By David Shaywitz, MD

In a piece just posted at TheAtlantic.com, I discuss what I see as the next great quest in applied science: the assembly of a unified health database, a “big data” project that would collect in one searchable repository all the parameters that measure or could conceivably reflect human well-being.

I don’t expect the insights gained from these data will obsolete physicians, but rather empower them (as well as patients and other stakeholders) and make them better, informing their clinical judgment without supplanting their empathy.

I also discuss how many companies and academic researchers are focusing their efforts on defined subsets of the information challenge, generally at the intersection of data domains.  I observe that one notable exception seems to be big pharma, as many large drug companies seem to have decided that hefty big data analytics is a service to be outsourced, rather than a core competency to be built.  I then ask whether this is savvy judgment or a profound miscalculation, and suggest that if you were going to create the health solutions provider of the future, arguably your first move would be to recruit a cutting-edge analytics team.

The question of core competencies is more than just semantics – it is perhaps the most important strategic question facing biopharma companies as they peer into a frightening and uncertain future.

Continue reading “Time For Biopharma To Jump On The “Big Data” Train?”

By Judy Stone, MD

Have you ever wondered about what goes on behind the scenes—how new drugs are magically produced and brought forth? We’ll continue to take the mystery out of clinical research and drug development and to provide background information so that both patients and physicians can make more informed decisions about whether they wish to participate in clinical trials or not.

Why care?

To develop a medicine, from the time of discovery of the chemical until it reaches your drug store, takes an average of 12-15 years and the participation of thousands of volunteers in the process of clinical trials (Fig 1).

Very few people participate in clinical trials—it is even less than 5% for patients with cancer—due to lack of awareness or knowledge about the process. We’ll go into detail about how drugs are developed in later posts.

An inadequate number of volunteers is one of the major bottlenecks in drug development, delaying the product’s release and usefulness to the public. Of course, many people may suffer or even die during this wait, if they have an illness that is not yet otherwise treatable. So if you want new medicines, learn about—and decide if you wish to participate in—the process. I have, as a volunteer subject, researcher, and advocate. Continue reading “Clinical Trials for Beginners”

By Trish Greenhalgh, MD

The most over-used and under-analyzed statement in the academic vocabulary is surely “more research is needed”.

These four words, occasionally justified when they appear as the last sentence in a Masters dissertation, are as often to be found as the coda for a mega-trial that consumed the lion’s share of a national research budget, or that of a Cochrane review which began with dozens or even hundreds of primary studies and progressively excluded most of them on the grounds that they were “methodologically flawed”.

Yet however large the trial or however comprehensive the review, the answer always seems to lie just around the next empirical corner.

With due respect to all those who have used “more research is needed” to sum up months or years of their own work on a topic, this ultimate academic cliché is usually an indicator that serious scholarly thinking on the topic has ceased. It is almost never the only logical conclusion that can be drawn from a set of negative, ambiguous, incomplete or contradictory data.

Recall the classic cartoon sketch from your childhood. Kitty-cat, who seeks to trap little bird Tweety Pie, tries to fly through the air.  After a pregnant mid-air pause reflecting the cartoon laws of physics, he falls to the ground and lies with eyes askew and stars circling round his silly head, to the evident amusement of his prey. But next frame, we see Kitty-cat launching himself into the air from an even greater height.  “More attempts at flight are needed”, he implicitly concludes.

Continue reading “Less Research Is Needed”

By Dr. Wes

The paper from the New England Journal of Medicine that reports azithromycin might cause cardiovascular death is not new to electrophysiologists tasked with deciding antibiotic choices in patients with Long QT syndrome or in those who take other antiarrhythmic drugs.   Heck, even the useful Arizona CERT QTDrugs.org website could have told us that.

What was far scarier to me, though, was how the authors of this week’s paper reached their estimates of the magnitude of azithromycin’s cardiovascular risk.

Welcome to the underworld of Big Data Medicine.

Careful review of the Methods section of this paper reveals that “persons enrolled in the Tennessee Medicaid program” were the subjects, and that the data collected were “Computerized Medicaid data, which were linked to death certificates and to a state-wide hospital discharge database” and “Medicaid pharmacy files.”   Anyone with azithromycin prescribed from 1992-2006 who had “not had a diagnosis of drug abuse or resided in a nursing home in the preceding year and had not been hospitalized in the prior 30 days.”  Also, they had to be “Medicaid enrollees for at least 365 days and have regular use of medical care.”

Hey, no selection bias introduced with those criteria, right?  But the authors didn’t stop there.

Continue reading “How Bad Is Azithromycin’s Cardiovascular Risk?”

By Rob Lamberts, MD

It was during my residency that the first indication of heart toxicity of antibiotics affected me personally.  The threat was related to the use of the first of the non-drowsy antihistamines – Seldane – in combination with macrolide antibiotics, such as Erythromycin causing a potentially fatal heart arrhythmia.  I remember the expressions fear from other residents, as we had used this combination of medications often.  Were we killing people when we treated their bronchitis?  We had no idea, but we were consoled by the fact that the people who had gotten our arrhythmia-provoking combo were largely anonymous to us (ER patients).

Fast forward to 2012 and the study (published in the holy writings of the New England Journal of Medicine) that Zithromax is associated with more dead people than no Zithromax.  Here’s the headline-provoking conclusion:

During 5 days of therapy, patients taking azithromycin, as compared with those who took no antibiotics, had an increased risk of cardiovascular death (hazard ratio, 2.88; 95% confidence interval [CI], 1.79 to 4.63; P<0.001) and death from any cause (hazard ratio, 1.85; 95% CI, 1.25 to 2.75; P=0.002).  Patients who took amoxicillin had no increase in the risk of death during this period. Relative to amoxicillin, azithromycin was associated with an increased risk of cardiovascular death (hazard ratio, 2.49; 95% CI, 1.38 to 4.50; P=0.002) and death from any cause (hazard ratio, 2.02; 95% CI, 1.24 to 3.30; P=0.005), with an estimated 47 additional cardiovascular deaths per 1 million courses; patients in the highest decile of risk for cardiovascular disease had an estimated 245 additional cardiovascular deaths per 1 million courses. (Emphasis Mine).

Continue reading “Z-Packing”

By Marc Siegel, MD

The Food and Drug Administration is considering removing prescription requirements for medications that treat common conditions, such as high blood pressure, diabetes, asthma, migraines and high cholesterol. This means that you would be able to go to your local pharmacy, fill out a questionnaire, receive a diagnosis and purchase a medication, all without intervention or direction from a physician.

As a doctor, I think this is a very bad idea. Although it is true that diagnoses are often missed — reports estimate that as many as 7 million diabetics in the U.S. remain undiagnosed — and although easier access to drugs could theoretically encourage patients to take their medications, I am concerned that expanding over-the-counter access will lead to wrong diagnoses with improper treatments, which carry side effects.

Remember, medicine is an art, practiced on an individual basis. A medication that works for one person doesn’t always work for another. I am constantly changing cholesterol or high blood pressure medications for my patients because of unanticipated side effects such as muscle aches or dizziness.

Lack of follow up

What would happen if I weren’t involved to monitor treatments and make necessary changes? The upfront cost savings from cutting out doctors and their office fees will be more than made up by longer term costs of improper diagnoses or unmonitored complications.

Advocates of expanding over-the-counter medications point to aspirin or allergy drugs as examples that have proved successful without a doctor’s prescription. But for every patient who is glad not to have to visit my office for an allergy prescription, I can point to another patient who has suffered side effects like fatigue that he or she didn’t realize were due to that same pill, or where the allergic reaction was due instead to food.

The fact that common painkillers have been available over the counter for decades also doesn’t provide a convincing argument for bypassing prescriptions. Consider that more than 100,000 Americans are hospitalized every year due to bleeding from aspirin or other OTC non-steroidal anti-inflammatory pills, and acetaminophen is the No. 1 cause of acute liver failure. Continue reading “Expand Over-the-Counter Medications? Very Bad Idea”

By David Shaywitz, MD

Reviewing “The Myth of The Paperless Office” for the New Yorker in 2002, Malcolm Gladwell argued that if the computer had come first, and paper didn’t exist, someone would have had to invent it.  Paper, it turns out, is a lot more useful than we typically appreciate.

It occurred to me that perhaps the same might be said of another product we seem to take for granted in the digital age – medicines.  (Disclosure: I work at a company that makes them.)

Medicines – you know, those little white pills that everyone loves to critique – are in many cases remarkably effective solutions to very difficult problems; it’s actually kind of amazing how useful some of these products can be.  What an incredibly powerful idea – addressing a difficult and complex health problem with a simple pill you can pop before breakfast.

I read a tweet recently asserting that physicians may soon prescribe health apps as an alternative to medications; my initial reaction: good luck with that one.  It’s certainly easy enough to envision how magical thinking about the power of health apps will soon be replaced by disappointment as app developers realize something drug makers have known for years: it’s hard to improve health, and it can be very difficult to get patients to stick with a treatment long enough to make a difference.

Continue reading “Pills Still Matter”

By Marya Zilberberg, MD

Reading Barbara Ehrenreich’s “Bright-Sided” has been liberating in that is has given me permission to let my pessimistic nature out of the closet.

Well, it’s not exactly that I am pessimistic, but certainly I am not given over to brightness and cheer all the time. My poison is worry. Yes, I am a worrier, in case you had not noticed. So, imagine how satisfying it is for me to find new things to worry about. As if climate change were not enough, lately I started to worry about science.

No, my anxiety about how we do clinical science overall is not new; this blog is overrun with it. However, the new branch of that anxiety relates to something I have termed “fast science.” Like fast food it fills us up, but the calories are at best empty and at worst detrimental. What I mean is that science is a process more than it is a result, and this process cannot and should not be microwaved. Don’t believe me? Let me give you a couple of instances where slow science may be the answer to our woes.

1. Lies and damned lies

Remember this story in the Atlantic that rattled us with its incendiary message? Researcher John Ioannidis has been making headlines with his assertion that most, if not all, of what we know in medicine is in doubt, given how we do and publish research. And how we do and publish research has everything to do with the speed of “progress.” Academic careers are made with positive results, to sell news the media demand positive results, and to respond to this demand academic journals prefer only to publish positive results (this last phenomenon is referred to as “publication bias,” and is something Ben Goldacre rails against at length). A further manifestation of this fast science is that “no replicators need apply.” I am, of course, referring to an extension of the publications bias, whereby journals are not interested in publishing even a positive study that replicates a previous finding — this is simply not sexy. Thus, results have to be quick and positive to grab a share of our attention and sell academic prestige, journals and news. Continue reading “Fast Science: The Uncertainty Paradox”

By Peter Doshi and Tom Jefferson

In the fall of 2009, at the height of fears over swine flu, our research group discovered that a majority of clinical trial data for the anti-influenza drug Tamiflu ― data that proved, according to its manufacturer, that the drug reduced the risk of hospitalization, serious complications and transmission ― were missing, unpublished and inaccessible to the research community. From what we could tell from the limited clinical data that had been published in medical journals, the country’s most widely used and heavily stockpiled influenza drug appeared no more effective than aspirin.

After we published this finding in the British Medical Journal at the end of that year, Tamiflu’s manufacturer, Roche, announced that it would release internal reports to back up its claims that the drug was effective in reducing the complications of influenza. Roche promised access to data from 10 clinical trials, 8 of which had not been published a decade after completion, representing more than 4,000 patients from every continent except Antarctica. Independent verification of the data seemed imminent. But more than two years later, and despite repeated requests, we have yet to receive even a single full trial report. Instead, the manufacturer released portions of the reports, most likely a very small percentage of the total pages. (One of us, Tom Jefferson, has been retained as an expert witness in a lawsuit relating to some of these issues.)

Continue reading “Drug Data Shouldn’t Be Secret”

By Claire McCarthy, MD

Every day, there is another medical study in the news. There’s another newspaper or TV story telling us that X can cure depression or make you thinner or cause autism or whatever. And since it’s a medical study, we usually think that it’s true. Why wouldn’t it be?

But what most people don’t realize, let alone really think about, is that there might be other studies that show that X does none of those things — and that some of those studies might never have been published.

Just this week, the journal Pediatrics released an article that perfectly demonstrates this problem. There have been a number of studies that have shown that a certain type of medication, selective serotonin reuptake inhibitors (SSRIs), can help stop the repetitive behaviors of autism, like hand-flapping or head-banging. If you were to do a search of the medical literature, as doctors and parents and patients often do, you’d think that using SSRIs is a good idea. But when researchers dug deeper, they found that there were just as many unpublished studies that showed that SSRIs didn’t help. If they had all been published (they were all good enough to be published), that same search of the medical literature would have shown that using SSRIs isn’t a good idea.

This is bad. We rely on studies to guide our decisions. What is going on?

The journals that publish articles certainly play a role. After all, it’s cooler to publish a study that has a grabby headline, that promises an answer or a cure. That’s much more likely to get readers than a study that says that something doesn’t do anything at all. But it turns out that the researchers themselves play a bigger role.

Continue reading “Medical Research We Never Hear About: The Problem of Unpublished Studies”