Retinal Specialists Get the Integrity Award--Genentech and Avastin

I am rather shocked to look back in the blog archives and see that I have not yet addressed the Avastin-Lucentis controversy. So I need to provide some background before handing out today's integrity award.

Quick overview--Genentech, the biotech firm, is maker of a very successful drug (brand name: Avastin) that is quite useful in colon cancer. The drug works by counteracting the tendency of tumors to create a lot of new, small blood vessels to keep the growing tumor supplied with blood. Some smart person figured out that the eye disease called wet macular degeneration is caused by a similar proliferation of new blood vessels and so the same sort of drug might help that condition too. (Wet macular degeneration occurs mostly in older folks but is not the most common sort of macular degeneration, a common cause of progressive vision loss. Still it affects a large number of people.)

So some retinal specialists tried Avastin by injection into the appropriate area of the eye and found that it really worked just great--highly effective and apparently very safe. The special bonus was the price. Avastin is extremely expensive for colon cancer, costing many thousands of dollars for a course of treatment. But the dose you need to treat an eye is a tiny fraction of the dose you need for colon ancer. So a single very expensive vial of Avastin can produce hundreds of relatively cheap doses for eye use.

Genentech had figured out the marketing angle on this pretty early on. They first did the usual "evergreening" trick, figuring out what portion of the Avastin molecule was the business end and creating a smaller molecule that contained that active portion. (Brand name for the new fragment of the old drug: Lucentis.) They then, based on some suspect animal data, declared that they just knew, without doing any further studies, that Avastin was too large a molecule to penetrate into the eye where it was needed. That was the excuse they used for not subjecting Avastin to any formal scientific trials to see if it worked in the eye. Then they did studies of Lucentis and showed that (surprise) it did work pretty well in the eye, and so they marketed Lucentis with a specific label saying this form, and only this form, was for eye use. Of course, since Lucentis was intended for eye use only, they prepared it in very tiny vials, each containing enough for one treatment, and priced each vial at a hugely expensive figure. Somebody calculated that at the price charged for Lucentis by Genentech, if all people with wet macular degeneration got treated with that drug, the entire present-day Medicare budget for eye treatment would go into the pockets of Genetech.

Now, stop for a minute and think what the average retinal specialist out in community practice is facing in the choice between Avastin and Lucentis. All the Genentech reps are heavily pushing Lucentis and giving a whole slew of phony reasons why Avastin is no good for eye use. We presume that there was all the usual bribery with fancy "educational" conferences at plush resorts for those who prescribed Lucentis. Coupled with all that marketing pressure is the threat that if any of them use Avastin in the eye, and there are any bad consequences, they'll have the pants sued off them for using an off-label drug that was not FDA approved for this purpose.

So if the retina guys acted like most docs act most of the time, when faced with the juggernaut of Pharma marketing, they would all be using Lucentis, and the patients and Medicare would be going bankrupt.

But that is not what happened. Despite all this pressure, the obvious rightness of using the good, cheaper drug continued to win out, and a significant number of specialists were using Avastin for wet macular degeneration and passing the savings along to the patient or the insurer.

Genentech was furious that the docs were refusing to be bribed, as usual. They cranked up their campaign, threatening to cut off supplies of Avastin to anyone who was making it available for eye use. They did this of course not for slimy financial reasons, but for good scientific reasons because they wanted to promote the very best quality of care.

On October 29, the American Academy of Ophthalmology put out a news release:
http://www.aao.org/advocacy/avastin20071029.cfm

The AAO and the American Society of Retina Specialists sent a high level delegation to meet with the Genentech bigwigs. Genentech agreed to hold off its threatened sales embargo, not to impede physicians or pharmacies seeking to use Avastin, and to seek advance comment from the two societies before putting out any new statements comparing Avastin to Lucentis. (Genentech, for its part, indicated that it was working in tandem with FDA guidance and that depending on what the FDA did or did not approve, it might later rescind this agreement.)

It is not clear what will happen in the future. A clinical trial to compare Avastin and Lucentis head-to-head for wet macular degeneration is now underway, with neutral funding I believe. In any event it seems that retinal specialists have as a group been singularly impressive and successful in standing up for the patient.

Yet More Evidence Linking Industry Funding to Biased Research Outcomes

HOOKED contains a considerable discussion of the evidence that pharmaceutical trials funded by industry are substantially more likely to favor the company's drug than studies funded by neutral parties (by about 4-fold). However, if people are going to prove it some more, I'm game, especially if they help us see how it's done.

A team of investigators hailing from Spain, Mexico, and Wisconsin reviewed 275 studies of inhaled corticosteroids that were company-funded and compared 229 studies of the same class of drugs that were non-industry-funded. The specific question they explored was how likely the study was to report significant adverse effects.

They discovered that only 34.5% of the industry-funded studies reported any adverse effects compared to 65.1% of the neutral studies. Once they adjusted for important features of the study design, the difference was no longer significant. This in turn indicated that the way industry-sponsored studies underreport adverse effects is by being deliberately designed with trial methods that are likely not to detect such events--such as by using the study drug in very low doses.

HOOKED explains that according to the best thinking in today's drug industry, research is a marketing tool--in fact, if the company CEO allows the scientists to design trials without the marketing depatrtment looking over their shoulder at every step of the way, the CEO should be fired. Here we see just one more example of this philosophy in action.

Nieto A, Mazon A, Pamies R, et al. Adverse effects of inhaled corticosteroids in funded and nonfunded studies. Arch Intern Med 167:2047-53, Oct. 22, 2007.

Newsweek Reports Fewer Docs Seeing Reps

Newsweek, this week, reports a trend among physicians and medical centers away from talking with reps and accepting company gifts (see the article: http://www.newsweek.com/id/57342). The article, of course, is music to my ears; but it would have been nice had it included just a little bit of data--any data--to back up the assertion that such a trend exists.

NEJM: Conflicted Editorialist?

I must have been taking an extended nap the week the May 3 New England Journal of Medicine came out, or curiosity alone would have prompted me to look up an article that claimed you only had to treat patients with a once-a-year dose of a drug. A group calling itself HORIZON, which stands for Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly by some alphabetical legerdemain that I cannot fathom, reported that when 3889 women with postmenopausal osteoporosis were randomized to either a once-yearly IV infusion of the drug or placebo, and followed for 3 years, the drug group showed significant reductions in both hip and vertebral fractures. The only downside was an increase in serious atrial fibrillation in the drug group. No surprise that the study was funded by the maker of the drug, Novartis.

Fortunately this study was pointed out to me by my colleagues Rick Bukata and Jerry Hoffman in their Primary Care Medical Abstracts monthly tapes (www.ccme.org). They went on to point out the editorial that accompanied the HORIZON paper, by Dr. Juliet Compston of Cambridge, England. The editorial reads like a long, glowing advertisement for zoledronic acid. Besides being sure to include the glitzty acronym HORIZON in the title of the editorial, she gushes about the relative risk reductions instead of the more informative absolute risk reductions (e.g. noting a 70% reduction in the rate of vertebral fractures, which translates into an absolute risk reduction of from 10.9% to 3.3%). The fine print at the end lists a number of drug companies for which Dr. Compston consults and speaks, and notes among other things that she serves on data and safety monitoring boards for Novartis.

At one time the NEJM prided itself on having strict policies that prevented editorials from being written by those with financial ties to the makers of the drug being studied. Apparently such policies are old-fashioned.

Rick Bukata also chided NEJM for leaving out the key fact that a single IV dose of zoledronic acid runs about $1000, independent of any administration fees or physician costs.

Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809-22, May 3, 2007.

Compston J. Treatments for osteoporosis--looking beyond the HORIZON. N Engl J Med 356:1878-80, May 3, 2007.

Conflicts of Interest Rife at IOM? Maybe Not

One of the writers whom I have relied on in the past is Merrill Goozner, who works with Center for Science in the Public Interest and wrote an important book on the drug industry, The $800 Million Pill, exposing the inflated claims made by the companies for their costs of doing research. He maintains a list called "GoozNews" for his personal views. So when I read his concerns about a new conflict of interest panel being assembled by the Institute of Medicine, I took notice:

http://www.gooznews.com/archives/000842.html

The prestigious IOM appointed a 15 member committee to produce model guidelines for dealing with conflicts of interest with industry. The committee, Goozner noted, was charged with developing guidelines that would not interfere with industry relations. So right away Goozner smelled a rat. The rat got more odorous when he discovered that 3 members of the committee had to have waivers to be allowed to sit on the panel due to their own ties to industry.

Goozner went on to give a list of prestigious members of the IOM who were not invited to serve on this committee despite having written important works on conflict of interest with industry, such as Jerry Kassirer, author of On the Take. (He left me off the list but that is neither here nor there.) Why, he asked, were IOM members known for their expertise on COI not appointed to the committee, while those known to be in bed with industry were?

While I was initially alarmed, I decided to check out Goozner's link to the committee composition. I was mainly interested in whether some of the very distinguished medical ethics folks who are members of IOM were appointed to that committee. After all, a 15 member committee can afford to have a handful of people who represent the pro-industry end of the spectrum, and probably needs them for balance if their final product is to be credible. But if people with expertise in ethics are left out, then I would be really worried.

So I was relieved to see that the chair of the committee is Bernard Lo, author of the textbook of medical ethics that I use with my students; and another committee member is Jim Childress, who is co-author of the best-selling textbook of bioethics. Also a member of the panel is Dennis Thompson, who wrote a seminal piece on COI several years ago for the New England Journal (though in HOOKED I found reason to dissent from the definition of COI that he offered there).

I then went down to the list of COI waivers/disclosures and found that Jim Childress was one of those listed as having conflicts. Now, call me naive if you wish; but when someone of his stature and reputation is named to a committee like this, I am inclined to give him a pass even if he has on occasion consulted with industry.

So all in all, I believe that the IOM may have appointed a reasonable panel to address COI issues and to develop model guidelines. I agree it would have been better had at least one of those known for writing specifically about Pharma, such as Kassirer, Lisa Bero, or yours truly, been asked also to serve. But the IOM process frequently has other members review a draft report after a committee has finished their work; so we may well be asked to be reviewers at a later time.

I am most worried about the apparently slanted charge to the committee, stressing making nice with industry over scientific and profesional integrity. I hope that the ethicists on the committee will make sure that balance is restored during their process.

Bashing Head-to-Head Drug Trials--from a Conflicted Source

This post is thanks directly to Dr. Roy Poses's "Health Care Renewal" blog, and indirectly thanks to the Prescription Project whose "weekly reader" directed me to it.

http://hcrenewal.blogspot.com/2007/10/whose-opinions-did-new-york-times.html

Dr. Poses quotes from a New York Times op-ed (Oct. 18) by Peter Pitts, writing on behalf of the Center for Medicine in the Public Interest, which the paper identified as "a nonprofit organization that receives financing from the pharmaceutical industry." (Try to find something that they have printed or disseminated that is not favorable to the drug industry.) Left unsaid by the Times is the fact that Pitts is also a senior vice president for a PR firm that includes many pharmaceutical giants among its accounts.

Pitts is upset that the SCHIP bill (health insurance for children) may not be dead despite Congress's failure to override the Presidential veto. The bill has a lesser known provision that would create a Center for Comparative Effectiveness for Medicare. This Center would have a $300M budget to do what the popular parlance calls "head-to-head" trials of drugs to see whether expensive new drugs are truly better than older, cheaper drugs.

Pitts proceeds to give several reasons why comparative effectiveness research is really a rotten idea--the studies may be flawed; and we cannot trust the government to do them fairly, as Medicare has a vested interest in cutting costs and not in finding out which drug is truly best.

Poses then goes on to dismantle these arguments detail by detail, and to note what Pitts leaves unsaid--that the current system is that no such head-to-head trials are done, or if they are done, they are done on the company dime and are aimed at providing marketing advantage, not at getting the best scientific answer. It is a far stretch to imagine that Medicare's conflict of interest would be worse than the industry's.

Poses leaves out yet another argument against Pitts. Medicare is a government program. For all the flaws that this might give it, the bottom line is that it is of necessity fairly open and accountable. If Medicare manipulated studies to be sure that the cheapest drug "won" all the time, there is a pretty good chance that somebody would get wise and blow the whistle. By contrast, the drug companies own their research data as proprietary, and HOOKED recounts numerous instances where if those data don't support the company's marketing message, they never see the light of day--or do so only after somebody files a lawsuit and company documents become discoverable in court.

The shamelessness with which the industry continues to put forth its preferred message, despite all logic and science to the contrary, via its numerous paid minions, continues to astound.

Academic Departments: Lots of Relationships with Industry

A recent study in JAMA has garnered a lot of attention, but in my opinion tells us little that we did not already know. The main value of the study is to quantify an area that had previously not been formally surveyed.

The target of this survey by a group at Mass. General (plus my good friend Susan Dorr Gould at University of Michigan) was chairs of selected departments in U.S. medical schools. Of the two-thirds who responded, 60 percent had some form of personal relationship with industry, and 2/3 of the departments had some form of relationships with industry. (I would have guessed, myself, that the numbers would be higher.) In general, the chairs were not worried about these relationships having any negative impact on their department (now where have we heard that before?)

Campbell EG, Weissman JS, Ehringhaus S, et al. Institutional academic-industry relationships. JAMA 298:1779-86, Oct. 17, 2007.