Pharmaceutical Industry

Shannon Brownlee has a new piece up over at TIME Ideas. This time, it's a preview of the whole mess of information patients will soon be able to get about their doctors' financial relationships. It doesn't look pretty.

"As of this year, doctors who accept gifts and payments from drug and device makers will see their names on the web, the result of the 2010 Physician Payment Sunshine Act, one of the most controversial provisions in the health care reform law. Companies will be required to report any gift or payment to a doctor or academic researcher over $10, whether it’s in the form of stock options, speaking fees, box seat tickets, knickknacks for the doctor’s office or travel to a medical conference. Doctors will also be required to disclose payments and gifts."

While those payments don't necessarily meet the classic definition of payola (they are not a literal quid pro quo), the evidence showing its effect on prescribing habits is clear: Docs who take money from Pharma use their funders' products more often. Given the already-rampant misuse and ineffective use of prescription drugs and medical devices, that's ample reason to be concerned. When the data come out, check your doctor: you may be surprised.

Imagine yourself in front of your computer, looking up information about a drug prescribed by your doctor. Your Internet search tells you that there is a cheaper, maybe even a generic version available, but you have just paid top dollar for the brand name drug. You also learn that another treatment may be safer than the prescription you just filled. Now imagine you discover that your doctor gets paid by the manufacturer to promote the drug to other doctors.

Conflict of interest is back in the news this week, with a new story in the Washington Monthly by medical journalist Jeanne Lenzer and Keith Epstein. The story, also reported on by the Wall Street Journal and co-published with BMJ, reports that three decisive votes on a recent FDA safety evaluation panel had financial relationships with Bayer--maker of the drugs in question.

Yaz, Yasmin, Beyaz, and Safyral are Bayer's birth control drugs that contain the hormone drospirenone. Such drugs have come under heavy fire in recent years for being unsafe. Consumers and researchers have argued that the drugs increase the likelihood of fatal blood clots, deep vein thrombosis, and other serious adverse events.

In light of those allegations, the FDA convened a panel to assess the evidence. Five or six members of that panel had financial relationships with Bayer; in what appears to be a violation or misapplication of the FDA's conflict of interest rules, they were still allowed to vote. That undermines the intent of conflict of interest rules, which should aim to protect public confidence in the FDA and avoid even the appearance of impropriety. In the end, all conflicted panelists voted that the drug was safe enough to stay on the market; if the their votes had switched, it would have reversed the 15-11 vote.

The truly absurd part of this story is the member the FDA chose to exclude from voting: consumer advocare Sidney Wolfe.  Wolfe had previously made statements critical of the drugs, and so the FDA deemed that he had an "intellectual conflict of interest." Such a charge is inane; if he was conflicted, surely any clinician who had ever prescribed (or declined to prescribe) one of the drugs would be similarly unable to vote! FDA panelists are responsible for doing exactly what Wolfe does: evaluating the evidence and coming to a conclusion. Making familiarity with the evidence a disqualifying factor is patently ridiculous and contrary to the purpose of the board.

This is a guest post from independent medical investigative journalist Jeanne Lenzer. She is a former Knight Science Journalism Fellow and a frequent contributor to BMJ, and has published works in  The Atlantic, The New York Times Magazine, Discover, The New Republic, and other outlets.

When doctors recommend tests, drugs or surgeries to prevent bad outcomes (think cholesterol-lowering agents to prevent strokes or cardiac stents to prevent heart attacks) they tap into our deepest sense of what constitutes commonsense: An ounce of prevention. Catch it early. A stitch in time.

It can’t be a bad thing to catch problems early, can it?

Unfortunately, one of the toughest things to explain is why detecting some illnesses at their earliest stages can cause more harm than good. Take this example: Since elevated cholesterol is associated with a higher risk of cardiovascular disease, doctors often prescribe drugs known as statins to people with elevated cholesterol levels in the hopes of reducing their risk of a heart attack or stroke.

Here comes the part that’s tough to explain – because it is so counterintuitive: Statins only help individuals who already have had a heart attack or stroke (with a few exceptions, and more on that later).

Of course, this makes no sense to most people. Isn’t the whole point of taking cholesterol-lowering agents to prevent a heart attack? Why should anyone wait until after a heart attack or stroke to begin taking a drug designed to prevent a heart attack or stroke?

The answer rests with disease creep and the simple statistical quirks that come with it. In the past, doctors treated diseases that caused symptoms. But now we have tests and imaging machines that can detect risk factors and illnesses in their earliest stages. Like cholesterol. Elevated cholesterol is not a disease. It doesn’t cause symptoms. It is a risk factor. People with high cholesterol levels are somewhat more likely to develop a heart attack or stroke, but they are at far less risk than individuals who already have cardiovascular disease. This is the definition of disease creep: when pre-conditions or risk factors are treated as if they are the same as the actual disease state.

Here’s a thought experiment (with purposefully exaggerated numbers) to help understand this puzzle: Imagine a group of people who have the rare but awful Disease A, which is so terrible that all of its victims will die. Now imagine the discovery of Wonder Drug X, which cures half of the patients with Disease A. Unfortunately, Wonder Drug X does have a pretty bad side effect profile – it’s a very powerful drug, after all – and 10 percent of people who take it will die from liver failure. Despite this worrisome side effect, Wonder Drug X is truly an advance for patients with Disease A: For every 200 patients with the disease who are treated, 100 will now survive and only 10 of the 100 survivors will die of the drug’s side effects. That means 90 more people out of 200 will survive thanks to Wonder Drug X.

But now imagine a different group of 200 people, who don’t actually have disease A, but instead have a genetic marker which “is associated with” Disease A. In this scenario only 1 in a million people in the general population will get disease A. If you have the genetic marker, the risk is much higher, such that 2 of these 200 people will develop the disease at some time in the future. The genetic test gets highly promoted – “find out your risk early, because we now have a treatment that works, and the sooner you’re treated, the better!” There is a tiny grain of truth to this – of the 2 people identified by the genetic test, 1 (50%) will now be saved by Wonder Drug A.   This might sound just as good as before; here’s a group of people with 10,000 times (!) the risk of the general population to develop a uniformly fatal disease. Surely it’s worth taking a drug that can cure that disease in half the cases, isn’t it?

But it really isn’t the same. Because saving that one life isn’t remotely worth the harm caused by Wonder Drug X in these 200 people. For while each individual is at a 10,000 fold risk of the disease, only 2 are destined to die from it. On the other hand, if they take Wonder Drug X, roughly 20 (10 percent of the 199 survivors) will die unnecessarily of liver failure.

The expiration of Pfizer's patent on atorvastatin--the chemical behind the blockbuster cholesterol-lowering pill Lipitor--marks a potentially transformative moment for the drug industry. Currently the best-selling drug in the world, Lipitor (and soon several of its fellows) will have to compete with cheaper generics for market share, putting pressure on drug companies to come up with the next round of blockbusters.

We hope that doesn't happen--and in her column over at TIME Ideas, Shannon Brownlee has some comments on why. Basically, the structure of the pharmaceutical industry pushes doctors toward prescribing and patients toward taking lots of pills that we don't really need. That's driving Here's her commentary on what might change to mitigate that pattern in the future:

"...even while Pfizer is now attempting to hold on to its market share by cutting deals with pharmacy benefits managers and directly targeting patients, there are several possible solutions to the blockbuster problem, some of which will happen all on their own. Genomics research will clarify who can really benefit from which drugs and who won’t be helped at all and will make it harder and harder to sell a pill to everyone. Through efforts like the National Physicians Alliance’s Top 5 project, doctors will become even more aware of marketing tactics and will be motivated to stop doing things that don’t benefit patients.Some experts have suggested changing patent law to give drug companies a set amount, say 15 years, of market exclusivity starting from the time they bring the drug to market. (Under current patent law, the clock starts ticking when the patent on the molecule is filed but development might take longer.) This might discourage the legal maneuvering they now engage in (tinkering slightly with the formula, etc.) to delay the moment when generics come in. I think it would be more effective to outlaw, or at least curtail, direct-to-consumer drug advertising, which has contributed mightily to the industry’s success in selling sometimes inappropriate drugs to patients."

You can read the full column here. We'll continue to cover any interesting developments in the blockbuster drug saga--to stay on top of all our posts, don't forget to follow us on Twitter!

Shannon Brownlee's newest piece at TIME Ideas calls the FDA's de-labeling of Avastin as a breast cancer treatment "one of the most important decisions ever made by a federal agency for the nation’s long-term fiscal outlook." We don't think that's an understatement.

The importance of the Avastin decision is twofold: it strengthens the institution, and it paves the way for making the hard-but-inevitable choices that will allow us to contain health care costs in the future.

As we've noted, the whole purpose of the FDA is to determine which drugs are safe and effective. Avastin used to treat breast cancer is neither for most patients, and until the manufacturer can show that there is a sub-population of patients that can benefit, women who take it are more likely to be harmed by the drug than helped.

Now, we need to go one step further, and acknowledge that when the FDA rejects a drug--not just when it has not approved it, but when it has actively rejected it--the fiscally and medically responsible choice is not to continue paying for the treatment. As Brownlee notes in the piece, it's not a small part of the cost problem:

"Avastin is just one example of the dozens, perhaps even hundreds of drugs, tests, surgeries and medical devices that offer marginal, if any benefit to patients, which we pay for nevertheless. To take just a single example, it’s estimated that about one-third of the imaging tests, the hundreds of millions of X rays, CT scans and MRIs that are performed each year, do little if anything to improve doctors’ ability to diagnose their patients’ conditions or change the course of treatment they recommend."

The FDA's credibility is on a roll lately.

Last week, they revoked approval of Avastin for treating matastatic breast cancer, after the evidence made it clear that the drug doesn't work.

Now, as Duff Wilson of the New York Times reports, Merck has agreed to pay federal and state governments $950 million for illegal marketing of its painkiller, Vioxx. $321 million of the settlement is a criminal fine; the remainder will go to reimburse Medicare and Medicaid for unwarranted use of the drug.

Vioxx was pulled from the market in 2004, after findings that it increased the risk of heart attack, stroke, and death, but this round of fines is unrelated to the drug's health risks. Rather, the fines and reimbursements are based on Merck's illegal "off-label" marketing. The company pushed Vioxx for rheumatoid arthritis before it had FDA approval for that use. That's why this is a victory for the regulator--hefty fines like this one are a credible threat that will (hopefully) deter other companies from marketing off-label uses of their products.

The total financial fallout around Vioxx now stands at nearly $6 billion. An earlier payment of almost $5 billion settled lawsuits from people whose family members were harmed by the drug. A case by Merck investors claiming they were misled about the drug's risks is ongoing.

Evidence-based medicine is critical to improving the effectiveness (and cost-effectiveness) of our medical system. In order to do expand its reach, we need doctors who understand medical evidence. Unfortunately, as recent debates about PSA testing and mammograms for women under 50 have shown, many doctors have (at best) a fuzzy grasp of statistical reasoning. Without a good understanding of statistics, physicians are as vulnerable as any other "man on the street" to serious statistical mistakes--mistakes that affect their clinical judgment.

Some of that can be reformed in medical schools: the medical curriculum reform movement, which often focuses on improving teamwork and coordination of care, has also incorporated calls to teach med students about medical evidence and how to properly interpret it when making clinical decisions.

What can we do, though, about the doctors already out there practicing medicine? PharmedOut, a project of the Georgetown Department of Pharmacology, is offering a new "5-Minute Fast Stats" powerpoint that provides information about a few critical concepts in medical statistics: the difference between absolute and relative risk (and between absolute and relative risk reduction), the number needed to treat (NNT), and the number needed to harm (NNH). The powerpoint is quite good for understanding the critical difference between absolute and relative risk--and most importantly, it points out the ways that drug manufacturers use the different numbers to emphasize benefits and minimize risk. The section on NNT and NNH is slightly more confusing--we would have focused more on interpreting the numbers and what they mean for patients, rather than computing them--but the concepts remain important.

We certainly hope that doctors will take advantage of the presentation (and the other resources on PharmedOut's website), and take the time to share it with their colleagues (download here). The more our doctors understand the messages they're getting from medical research and pharmaceutical marketing, the better off we'll be.

Larry Husten, a medical reporter who specializes in cardiology, wrote a post over the weekend responding to my piece on the blog last week about a donation from the Parsemus Foundation to the "Less is More" series in the Archives of Internal Medicine. The Parsemus Foundation, in Husten's view, is biased against angioplasty and stents, and the grant to the Archives represents a conflict of interest. Husten goes on to suggest that the Archives didn't want to disclose the fifty grand it got from Parsemus Foundation, which he calls, "medical Luddites who stand against one of the most important advances in modern medicine."

Wow. "Medical Luddites." We're talking about a family foundation with nothing to gain financially from a decline in the use of angioplasty and stents. When we talk about conflict of interest in medicine, the topic is usually the billions of dollars spent by the drug and device industries to influence physicians, systematically bias medical science, and pack medical journals with studies that amount to what psychiatrist and medical critic Barney Carroll calls "experimercials." Richard Horton, editor of the British medical journal, The Lancet, went further in an essay in The New York Review of Books:

"Indeed, medical journals have become an important but underrecognized obstacle to scientific truth-telling. Journals have devolved into information-laundering operations for the pharmaceutical industry."

The Parsemus Foundation hardly seems to be in the same league in terms of its power to sway medical opinion, but maybe there's a deeper issue here with regard to the Less is More series. In an editorial launching the series in 2010, Archives editors wrote that it was intended to "highlight situations in which the overuse of medical care may result in harm, and in which less care is likely to result in better health." The fact is, Less is More represents a tiny dissenting voice in a medical literature that for the last 50 years has been saying, in effect, More is More.

For those who have been following the back and forth over the Less is More blog I posted last week, here's the poster that upset some cardiologists when it was up on the Parsemus Foundation's site.

Over the top? Of course it is -- it's satire! And like all good satire, it contains a few grains of truth mixed with a hefty dose of exaggeration. 

Still, it's only fair to point out that stents aren't really the modern equivalent of leeches. Back when bloodletting was in vogue, it was believed that an excess of blood (one of the four "humors") was to blame for everything from epilepsy to rheumatism to tuberculosis. Got a fever? Let's bleed you! Given the prevailing view of physiology, leeches were an obvious, if entirely wrong-headed, way to rid the body of disease. 

Angioplasty and stents, on the other hand, are backed up by more than belief and theory. In fact, to cardiology's credit, there is a wealth of valid scientific evidence to guide their use. (These two treatments are often called percutaneous coronary intervention, or PCI.) Among the most important studies was the COURAGE trial, published in 2007, which prompted cardiologists to re-examine their assumptions about the effectiveness of PCI, and according to a thoughtful post by Larry Husten (@cardiobrief) at Forbes, has led to a steep decline in their use.