More on Device Industry, from ASLME COI Conference

Continuing my blogging post-conference for the American Society of Law, Medicine and Ethics, "Conflicts of Interest in the Practice of Medicine" (see previous post for link), two tidbits on the medical device industry. Two speakers addressed this topic, Dr. Rita Redberg, UCSF cardiologist and editor of Archives of Internal Medicine with its splendid "Less is More" feature, and Kelly Dineen, JD, St. Louis U law school. (Dr. Redberg was co-author of the excellent New England Journal commentary on the recent IOM report on FDA regulation of medical devices: http://brodyhooked.blogspot.com/2011/08/more-on-iom-report-on-fda-scrutiny-of.html.) I'm reporting my own impressions based on what they said, so don't blame them for what follows.

First, there was much discussion at the conference of the recent New York Times expose of the role of venture capitalists in lobbying against stricter FDA regs on devices, which is what the IOM recommended:
http://www.nytimes.com/2011/10/26/business/venture-capitalists-join-push-to-ease-fda-rules-for-medical-device-industry.html?scp=6&sq=health%20law&st=cse

The general comment was that it is notable how the device industry, and the venture capitalists that seek to profit off devices, have really taken the gloves off and come out swinging against the IOM and the scientific community generally. Dr. Redberg reported testifying on Capitol Hill and encountering Congressional committees that had been captivated by a device-industry-funded report that slammed "unnecessary" government regulation and threatened job losses of the FDA tightened its rules, and did not want to address patient safety or effectiveness at all. Apparently all patient concerns must give way before the almighty dollar.

Second, Ms. Dineen described in some detail the role of medical device reps in one area of medicine, neurosurgeons who specialize in implanting devices that give electrical signals to nerves (neuromodulation) for a variety of conditions. I have previously been fairly sympathetic to the difference between device reps and drug reps, based on the argument that devices need hands-on technical expertise that sometimes requires trained company reps to be in the operating room or at the bedside to advise the doc on how best to adjust the device. Ms. Dineen revealed an important qualifier I had not been aware of.

As I took her point, implanted neuromodulation device reps are functioning as basically unpaid labor for the neurosurgeons--a substantial company-funded subsidy for their practices. With device reps being ubiquitous, surgeons can turn to them for all the technical parts of the device, leaving their own role simply that of making the incision and sticking the device in. How the device is programmed to do its work, and what to do if something goes wrong later, can all be delegated to the company rep, who's more than eager to oblige, in exchange for the neurosurgeon's devotion to that company and its expensive products. In everyday practice the neurosurgeon can even "supervise" what the rep does (often from a considerable distance) and then proceed to bill hundreds of bucks for the visit. Now, the surgeons could take a course and learn how to do this programming function for themselves; or they could hire their own technicians to become part of their office and OR staff and do it for them. But why spend that time or money when the device company is eager to supply the reps for free?

End results: patients are cared for by staff who have the company's rather than the patient's interests at heart; neurosurgeons make more money for less work; and the device gravy train keeps rolling. Must keep those venture capitalists happy, after all.

The take-home message is that once again in medical devices, things are not as they seem. The "need "for hands-on assistance with the device, that justifies reps running free range through the hospital and clinic, may be more manufactured than real.

COI Update from the ASLME--Capsules

I'm in Pittsburgh just having attended the conference, "Conflicts of Interest in the Practice of Medicine," sponsored by the American Society of Law, Medicine and Ethics, which you can read all about at: www.aslme.org/2011COIconference
ASLME also plans to publish all the papers from the conference in its journal.

So what's new in the field? The quick answer for regular readers of this blog is, apparently not much. There were few new issues and virtually no possible solutions raised that have not already been discussed here and elsewhere. The presentations were nevertheless interesting and the interplay between the legal and medical viewpoints was illuminating. I have listed a few capsules below of possible interest and will do at least one more post on a particular issue.

>>The conference began with the usual ceremony of the highly placed official welcoming everyone, and in this case it was the Dean of the Pitt School of Law. She began by saying that COI is "almost impossible to eliminate" and that the conference would address the "challenge of managing" COI. At that point I was getting worried that we were going to hear a rehash of really old ideas. Fortunately the subsequent sessions all paid appropriate attention to the desirability of eliminating and not merely managing COI.

>>Christopher Robertson, JD, PhD of U-Arizona law school was given the task if laying out the evidence for the seriousness of COI in medicine. He began by reviewing the evidence relating to physician self-referral (e.g., sending patients to the imaging center that the physicians' group owns instead of to get their scans at the local hospital x-ray dept.) and said what we all know, that evidence shows that the rate of ordering tests and procedures jumps astronomically with self-referral. I had generally not thought to connect the self-referral data to issues of COI at the medicine-Pharma interface. But I think Robertson raised a good point. Physicians commonly deny that they overorder tests and insist that when they send patients to the testing center they profit from, that either the patient benefits greatly from the test, or they have saved the patient a trip across town or to another city, etc. So we have clear evidence that 1) money changes physician behavior (duh) and that 2) physicians commonly rationalize that association away. I think one can reasonably argue that such is presumptively relevant to other money-laden relationships, until proven otherwise.

>>Bernard Lo MD from UCSF, a chair of the IOM panel that wrote their report on COI in medicine, was first to raise this issue but it was echoed by other speakers. As we enter the era of heightened, required disclosure, many physicians fear the liability of multiple, perhaps inconsistent disclosures, as different forms and bodies have different rules (such as whether to report relationships for the past 2 years or 5 years or whatever), and then providing fodder to investigative journalists who can check out all these disclosures on line and play "gotcha" with any inconsistencies that are revealed. Now the extreme pharmascold might say, so much the better, yet another good reason to divest oneself from these conflicted relationships. But the point the speakers made seemed very reasonable, that it would be far superior to have a single, uniform and common disclosure process so that each individual had to disclose in one place only for all purposes.

>>One of the most appreciated speakers was Sunita Sah, MD, PhD of Duke, who has co-authored several well-designed studies of how disclosure practices might impact physicians and patients. During the Q&A the point emerged of how reluctant patients are to appear to criticize their own physician's COI, assuming the relationship to have been established before the COI becomes known. Some studies that are cited to show that COI is no big deal for patients and does not decrease their trust are studies in which patients are basically asked about their own physician's COI. A fairer study design would be to get patients to imagine that they are seeking a new physician, and can choose among several physicians on a panel, some of whom are disclosed to have COI. The outcome of interest would be how willing patients are to select the physicians with COI, and at least some preliminary data, I understand, would suggest that they'd be less likely to select those docs.

>>A couple of speakers commented on the recent pullback at NIH in backing off proposed COI policies, that would have required academic medical centers to post faculty COI on accessible websites (http://brodyhooked.blogspot.com/2011/08/nih-conflict-of-interest-rules-weakened.html) Blame was placed on the White House, feeling under fire to do something about the supposedly out-of-control government regulations that the Republicans are raising Cain (no pun intended) about. The timing was bad; the time that the NIH stringent guidelines would have gone into effect was precisely the moment that the White House decided they had to make a show to scaling back on regulatory load.

Farewell to Xigris--Counting the Lessons

One of my most faithful readers sent me a link to David E. Williams blogging on the Health Business Blog:
http://www.healthbusinessblog.com/2011/10/xigris-withdrawal-highlights-conflict-of-interest-problems/?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+HealthBusinessBlog+%28Health+business+blog%29

Williams in turn comments on news that Eli Lilly has withdrawn its drug Xigris (recombinant human activated protein C) from the market after a new, major study failed to show any benefit in survival from sepsis:
http://www.medpagetoday.com/ProductAlert/Prescriptions/29250

The bulk of Williams' post is actually a reprisal of an old post, but it's still very timely, and for readers of this blog, provides a view of physician responsibility for drug industry marketing excesses from a vantage point outside of medicine.

I told the Xigris story in HOOKED as of 2006 or so. Basically Lilly gets credit for really trying to come up with a novel compound that attacked disease (life-threatening infection or sepsis) in a novel way. The sad news was that the initial trial showed that Xigris was only occasionally effective and also carried major bleeding risks.

The part of the Xigris story that especially caught my attention was how some of my colleagues in bioethics were caught up in the company's PR campaign without apparently realizing it--or else taking the money and not caring. As one prong of the marketing strategy, Lilly decided that since Xigris cost so much, and since so few ICUs were purchasing it (since the studies had been so equivocal), then there must be rationing of life-saving treatment going on. Of course one solution would have been to lower the price, but perish the thought. So Lilly instead forked over $1.8M to fund an "ethical" study of rationing in the ICU, with the intent of bringing pressure to bear on recalcitrant units with the dreaded "R word."

The part of the story that I did not cover in HOOKED, as Williams reminds us, was actually addressed in a 2006 commentary in the New England Journal (subscription required) by Eichacker and colleagues. Having managed to get the FDA to approve Xigris despite iffy data of efficacy and safety, Lilly bankrolled a big PR firm to do three things--set up the rationing "ethics" inquiry, and get major medical societies to write guidelines for sepsis care that included the use of Xigris (by funding the guideline panels and making sure that numerous docs with Lilly money in their pockets served on the panels). The third thing however was what made Eichacker and company worried. It was Lilly's subsequent effort to lobby the organizations that create quality indicators for hospitals and insurers to include those guidelines in their quality measurements. That is, if an ICU did not use Xigris, because they deemed it insufficiently useful and overly dangerous (a reasonable evidence-based position at the time), the hospital might get a lower score for quality of care and then have problems with insurance reimbursement as well as the bad publicity. Eichacker et al. very reasonably said this was a blatant hijacking of these quality indicators for commercial purposes.

I have commented numerous times on Kalman Applbaum's concept of controlling the drug channels. Lilly did this beautifully, gathering in its hot little hands all the threads that controlled the way hospitals were likely to use Xigris. Why bother sending drug reps into thousands of doctors' offices if you can buy off the people who write the guidelines and the people who ding the hospitals for bad quality of care?

So now we find out, at this late date, what many suspected from the start--that even the small degree of benefit for Xigris, that was seen in the initial study and that earned FDA approval, was probably a fluke. Farewell to yet another overmarketed and dangerous drug--though too bad that Lilly did not go back into the laboratory and try to use the basic understanding of the disease mechanism to find a better successor.

Here are Williams's take-home messages for the industry and for physicians, worth repeating here:

Here’s some free advice to the different players in health care:

--Industry: Feel free to market your products and services aggressively, but don’t take things too far. If you do you’ll end up killing the goose that lays the golden eggs. No one will trust doctors, guidelines or journals anymore
--Physicians: Remember that pharma and device companies are not stupid. If they spend money supporting your research or sending you to conferences or sponsoring continuing medical education it’s because they expect to get a return on their investment. It’s awfully hard to remain objective in such instances. Your job is to adopt the best medical practices and put the patient first –sometimes that requires expensive new treatments and sometimes old, cheap standbys are better

Eichacker PQ, Natanson C, Danner RL. Surviving sepsis--practice guidelines, marketing campaigns, and Eli Lilly. New England Journal of Medicine 355:1640-42, 2006.

The $43M Pill instead of the $800M Pill?

I am worried about my friend Donald Light of University of Medicine and Dentistry of New Jersey/Stanford. First he came out with his book, The Risk of Prescription Drugs, in which he documented 100K deaths annually in US hospitals from prescription drugs taken properly as directed, making drug adverse reactions the 4th leading cause of death in the US. This finding would seem to challenge the standard industry line that discovering lots of new drugs and getting them onto the markket as quickly as possible means longer lives and more disease cures. Then, just to follow up that performance, Light and his colleague Rebecca Warburton of University of Victoria, BC decided to demolish the myth of the high R&D costs that the industry appeals to in justification of the out-of-sight prices charged for drugs nowadays (at least in the US where we refuse to follow the intelligent part of the world in using volume discount buying power to drive down drug costs). I am now worried that Dr. Light will be on Pharma's hit list. (See the end of the post for why I am actually not worried about any such hit list.)

I actually covered much of the ground that Light and Warburton traverse back in HOOKED, but since they provide additional details and calculations, and we have not discussed the issue for a while, I figured it was time for a revisit.

In 2004 Merrill Goozner, formerly economics reporter for the Chicago Tribune (and now blooger at GoozNews), published his expose, The $800 Million Pill. The title came from the research by DiMasi and associates at the Tufts Center for the Study of Drug Development, which is primarily funded by industry. That group published their estimates of what it cost industry to discover one new drug (that is, a novel molecule never before used) given all the dead ends that have to be navigated before one good drug emerges. They came up with the figure of $802M. Light and Warburton follow in the footsteps of Goozner and Marcia Angell (The Truth about the Drug Companies) in deconstructing this myth.

The brief highlights of their analysis:

• The data DiMasi et al. used for their study was secret industry data that has never been revealed, so we have no way to check its accuracy. There are a number of sources of independent information that would call its accuracy and representativeness into question.


• The costs of actual drug discovery are essentially unknown and highly variable. What did it cost Alexander Fleming to discover penicillin? Sometimes you just trip over a useful new drug by chance, sometimes a new drug emerges after 30 years of arduous research. Light and Warburton note in passing other findings that some 84% of new drugs are not discovered in house by the drug companies but by university and other noncommercial labs.


• The drug industry rakes in considerable tax savings that represent as much as 50% of the actual costs of their R&D. Light and Warburton go into a long economic talk about this that goes way over my head, but seems to amount to noting that drug companies regard R&D costs as operating expenses and not capital investments for purposes of getting their tax breaks. Then when somebody asks why they don't deduct the tax savings from their reported R&D costs, they answer as if the R&D expenses were capital investments, so that tax savings if any would accrue only slowly over many years. They can't have it both ways.


• As I noted in HOOKED, the industry then pads its R&D costs by adding in the profits that that same money would have earned had they invested it in the stock market for the same number of years, and saying that they deserve to be repaid for the foregone profits as well as for the actual costs. Light and Warburton note that no other research-intensive industry makes any such claim. If you purport to be in the business of discovering new drugs, of course you invest your money in drug R&D, and of course you don't put that same money in the stock market instead. Claiming that the company should effectively be reimbursed for profits forgone as well as for actual costs nearly doubles the estimated cost of discovering a new drug.


• DiMasi et al. appear to have used unrealistically high estimates both for how long research trials go on and how many subjects are enrolled. Finally, instead of using median figures they use means, which can be inflated by a few high-end outliers.


• Light and Warburton are so impolite to add that only a small proportion of the new drugs marketed by the industry are genuinely new molecular entities; and an even smaller percentage actually represent significant therapeutic over existing drugs.

So what does it actually cost to discover one new drug? I believe that in HOOKED I settled on the figure of maybe $100-200M. Light and Warburton suggest that the best answer is"we don't know" but did some calculations to show that the true number could even be as low as $43M.

I think the real take-home message is this: even if we don't know the exact right answer, there has been a lot of reason to regard the $800M as spurious practically from the moment it was released. It is surely at least twice the real figure and more likely, at least four times. Yet PhRMA and the media continue to bruit about that figure as if it were gospel. That just shows when you have a lot of money at your back, you can specify the "truth" to be pretty much whatever you wish.

So--why am I not worried about Don Light being on a Pharma hit list? The only example I know of, of the drug industry murdering people who they don't like, is John Le Carre's novel The Constant Gardener (and the film version). Le Carre was careful to document that all the industry skullduggery he used for the plot of his novel was based on real events, except for the murder part. When I met with a group of students recently who had seen the film, I asked them why they thought Pharma didn't actually go around killing people. The students immediately got the right answer--Pharma doesn't have to. They get what they want just fine, thanks, without the need for any such crude tactics.

Light DW, Warburton R. Demythologizing the high costs of pharmaceutical research. Biosocieties 6:34-50, 2011.

Light DW, ed. The Risk of Prescription Drugs. New York: Columbia University Press, 2010.

DiMasi JA, Hansen RW, Grabowski H. The price of innovation: new estimates of drug development costs. Journal of Health Economics 22:151-185, 2003.

Goozner M. The $800 Million Pill: The Truth Behind the Cost of New Drugs. Berkeley, CA: University of California Press, 2004.

Angell M. The Truth About the Drug Companies: How They Deceive Us and What To Do About It. New York: Random House, 2004.

What To Do about Pay-for-Delay

Dr. Aaron Kesselheim and colleagues provide a useful review/commentary in last week's New England Journal (subscription required) on a problem I addressed in HOOKED--"pay-for-delay" when a brand name drug company and a generic company reach a settlement on the latter's patent challenge to the former, which results in a substantial delay in a cheaper generic drug reaching the market.

In quick summary, here's what happens in a typical case:

• A lucrative brand name drug is about to go off patent. Typically, however, the company has a number of subsidiary patents on things like coating, etc. that have little to do with the actual active drug ingredient.


• A generic company bids to come onto the market with the drug--by the Hatch-Waxman Act, the first company to do so gets a plum in the form of 6-month generic exclusivity, during which it can charge almost as much as the brand name price due to lack of competition from other generic makers.


• The brand name company sues the generic company for patent infringement, often citing one or more of the subsidiary patents.


• A major and potentiallly protracted court battle ensues.


• The brand name company offers the generic a cash settlement, in effect paying them to drop their suit and take the cash, on the condition that they delay their product's marketing and preserve the brand name exclusivity for a longer period.

It seems at first that this process hardly serves the public interest. But the authors note that a prolonged court battle could just as easily keep the cheaper generics off the market even longer.

Kesselheim and colleagues make a number of good legal points and discuss some statutory fixes, most of which have little chance of passing the present Congress. But I think their most important argument is about the root cause of all this--silly patents. They propose two measures that could occur either at the Patent Office or at the FDA levels that would allow administrative challenges to minor patents that do not protect truly innovative drug development, leaving the courts free to decide the really tough cases, and industry free to patent and profit from real innovations. These reforms in my view should be the highest priority.

Kesselheim AS, Murtagh L, Mello MM. "Pay for delay" settlements of disputes over pharmaceutical patents. New England Journal of Medicine 365:1439-1445, Oct. 13, 2011.

More on the Medtronic-Yale "Model"

A while back I commended Medtronic for agreeing to fund an independent review of its controversial bone-regrowth product:
http://brodyhooked.blogspot.com/2011/08/in-praise-of-good-corporate-behavior.html

More information on the model that Dr. Krumholz at Yale has pioneered in this case was recently provided in JAMA (subscription required) and also can be seen at:
http://medicine.yale.edu/core/projects/yodap/index.aspx

The model calls for the company to fund a study and to agree to turn over all their raw data, in a form that can be carefully reviewed for the quality of the research, to an independent organization. An steering committee (with public representation as well as experts) then oversees the creation of two separate academic teams to review and report on the data. Drs. Krumholz and Ross argue that the use of two separate teams both provides an accuracy check on each other's work and also further assures independence from the manufacturer.

We must of course await the results of the Medtronic study, but this model appears to be about the best that has yet emerged to restore integrity to the process of pharmaceutical research. An obvious question is how to address and assure integrity on an ongoing basis, and not merely once a scandal has arisen.

Krumholz HM, Ross JS. A model for dissemination and independent analysis of industry data. JAMA 306:1593-1594, Oct. 12, 2011.

Postcard from NPA Annual Meeting

So long as the battery holds out and I don't lose the WiFi connection yet again, I'll send a brief postcard from the National Physicians Alliance annual meeting (actually from National Airport, on my way back home, as I unfortunately was unable to stay for much of the meeting). Those of you who don't know the NPA:
http://npalliance.org/
--should check out their excellent Unbranded Doctor Campaign that gives practitioners the resources to develop a drug-rep-and-sample-free office. The NPA has been very active in promoting health reform, physician professionalism, and physician-led cost containment. It was the latter issue that I was invited to speak about on a panel.

Among the many delightful people I met in person for the first time at the meeting, another panelist was Dr. Rita Redberg, the UCSF cardiologist who is editor of Archives of Internal Medicine and there pioneered the superb "Less Is More" feature, providing evidence in support of reducing the overuse of non-beneficial tests and treatments. NPA formed the Good Stewardship group that assembled panels from the three main primary care specialties and asked each to compile a "Top Five List" of the most frequently used interventions in each field that could be eliminated so as to improve the quality of patient care. The focus in that publication was quality, not cost--noting that when unnecessary and nonbeneficial tests or treatments are used, the patient may suffer harm without any compensating benefit.

What we learned today from Dr. Redberg is that in a new study, published on line today in Archives, Dr. Minal Kale and colleagues proceeded to do the cost calculations from the three primary care "Top Five" lists. (subscription required) They utilized conservative estimates to conclude that the total annual savings from eliminating these useless tests and treatments would be about $6.7B. There are two main take home messages in my view. First, this tends to support the view that primary care is not the cost-overrun problem in American medicine. Given estimates from groups such as the Institute of Medicine that we throw away annually some $760B in tests and treatments that produce no patient benefit, what primary care contributes is chump change. Still, if we want the big spenders like cardiology and orthopedics to mend their ways, it is very good that primary care looked at itself in the mirror first and called on the other specialties to do likewise.

The second take home message is that one single item on the Top Five list from internal medicine accounted for the lion's share of the total cost--the recommendation that physicians prescribe generic rather than name brand statins would alone save the country more than $5B. This in turn highlights the low-hanging-fruit issue, that it behooves us in cutting the costs of health care to make care more affordable for everyone to seek out these relatively small and simple steps that can save the most money without harming patients. It also reminds us once again how often picking the low hanging fruit will cause us to go contrary to the messages sent out by Pharma marketing.

We learned from Dr. Steve Smith, head of the Good Stewardship effort, that NPA now plans to produce videos for office use, helping physicians to explain to patients why they don't need some of these expensive but useless tests and treatments. This is a good example of NPA's view-from-the-trenches approach that picks out the critical steps needed to put good ideas into practical action.

Kale MS, Bishop TF, Federman AD, Keyhani S. Top 5 lists top $5 billion. Archives of Internal Medicine, doi:10.1001/archinternmed.2011.501, published on line 10/1/11

Good Stewardship Working Group. The top 5 lists in primary care--meeting the challenges of professionalism. Archives of Internal Medicine 171:1385-90, 2011;
http://archinte.ama-assn.org/cgi/content/abstract/171/15/1385?ijkey=5947b2777392ebfde658ef4eceb42ba0da248904&keytype2=tf_ipsecsha