The Disappearance of Generic Drugs

(My source for this post is Elisabeth Rosenthal's article in the New York Times:
http://www.nytimes.com/2013/10/13/us/the-soaring-cost-of-a-simple-breath.html?_r=0
--which has actually published almost a year ago, but seems to have some important information that others besides me may have missed.)

Once upon a time, we knew that almost all drugs would eventually turn generic. Under the influence of the Hatch-Waxman Act of 1984, most drugs made the transition from expensive brand-name to cheap generic after 20 years (which actually amounted to 10-12 years after a drug first came onto the market). Walmart inaugurated the sales pitch of the "$4 generic" and generally generic drugs were quite affordable.

During the first decade of the twenty-first century, savings picked up. More and more older drugs went generic, and the companies had fewer brand-name drugs to replace them with.

Or so it was supposed to go. Rosenthal tells us what has actually happened. She focuses her story on asthma drugs.

Very few new asthma drugs are on the market, so treating this common disease should be cheap. It is certainly cheap in other countries, where the government intervenes to keep medicine affordable. But in the U.S., virtually every inhaler costs what we'd expect to pay for brand-name drugs, even if the active ingredient is as old as the hills.

One of the oldest drugs for asthma is the basic bronchodilator, albuterol. You'd think that you could get a simple albuterol inhaler for a few bucks, right? That was true until a few years ago when the FDA got environmentally conscious and demanded the drug companies remove chlorofluorocarbon propellants from inhalers because they harmed the environment. The companies were happy to do so--and were promptly issued new patents for their drug products, despite the fact that the basic drug was the same. So now we're on another 20-year rollercoaster until these drugs get cheap again (pending whatever new wrinkle the companies can throw at us in the meantime).

The FDA says that "difficult, longstanding scientific challenges" make it hard to measure drug activity deep in the lung and so assure that a new propellant or other vehicle really produces the same drug product. Meanwhile, other nations have managed to demand that drug companies sell these inhalers at much lower than brand-name prices, and nowhere in the world, to my knowledge, have any medical difficulties arisen because the dose of a drug from a new inhaler is actually different than the old dose. The US is basically the only country in the world where these drugs cost so much. (Many European countries have forced the common asthma drugs over-the-counter.)

Rosenthal writes, "The Centers for Disease Control and Prevention puts the annual cost of asthma in the United States at more than $56 billion, including millions of potentially avoidable hospital visits and more than 3,300 deaths, many involving patients who skimped on medicines or did without."

As usual, the uninsured in the US pay top dollar for these drugs. As Rosenthal notes, "Lawmakers in Washington have forbidden Medicare, the largest government purchaser of health care, to negotiate drug prices. Unlike its counterparts in other countries, the United States Patient-Centered Outcomes Research Institute, which evaluates treatments for coverage by federal programs, is not allowed to consider cost comparisons or cost-effectiveness in its recommendations.....California's Medicaid program spent $61 million on asthma medicines last year, paying more than $200--not far from full retail price--for many inhalers."

A few years back, the generic drug market appeared to be one of the areas where the large drug manufacturers were losing their clout. Now, at least for some medical conditions like asthma, they seem to have their way again.

Sunshine Act Goes Live, Sort Of

According to ProPublica's Charles Ornstein--
http://www.propublica.org/article/what-to-be-wary-of-in-the-govts-new-site-detailing-industry-money-to-docs
--as the Sunshine Act (of the 2010 Affordable Care Act) finally goes live today, some 18 months after the scheduled first release of data, we still can't expect all that we had anticipated.

Recall that the Sunshine Act was supposed to list all payments from drug companies to individual physicians so that consumers could check on which doctors were receiving which sorts of money.

Ornstein lists the current complications:

• The current release of information only covers August through December, 2013.
• Data on payments related to new products, and sometimes new uses for existing products, are held back for as long as 4 years.
• Some practitioners are not included--despite more frequent company payments recently to nurse practitioners and physician assistants, they're not on the bus.
• Because of initial errors with similar physicians' names, etc. up to 1/3 of data is not being released currently.
• Many different sorts of payments are included and they have different ethical implications--expect it to be a while before we can make sense of all the numbers.
• As usual, expect errors.

Ornstein puts in a good word for ProPublica's own website, Dollars for Docs:
http://projects.propublica.org/docdollars/
--which currently lists about half of all drug company payments to physicians and is current through the end of 2013.

The Anechoic RUC: Some Small Efforts at Reform

I have previously written about the Resource-Based Relative Value Scale Update Committee, or RUC:
http://brodyhooked.blogspot.com/2011/05/more-conflicts-of-interest-at-high.html
http://brodyhooked.blogspot.com/2013/07/piling-up-on-ruc-about-time.html
http://brodyhooked.blogspot.com/2013/07/the-ruc-revisited-more-corruption-in.html

Now, along comes a long and thoughtful synopsis of RUC from our friends over at Health Care Renewal:
http://hcrenewal.blogspot.com/2014/08/now-politico-tries-ruc-raking.html
--which in turn highlights a piece in Politico by Katie Jennings:
http://www.politico.com/magazine/story/2014/08/health-care-costs-110184.html#.U_zgQYcg-ig

When I asked Dr. Roy Poses of HCR about RUC, his reaction was: "It's amazing how little traction this issue has gotten, despite its importance, and the fact that there is something in the RUC for nearly everyone to hate..."

Now, what's it about the RUC that should make people hate it?

• Is it the fact that it's run by the AMA on a nearly-secret basis, despite the fact that it more or less sets Medicare and Medicaid policies?
• Is it the fact that it overwhelmingly represents specialty societies who generally manage to practice "you scratch my back, I'll scratch yours" as a way to assure good payments for procedures?
• Is it the fact that primary care specialties are woefully underrepresented and usually end up with the short end of the stick when it comes to payment--assuring that primary care will continue to pay well below average and drive away med students despite the great need?
• Is it the fact that these high medical prices for procedures fit in well with the corporate interests that continue to dominate medicine?

I'll let Dr. Poses speak to this issue at some length in his conclusion:

"So since 1992, the RUC has had an outsize role controlling what Medicare pays physicians, and hence physicians' pay in general.  Over this time, the playing field has become increasingly tilted in favor of procedural services and away from cognitive services, especially primary care.  The result is that the US has the most expensive health care system in the world, but hardly the best health care or health care results in the world. 

"Economists have beaten us over the head with idea that incentives matter.  The RUC seems to embody a corporatist approach to fixing prices for medical services to create perverse incentives for physicians to do more procedures, and do less conversing with and examining patients, examining the best clinical research evidence about their problems, and rigorously thinking about how best to help them.  More procedures at higher prices helps physicians who do procedures.  It may help even more the corporations that provide the devices and drugs whose use is necessitated by such procedures, and the hospitals who can charge a lot of money as sites for performance of procedures.  It may even help insurance companies by driving ever more money through the health care system, and thus allow rationalization for higher administrative expenses as a function of overall money flow.

"Yet incentives favoring procedures over all else may lead to worse outcomes for patients, and more costs to patients and society.  If we do not figure out how to make incentives given to physicians more rational and fair, expect health care costs to continue to rise, while access and quality continue to suffer.

"Since we started writing about the RUC in 2007,  there have been some small changes in the RUC.  It has slightly more primary care representation, and its membership is no longer secret.  That is, however, about it.

"As I wrote last time, hopefully the Politico article, added to all the other attempts to shine light on the RUC, will succeed in increasing awareness of the RUC and its essential role in making the US health care system increasingly unworkable.  Of course, such awareness may disturb the many people who are making so much money within the current system.  But if we do nothing about the RUC, and about the ever expanding bubble of health care costs, that bubble will surely burst, and the results for patients' and the public's health will be devastating."

Dr. Poses' blog is based on a central metaphor which for some reason I find mildly irritating, the anechoic effect--the idea that something happens but it never leaves an echo, and so it gets ignored. (Why I find that irritating can be left for elsewhere.) But RUC seems to be a great example. It does all sorts of things wrong, in a huge way, and it just keeps rolling and rolling on the same pathway, and whoever criticizes it seems to be talking to nobody and never gets an answer. The basic factor favoring RUC is that even most physicians have no idea that it exists.

Not-So-Personalized Medicine

Jack E. James, who appears to hail from either Reykjavik University in Iceland or the National University of Ireland in Galway, or both, kindly sent me a copy of a paper published in June in the European Journal of Epidemiology:
http://link.springer.com/article/10.1007%2Fs10654-014-9898-z

The paper addresses "personalized medicine" from the perspectives of Julian Tudor Hart's "inverse care law" and Don Light and yours truly's "inverse benefit law":
http://brodyhooked.blogspot.com/2011/01/inverse-benefit-law-making-sense-of-how.html
http://brodyhooked.blogspot.com/2011/03/synthesis-why-drug-industry-tries-to.html

James starts off reminding us of the promise of personalized medicine: instead of "one size fits all," we will have "the right drug to the right patient at the right time." Instead of 100 people getting a drug, and 5 of them having a nasty allergic reaction to it, we'd get the message in advance that these particular 5 folks should not be given that drug. Personalized medicine seems to be quite effective nowadays, for example, in breast cancer treatment, where patients are tested and their tumors are found to be sensitive or insensitive to various chemotherapies before they are administered.

James goes on to discuss personalized medicine in some depth. Why the gap--why, at least so far, has personalized medicine seemed to hover just beyond reach? Theoretically, there's the problem that personalized medicine is yet one more way we've devised to believe in a false genetic determinism, when as James reminds us, "disease and health are the result of complex interactions between networks of genomic and epigenetic processes, behavior, and the environment." On a more practical level James suggests that personalized medicine depends on clouds of billions of data points for each individual, which would first be extremely expensive, and second, more importantly, would not guarantee that any resulting associations would have either a large effect size or a high predictive probability.

There's a difference, for instance, between our ability to "prove" that high blood pressure causes more cardiovascular disease, which is consistently true at the population level, and our ability to make predictions at the individual level, where many low-blood-pressure folks continue to develop heart disease and high-pressure folks remain healthy. James summarizes, "Empirical evidence across a range of medical conditions indicates that prediction based on individual genomes compares poorly in clinical value to that of clinical risk markers currently employed in conventional medicine."[1] He also noted, "When identical DNA samples were sent to leading commercial suppliers, a comparison of genomic test results found that the information supplied about individual risk profiles was not merely without clinical value but that the level of risk reported differed markedly between the companies."[2] Thus those firms that claim to be able to assist one in obtaining personalized medicine results seem incapable of this--yet quite capable of pocketing their fees.

The story so far at least seems to be that some genetic traits, which are now mostly well known (such as Huntington's disease and cystic fibrosis) have a clear and significant linkage between one's genes and one's medical prognosis, and tests are now available for many of these. By contrast, what has come forth since the mapping of the human genome is genome-wide association studies, which (for instance) have shown numerous small associations related to one's risk of developing type 2 diabetes, but even in higher-risk groups these have been mostly worthless in predicting individual risk. James adds that no group has yet been shown to have a different life span due to the cumulative effect of genome-wide associations with increased risks for coronary artery disease, type 2 diabetes, or cancer.[3]

James then turns to the two "laws." He states, "To the extent that health expenditures draw upon finite resources, development of the genomic and information technologies that underpin personalised medicine will have the unintended consequences of diverting resources away from other healthcare priorities. The inverse care law predicts that any such redirection of resources will disproportionately disadvantage those with lowest income and greatest healthcare need, who in turn have fewer resources to offset shortfalls arising from any diminution in existing healthcare."

He then addresses the inverse benefit law: "Whereas the inverse care law elucidates harm that exposure to market forces may have on the distribution of healthcare, its generalisation in the form of the inverse benefit law illustrates market-related harm of a different kind; namely, the treatment of ever more healthy populations." He gives the example (only one of many possible) of shifting treatment from osteoporosis (bone mineral density 2.5 times or more below population mean) to osteopenia or "pre-osteoporosis" (BMD as little as 1.0 SD below mean). This leads predictably to two outcomes--first, treating many more healthy people with drugs that will do them no good, and second, exposing many more of them to the risks of adverse drug reactions. James notes this amounts to drug treatment for those "at risk of being at risk."[4]

James summarizes, "the extreme levels of human and material resources required by the genomic and information  technologies upon which personalised medicine is based threaten to disproportionately disadvantage those with greatest healthcare needs (inverse care law)... while simultaneously posing harm to ever larger populations of health individuals (inverse benefits law)....A mix of excessive confidence in personalised medicine,  high expectations of benefits, perceived commercial opportunities, and insufficient attention to harmful consequences has the potential to 'colonise the future' of healthcare...wherein attention and resources are captured at the expense of alternative behavioural and social pathways that have the potential to effect greater improvements in population health."

I would, in all this, stress the role of commercial interests.

[1] Smolen JS, Aletaha D. Forget personalised medicine and focus on abating disease activity. Ann Rheum Dis 72:3-6. 2013.
[2] Adams SD, Evans JP, Aylsworth AS. Direct-to-consumer genomic testing offers little clinical utility but appears to cause minimal harm. NC Med J 74:494-499, 2013.
[3] Beekman M, Nederstigt C, Suchiman HED, et al. Genome-wide association study (GWAS)-identified disease risk alleles do not compromise human longevity. Proc Natl Acad Sci 107:18046-18049, 2012.
[4]Alonso-Coello P, Garcia-Franco AL, Guyatt G, Moynihan R. Drugs for pre-osteoprorsis: prevention or disease mongering? BMJ 336:126-129, 2008.

Overall: James JE. Personalised medicine, disease prevention, and the inverse care law: more harm than benefit? Eur J Epidemiol 29:383-390, June 2014.

Research on Pharmaceuticals: From Confidence to Commercialism

The main thrust of this commentary comes from Dr. Roy Poses and:
http://hcrenewal.blogspot.com/2014/08/desperate-vulnerable-research-subjects.html
--which in turn draws on two prior posts:
https://medium.com/matter/did-big-pharma-test-your-meds-on-homeless-people-a6d8d3fc7dfe

https://medium.com/matter/why-are-dope-addicted-disgraced-doctors-running-our-drug-trials-aff6d20843bf

A little background: HOOKED described a major shift in pharmaceutical research. Initially, the vast majority of drug trials were conducted by universities. Over the past 30 years, companies found that universities were too slow in doing this research for maximum financial gains, and so gradually, contract research organizations replaced universities as the major players. Dr. Carl Elliott (first of two prior posts) has been one of the major writers about the fallout from these policies.

Dr. Elliott describes in some detail a group of subjects who can be found in typical contract research organizations, who talk openly about their ways of qualifying for research trials, and also of dodging the painful and burdensome procedures that typically form a part of some trials. It seems quite clear that the money, and not any goal of contributing to science, is the main and indeed the sole motivator. Dr. Elliott had previously described this "guinea pigging" in earlier published work.

The second prior post, by Peter Aldhous, describes some of the physicians who run the contract studies, and focuses on those who have been censured and who have various licensure problems. Aldhous admits that these misfits count as a minority of all the doctors running the contract research organizations, but adds, "My trawl netted dozens of doctors selected to work on clinical trials over the past five years who had previously been censured by state medical boards. Thousands of doctors are hired each year to test experimental drugs, making this a small minority. But most doctors have clean records, so companies should have few problems finding recruits without red flags against their name."

Aldhous concludes, "Some experts argue that the FDA’s entire rulebook for clinical trials, with its talk of things like 'institutional' review boards, reflects the academic past of clinical research—not today’s industrial juggernaut of for-profit clinical trials firms and for-hire review boards, which oversee a workforce of doctors drawn from regular medical practice. 'They are regulations for a world that doesn’t exist anymore,' says Elizabeth Woeckner, president of Citizens for Responsible Care and Research, which campaigns for the safety of medical research volunteers."

Dr. Poses then notes: "So given the push to do research rapidly at the lowest cost, the lack of supervision and regulation by the FDA, the hiring of physicians with problematic backgrounds, the willingness to take vulnerable patients desperately motivated by money, can we trust that the nice, clean, detailed descriptions of clinical trials implemented by contract research organizations presented in research articles and trial registries have anything to do with the reality of what went on? If not, what then should we make of the validity of the results of such trials?...This is yet another reason to ask whether we need to take research on human subjects meant to evaluate commercial products or services out of the hands of the companies that make those products and provide those services."

In other words, bait and switch. Get everyone used to research on human subjects while research institutions are running the shop and people who sign up as subjects have at least some motivation to behave in the interests of science. Then gradually change the system so that it's all about money and one can no longer trust the results. The money affects different players in different ways-- the companies and the CROs have their financial motives, the "guinea pigs" have theirs--but the one thing we can count on is that the money plays a role that's different from the ideal of scientific research. The end result is that things look legitimate up front, and all the people involved have strong motives to do what's less legitimate behind the scenes. We have no idea how that plays out in terms of scientific rigor.

And this is now how drugs are tested before we use them.

From Christopher Gregory: What's Wrong with Profits in Medicine?

Now I'm turning the blog over to Dr. Christopher M. Gregory, a fellow Texan who runs the DocOnomics blog (http://www.doconomics.com/blog/). He sent an e-mail recently which so nicely, and briefly, captured a large issue that has perplexed me that I couldn't help but ask him to reprint, and he kindly consented:

This Modern Healthcare article Another Year of Pay Hikes for Nonprofit Hospital CEOs galls me. Almost as much as this article that reported the director of interventional cardiology at NY Mt Sinai was paid almost $5 million a year for being the rainmaker there, where far more stents are done than the national average.    

As I consider the proliferation of waste in the form of freestanding ERs, urgent care clinics, and shiny new hospitals popping up, and more doctors being bought off into economically forced subservience, I see nothing but the extreme excesses in our system. And for that there is a small group of these so-called “not-for-profit” CEOs getting pay packages that would choke a horse. Boards and compensation consultants continue to cite market forces—the need to keep up with peers to hold onto skilled healthcare leaders—as the main reason for the increases. The market forces they refer to are the market forces of excess, waste and profits that continue to make life increasingly intolerable for the group of physicians – primary care physicians – that would make this system much better if we let sanity retake the high ground. These high-talent CEOs are especially valued for the business smarts needed to make sure we are continuing to pay such disproportionate amounts for the unnecessary, costly care in this country .

To be precise, these pay packages are needed to keep these high-power hospital businessmen in the business of maintaining the well-oiled machine that is swallowing up nearly 20% of our GDP. And yet, millions of Americans can’t afford to get the care they need.  

Total cash compensation grew an average of 24.2% from 2011 to 2012 for the 147 chief executives included in Modern Healthcare's analysis of the most recent public information available for not-for-profit compensation. Of those 147 CEOs, 21, or 14.3%, saw their total cash compensation rise by more than 50%.

I talked with Dr Bob Kramer this morning. He said that it will be an uphill battle getting ologists to passionately endorse a cutback in the sorts of conspicuous consumption that nets them many multiples of what PCPs are paid, and continues to siphon off the ranks of potential primary care doctors in training. We are going to reap a medical, economic whirlwind for all of this foolishness as we continue to lose the numbers of physicians who would serve us best on the front lines. If only we could overcome the entrenched stupidity of organizations like the AMA and the RUC, that keeps PCPs from making the economic and care-centric progress that would make our healthcare system run so much better.

What can be done – what group of physicians around the country – will stand up and make a definitive statement that the intensifying black hole of the overheated healthcare “business system”, with its goal for more money and more influence, is taking us in a terribly wrong direction? As my Canadian healthcare friend once pointed out, there is a healthcare noose around our national neck, and the “system” is the hangman. 

Christopher M. Gregory

DocOnomics
1705 River Birch Drive
Flower Mound, TX 75028

From Health Care Renewal: The Free Market and Drugs

Let's see what's going on over at the Health Care Renewal blog, courtesy Dr. Roy Poses.

Dr. Poses has been noting that there are some pharmaceutical developments that could easily help us out in the case of Ebola virus, which seems right now to be expanding its presence and going out of control in West Africa. Unfortunately, while new vaccines and other drugs could be helpful (even if drug treatment is a small part of the immediate response to the deadly virus), the world's pharmaceutical industry has largely tuned out. From a capitalist standpoint, this is simply not an attractive investment. Not enough people with enough cash in their pockets are at risk for coming down with Ebola to make it profitable for any company to develop the necessary drugs.

Dr. Poses has been comparing the real human needs posed by Ebola virus with the made-up needs which are met, at great profit, by the drug industry. His latest case is Acthar gel, an obscure drug made from pigs' pituitary glands. The use of this drug, made by Questcor, has grown more than 20-fold between 2008 and 2014, reaching about $220M on Medicare. (Notice that as a million- and not a billion-dollar drug, Achtar is not even on many people's interest lists.)

Here's Dr. Poses' summary of this drug and its implications:

  The sorry case of Questcor and Acthar reveal how crazy the costs of health care in the US have become, driven now by a system that itself now seems crazy.  Through clever use of regulatory loopholes, the company acquired rights to an old drug whose efficacy was unproven, hugely increased its price, began aggressive marketing even though the drug's efficacy was completely unproven, while remaining largely silent about the drug's substantial risks.  Fueled by hundreds of millions of dollars in revenue thus generated, mainly from the US government, the company richly rewarded its top hired executives, who then have decided to sell it to a company outside of the US in a deal that will make these executives millions more.  So patients received a drug whose benefits are unknown, and whose risks may be much higher than they were told, at a cost of hundreds of millions of dollars, much of it borne by US taxpayers, while company executives got rich.

 Just coupling for now the story of how we spent hundreds of millions on Acthar to enrich company executives with the story that we have no money to develop vaccines or treatments for Ebola virus... demonstrates the massive failure of our experiment to turn our health care system over to market triumphalists and laissez faire mercantilists.  As long as we let the health care system be run by people who put their own enrichment ahead of patients' and the public's health, things will only get crazier.

Dr. Poses also added that many of the docs who are busy prescribing this questionably-useful drug to their Medicare patients are being paid by Questcor. He noted that if a proposed sale of Questcor to Mallinckrodt goes through, 6 top execs at Questcor stand to make an additional $63M. So they have every reason to portray Acthar in a solid light, and particularly to hide any ill effects caused by the drug.

Meanwhile, there's Ebola, for those silly enough to be worried about such things.

More on Guinea Pigging--The Quality of Pharmaceutical Research

Two longish articles by our old friend Dr. Carl Elliott and by Peter Aldhous:
https://medium.com/matter/did-big-pharma-test-your-meds-on-homeless-people-a6d8d3fc7dfe
https://medium.com/matter/why-are-dope-addicted-disgraced-doctors-running-our-drug-trials-aff6d20843bf
--raise interesting questions about clinical research on pharmaceuticals.

Dr. Elliott addresses the selection of subjects for research on new drugs, and shows that in many instances, they are taken from places that raise suspicions about the quality of the research--such as homeless  shelters, and other places that have a high incidence of mentally ill. Aldhous looks at the credentials of the physicians who do this research and shows that some cases, the physicians have been disciplined for serious violations.

Perhaps the best short summary of these two pieces appears toward the end of the Aldhous piece:

"Some experts agree that the FDA's entire rulebook for clinical trials, with its talk of things like 'institutional' review boards, reflects the academic past of clinical research--not today's industrial juggernaut of for-profit clinical trials firms and for-hire review boards, which oversee a workforce of doctors drawn from regular medical practice. 'They are regulations for a world that doesn't exist anymore,' says Elizabeth Woeckner, president of Citizens for Responsible Care and Research, which campaigns for the safety of medical research volunteers."

Therefore, when one reads that scientists have tested new drugs on patients and have yielded the following information, one has to wonder, first, whether those "patients" actually have the diseases the scientists are studying and have honestly reported their status (as opposed to making up what seems most fitting for payment for inclusion in the study, and getting away alive afterwards); and second, whether those "scientists" are properly trained physicians and can observe the variables required. There seems little concern, presently, to reassure the public that either is the case.

Rating New Hepattits Drugs: What Standard?

There seem to be two problems with the newest drugs for hepatitis C,  simeprevir (Olysio) and sofosbuvir (Sovaldi). The problem most discussed these days is "miracle drugs cost too much." For example, guru David Blumenthal, MD, holds forth on the Commonwealth Fund website--
http://www.commonwealthfund.org/publications/blog/2014/jul/drugs-and-dollars?omnicid=EALERT526507&mid=brody@msu.edu
--that Sovaldi is "dramatically effective and extraordinarily expensive." Robert Steinbrook and Rita F. Redberg, in an editorial in JAMA Internal Medicine, declare the new drugs "a scientific triumph". They then go on to note the problem--that Sovaldi can cost $1000 per tablet for 12 weeks' treatment, putting the cost at $84,000 ($168,000 for 24 weeks).

Our old friend Dr. Roy Poses at Health Care Renewal seems to be one of the few who's discussing a radically different problem--"maybe the drugs that cost so much are not miracle drugs at all." In his latest post: http://hcrenewal.blogspot.com/2014/07/sovaldi-quantum-leap-backwards-to-days.html--
he highlights the most recent article in JAMA, which is fawned over in an accompanying editorial despite the fact that it's non-randomized and non-controlled. Dr. Poses points out that the FDA decided to approve Sovaldi as a "breakthrough drug" which seems to have undercut the requirements that it be documented by something akin to science.

The article that accompanied the editorial in JAMA Internal Medicine addressed an evidence report by the Institute for Clinical and Economic Review, Boston, prepared for a meeting of the California Technology Assessment Forum. They concluded a need for caution regarding the two newest drugs:
"First, the evidence base on the comparative clinical effectiveness of these 2 new drugs remained thin in most areas and notably incomplete in others. For example, in some subgroups, such as patients who have failed earlier treatments, there were little or no data available. There were no long term data demonstrating the durability of short-term sustained virologic response rates for either drug; nor had either drug been compared head-to-head in a randomized clinical trial with each other or with a first-generation direct-acting antiviral drug. Finally, the evidence necessary for sofosbuvir to gain marketing approval through the FDA’s breakthrough designation was particularly sparse and did not include requirements for controlled trials." They noted that as a result of this presentation, the California forum voted the use of these drugs a "low value" for the health system.

Steinbrook and Redberg noted that Sovaldi had grossed $2.3B in the first quarter of 2014. So "low value" by one standard seems to be pretty high value by another. If the past is any indication, it will be some years before we find out which standard is the correct one; and meanwhile, the profiteers at the makers of the two drugs can expect a killing.

Steinbrook R, Redberg RF. The high price of the new hepatitis C virus drugs. JAMA Internal Medicine 174:1172, 2014.

Ollendorf DA, Tice JA, Pearson SD. The comparative clinical effectiveness and value of simeprevir and sofosbuvir for chronic hepatitis C infection. JAMA Internal Medicine 174:1170-71, 2014.





   

USA: Worse than Two Countries in Health Costs

Every so often, it’s worth taking a look at how badly we’ve allowed ourselves to distort reality. We generally think that health care costs in the U.S. are about what they are in the rest of the world, or maybe just a bit worse. We seldom allow ourselves to see the true state of affairs. Accordingly, when a wake-up call comes along like the recent announcement from the Commonwealth Fund:
http://www.commonwealthfund.org/publications/fund-reports/2014/jun/mirror-mirror?omnicid=EALERT495214&mid=mh@cmwf.org
--we either don’t know what to do with it at all, or quickly look for someplace to hide.

A while ago, I was glancing at a talk given by Michael Fine, head of public health in Rhode Island. He made the interesting point that health care in the U.S., calculated on a per capita basis, costs more than it does in the United Kingdom and Japan. Let me be very clear about this: The average annual cost of health care, per person, in the UK, plus the average annual cost of health care, per person, in Japan, is less than the cost of health care, per person, in the U.S.

Maybe a few Americans have an idea that health care costs more in the U.S. than elsewhere, and that we actually get less for what we spend here than elsewhere. But I rather doubt that most Americans realize just how bad it is—that people in two other advanced nations of the world pay as much as we do per person (actually, not quite so much) for health care.

I was reminded of these figures thanks to the Commonwealth Fund’s handy reminder. They don’t include Japan in their list of 11 countries, but they give several other examples. You can assemble the figures for “almost as much as the U.S. spends on health per person per year” in several different ways:

The U.K. or Sweden or New Zealand or Australia

Plus

Canada or France or Germany

Either approach would come in less than the U.S., which tops all of the countries at $8508 per person per year. The next highest country is Norway, far back at $5669. (The first batch of countries I picked all spend between $3000 and 4000 per person per year; the second set spend between $4000 and $5000.)

The remainder of the report is not terribly auspicious for the U.S. America often spends the most money and gets the worst results. A few areas show some modest improvement since the last time the people looked, but generally things are down in the cellar and mostly staying there.

For many decades we have been used to hearing that the U.S. has “the best health care system in the world.” This has pretty much gone by the boards, though we’ll still find some dumb politico repeating it occasionally. But how far we have sunk from that status is not seen clearly by the vast majority of citizens.

Pharmaceutical costs play a relatively small role in the excessive costs of U.S. health care, making up only about 10 percent of American total health care costs. But the average American has no idea whatsoever of how incredibly pricey American health care is, compared to any other country.

The Top Five Ways that Pharma Affects You

Salon.com recently published a piece:
http://www.salon.com/2014/01/25/5_evil_ways_the_multi_billion_dollar_drug_industry_is_in_bed_with_your_doctor_partner/
--that cuts to the chase in the ways that the media can either bring us up to date or else pull the wool farther over our eyes.

The main thrust of the piece is a review of the five most common ways that the pharmaceutical industry manipulates physicians and keeps things favorable to their own goals--which means, replacing what's true with what's valuable. The five ways are no surprise to anyone, but as we increasingly get into the thick of the swamp, it's valuable to be reminded of the big picture every so often:

• Spying on prescribing
• Easy CME access for shilling docs
• Ghostwriting
• Speakers' bureaus
• Clinical trials (how the enterprise is conducted so that who pays the piper calls the tune, when at least 70 percent of the piper is paid by Pharma)

It's valuable at times to recollect certain aspects of the big picture. Take ghostwriting. The main features of the extent of medical ghostwriting, how as many as half the stories in med journals on some sensitive topics might be ghostwritten, have been out for at least 10 years. What has happened? About zilch. Everyone agrees that ghostwriting is an especially egregious offense, and so far as I can tell, it goes on just about as before. Ditto for most of the other sins.

In another smart move:
http://blogs.bmj.com/bmj/2014/05/30/jane-feinmann-is-the-current-system-of-publishing-clinical-trials-fit-for-purpose/
--the BMJ ran a study of the current state of the publication of clinical trials. Not surprisingly, there was disagreement over most issues. But at least there was finally a sense that something was starting and that the end results might be useful.

We're getting out toward a decade from the publication of the first wave of studies that started to shed light on the real implications of Pharma's rigid control over the system. What's changed? To a large extent, nothing.

Are KOLs drying up? Praise be

Back in 2011 I heard from Cutting Edge Information on the subject of key opinion leaders (KOLs):

http://brodyhooked.blogspot.com/2011/06/keeping-kols-fat-and-sassy-these.html

I figured that once I outed them on this blog, they would know better than to send me any more e-mails, but apparently they are still at it; the cold-call e-mail that’s reprinted below arrived this week. The content would seem to suggest that Pharma firms are having greater difficulties finding “Key opinion leader” physicians (aka shills) due to the increased transparency requirements of the pending Sunshine Act. If this is the case, then of course it is what I have been advocating for years. I read both the e-mail and the attached detailed brochure but could not find a figure as to the actual cost of this 179-page report, so you’ll have to contact Cutting Edge Information directly if you want to buy a copy. (I have a feeling there might be some sticker shock…)

Unsolicited E-mail message:

Howard,

Key opinion leading physicians face pressure from increasing transparency via the Sunshine Act and organizational restrictions on pharma-physician relationships. Has your organization made the strategic, resource and operational shifts necessary to compete for KOL services in this new environment?

Cutting Edge Information worked closely with senior-level medical and KOL management executives at more than 30 leading pharmaceutical and biotech companies to distill the latest strategies, benchmark data, executive insights and best practices that are enabling the top-performing KOL management organizations to continue to achieve results for their companies in our new report, “Pharmaceutical Key Opinion Leader Management: Effective Strategies for Segmenting Thought Leaders.” Use this report to:

• Benchmark extensive, deep thought leader segmentation data and analysis
• Prepare your KOL management team(s) to combat shrinking KOL pools
• Leverage third-party vendors’ expertise to develop and refresh robust thought leader directories
• Reach beyond traditional specialist KOLs to fill out thought leader listings
• Compare your company’s organizational structure, staffing and budget support to those of your peers and competitors

I have attached a summary document with more details about this new report for your review. I would appreciate the opportunity to answer your questions about how this report will be of value to you and your organization. Please call me directly at +1-919-433-0211 or reply by email. I look forward to hearing from you soon.


REPORT SUMMARY:
Pharmaceutical Key Opinion Leader Management: Effective Strategies for Segmenting Thought Leaders
Pages: 178
Data Charts/Tables: 95+
Metrics: 500-plus
Companies Consulted: more than 30, including Boehringer Ingelheim, CSL Behring, Ferring, Novo Nordisk and Sanofi


ADDITIONAL MEDICAL AFFAIRS REPORTS:

For more information on any of our other medical affairs reports below, please reply by email and I will be happy to send a brochure:

1. Pharmaceutical Advisory Boards: Uncovering Clinical, Market and Payer Insights to Enrich Product Opportunities
2. Promotional Speaker Programs: Successfully Managing Speaker Bureaus and Recruiting Thought Leaders
3. Educational Speaker Programs: Medical Event Management and Recruitment in a Complex Regulatory Environment
4. MSL Activities and Performance Measurement: Harnessing KOL Relationships for Optimal Clinical Support
5. Managing MSL Teams: Budget, Staffing and Compensation Benchmarks
6. Medical Information Teams and Call Center Management


Kind Regards,

Jon Hess
Account Executive, Cutting Edge Information
1000 Park Forty Plaza, Durham, NC 27713
O: (919) 433-0211 | F: (919) 433-0220
Jon_hess@cuttingedgeinfo.com | www.cuttingedgeinfo.com

The Ongoing Statin Debate, or Is It?

Those of you who are heartily sick of my talking about statins, please skip this post.

By way of joining in on the controversial new statin guidelines:
http://brodyhooked.blogspot.com/2013/11/new-cholesterol-guidelinesthe-devil-in.html
--the New England Journal offered in their April 24 issue a debate over the guideline recommendations. Three authors were assigned to take positions on a hypothetical 52-year-old male smoker with a normal cholesterol and LDL level (subscription required):

• Do not treat with statins: Dr. Benjamin J. Ansell
• Treat with statins and monitor LDL levels: Dr. Samia Mora
• Treat with statins but do not monitor LDL: Dr. Harlan M. Krumholz

OK, so this sounds at first like one person taking the position I have argued for in this blog, and two others taking positions more favorable to the drug manufacturers. But things may not be quite as they seem.

Dr. Ansell does indeed argue against statins, using arguments we've reviewed previously, and noting the much bigger bang for the buck with lifestyle interventions, notably smoking cessation. But Drs. Mora and Krumholz don't dispute the importance of lifestyle--indeed you could say that we have here three arguments, all in favor of pushing lifestyle modification as the first step.

Dr. Mora makes out his favorable case for statin treatment and monitoring LDL by selecting some studies that seem to him to support this approach, but his concern seems to be that by closely watching LDL levels, the physician might find a low dose of statin that reduces risk sufficiently while avoiding the potential adverse effects of statins. So at least one of the "statin advocates" in this debate admits that statins can be harmful and should be used in lowest possible doses.

Dr. Krumholz is not really advocating for statins at all, it seems, but rather for patient choice and shared decision-making. And what information would he give the patient for this purpose? He'd stress that 50-60 people like this patient would have to be treated with statins for 10 years for a single one of them to avoid having a heart attack. He says that if he told the patient this, and the patient still wanted to take statins, he'd prescribe them--certainly a reasonable choice in my view.

In short, even the debaters that supposedly take the pro-statin positions in this "debate" actually have more negative things to say about statin therapy than the title would suggest.

D'Agostino RB, Ansell BJ, Mora S, Krumholz HM. The guidelines battle on starting statins (clinical decisions). New England Journal of Medicine 370:1652-1658, April 24, 2014.

Yet More Corruption in Pharma

Once again I'll move over and give the floor to Dr. Roy Poses at Health Care Renewal:
http://hcrenewal.blogspot.com/2014/04/the-pervasiveness-of-health-care.html

In the past, also following Dr. Poses' lead, I have blogged about corruption in the pharmaceutical industry:
http://brodyhooked.blogspot.com/2013/07/the-corrupt-us-health-system-and.html

This new post reviews five recent cases in which  drug companies have paid out large settlements in Federal court actions. While one or two of the cases mainly deal with financial wrongdoing (such as price-fixing), most have implications for the safety and quality of drugs supplied to patients. In none of these cases were any individuals working for the companies assigned any blame--Dr. Poses suggests that, since the whole purpose of most of the skullduggery was to make more money for the company, it is likely that instead a number of primary actors earned big bonuses. He then reminds us of the basic definition of 'corruption'--using one's power and position for personal gain. By this definition the behavior of these corporate executives was clearly corrupt.

And yet, for some reason, we think it impolite and indelicate to use such terminology in describing the behavior of U.S. corporations and their leaders. Dr. Poses suggests, and I agree, that it's time for this false delicacy to end.

What Dead Salmon Are Thinking--and How That Relates to Drug-Industry-Sponsored Research

The Hastings Center Report, a prominent bioethics publication, published a special supplement (March/April 2014) on "Interpreting Neuroimaging," which contained an especially useful article by Dr. Martha J. Farah of the University of Pennsylvania Center for Neuroscience and Society. (If you want to know what this has to do with the topic of this blog, hang in with me for a little bit.)

What Dr. Farah is basically up to here is finding a middle course between extreme advocates of the new wave of neuroimaging studies in psychology, who claim incredible insights into human brain function and thinking, and extreme critics, who attack these findings as nothing but misguided statistical manipulations and artifacts.

I'm especially grateful to Dr. Farah's article because it referred me to a fascinating paper by a group of psychologists led by Craig M. Bennett of UC-Santa Barbara:
http://faculty.vassar.edu/abbaird/about/publications/pdfs/bennett_salmon.pdf

Dr. Bennett and colleagues are concerned about one particular error that they believe is all too common in the neuroimaging field (with around a quarter of papers in widely cited journals exhibiting the error at the date the article was written). A typical functional magnetic resonance (fMRI) scan of the human brain gathers data on 130,000 units of activity and makes many tens of thousands of comparisons. When we set the standard for statistical significance at the traditional p < 0.05, we accept that there's a 1-in-20 chance that any comparison that produces a positive result could do so by chance rather than because of a true causal link. When there are tens of thousands of comparisons, then a 1-in-20 chance produces an incredibly large number of findings that are actually due to random noise.

Bennett and colleagues recommend two particular statistical tests to avoid this problem, that are especially designed to address the way these large data sets behave. By contrast, the way some investigators typically try to resolve the problem is to set the bar higher for statistical significance, such as p < 0.001. There are so many comparisons in a typical fMRI study that this method, say Bennett et al., that this ploy does not work reliably.

They chose to demonstrate what they are talking about by setting up a parody of a real psychological study, in which a human subject is put in an MRI machine, shown photos of people in social interactions, and then asked to imagine what emotions those people must be experiencing. In their experiment, the subject was a dead salmon (about 18 inches long). They put the salmon in the MRI machine, told it what to do when looking at the photos, and then scanned its brain.

When they processed the scans in the usual way, they found two areas of heightened activity, in the dead salmon's middle brain and upper spinal cord. When they set the higher threshold for statistical significance, they still found these two areas of supposed activity. When they used instead the corrections that they recommended, there was no significant brain activity recorded. Bennett et al. concluded that unless you use the right statistical approaches, it was easy to get spurious results from brain scans.

As I read this study, I was reminded of one of the themes we've previously discussed many times in this blog--how industry-sponsored studies can be doctored to make new drugs look better than they are. One way we've seen this done is--you guessed it--multiple comparisons. If you look at enough different variables in the drug vs. placebo group, by chance, one is likely to be favorable to the drug. If you can spin the study to pretend that that particular measure was the one you were really interested in all along (instead of something you just happened to trip over when you analyzed the data at the end of the study), you can make a study sound impressively positive.

Bennett and colleagues mentioned in passing another statistical flaw that is not addressed by their favored methods, a form of circular reasoning. Because there are so danged many regions of the brain all firing off at various times, most of which have nothing whatever to do with the process psychologists want to investigate, it is tempting to use some statistical tools up front to narrow the field of vision to look only at the brain regions thought most likely to be informative. If one is not careful, one may then use the same statistical tools to decide that the information gleaned from those regions is of significance. (This is a variant of the classic joke about the drunk looking for his lost quarter under the lamppost because the light's better there.)

That trick, too, we have frequently seen in industry-sponsored pharma research. The major tools used are run-in and wash-out periods before the start of the formal data gathering. The pre-trial manipulations are designed to eliminate those subjects who respond too well to the placebo, or those who don't respond well to the drug, or other things the researcher does not want to see. This helps assure that when the "study" begins, the scale has already been tipped in the direction of the drug looking better than it really is.

Dr. Farah admits that neuroimaging data can be spun in incorrect ways due to insufficient attention to these statistical booby traps, but she immediately adds that this does not make neuroimaging research unique (or uniquely unreliable when done well). She gives examples from other fields of research where the same statistical flaws can be found.

She did not mention pharmaceutical clinical trials.  But she could have.

Bennett CM, Baird AA, Miller MB, Wolford GL. Neural correlates of interspecies perspective taking in the post-mortem Atlantic salmon: an argument for proper multiple comparisons correction. Journal of Serendipitous and Unexpected Results 1: 1-5, 2010. (Note: for people suspicious that the dead salmon paper is nothing by a hoax, there does indeed appear to be a journal of this title; and one would think that someone as familiar with the neuroscience field as Dr. Farah would know if the paper was phony. For more on the "study" see: http://blogs.scientificamerican.com/scicurious-brain/2012/09/25/ignobel-prize-in-neuroscience-the-dead-salmon-study/)

UCLA Whistle-blower Suit: Does Industry Money Corrupt Academic Medicine?

According to the story in the L.A. Times:
http://www.latimes.com/business/la-fi-ucla-doctor-conflicts-20140423,0,3924175.story#axzz2zwLITYhU
--there are two versions of what happened; so to be as fair as possible I'll first give UCLA's version.

Dr. Robert Pedowitz became chair of the orthopedic surgery department at the medical school in 2009. After voicing his concerns to higher officials about how many of his colleagues were taking industry money, in a manner he described as negatively affecting patient care, he stepped down in 2010. In 2012 he sued UCLA and some of his colleagues, charging retaliation for his speaking out, in the form of interfering with his getting research grants and patient referrals.

UCLA investigated the charges Dr. Pedowitz had brought and found a few irregularities, but mostly that no laws or university rules had been violated, and patients had not been compromised. Despite this clean bill of health, the UC regents have now decided to settle with the doctor to the tune of $10M, not because they're admitting any wrongdoing, but to "avoid the 'substantial expense and inconvenience' of further litigation."

Now for the other side of the story. Dr. Pedowitz (noting that the problems he faced are rife among academic medical cents and hardly are unique to UCLA) found when he came on board that one surgeon in his department was being paid $250,000 by the device maker Medtronic for consulting work. That same physician was trying to enroll patients in a research project involving Medtronic products. Sen. Charles Grassley (R-IA) had previously spotlighted a UCLA spine surgeon who had accepted $460,000 from Medtronic and other companies but had somehow failed to disclose these payments. UCLA, Pedowitz and his attorney charge, was too interested in the money to be made by these surgeons and by their potential commercial discoveries to rein in these practices.

I won't say who's right in this dispute, except to note that last time I checked, you could buy an awful lot of legal expense and inconvenience for $10M; so you can draw your own conclusions of which side the UC regents thought was going to win had the case gone all the way through the court.

“Breakthrough Cures”? Reasons for Skepticism

Earlier this week I posted about the current issue of the New England Journal, and mentioned in passing the appearance of antiviral drugs for hepatitis C that are being touted as new miracle cures. My focus in that post—
http://brodyhooked.blogspot.com/2014/04/summarizing-market-failure-special.html
--was how our so-called free market fails to protect the public interest, so I looked only at the outrageous cost of the hepatitis C drugs and gave a free pass, more or less, to the “cure” claims.

In doing so I overlooked an older and a more recent blog post by our good pal Dr. Roy Poses at Health Care Renewal:

http://hcrenewal.blogspot.com/2014/04/knee-deep-in-hoopla-triumph-of-medical.html
http://hcrenewal.blogspot.com/2014/03/too-good-to-be-true-sovaldi-kerfuffle.html

Dr. Poses takes care to show the extraordinarily flimsy evidence on which these new drugs are being ballyhooed. He says a number of things about study design and so on, all of which seem pertinent. But if we try to get a sense of the big picture, all I think we need to know is the natural history of hepatitis C. As Dr. Poses reviews for us, hepatitis C can be a very bad disease leading to liver failure and death. But the total number of folks with the virus who end up with this extreme version of the disease is not that large. A goodly number of people who carry the hepatitis C virus never develop any obvious disease at all. Another good chuck of them develop some liver inflammation, but it never develops into the extreme life-threatening forms.

So before one can get all that excited about a new treatment for hepatitis C, insofar as actual patient-centered outcomes are concerned, we’d need a large-scale follow-up study that showed that people getting the new drugs actually had improved health over the long haul. That would in turn depend on showing that the apparently decent (but hardly perfect) side effect profile of the new drugs is maintained long-term, else the chance of having a bad side effect might be as great as the chance one would have had the bad kind of rapidly-advancing hepatitis C infection with liver damage.

According to Dr. Poses who’s checked out the literature much more carefully than I have, what we know so far is that the new drugs do a pretty good job of clearing the hepatitis C virus from the bloodstreams of patients when followed for a period of up to 24 weeks.

It may well be that a drug that does this good a job of clearing the virus in the short term does an equally good job of saving the patient from long-term, serious consequences of having the virus. Or that may not be the case—we’ve seen many, many instances of initially promising treatments that ultimately fail to pass that test. (This may also be a good time here to remind ourselves of Dr. John Ioannidis’s warning:

http://brodyhooked.blogspot.com/2011/03/how-honest-reports-of-research-can.html
--about how it’s a mathematical near-certainty that the first reports about any new drug will give an unduly rosy picture of its effectiveness.)

Now, let’s be fair to the advocates for the new drug. It will take years, to say nothing of tons of money, to do the studies needed to show the real effectiveness of these new hepatitis C drugs. So in the meantime, the data we have so far is probably what’s to be expected at this stage. And so far, the drug is performing more or less as one would expect if indeed it is going to turn out to be a breakthrough drug.

OK, I’ll buy all that. So how about some recognition of the actual limitations of what we know, when this drug is being talked about? Why should supposedly scientifically-aware advocates for the drug feel a need to talk like used car salesmen? (Unless, in fact, their ultimate goal is to sell us a clunker?)

So mea culpa for my earlier post, if I inadvertently added to the hype around these new drugs, instead of joining Dr. Poses in raising the appropriate skeptical concerns. One can hope that the drugs turn out to be what they are hoped to be; and one can also hope that somehow, if that’s the case, people who need them will be able to afford them.

The History of US Drug Policy Since the Cold War

One theme in HOOKED is the need to see today’s relationship between the medical profession and the pharmaceutical industry in proper historical context. When HOOKED was written, I had to struggle, as a non-historian, to try to put together an adequate historical background picture. Since then, useful books have appeared that make that task easier.

Prof. Dominique Tobbell of the University of Minnesota has contributed Pills, Power, and Policy: The Struggle for Drug Reform in Cold War America and Its Consequences. She makes two basic points about our struggle today to reform drug policy, in a direction that brings pharmaceutical manufacture, research, and marketing better into line with public health and public interest. The first point is that this struggle is not new; basically the same issues have recurred ever since the end of World War II. The second point is that the pharmaceutical industry has never waged this battle against what it considers burdensome government regulation on its own; it has always had allies among medical organizations and academic physicians who had a strong interest in defending the status quo.

Prof. Tobbell points out that by the mid-1960s, the drug industry had achieved an impressive enough record in fighting off government regulation that the tobacco industry turned to Pharma for advice and help. During all those years, medical practitioners were primed by the AMA to fear the bogeyman of socialized medicine, and academic physicians worried about excessive federal influence over research policies. It was easy to get these fellow travelers on board when Pharma wrapped itself in the mantle of “free enterprise” and presented a less-regulated industry to Congress and to the American public as a bulwark against communism.

In the heady postwar days, when everyone was thrilled with the tremendous advances in antibiotic, hormonal, and psychiatric therapy, the climate of ethical thought was quite different from what reigns today. For example, Prof. Tobbell describes the efforts at the University of Pennsylvania to create a training program in clinical pharmacology in 1955: “Norman Topping, the university’s vice-president in charge of medical affairs, sought to create an institutional structure that would ensure the program could be responsive to the industry’s needs. Indeed, Topping believed the new program should function, essentially, as a service unit for the drug industry.”While today such a stance would at least raise some eyebrows, apparently no one gave it a second glance in the 1950s.

Similarly, when the National Academy of Sciences formed the Drug Research Board in 1963, to help conduct the massive amount of research required to implement the new FDA amendments Congress had just passed to require that drugs be shown to be effective as well as safe, some in Congress looked askance at the inclusion of scientists with strong industry ties. The Board basically pooh-poohed any such concerns, insisting that it was a great advantage to have these scientists as part of the effort because of their inside knowledge and policy smarts. Conflict of interest—who, us?

One theme that I have addressed at some length in earlier posts—most recently:

http://brodyhooked.blogspot.com/2014/03/a-bit-of-history-louis-lasagna-and.html
--is the impact of the ideology that I prefer to call economism and others call neoliberalism on today’s Pharma policy. Prof. Tobbell was kind enough to respond to an e-mail query, since I noted that the word “neoliberalism” is virtually absent from her volume. Consistent with her thesis, she states that the anti-government-regulation, pro-free-market stance that the drug industry has adopted was present all through the 1950s and 1960s. When neoliberalism/economism entered the US political discourse in a big way in the middle to late 1970s, Pharma was happy to hitch its wagon to that rising star, just as it was happy to jump on the anticommunist bandwagon in earlier decades; but one cannot say that neoliberalism played a major formative role in Pharma’s policy or strategic thinking.

Dominique A. Tobbell, Pills, Power, and Policy: The Struggle for Drug Reform in Cold War America and Its Consequences. Berkeley, CA: University of California Press/Milbank Books on Health and the Public, 2012.

Yet More on Statins and the Recent Guidelines

Not to make this blog the “Statins Blog” or anything, but since I have been on a tear regarding the unfortunate ACC/AHA guidelines on cholesterol:
http://brodyhooked.blogspot.com/2013/12/more-on-cholesterol-guidelines-cochrane.html
--and since my pals at Primary Care Medical Abstracts keep feeding me more ammunition, I wanted briefly to mention two more commentaries that take aim at the guidelines (subscriptions probably required to access).

First, John Abramson, who’s been mentioned here numerous times, and his colleagues wrote in BMJ about the CTT meta-analysis, on which the new guidelines heavily relied. They challenged the rosy picture painted by the CTT by drilling down and recalculating the CTT’s own numbers. The CTT, recall, claimed that if one carefully summed the data from numerous previous clinical trials (none of which showed any reduction in all-cause mortality from taking statins for primary prevention), you could see that statins in low-risk patients save lives and prevent strokes and heart attacks.

So when Abramson’s team went back and crunched the numbers themselves they found, for the populations included in these studies:

• No significant difference in all-cause mortality
• You’d have to treat 140 low risk patients for 5 years to prevent one heart attack or stroke
• The studies overall either fail to report any adverse reactions to statins, or else report adverse reactions at a much lower rate than has been shown in independent (non-manufacturer-sponsored) studies. If the rates of adverse reactions in the independent studies are valid, it is very likely that the chance of suffering an adverse reaction from a statin is notably greater than the chance of preventing a bad outcome.

Skip now to another old acquaintance, John Ioannidis, commenting more recently in JAMA. Ioannidis addresses the new guidelines head-on and is more interested in two issues. One is the total global impact—he calculates as his title suggests that if applied across the world, the “statinization” of humankind would result in at least 1 billion folks being told they needed statins, which would be a huge impact on the health systems of those nations and would conceivably shift resources away from much more desperately needed stuff. The main issue Ioannidis focuses on is the risk calculator employed by the guideline—a calculator that’s new, and that was shown right from the get-go to have significant weaknesses, that have been since confirmed. He gives us the math to show why it’s not very reliable.

Ioannidis takes a step back then and asks the question—we’ve been in the business of trying to calculate risk of coronary artery disease for more than 30 years; so how come we still can’t get it right? He also notes that the decision on the part of the guideline writers that a 10 year risk of developing cardiovascular disease of 7.5% ought to be the cutoff for recommending statins is a completely arbitrary number, unsupported by any empirical evidence—the “right” number could be 2% or 20% for all we know.

What these commentaries have in common is that both point out how messed up the basic data are due to all the major studies being supported by the drug industry, and how serious conflicts of interest contaminate this entire enterprise.

Abramson JD, Rosenberg HG, Jewell N, Wright JM. “Should People at Low Risk for Cardiovascular Disease Take a Statin?” BMJ 347:f6123, 2013.

Ioannidis JPA. “More Than a Billion People Taking Statins? Potential Implications of the New Cardiovascular Guidelines.” JAMA 311:463-464, Feb. 5, 2014.

Summarizing the “Market Failure” Special Issue of the New England Journal

Three articles in this week’s New England Journal of Medicine all combine to illustrate “market failure” in the pharmaceutical industry. As you can guess, the editors of NEJM didn’t adopt my suggested title for their issue. (See the end if you want more explanation as to why I’m calling it that.)

First is the editorial by Drs. Hoofnagle and Sherker—

http://www.nejm.org/doi/full/10.1056/NEJMe1401508--
--that talks about what would ordinarily be considered unalloyed good news elsewhere in the issue. Hepatitis C, which up till now has been quite resistant to treatment, appears to be well controlled by a new family of antiviral medications, with a minimum of side effects. This indeed appears to be one of those all-too-rare-today “breakthroughs” in drug treatment.

So what’s not to like? As the editorialists explain, the price tag. A complete course of one of the drugs comes in at $84,000, which works out to $1000 per tablet. The authors note a collision course between newly expanded public health efforts to do a better job of detecting the additional 1.6 million Americans who have Hep C and don’t know it, so that they can get this wonderful new treatment, which then many of them will not be able to afford—or if we could provide it for them, would break the bank of what the authors delicately call an “already overburdened medical care system.” The authors work for the NIH and as dutiful government employees are apparently discouraged from saying anything bad about the pharmaceutical industry, so they offer no ideas on what might be done about this problem.

Now jump to two “Perspectives” pieces in the same issue. One is from our good friends at the Harvard-Brigham and Women’s program in Pharmacoepidemiology and Pharmacoeconomics, including Dr. Jerry Avorn:

http://www.nejm.org/doi/full/10.1056/NEJMp1400488

The P&P gang describes what has happened under a program begun by the FDA in 2007, the Risk Evaluation and Mitigation Strategy. The idea when this passed Congress was to speed the entry onto the market of useful new medications that also posed safety issues. If the company could come up with a special plan to limit the use of the drug in such a way as to lower the risk of adverse reactions, then the drug could go on the market. But the proviso added on was that this plan ought not be used as a way to stop generic products from entering the market later.

Unfortunately the amendments that passed Congress also included a monkey wrench that was virtually guaranteed to undermine this intent (assuming that Congress intended what they said, and that Pharma lobbyists did not rewrite the law in the back room). The company that developed this special safety plan for the new drug could also patent the plan.

So Dr. Avorn and colleagues list several cases where the drug company has sued generic competitors claiming patent infringement if the generic guys use the same safety plan, and also filing suit to stop any generic that uses a different safety plan as raising the risk level for the public unacceptably. The only sensible way to fix this problem, say the Harvard guys, is to use the same safety plan for all versions of the drug regardless of manufacturer, but to make this happen Congress would probably have to amend the 2007 act. Bottom line—a policy that was intended to allow patients access to drugs while assuring safety, that was not supposed to interfere with generics entering the market, is being used by Pharma precisely as an “evergreening” tool to prevent generic competition.

Now we come to another Perspectives article authored by Drs. Sham Mailankody and Vinay Prasad:

http://www.nejm.org/doi/full/10.1056/NEJMp1400104

They also address the cost of new drugs, in this instance for cancer. Their basic point is—there are newly developed drugs for cancer treatment that provide small but apparently real benefits, such as an average extension of life by a few months. These drugs work by mechanisms very similar to old, generic drugs. (They give the example of the new drug abiraterone, which works in much the same way as an old anti-fungal antibiotic, ketoconazole.) So the ideal scientific question now to be asked is how well these same cancer patients would do if instead of getting the very expensive new drug, they got the very cheap old drug, ketoconazole. They might do just as well, or it might be that the new drug has some advantage—until we did the study we wouldn’t know.

The kicker that Mailankody and Prasad now note is—how would this new study be paid for? No way that the drug company that’s making a mint off abiraterone is going to bankroll a study that might pull the rug out from under its golden goose. So suppose some neutral investigators try to organize the study? Well, assuming that for the very same reasons, the manufacturer won’t just give away abiraterone for free (especially knowing for what purpose it’s going to be used), the investigators would have to pay market price and buy the drug. And the authors calculate that for a study large enough to answer the question of non-inferiority of ketoconazole, the cost of the drug alone—forget the rest of the cost of the study—would be about $69 million. In other words, no study of this sort will ever be done.

These authors also work for the NIH, and so are also apparently leery of saying anything controversial, and so don’t offer any proposals for a solution to this problem.

 
OK, so we have three articles in the same issue of NEJM, all of which have the same basic theme—in the name of profits, the drug industry is working contrary to the public health and the advancement of science. This is what old-time economist Kenneth Arrow famously called the market failure of health care—it simply does not follow the laws of supply and demand. Those who continue to extol the supposedly “free” market as the right way to manage all of our affairs, pharmaceuticals and health included, have to stick their heads in the sand and pretend that market failure never happens. As this blog has shown extensively, it happens all the time.

More on Flu Drugs and the Broken Drug Research System

We’ve discussed the debate over oseltamivir (Tamiflu) and the problems in determining whether it offers advantages to flu patients, given how hard reviewers had to search to get all the data:

http://brodyhooked.blogspot.com/2009/12/bmj-medical-research-is-broken.html
http://brodyhooked.blogspot.com/2012/09/more-on-tamiflu-challenges-of-getting.html

The story led the editor of BMJ back in 2009 to proclaim about the scientific evaluation of drugs, “The current system isn’t working. Worse than that, it gives a false sense of security.”

The latest BMJ readdresses the oseltamivir story, and if the system was broken in 2009, it has not gotten fixed since. The summaries of what they have to say can be found in two editorials:

http://www.bmj.com/content/348/bmj.g2630
http://www.bmj.com/content/348/bmj.g2548?ijkey=ded5662cf46f75236fb45a9cda0bb2a671ec0e98&keytype2=tf_ipsecsha&linkType=FULL&journalCode=bmj&resid=348/apr09_2/g2548&atom=/bmj/348/bmj.g2630.atom

In the previous blog posts, I reviewed how difficult it was for the authors of a Cochrane review of neuroaminidase inhibitors for influenza (the class of drugs to which oseltamivir belongs) to get their hands on all the relevant data from unpublished studies conducted by the manufacturer. Once they did get a reasonable amount of data, they found the data so voluminous that it took several person-years of labor to sort through it all. But they persevered, and what we now know is that drugs like oseltamivir may shorten your bout of flu, if you start taking the drug within the first two days of symptoms, by half a day. It may cause a number of worrisome side effects. And we have no reason to believe that the drug will prevent the bad complications of influenza requiring hospitalization and admission to an ICU (which is the anticipated benefit that led the WHO to champion the drug and many nations to spend billions of dollars stockpiling the drug as a public health precaution).

We also know that the published studies on these drugs, virtually all of which were conducted by the manufacturers, overstated the benefits and understated the adverse reactions. In short, if you went to legitimate, prestigious medical journals for information, as all us docs were taught to do in med school, you’d be mostly clueless.

The editors of BMJ gamely propose a list of reforms. But I believe that two conclusions are inescapable. First, if it took this much time and effort to get the goods on oseltamivir—and we still don’t know what the drug is really good for, if anything, since the really important studies of its potential value have not yet been conducted—then what about the hundreds of other drugs that have been introduced with great fanfare in the last few decades, and none of which have been subjected to anything like this degree of inquiry and investigation? Second, on what basis can we claim any longer that we should have any faith at all in drug research sponsored by manufacturers?

AMC Leaders on Corporate Boards—A Modest Proposal

Dr. Roy Poses over at Health Care Renewal has for some time been speaking out about conflicts of interest posed by leaders of academic medicine and supposedly “not-for-profit” health systems who also rake in big bucks for sitting on the boards of large corporations such as drug companies and other firms that often do business with those same health centers. He most recently called attention to a research letter in JAMA that provides some of the first data on the frequency of these ties (see link in blog post):
http://hcrenewal.blogspot.com/2014/04/finally-article-in-large-circulation.html

Dr. Poses notes a number of serious ethical concerns that result from these board relationships. He is most worried about the way that a small group of very wealthy corporate insiders seem to have formed an old-boys-and-girls club that runs not only the corporate sphere but increasingly the world of health care as well, and how in the process the interests of ordinary folk get left behind. There is also the narrower question of the role of these people on those corporate boards which forms a sort of Catch-22. These corporations, as we have detailed ad nauseam in this blog, often take actions that go against the public interest. If (say) a university president is a member of the board of directors, then the prez presumably should speak up and demand that the corporation cease and desist all such behaviors. If the prez says that really, don’t blame him, he has no control over that behavior, then he is admitting that he’s failed in his role as a corporate overseer, which is what legally the board of directors is supposed to be about.

In the middle of this debate I have one of my occasional modest proposals. It does not address the deeper issues, which would entail leaders of academic medical and health centers not being on those corporate boards at all--but see my Modest Prediction at the end.

Whenever do-gooders like us complain about these conflicts of interest, apologists for the One Percent crowd claim that after all, these board relationships are very valuable for the university or the AMC or the health system. They expose the board to the presumably enlightened views of academic and health care leaders. They expose the leaders to important information about what’s happening on the corporate side, thereby stimulating productive university-industry partnerships for the future. So how could anyone be so narrow-minded as to object to these relationships?

Hence my modest proposal—demand that any academic or health care leader who serves on a corporate board do so without pay and at his/her own expense for travel and lodging. If their being on the board is so all-fired valuable to the academic or health institution, then let that board service be a part of the CEO’s job at that institution. Last I heard, none of these high rollers were being underpaid for their leadership roles. They have funds to cover their activities if they travel on university or hospital business, so why not regard board service under that category?

I would along with the modest proposal make a modest prediction. If you ceased paying these CEOs personally for their board service, commonly nowadays in the six-figure-per-year range, suddenly none of these CEOs would want to be on corporate boards any more. So much, if so, for all the wonderful intellectual advantages of board service and industry relationships.

Pharma Lobbyists Have Their Way: FDA “Breakthough-Drug” Policy

A group from the excellent Pharmacoepidemiology-Pharmacoeconomics center at Harvard, a.k.a. Dr. Jerry Avorn and friends, wrote this commentary in the current New England Journal:
http://www.nejm.org/doi/full/10.1056/NEJMhle1311493

If you skip to the very end to see their conclusion: “In the next few years, evidence will accumulate to indicate how well the new breakthrough-therapy designation improves the options of patients with serious and intractable diseases and to what extent it facilitates the market entry of treatments that promise more than they can deliver.”—then you’d guess that they are pretty wishy-washy about the new category of “breakthrough therapy” that Congress enacted in 2012. A close reading shows that you’d be wrong; if you check out all the fine print you’ll see that the authors are very negative about this new FDA category aimed at hastening new drug approval.

Why the negativity? The points they make are:

• There’s really no good evidence that currently, patients suffer as a result of slow FDA approvals. FDA approval times are steadily decreasing.
• There’s some evidence at least that unsafe drugs are getting onto the market because of current FDA approval practices. The authors mention among other examples the leukemia drug, ponatinib, approved on an accelerated basis in 2012, then temporarily suspended in 2013 when it was shown that nearly half of patients on the drug followed for 2.7 years developed serious blood-clotting events like heart attacks and strokes.
• Before Congress enacted this new “breakthrough” category, there were already several pathways for “fast track” approvals.
• In the first year after the “breakthrough” category was approved, the FDA received 92 new drug applications for this designation. As I noted in HOOKED and previously on this blog, in recent years, sober appraisals of new drugs have shown repeatedly that no more than a small percentage of new drugs qualify as significant advances over existing therapies. If this many drugs are seeking approval under the new designation, it is certainly being used for drugs that aren’t “breakthroughs” in any meaningful sense of the term. (The FDA approved only 27 of those applications.)
• We’ve seen many times here how a good way to approve a useless or a harmful drug is to look only at surrogate endpoints and not at meaningful patient outcomes. Under previous rules, a drug had to show activity first against a “well-established surrogate endpoint,” and then later, it was all right to address a “less-than-well-established surrogate endpoint,” whatever that is. Apparently even that was not loosey-goosey enough for Pharma, so this “breakthrough” category allows approval based on “an effect on a pharmacodynamic biomarker(s) that does not meet criteria for an acceptable surrogate endpoint, but strongly suggests the potential for a clinically meaningful effect on the underlying disease.” (And here I would have thought that would be the definition for an “acceptable surrogate endpoint”—shows how much I know.)

The bottom line seems to be that the drug industry lobby continues to have its way in Congress and can get most any legislation passed they want. I suppose the next thing is that they will decide that even with this new category, drugs are not being approved fast enough, and so they will come up with a new category that requires that the FDA approve a drug if the company promises (cross its heart and hope to die) that the drug will do something to an almost-acceptable sort-of-surrogate endpoint, sometime in the next 5 years.

When the industry lobbies for a slicker greased pathway through FDA approval, it never comes to Congress by itself; it always comes along with “consumer” lobbyists supposedly representing patients desperate for cures. We’ve also seen numerous times how often those “consumer” groups are actually bankrolled by Pharma, so that pretty much disposes of that argument—but Congress laps it up nonetheless.

I explained in HOOKED how back around 1972, some brilliant Pharma lackey invented the “drug lag,” the claim that people were dying like flies in the U.S. because wonder drugs approved years ago in Europe were being held up by a stodgy, unresponsive FDA. I there compared the “drug lag” to John F. Kennedy’s famous “missile gap.” There are two analogies. One, the “lag” and the “gap” both turned out on investigation to be purely mythical. Two, once given voice, they refused to die, no matter how much proof was amassed on the other side. And so today we still operate under the myth that the FDA is too slow to approve marvelous new wonder drugs and somehow we have to speed up the process. Or at least Congress operates under that myth when huge piles of Pharma lobbying cash are spread around along with it.