don't report stories about conflict of interest, it goes away--and gave a long list of examples of helpful collaborations between academic physicians and industry (without explaining how the proposed COI restrictions would have eliminated or restricted those contacts).
Perhaps unfairly I found myself focusing on this last portion of their meeting summary, as a sad commentary on the intellectual tone of the organization:
Toward the end of the meeting, the presenters seemed to engage in an informal horse-race about their financial disclosure listed in the program. Michael Weber, a professor from SUNY Downstate Medical Center College of Medicine, began his talk this way: “My disclosures are in the booklet, and I’m proud to say my list is longer than anyone else’s.” But when Fogarty got up to the podium, he said he thought he probably had Weber’s list beat.
“I am so conflicted I’ve become un-conflicted,” he said.
Ha ha, mine is bigger than yours--what a great bunch of guys this sounds like.
Note added later 7/24: Danny Carlat also attended the ACRE meeting and provides a more in-depth summary and analysis--I congratulate him on his relative even-handedness: http://carlatpsychiatry.blogspot.com/2009/07/acre-meeting-welcome-to-anger-village.html
Thursday, July 23, 2009
The authors, from Israel and UC-Davis and representing schools of business, management, and public health, looked at available data on pharmaceutical companies whose stocks are exchanged on the major US exchanges. Dividing costs into three categories: manufacturing, research and development, and marketing and administration, they discovered, as we have known for a long time, that over the last three decades, companies spent about 3 times as much on marketing/administration as R&D (36% vs. 12% of revenues). The news, however, is that recently, R&D spending has been increasing more rapidly than marketing-- since about 2000, R&D has gone up from about 10% to 17%, while marketing has been just about flat near 39%.
Weiss et al wanted to know what this meant for company profits and value. They used stock prices as a guesstimate of what investors thought of the company's long term value and profitability. They found that spending more on R&D was associated with higher stock prices and spending more on marketing with lower stock prices--and this held true for both small and large firms.
This explains why companies would increase their R&D spending, but not why they'd maintain such a high rate of marketing spending. Weiss et al. then analyzed companies' annual profits and found that increased spending on either R&D or marketing was associated with higher profits within the year. If a company CEO is being judged more on short- than on long-term performance, he'll want to spend more on marketing. In addition, if he wants more short term profits to have more revenues in turn to add to future R&D investment, he might also choose to spend more on marketing.
Weiss et al. conclude that the industry has discovered the fact that its long term financial interests lie with R&D more than with marketing, and that it is taking some steps at least to redress the current imbalance. If we want to see the industry actually discover useful and safe new drugs in the future, and not to merely put lipstick on the pigs of "me-too" drugs that are neither safer nor more effective than existing drugs, we can only hope they heed this advice.
A quick footnote on how to deal with reports of costs of "administration and marketing"--as I explain in HOOKED, when we can get (rarely) figures that actually break down marketing vs. administration costs, it appears that the administrative costs of a large drug firm run about 5%. Moreover, such costs would be expected to be largely stable over the years, so if we see the total fluctuating substantially, we can anticipate that it's the marketing component that is probably accounting for most of the change. So I am making the assumption that if the total of marketing plus administration is 39%, roughly 34% is due to marketing alone. There is virtually no way that one can manipulate these numbers and come up with the canard that industry flacks keep repeating--that they spend more on R&D than on marketing.
Weiss D, Naik P, Weiss R. The 'big pharma' dilemma: develop new drugs or promote existing ones? Nature Reviews/Drug Discovery 8:533-34, July 2009.
Tuesday, July 21, 2009
According to Alan Fram of the AP (http://www.google.com/hostednews/ap/article/ALeqM5i8WeRh2k2W2UW9iQ1rgo9ja8ChowD99IJRI82)
the health industry is now the top-spending lobbyist on Capitol Hill. The big spenders in order include PhRMA ($13.1M), Pfizer ($11.7M), AMA ($4M), Eli Lilly ($3.6M), American Hospital Assn. ($3.5M), Blue Cross/Blue Shield ($2.8M), GlaxoSmithKline ($2.3M), CVS Caremark ($2M), Bayer Corp. ($1.9M), America's Health Insurance Plans ($1.9M), Novartis ($1.8M), Biotechnology Industry Organization ($1.8M).
I find it interesting to see that the pharmaceutical industry's main lobbying organization is outspending the health insurance industry's comparable organization (which would seem to be the most at-risk and beleagured group if the government really decided to get serious about health reform) at a ratio of more than 6 to 1.
Just how some of that money is being spent is in turn revealed by Lisa Wangsness of the Boston Globe, in her coverage of the Biotech industry's lobbying (http://www.boston.com/news/health/articles/2009/07/21/biotech_firms_lobby_hard_for_say_on_healthcare/?page=1). One of the reform bills now in the Senate briefly contemplated an amendment that would have reduced the 12 year patent exclusivity that biotech products now enjoy (or are planned to enjoy) before they are open to generic competition. Among those rushing to the defense of biotech was former Democratic Party national chairman Howard Dean, a former physician and Vermont governor. In the haste to turn back this threat to biotech, Dean failed to mention in an op-ed he wrote that he was a paid adviser to a law firm that advises the Biotechnology Industry Organization.
While traditionally Pharma has found many of its friends among the conservatives, biotech has scored major inroads among liberal lawmakers, primarily by stressing the high-quality jobs it brings to their states' economies. I had a chance to see the lobbying style of biotech up close a couple of years ago in Texas. I was asked to testify in favor of a sunshine bill requiring disclosure of payments from commercial firms to physicians. The rep from PhRMA who spoke at the hearing, opposing the bill, made a series of standard points about why the relationship between Pharma and medicine is a social good. The state rep of the biotech industry used a much more gloves-off approach--simply promising that if the bill passed, Texas would lose biotech industry jobs. Biotech's scorched-earth lobbying policy seems to be paying dividends.
Danny was right on top of the Accreditation Council for Continuing Medical Education's (ACCME's) 2009 annual report, so he picked up the three key facts that it showed:
- Overall CME spending in the US is down from $2.54B in 2007 to $2.36B in 2008, the first year-to-year drop since ACCME was founded.
- The reduction is almost completely due to reductions in commercial CME sponsorship, which fell from $1.2B to about $1B.
- In turn, this reduction was highly selective among CME sponsors. The medical education and communication companies (MECCs) that are almost solely engaged in for-profit work on behalf of commercial sponsors, had their revenues hit by $131M, or a 22% reduction.
As Dr. Carlat then astutely notes, more recent years have seen further changes. The IOM report came out four-square for a serious divestment by Pharma from CME programs: http://brodyhooked.blogspot.com/2009/05/iom-report-on-coi-yes-we-really-mean-it.html The American Psychiatry Association has announced its intention to end all programs sponsored by MECCs at its annual meeting. The AMA's Council on Ethical and Judicial Affairs took a serious swipe at MECC-run CME programs in its draft report on physician conflict of interest. One could say that the handwriting was on the wall that this activity was due for increased regulatory scrutiny and ethical condemnation. The industry may have decided to cut its losses.
Does this mean that the MECCs will go belly-up? Not necessarily. So far as I have been able to learn, an MECC can function in two different ways. It can administer CME courses for which credit is given to physicians in accord with the ACCME rules. Alternatively, it can plan and conduct "educational" programs on behalf of commercial sponsors for which no CME credits are awarded. In the latter case, the rules can be just about as loose as you want, and the meeting can be frankly a marketing session. The new code of conduct from PhRMA suggests that the industry is not about to give up its policy of handing out free meals to docs in exchange for their getting "educated." So it remains to be seen if the drug industry has pulled $200M annually out of physician "education" across the board, or whether it has shifted that money into less regulated, non-CME-credit-granting activities over free dinners. If any readers have any insights into that please comment.
Friday, July 17, 2009
In HOOKED, the story I told about Xigris mostly postdated the time of approval. I stated that this much-heralded drug for sepsis turned out to be quite disappointing, offering relatively low rates of success in the face of extremely high costs. The result was that many hospital ICUs balked at the price tag. The manufacturer, Eli Lilly, responded with a bold PR counterattack, claiming that any hospital that withheld Xigris from its patients was engaging in unethical bedside rationing of care. They also hired on Sandra Tiffany, a Nevada state senator, who believed that her life had been saved by Xigris and then gave numerous TV interviews.
Poole and colleagues now expand the account by looking more carefully at the approval process both in the US, at the FDA, and in the counterpart European agency (EMEA). They found that both agencies broke their own rules by approving Xigris based on only one randomized trial. The trial that documented the supposed benefits of Xigris, called PROWESS, was as noted disappointing from the manufacturer's viewpoint. On the one hand it showed a statistically significant improvement of drug vs. placebo. On the other hand the effect size in favor of the drug was nothing to write home about. That apparently led the investigators to perform a large number of posthoc subgroup analyses. They found one such subgroup, those with severe sepsis according to APACHE III score, that seemed to do better on Xigris than the other subgroups.
It would seem as if the FDA and the EMEA, having violated rule #1 by approving a drug based on a single study, proceeded to try to make up for it by violating rule #2--don't approve a drug based on a posthoc subgroup analysis. That is, having approved Xigris, they then put a label restriction on it, that it was only for use in severe sepsis. The folly of that move, according to Poole et al., is that later studies revealed that the beneficial results in that subgroup could not be replicated and probably were a statistical fluke--which is precisely why we are warned by statisticians not to trust posthoc subgroup analyses, commonly poo-poohed as "data dredging."
Against these critical views of the drug approval process go our understanding of the pressure that was undoubtedly felt by the agencies to approve this drug, for two reasons--first, that sepsis has no effective treatment and is a high-mortality condition; and second, that Xigris is something of a breakthrough product that replies on a new chemical mechanism of action. Today we can say that it has proved much less effective than was initially thought, and in addition seems to cause a serious amount of bleeding as its major adverse reaction. It can probably said with justice, even in hindsight, that if the FDA and the EMEA were going to approve the drug contrary to their own rules of best evidence, they might at least have done so with the mandate that the company perform more extensive follow-up studies. As it was, Lilly was left totally on its own as to whether or not to do those studies.
Thanks incidentally to Rick Bukata and Jerry Hoffman of Primary Care Medical Abstracts for calling my attenton to this paper.
Poole D, Bertolini G, Garattini S. Errors in the approval process and post-marketing evaluation of drotrecogin alfa (activated) for the treatment of severe sepsis. Lancet Infectious Diseases 9:67-72, 2009.
Thursday, July 16, 2009
--a handy summary of a recent editorial in the Journal of the American College of Cardiology by the College's president, Dr. Alfred A. Bove. Dr. Bove was taking exception to the previous editorial by Rothman et al. in JAMA calling for more arms-length relationships between industry and professional medical organizations such as the College of Cardiology.
Dr. Poses gives us a two-part analysis of Dr. Bove's diatribe. First, he dissects the editorial itself as a professor would a student's paper in a basic course in informal logic. He counts up the logical fallacies committed in the editorial and notes that the entire argument rests on these fallacies without a single sound premise among them. Next, Dr. Poses lists the sums of money that the ACC receives from industry sources--amounting to about 38% of its total revenues, which, as I show in HOOKED, is not out of line with other major professional societies, to the extent that we can even find out as their finances are generally shrounded in secrecy. Among other tidbits, Dr. Poses reveals that unlike common practice at most professional societies, ACC enjoys today sufficient revenues to allow it actually to pay salaries to its elected officers. If the salaries this year are the same as in 2007, Dr. Bove is being paid about $147,000 for his service for one year as president of ACC, a sum that might not be paid if ACC were to forgo its cushy relationships with industry and the stream of industry cash flowing into its coffers.
Dr. Poses does not mention, but I did in a previous post (http://brodyhooked.blogspot.com/2009/04/not-passing-sniff-test-acc-pipc-and-ce.html) that the ACC was one of the first and biggest medical organizations to join PIPC, or Partnership for Improving Patient Care, a largely-drug-industry-funded stealth campaign to gut comparative effectiveness research. The organizations that are members of PIPC show thereby that they are much more anxious to do the bidding of industry than to further the goals of scientific medicine or the true interests of patients.
So let me come at this in a slightly different way from Dr. Poses. Dr. Bove apparently thought that by writing this editorial, he was undermining the case of Rothman et al, and effectively convincing the world that it's a good thing for medical societies to be open to taking industry money to pursue their ends. What he has managed to demonstrate is quite the opposite. First, he has shown that he has not a single logical argument to offer to rebut Rothman et al. Second, he has shown that everything he knows how to say, in defense of his own position, really boils down to "trust me"-- and as I was pleased to quote from P.G. Wodehouse in HOOKED, "When an Englishman says 'trust me' it's time to start counting the spoons." Finally, if we look at the big picture of what the ACC has been involved in recently (and for some years previously as I note in my earlier post), we see the opposite of what Dr. Bove claims--clear and serious danger signals about what happens to a medical organization when it decides to climb aboard the industry gravy train. It seems clear that if the organization goes down that pathway, it readily confuses its own (and its patients') interests with the behest of the industry; and its officers' brains turn to mush as they struggle to rationalize all this and pretend that it's all on the up and up.
Rothman DJ, McDonald WJ, Berkowitz CD et al. Professional medical associations and their relationships with industry. JAMA 2009; 301: 1367-1372.
Bove AA. President's page: relations with industry: thoughts on claims of a broken system. J Am Coll Cardiol 2009; 54: 177-179.
Wednesday, July 15, 2009
--thoughtful and faithful reader Marilyn Mann added some challenging comments which I suggest that you review. She alluded to the PROVE IT study as possible evidence that some statins may be better than others and generally supporting the cholesterol-lowering hypothesis of how statins work, which I had been calling into question.
This offers an opportunity to do two things--first, explain better what I believe that my intended message is when I keep harping on statins; and second, share a bit of information that happened to come my way today about the sorts of harm that unbalanced drug industry marketing about heart disease prevention causes.
What I think Marilyn may have been responding to in part was what she perceived to be my going too far out on a limb to argue a contrarian case re: statins. So let me back up and state as clearly as I can what I think I am and am not trying to say.
Things I do not mean to say:
- Patients who have some risk factors for heart disease, and have high cholesterol, should not take statins.
- We have proven that statins are no good for primary prevention of heart disease.
- We have proven that the cholesterol-lowering hypothesis of why statins work is bogus.
Things I do mean to say:
- The contrarian view, that maybe statins do not work as well as they are cracked up to be, and that their efficacy depends on an effect separate from their cholesterol-lowering effect, is a view that should be taken seriously under consideration (the people saying those things are not crazy).
- The amount of evidence favoring statin use for primary prevention, and the value of cholesterol screening and adjusting statin dose carefully to achieve a target cholesterol level, may have been seriously overstated in the portion of the literature influenced by drug industry marketing, and in the associated practice guidelines.
- Before patients are placed on statins for primary prevention, they deserve at least to be told the number needed to treat (NNT) statistics as well as the costs and adverse effects of statins. Told the NNT, as Marilyn indicates, a number of patients would no doubt elect to take statins--but at least some, and perhaps many, would not. (Like many other aspects of medicine, the right answer is shared decision-making.)
Now, you might ask, where's the harm, since fortunately serious adverse reactions from statins remain quite rare? Thanks to my friends Rick Bukata and Jerry Hoffman and their "Primary Care Medical Abstracts" program, I learned today of a recent editorial by Bethell et al. decrying the widespread failure to use cardiac rehabilitation programs post-heart-attack, despite the mountains of evidence supporting the use of such programs. In turn Bethell and colleagues cite a meta-analysis published by Taylor et al. in 2004. Taylor looked at 48 randomized trials of cardiac rehab involving 8940 subjects. Now, Taylor and company reported their findings primarily by odds ratios and not by NNT, so you have to do a couple of fishy things from a statistical point of view to generate an estimated NNT for the mass of studies as opposed to any individual study. Looking at their summed numbers for outcomes in the rehab vs. control groups, I calculated the following estimates: NNT is 62 to prevent one death from any cause; 45 to prevent 1 cardiac death; and 143 to prevent one heart attack. (Sharp-eyed readers will ask: you need to treat that many patients for how long to prevent one bad outcome? and the answer is that it varies as the studies had different lengths of follow-up; but most formal cardiac rehab programs run only for a certain number of weeks, so they are not like pills that you have to take for the rest of your life. The benefits achieved from the cardiac rehab programs tend to substantially outlast the formal length of the program itself.)
Why do I bring this up at all? Cardiac rehab seems to me to be one of many poster children for the "anti-reps"-- the reps that do not show up at the average doc's office trying to sell that treatment and offering the staff free food in the bargain. So what is true of cardiac rehab in patients who have had heart attacks or similar coronary events?
- The efficacy is demonstrated in a large number of studies
- The cost is minimal to moderate, and is reimbursed routinely by Medicare
- There are hardly any adverse effects
- The NNTs, as a measure of the effect size, generally look much better than NNTs for statins--certainly better than the NNTs seen in the PROVE IT trial to be specific.
Our rush to add statins to the water supply, at the same time as we routinely forget to order cardiac rehab for patients whose lives might be saved by that well-proven but nonpharmacologic intervention, highlights how heavily skewed medical practice has become under the influence of Pharma marketing.
Bethell HJN, Lewin RJP, Dalal HM. Cardiac rehabilitation: it works so why isn't it done? British Journal of General Practice 58:677-79, 2008.
Cannon CP, Braunwald E, McCabe CH, et al. Intensive vs. moderate lipid lowering with statins after acute coronary syndromes. New England Journal of Medicine 350:1495-1504, 2004. [PROVE IT trial]
Taylor RS, Brown A, Ebrahim S, et al. Exercise-based rehabilitation for patients with coronary heart disease: systematic review and meta-analysis of randomized controlled studies. American Journal of Medicine 116:682-92, 2004.
Tuesday, July 14, 2009
I guess I should start off with a blanket apology. I have on many previous occasions (for example, most recently, http://brodyhooked.blogspot.com/2009/04/pharmascolds-strike-back-latest-from.html) used this blog as a forum to rebut the writings and ideas of Dr. Thomas Stossel of Harvard, apparent national leader of the group we have come to call "pharmapologists." These folks think that "conflict of interest" is basically a lot of hooey, that there exists no empirical evidence to show that taking money from pharmaceutical companies has ever caused any harm to anyone, and that we "pharmascolds" who object to these cozy financial relationships are a bunch of envious busybodies who are creating ill health by standing in the way of productive, entrepreneurial relationships between medicine and business, out of which will come new cures for all disease.
The apology is simply that offering rebuttals to this gang feels a lot like shooting fish in a barrel--it just somehow does not seem sporting. Be that as it may, I am here in part to keep you posted on relevant new developments, so here goes.
Stossel and his pharmapologists have formed a new national organization called ACRE, Association of Clinical Researchers and Educators (http://www.acreonline.org/). The reason for the organization is for the beleaguered and outnumbered pharmapolgists to circle their wagons to face the onslaught of us marauding pharmascolds. (Well, OK, they are not outnumbered; they claim to be the "silent majority.") Pointing out that their organization is paid for totally by its members, ACRE proceeds to inform us:
ACRE is to be a forum for what we believe is a hitherto silent majority of individuals engaged in clinical service, medical education and medical innovation ready to oppose (but not debate) a small but well organized and well-funded coterie responsible for an anti-industry movement. This movement has inverted reality by extrapolating from an astonishingly small number of adverse events related to industry compared to the incontrovertible evidence of social good that has eventuated from thousands of industry actions over my lifetime in medicine. The movement particularly demonizes industry marketing, despite the lack of any evidence that, on balance, such marketing impacts anything but positively on patient care.The movement’s success rests in part from its tactical skill. Its initial target, gifts and meals, were too trivial to oppose. But by conceding trinkets, physicians and industry tacitly admitted to an “ethics” problem justifying further sanitizing of medicine from commercial influence. ... The movement also panders to archaic notions of professionalism rooted in pre-scientific medicine and based on contempt of business and trade.The movement has therefore succeeded in goading medical leaders to impose increasingly onerous regulations on physicians and researchers. These rules include forced confession (massive disclosure), censorship (limits on writing, speaking or advising) and coercion (restrictions on association, action and rewards). These rules have no basis in empiric fact and have no benefits. The movement is deeply disrespectful of physicians and industry alike. It is hypocritical, because it has its own conflicts of interest in that its members gain power and wealth by controlling medical education and by managing conflicts of interest. And it has costs: the regulations in force and desired will decrease medical education and innovation.The movement’s overreach, however, has finally begun to dawn on the rank and file. In particular, working physicians are becoming aware of the confusion and potential for embarrassment and even litigation embedded in the soon to be enacted Massachusetts State regulations and how bans on product-based (promotional) speaking will affect their life and livelihood.
Those of us who have been in the pharmascold camp for a while have to be struck by this description in a number of ways. For the vast majority of the time that we have been working at this (I would date "pharmascolding" to 1961, when pediatrician and educator Charles May wrote a ground-breaking critique for the Journal of Medical Education), the David seemed very much to be the pharmascolds, while the role of Goliath was played by the pharmaceutical industry and the reported $57B it spends annually in the US on marketing, plus the 94 percent of US physicians who have one or another sort of relationship with the industry according to Campbell's widely quoted NEJM study. It is only very recently that the scolds seemed to be making any headway at all, though admittedly the degree of momentum that has been generated just in the last year or so is quite impressive. But to imagine that somehow the David and Goliath roles have been switched seems inaccurate to say the least. As interesting as it is to discover for the first time that my friends and I are "well-organized, "well-funded," and have unusual "tactical skill," I have to ask what planet these people come from. I won't address the charges that we are anti-business or rely on an outmoded definition of professionalism as we have hashed over those charges in the past. I note that ACRE promises to "oppose but not debate" us-- draw whatever conclusion from that you wish.
The fun (and unsporting) part of all this is that somebody has already put up a spoof website: http://www.acrenow.com/, which purports to be the home page of "Academics Craving Reimbursement for Everything." It's a real hoot of a spoof and I heartily recommend it, but I am sure that from the point of view of Stossel and Company, its existence merely increases their paranoia about the hostile world that they inhabit.
Monday, July 13, 2009
- The Story We Hear: Statins are very effective in saving lives by preventing heart disease. The smart patient keeps an eye on cholesterol and at the first sign of its going up, asks the doc for a prescription for a statin. The doc and patient then monitor the cholesterol levels carefully to keep them as low as possible to get maximum benefit. Practice guidelines based on compelling recent studies are regularly revising downward the threshhold level of cholesterol that should trigger statin prescription.
- The Story We Don't Hear: Statins are pretty good for one group of patients--those with existing heart/vessel disease--to prevent future events such as heart attacks. We cannot be sure that they achieve their benefits in this group by lowering cholesterol and indeed a different mechanism, such as anti-inflammation effects, may be responsible. There is much less evidence that statins work for primary prevention--preventing heart/vessel disease where it does not yet exist. As a rule, hundreds of patients must be treated in a primary prevention study to have one who benefits. There's no good evidence that measuring cholesterol levels or monitoring cholesterol levels after treatment adds anything useful to statin therapy.
As somebody who argues for the second story at least getting equal time, if not actually being accepted as the more correct account, I naturally wonder about what newer data will reveal about the statin/cholesterol hypothesis. As I previously posted (http://brodyhooked.blogspot.com/2008/11/by-jupiter-part-ii-more-skeptical-view.html), it was intriguing how the JUPITER study actually blew a huge hole in the standard hypothesis, yet was covered by the media as if it was just one more reason why everyone and his duck should be taking statins.
So now-- thanks to the tip from Doug Bremner's blog-- comes the online advance publication in BMJ of a meta-analysis on stains for primary prevention--
--which aims to answer just about exactly the question I pose above--how do statins perform in patients without existing heart/vessel disease, considering not surrogate endpoints like cholesterol measurements, but hard patient-oriented outcomes like death, heart attack, and stroke?
The first thing to note is that the list of financial conflicts of interest among the authors occupies a long paragraph, so this is clearly a group used to seeing the green of drug company money.
The authors then analyzed ten randomized trials of statins for primary prevention (or primary prevention subgroups within other trials), including JUPITER. They concluded that when the trials were all summed, the statin group showed statistically greater improvements in all cause mortality; major coronary events; and major cerebrovascular events.
Based on the data provided, one can calculate the critical statistic, number needed to treat (NNT). You would have to treat 167 people for 4.1 years to prevent one death; 77 people for 4.1 years (or 316 people for 1 year) to prevent one major coronary event; or 250 people for 4.1 years to prevent one major cerebrovascular event.
Here is what may be the most important take-home message--the authors admit in their discussion that the overall baseline mortality rate across all ten studies is 1.4 %. They note that this is a high number--indeed, it is nearly the same mortality rate found in many secondary prevention trials of patients with known heart disease.
Now, if the story we usually don't hear is the correct story, what would we expect such a meta-analysis to show? First, we should not be surprised if the statin group does statistically better than the control group. Second, we'd expect that the NNT would be high--generally in the 100-300 range. Third, we'd expect that the NNT would get lower in proportion to the patient's risk status for later heart/vessel disease going up.
And what did this meta-analysis by Brugts et al. demonstrate? Exactly that. Statins offer a statistical advantage but the advantage in terms of absolute risk reduction is low, so it yields a high NNT--but a lower NNT than in some studies taken individually. But the lower NNT is not unexpected when we realize that this population of patients is actually a very high risk population--indeed, in just about the same risk category as those with known heart disease, who clearly show benefit from statins. Finally, there is yet once again no evidence at all that using any particular statin, or using any particular dose of statin, or achieving any particular cholesterol target level, makes the slightest bit of difference (though to be fair those variables were not the major outcomes looked at in the study design).
Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomized controlled trials. BMJ 2009:338:b2376, doi:10.1136/bmj.b2376
Thursday, July 9, 2009
Gary Schwitzer of the University of Minnesota comments on fellowships paid by Pfizer to send journalists, all expenses paid, to conferences on cancer care; and free tours of the Eli Lilly headquarters also paid for by the company. He points out the codes of ethics of major organizations of journalists that prohibit taking such gifts; and he then notes that when he complained about these gifts to the respective organizations (National Press Foundation and Society of Professional Journalists), he received only a ho-hum reply.
(Thanks to our friends at Healthy Skepticism for this tip.)
Tuesday, July 7, 2009
All gifts to physicians are now put into three categories--banned; allowed but must be disclosed; allowed and not disclosed. Most traditional gifts, such as meals, go into the "banned" category. Exceptions are drug samples provided free to patients; short term loan of devices for evaluation; and journal article reprints and equivalent "educational" material. Speaking, consulting, and research payments are allowed but must be disclosed. Royalties and licensing fees and rebates and discounts are exempt from disclosure.
Comments on the new law can be found at:
The latter compares the new Vermont law to the federal Physicians Payment Sunshine Bill. The federal bill, if passed, would probably pre-empt the reporting provisions of the Vermont law, but would not affect the bans.
--who tells us about more fallout from the DSM-V drafting and research process. The most important exhibit is a letter to the American Psychiatric Association (APA) Board of Trustees by Drs. Robert Spitzer and Allen Frances. Both were heavily involved in the earlier iterations of DSM (particularly III and IV). They make no bones about their concerns that the DSM-V process has gone totally off the track and that the APA must now take drastic action to regain control and rein in the excesses.
In their letter (http://www.scribd.com/doc/17172432/Letter-to-APA-Board-of-Trustees-July-7-2009-From-Allen-Frances-and-Robert-Spitzer), Drs. Spitzer and Frances make these points:
- "...the rigid fortress mentality that has prevented the DSM-V process from learning and adapting. The DSM-V leadership has lost contact with the field by restricting the necessary free communication of its workgroups and by sealing itself off from advice and criticism."
- "The suggested subthreshold and premorbid diagnoses.... If these were to become official categories in DSM-V ... could add tens of millions of newly diagnosed "patients"- the majority of whom would likely be false positives subjected to the needless side effects and expense of treatment. The APA might well be accused of a conflict of interest in fashioning DSM-V to create new patients for psychiatrists and new customers for the pharmaceutical companies. Certainly, the DSM-V Task Force does not have these motives but, in its effort to increase diagnostic sensitivity, it has been insensitive to the great risks of false positives, of medicalizing normality, and of trivializing the whole concept of psychiatric diagnosis."
- "Keeping rigidly to a fixed publication date even at the risk of producing an inferior and problematic product might suggest that publishing profits are given undue weight in DSM-V considerations."
- "You must understand that the APA has never held a guarantee on the DSM franchise. There have been serious objections in the past that it is inappropriate for one professional "guild" to control a document with such wide usage and great public health importance. The privilege to prepare the DSMs has been extended only because of the credibility of previous DSMs and it depends upon the continuing trust in the openness and disinterestedness of the process. You need to weigh the risk that the constant airing of DSM-V mistakes may result in this issue being reopened."
- "The closed and secretive DSM-V process is insulting to the other mental health professions whose acceptance and support is crucial to its legitimacy. All mental health disciplines should be openly invited to participate in troubleshooting DSM-V options."
These comments reinforce the concern I raised in my previous post--that the APA has been hanging out with industry so long that it is starting to think like a for-profit corporation and no longer like a professional society. A manual such as DSM-V is supposed to be a public health and public service tool informed by the best available science. It is not supposed to be managed as a cash cow to bring profits to its publisher (the APA). But the process that is currently being followed raises the specter of the latter, not the former.
Dr. Carlat tells us that besides Drs. Frances and Spitzer, another unhappy camper at DSM-V is Dr. Jane Costello of Duke, who has resigned from the DSM-V working group on child-adolescent disorders. Her letter of resignation is also making the rounds (http://www.scribd.com/doc/17162466/Jane-Costello-Resignation-Letter-from-DSMV-Task-Force-to-Danny-Pine-March-27-2009). Some highlights:
- "I am increasingly uncomfortable with the whole underlying principle of rewriting the entire psychiatric taxonomy at one time. I am not aware of any other branch of medicine that does anything like this. (The ICD revisions make no attempt to rewrite the details of each diagnosis.) There seems to be no good scientific justification for doing this, and certainly none for doing it in 2012."
- "When we began this process, we agreed that changes would only be made if there were empirical evidence to support them. Sometimes ... this has been the case. But as time has gone by, the gap between what we need to know in order to make revisions and what we do know has grown wider and wider, while the time to fill these gaps is shrinking rapidly. More and more, changes seem to be made for reasons that have little basis in new scientific findings or organized clinical or epidemiological studies."
- "One reason why it took so long to get a data base in place was that a decision was made that the work had to be done via a grant application to NIMH, with all the time delays entailed by that process. The reason given was that the funding allocated by the APA for research for DSM-V was not enough to support the necessary work. I continue to be shocked that the APA would even consider revising the DSM without being willing to allocate the funding necessary to carry out the underlying scientific studies. A drug company that tried to bring a product to market on the basis of inadequately-funded research would rightly be censured. This is what the APA is doing, and now that it is quite clear what is happening I am afraid that I cannot bring myself to be part of the process any longer."
We hear from numerous experts in psychiatry that nothing has happened to the basic science of mental illness since DSM-IV to justify a top-to-bottom revision of diagnostic taxonomy. If the goal was to produce an evidence-based document, such a plan would be weird to the extreme. If the goal were to assure maximum sales of the resulting book, it sounds like a good marketing ploy. An even better marketing ploy is to be sure that APA collects all the profits from book sales, while charging all the expenses of gathering the needed scientific data to NIMH!
Finally, we need to make mention of another blogger, Dr. Doug Bremner, whose ongoing criticisms of the pharmaceutical industry and of the DSM-V process in particular seems to have landed him in hot water. He explains (http://www.beforeyoutakethatpill.com/index.php/2009/07/07/in-praise-of-intellectualism-or-notes-from-the-corpademy/ as well as in previous posts) that he was recently instructed by the university at which he is employed no longer to mention its name in connection with his blog, "Before You Take That Pill." (I will of course not mention the university's name, but it rhymes with Emory.) Like the rest of us, Dr. Bremner had never suggested that that university endorsed his opinions; he merely included it for purposes of identification. Anyone who has compared my blog with Dr. Bremner's knows that he and I have very different blogging styles--he's a lot more in-your-face and over-the-top, whereas I favor a stodgy, academic line. So I can see a reason why a university might feel ill at ease having its name linked with that sort of blog--assuming that a faculty member's merely saying that he works at Em--sorry, at that place-- is any sort of connection with approval or disapproval of the person's blogging style, which of course it isn't. But the real issue does not seem to be style but content. Given the past behavior of Emory, and the sorts of folks who have previously been defended by the administration there, it does seem as if the ire is raised much more by Bremner's anti-drug-industry and anti-APA stance than by the specific way he goes about expressing himself. And any such challenge to academic freedom is something that we university professors must unite in opposing. [Comment added 7/13/09: Doug posted today that Emory has seen the light and has withdrawn its indefensible demand that he not identify himself as affiliated with them.]
Monday, July 6, 2009
I propose, with broad brushstrokes in HOOKED, that the period of roughly 1945-1960 was characterized by an "alignment of the planets" that shaped the relations between medicine and Pharma up to the present time:
- A huge increase in the number of new, mostly useful drugs
- The AMA's retreat from its older stance of providing scientific analyses of new drugs for physicians
- Academic medicine's abandonment of the continuing education of practitioners to industry
Greene and Podolsky's new essay adds detail to this "alignment" account without calling any of its basic elements into question, so far as I can tell. They explain more about the careers and beliefs of the first generation of academic physicians to challenge the drug industry's influence over medical education--most of whom represented either the new infectious disease movement or the new clinical pharmacology movement, both of which, had there been a term in use at that time such as "evidence-based medicine," would have claimed to be part of that. Arrayed against them, besides the actual leaders of the industry itself, were some other key physician leaders who were financially committed either to medical publishing or to medical marketing and advertising--and to them, the issue was simply one of modernization. The advertising firms had invented effective new ways to get information about new drugs quickly into the hands of practitioners; academic medicine should be cheering this discovery rather than quibbling about the details. What would count as "modern" medicine was effectively in dispute in this debate. Finally they explore the anbiguous role of the AMA, on the one hand trying to hang onto as much control as it could over the accreditation of continuing medical education, yet eagerly allowing the industry to take over CME funding.
Greene and Podolsky mention in passing one intriguing figure of the day, Hopkins pharmacologist Louis Lasagna. Initially a major critic of industry influence, Lasagna ended up largely switching sides and becoming a strong advocate for the industry perspective, even to the extent of becoming what many would deride as a "shill." A detailed study of Lasagna's conversion, they suggest, would be of considerable historical interest.
Greene JA, Podolsky SH. Keeping modern in medicine: pharmaceutical promotion and physician education in postwar America. Bulletin of the History of Medicine 83:331-377, Summer 2009.