Beware Surrogate Endpoints: Yet More Evidence

Thanks to my pals Rick Bukata and Jerry Hoffman over at Primary Care Medical Abstracts for telling me about this study (subscription required). A team from Naples, Italy led by Dr. Pierluigi Costanzo did a meta-analysis of 41 randomized trials, all of which allowed a comparison between carotid intima-media thickness (IMT) and cardiovascular outcomes.

Let's stop for a plain-English break. You can do a fairly simple, noninvasive ultrasound test and measure thickening in the wall of the carotid artery in the neck. This measure has for a long time been viewed as an aspect of atherosclerosis, or hardening of the arteries--and indeed, if you divide a large population into those with a lot of thickening and those with a little, the former group ends up showing more heart disease in the end. This has led investigators who want to test whether their drug or other treatment works to lower cholesterol and to prevent cardiovascular disease like heart attacks and strokes to measure IMT as their favored outcome measure. The theory is that it might take many years to see a difference among your treatment groups in heart attack, stroke, or death rates; but within a few months to a year you might be able to measure changes in IMT, so it's much quicker and cheaper to measure IMT than to wait for the "hard" clinical endpoints.

The Costanza group sugegsts that there's only one problem with this quick-and-cheap approach. Their meta-analysis showed that there is no consistent relationship between improvements in IMT and any of the outcomes that really matter. In short, IMT is just like too many other "surrogate endpoints" in medical research--just because it gets better, you cannot assume that what really is of interest gets better too. Costanza et al continued to agree with what we thought we knew in the past--that a high IMT at baseline is a risk factor for worse heart or vessel disease on a population basis. It's the later change in IMT that seems not to be correlated with anything of importance. (Just why this is so, they offer a number of possible explanations for, which need not concern us here.)

I have to note in fairness that these meta-analysis results can cut both ways. Guess who wants to do quick and cheap studies to show that a drug works for reducing your cardiovascular risk? Our old friends the drug industry, of course. So showing the lack of any linkage between IMT improvements and real risk reduction means that a number of studies that seemed to show great promise for any given drug are of no real scientific value--no matter how many drugs may have been sold to unwary docs based on those findings. But it also means that a drug that fails to improve IMT could, presumably, still end up being valuable in reducing heart risk. Consider Zetia or ezetimibe (http://brodyhooked.blogspot.com/2008/01/now-that-weve-been-enhanced-whats.html). The manufacturer got stung because they put a lot of weight on a study, ENHANCE, trying to show that their drug reduced IMT, and it ended up maybe making it worse. We now can see that those findings may not have really told us much about whether or not ezetimibe is a good drug. (I understand that the manufacturer is now sponsoring a longer-term study to measure actual outcomes--which of course is what they should have done from the get go.)

In a way this is all a crying shame. It makes really good sense that IMT ought to be a reliable measure of the progression or improvement of atherosclerosis. Physicians and scientists who thought this has to be true are not smoking something; the hypothesis seemed to make excellent physiological sense. And this in turn illustrates a point that's becoming an old refrain in this blog. The Pharma marketers very seldom tell docs something that we all know to be untrue and get us to swallow it. They are, on the other hand, extremely adept at taking something we already believe to be true, even if it isn't, and then using that belief to manipulate us into a course of action that ends up with more revenue in their pockets. So the problem is us fooling ourselves as often as it is them fooling us--or more accurately, us helping them to fool us.

Costanzo P, Perrone-Filardi P, Vassallo E, et al. Does carotid intima-media rthickness regression predict reduction of cardiovascular events? A meta-analysis of 41 randomized trials. Journal of the American College of Cardiology 56:2006-20, 2010.

Keeping KOLs Fat and Sassy: These Consultants Can Help

I am not usually pestered with e-mails from consultants who serve the pharmaceutical industry, and so it was an interesting experience to get one e-mail directly and have another forwarded to me by a colleague, within 24 hours. As I described last month--http://brodyhooked.blogspot.com/2011/05/on-care-and-feeding-of-kols-attend.html
--the care and feeding of KOLs ("key opinion leaders" for those who just joined us, aka paid physician shills for industry) seems to be a hot topic just now.

I received this message:

• Howard,
  
  I hope things are well at University of Texas Medical Branch. As you may already know, the Sunshine Act is the most pressing set of regulations that will impact how companies approach KOL compensation. University of Texas Medical Branch will need to start implementing aggregate spend tracking processes now, because in January 2012, your company will be required to disclose all payments for key opinion leaders' services. Companies like University of Texas Medical Branch need to have a progressive and compliant infrastructure in place to establish fair-market value compensation and meet regulatory challenges. Regulatory agencies that have focused heavily on top drug makers have begun to turn their attention toward mid-size and smaller companies' KOL compensation practices. Cutting Edge Information’s latest study, "KOL Fair-Market Value and Aggregate Spend: Documentation, Tracking and the Sunshine Act," is designed to help companies of all sizes compete in today's highly regulated environment.
  
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These folks appear to think that the academic medical center I work for is a mid-sized company that sells drugs. We do, I suppose, employ "key opinion leaders" but we call them faculty, and expect them to teach students and do research and take care of patients, not sell products for us. (There is the whole debate about whether academic centers are becoming too commercialized, but that's a different post.) They also seem to suggest that the threat of shining the light of publicity on KOL-related activities will have us running scared and hence in need of consultant assistance.

Meanwhile a colleague of mine received this e-mail solicitation:

Dear XXX,
I wanted to get in contact, as we're organizing speakers for a very focused and unique conference looking at the important issue of:

KEY OPINION LEADER & STAKEHOLDER MANAGEMENT IN
SPECIALTY & ORPHAN THERAPEUTICS
Integrating innovative communication approaches and new best practices to reinvigorate the pharma high-value commercial model
Miami, USA 14th-15th November 2011

This will be the only focused event looking at the latest "best practice" approaches to selling and marketing high-value specialty drugs to distinct consumer groups, and working in partnership with therapeutic specialists & pharmacists as well as with hospitals & healthcare providers to provide real value and to improve patient access.
One of the goals, will be to improve seamless coordination between all internal & external stakeholders in strategic, operational and tactical roles. Such roles would typically include marketing, commercial operations, sales, sales force effectiveness, talent development, training, market access, pricing and reimbursement, product and brand management, as well as medical affairs & liaisons. As specialty & orphan marketplaces are growing rapidly, with a lot of new, high cost therapies entering a saturated market, where payers are more risk averse and budget-conscious, most would agree this topic deserves specific and detailed attention and discussion.
Would you perhaps be interested to speak/present there? If not, perhaps you could recommend somebody or a specific organization who we could invite?

Possible topics will include:
· Specific examples & focused case studies from across Specialty disease & medical areas i.e. Oncology, Orphan, Inflammatory, Pediatrics + others.
· What do specialist prescribers want and how can we better communicate value?
· New approaches to customer-centric, ethical, trust-focused, value-based sales of innovative drugs in the face of increasingly available and lower-cost generic products
· Best practices in specalist account management
· Mapping and targeting Key Opinion Leaders, payers, and today's new stakeholders
· Understanding, adapting to and selling in, the new cost containment, health technology assessment, evidence-based environment
· Interacting with specialists treating multicultural populations
· Increasingly important role of the Medical Science Liaison to engage KOL
· Marketing approaches to: Healthcare providers, Hispanic, African- American, Asian-Americans, Women, Parents, Elderly
· Digital and social media advances and how to adapt marketing methods to communicate effectively with specialists
· Benefits from supporting investigator initiated trials & publications
· Responding to the growing need of gathering & presenting real world data to demonstrate product value and acheive market access
· How to best incorporate all stakeholders' insight and analysis into company activities
· What differences exist for marketing specialty products to niche & emerging markets?

Consultants and solution providers please note: As we have a high demand for speaking positions and very limited positions available, solution providers who sponsor/exhibit will be given first right of refusal for limited speaking opportunities.

Thanks and best regards
Geraint Collingridge
Event Producer
T: +381 690 307 462
www.nextlevelpharma.com
"Knowledge Solutions for Life Sciences"

I am thrilled that "ethical" got thrown into their laundry list. As best as I can tell, these various firms want to assist companies who now employ KOLs to keep doing what they are doing, which presumably includes making a lot of money, despite a hostile environment in which some people are mean enough to say that the odor arising from these activities is starting to seem a bit rank. There seems to be no one considering telling us that maybe the reason there are problems and stresses is that KOL-related activities are inconsistent with medical professionalism and should be curtailed or completely rethought.

By the way, if you don't know the classic joke about consultants, see http://daveola.com/Resume/Joke.html.

The Bottom Feeders Are Out In Force: Physician-Owned Device Distributorships

John Carreyrou in the Wall Street Journal online--
http://online.wsj.com/article/SB10001424052702304778304576373592455703056.html

--tells us that 5 senators, including our old acquaintance Chuck Grassley of Iowa, have asked the Inspector General of DHHS to investigate physician-owned distributorships. These PODs are owned by physicians and act as middlemen, buying medical devices such as spinal surgery implants from the manufacturer and selling them to hospitals. They apparently are sometimes able to offer the device at a slight discount, which the owners claim makes them a good thing.

The senators are prompted by press coverage of a Portland, OR case in which a neurosurgeon was charged with doing a lot of unnecessary surgery, which could have been motivated by his being an investor in a POD and making more money the more devices the POD sold (to the tune in that case of a cool half million a year). He denies thart he did any unnecessary surgery but he has lost his privileges and is being investigated by the state medical board. A telling point is that once the POD had the media spotlight shown on it, device manufacturers stopped doing business with it and it had to shut down.

The senators' concern is also prompted by the apparent near-exponential growth in PODs, even though they exist in a "legal gray area" according to Carryrou. (Besides the PODs themselves, another growth industry seems to be law firms promising that they'll help you set up your POD in a way that protects you from the legal system coming down on your head.)

Does anyone recall the olden days, when it was sometimes necessary to explain to physicians why they should not own a drug store on the side, and then send their patients to that drug store with their prescriptions? Maybe time for a refresher course...

Who's at Fault: The Company or the Physicians?

For this sad tale of woe and intrigue check out the Health Care Renewal post by Roy Poses--
http://hcrenewal.blogspot.com/2011/06/stealth-marketing-of-medical-devices.html
And then the New York Times article by Barry Meier that Dr. Poses links to:
http://www.nytimes.com/2011/06/01/health/01device.html

Quick summary and attach "allegedly" in front of everything as none of this has been proven--a relatively small German firm, Biotronik, that makes pacemakers and implantable defibrillators, is now answering questions based on a trove of internal documents sent to the New York Times by a disgruntled former employee--an employee who claims he was fired because he complained about the corporate wrongdoing that his documents demonstrate. (The company protests that he's cherry-picked and that the documents don't tell the whole story.) PS-- a little change here in the usual script; usually it's a lawsuit or a Federal investigation for fraud that triggers release of these hidden documents.

The documents reveal a pattern of payola to get cardiologists to use Biotronik devices rather than one of their competitors'. The payola takes the form of "seeding trials"-- trials of no scientific value that are really excuses to get practitioners to enroll "subjects" for fees, and to promote the wider use of the company's product. (Biotronik sales officials even referred to these trials candidly in their internal documents as "unscientific studies.") Hiring physicians or their family members as "consultants" based solely on volume of product used or referrals for product use is the other major activity documented.

Here's a typical passage from Meier: "An implant specialist in Fullerton, Calif., Duane E. Bridges, became a consultant to Biotronik in mid-2008, company records indicate. The monetary volume of company products used by Dr. Bridges from early 2008 to early 2009 reached about $360,000, then jumped to $1.6 million over the next 12-month period, a greater than fourfold rise, the company data indicates. Dr. Bridges did not respond to comment; also a lawyer, Anthony Willoughby, who said he represented Dr. Bridges could not be reached for comment."

Also: "For example, in plotting strategies to gain sales at one California hospital, Biotronik officials suggested that an implant specialist, whose son and wife both worked for a competitor, might be wooed if Biotronik offered him concessions “such as studies or even the hiring of his son,” according to an internal company report."

The article also details a non-implanting cardiologist in Tucson, who was hired on as a Biotronik consultant and immediately informed his colleagues that he would not refer patients to them for implants unless they agreed to use Biotronik stuff. One of the area cardiologists to whom this doc referred patients (who was not apparently a paid consultant himself) increased his use of Biotronik devices eightfold, netting the company $1.1M in revenues.

Dr. Poses offers two astute comments. First, he notes that even people critical of financial ties with the drug and device industries tend to be less concerned about consulting relationships, and willing to give the doc the benefit of the doubt that the "consulting" is real and involves a true contribution of expertise in exchange for reasonable pay. He then notes that memos like those exposed here show that from the industry's point of view, "consulting" looks like bribery pure and simple. I would add a footnote--I expect if anything, and some of my surgeon colleagues agree, this is even more true in the device industry than in drugs. Why? Since device makers virtually never sponsor head to head trials, there's no scientific data as a rule as to which device is better. So if three firms sell similar devices, it's a wide-open arms race to get the docs to use your device and not the other guy's. The Biotronik memos seems to make clear that competition with other, bigger firms was the main driver behind these activities. (And incidentally reveals that almost for sure, the other firms were using the same tactics.)

Second point: Dr. Poses notes the by-now-pretty-tired excuse, that financial ties between docs and industry are required to promote scientific advance and innovation. It's quite clear that nothing about this entire Biotronik episode relates in any way to innovation.

Let me add my own two cents and bring up another huge point. Here is how Meier began his story: "The message from cardiologists was loud and clear, according to a top executive at a heart device company. The doctors wanted implant makers to produce more clinical trials of devices to help them generate income from research fees. To compete, 'we must be able to "answer the bell," ' wrote Thomas V. Brown, an executive vice president at the American subsidiary of Biotronik..."

In HOOKED I wrote about what seemed to be to be the saddest depths of professional ethics that physicians could fall to--not drug reps tempting physicians with generous payola to prescribe their products, but greedy physicians actually shaking down the reps for even more goodies and threatening to stop prescribing their drugs if they didn't come across. (To the point where even the drug reps felt ethically offended by the docs' behavior!) One has to conclude that a number of the cardiologists who ended up in the pockets of Biotronik were not seduced there by the big bad corporation; they pretty freely and eagerly crawled in. And what does that tell us about the state of professional ethics when these practices are permitted to flourish?

Pro-Con: Off-Label Anti-Psychotic Drugs for the Demented Elderly

Here's the pro-con debate from CNN:
http://www.cnn.com/2011/OPINION/05/31/levinson.nursing.home.drugs/index.html
http://www.cnn.com/2011/OPINION/05/31/carlat.nursing.home.drugs/index.html

Daniel Levinson, Inspector General of DHHS, weighs in on their recent report viewing with alarm how many demented elderly are receiving atypical antipsychotic drugs, which Levinsom notes are not approved by the FDA for this use, and can pose serious risks, including a higher death rate. On the other side is Dr. Danny Carlat, whose work has often been noted in this blog.

Dr. Carlat is no slouch when it comes to revealing the misbehavior of the pharmaceutical industry and of physicians who do its bidding (for just one example, see http://brodyhooked.blogspot.com/2009/07/more-on-psychiatrys-dsm-v-mess.html). So it's significant that in this debate, he goes toe to toe with OIG-DHHS and defends the use of these drugs.

Dr. Carlat makes a number of good points. He stresses, as I have tried to myself, that "off-label" does not necessarily equal "wrong use" or "bad use" of a drug. He makes the important point that as of now no drug is approved specifically by the FDA for treatment of agitation caused by dementia, despite the way this condition can make life miserable for both patients and families as well as for staff. Moreover, he notes that several clinical trials support this use of antipsychotic medication. He therefore concludes that it's a matter of individual medical judgment whether for any given patient, the potential harms of these drugs are outweighed by the benefits--and OIG should back off.

Given Dr. Carlat's excellent record I hate to quibble with him, especially in an area where his psychiatric smarts trump any medical knowledge that I possess. But I would pose just one question. The atypical antipsychotics seem to pose one unique risk that especially is worrisome for the elderly--weight gain that could trigger diabetes--that is not shared by the older antipsychotics. And recent literature reviews (see for instance http://brodyhooked.blogspot.com/2009/01/are-second-generation-antipsychotic.html) have demonstrated pretty convincingly, I would judge, that there's no real benefit of the newer antipsychotics over the older, to the extent that calling them "second-generation" or "atypical" is probably a serious misnomer. So given that all drug use for this unfortunate problem is going to be off-label anyway, why not use a cheaper, older drug that many primary care physicians understand much better?

More Signs of the Empty Pipeline

I have referred at various times to the problem the drug industry faces of the empty research pipeline, with fewer useful new drugs coming out of their research labs, meaning that if they want to continue making the profits they (and their stockholders) have grown accustomed to, they have no choice but to market the hell out of less-satisfactory drugs. I have also referred to the Medical Letter, a long-term standby for non-commercial drug information for practicing docs, tho sadly so few US practitioners subscribe to it.

The pipeline problem is, I believe, well illustrated by two items from recent Medical Letter issues (May 2 and May 16):

• Duloxetine (Cymbalta), basically an antidepressant but one that has been viewed as having a specific anti-pain component, has just been approved for treatment of chronic musculoskeletal pain. ML notes that the mechanism by which duloxetine might relieve pain is unknown, and that the studies supporting its efficacy were all performed by employees of the manufacturer. All studies are placebo-controlled; there is no comparison with either commonly used over-the-counter analgesics, or with other (cheaper) antidepressants. A 30-day supply of Cymbalta costs $160. The reviewers conclude that if duloxetine has any superiority over placebo, it seems to be "modest at best."


• Medoxomil (Edarbi) is the 8th drug of the angiotensin receptor blocker class to be marketed. (There is one, losartan, that is now available generically, but interestingly its cost is not that much lower than all the brand name drugs.) Like all other ARBs it works for hypertension. ML admits that medoxomil "might" be more effective than some other ARBs for that condition. But it also has a major practical disadvantage--the tablets are sensitive to light and moisture and so cannot be taken out of their original container until you swallow them. Just why we need yet another ARB, and one that is so difficult to use to boot, is never explained.

I think these examples highlight what the drug industry is up against, due to the lack of real breakthrough drugs these days. While we might have some pity for the poor marketers who have to convince us that these pigs look good in lipstick, that still does not justify the shady marketing practices that we discuss in this blog practically every week.

Ghostwriting: Bolder than Ever

The current status of ghostwriting seems well summarized by an article on a blog of UK's Guardian:
http://www.guardian.co.uk/science/2011/may/20/drug-companies-ghost-writing-journalism

What we have been calling "Medical education and communications companies" (MECCs) on this side of the pond seem to be called "publication planning agencies" in the UK, but other than that there does not seem to be any trans-Atlantic difference.

The Guardian blogger discovered a considerable degree of what some would call chutzpah among the "publication planners" he spoke with. They talked about providing a real service and moving their activities from the realm of marketing into the realm of science. (Remember the drug rep's, and the physician apologist's, chorus: "It's not marketing, it's education"?) They spoke of a new level of openness in their activities.

All of which was quickly debunked by various expert commentators. The replies included:

• Dr Leemon McHenry, medical ethicist at California State University: "They've just found more clever ways of concealing their activities. There's a whole army of hidden scribes. It's an epistemological morass where you can't trust anything."


• Alastair Matheson, British medical writer: the planners' claims to having reformed are "bullshit...The new guidelines work very nicely to permit the current system to continue as it has been. The whole thing is a big lie. They are promoting a product."

So just what is going on here? My interpretation: Demands for disclosure appear in this case actually to have backfired, to some degree. The ghostwriters and their handlers used to work strictly in the dark. It then became obvious to them that the very fact that they operated out of sight gave credence to charges that they were up to no good. So they decided that the wiser strategy was to pretend to come out into the daylight. They talk more openly about what they do and crow about what a valuable service it is, thereby creating an aura of transparency.

But there is still no real transparency. They say that they simply "help" the academic guest author to write the paper, when in actuality, it's the same ol' same ol'--the company-directed ghostwritwer writes a detailed draft and if anything, the academic (who's of course "too busy" to be bothered with the whole thing, except to pocket his fee) maybe changes a few words here and there to keep up appearances. And what ends up published is the company's chosen spin, with the academic credibility of the supposed author and his institutional affiliation pasted on. What is never disclosed is the actual amount and type of work on the manuscript that the "ghost" and the "guest" each contributed, or what each was paid by the drug company for their deeds.

Two lessons here--first, demanding disclosure, rather than an end to nefarious practices, may not be a half-way step toward a solution but actually a regressive step. Second, when enough money is involved, expect quick adaptation to new realities, but no basic change in behavior or attitudes.