The Blockbuster Drugs and SPIT: Can You Trust the Evidence?

From the American College of Physicians

PHILADELPHIA—At the 2006 annual session of the American College of Physicians, Thomas E. Finucane, MD, professor of medicine, Johns Hopkins University School of Medicine, Baltimore, Md, advised primary care physicians to be skeptical and vigilant concerning the safety and efficacy claims made by the drug industry, or even when presented as journal publications, about the new “blockbuster” drugs. Every aspect of study design, conduct, analysis, rhetoric, and decision to submit for publication has been modified in various industry-sponsored trials, producing a plethora of “what we in Baltimore call SPIT”—Small, Positive, Industry-sponsored Trials, Dr Finucane says.

Even publications in respected peer-reviewed journals should be viewed with a grain of salt, since many of these authors as well are emotionally indebted to the industry. Dr Finucane discusses several drugs and drug classes regularly prescribed by internists and why paying attention to the nature of the evidence as well as the side-effect profile and costs is not merely an intellectual exercise.

Proton-Pump Inhibitors

Commonly used to treat or prevent stomach and duodenal ulcers, gastroesophageal reflux disease (GERD), and Zöllinger-Ellison syndrome, proton-pump inhibitors (PPIs) are among the most widely prescribed drugs. And although PPIs may be considered the cornerstone of therapy for symptomatic GERD, the data point to a lack of efficacy in preventing the progression of Barrett’s esophagus to adenocarcinoma of the distal esophagus, he says. “If you look at what’s happened to the incidence of adenocarcinoma of the distal esophagus during the multibillion-dollar decade of PPI utilization, the incidence of the disease has been rising steadily,” he observes. “So in a patient who has GERD, basically you’re treating a bellyache with these medications.”

Dr Finucane compares the human organism to a bagel, “a solid object with a single hole (the gut) through it; and at the proximal end, in the distal foregut, there is supposed to be a bath with a pH of 2—the intent is to try to sterilize everything that’s passing through the bagel.”

This pH of 2 is present in carnivorous mammals, and “it is implausible, in my opinion, to think that something that was invented 20 years ago by a drug company is an improvement on that design feature that evolved over a million years. And we are doing away with it by PPIs,” he says.

Clostridium difficile

Furthermore, epidemiologic evidence has shown that the PPIs are associated with a doubling of the risk of pneumonia and of diarrhea.

SSRIs

Commonly prescribed for depression, the selective serotonin reuptake inhibitors (SSRIs) are effective in treating major depression in about half of the patients who take them, says Dr Finucane. “Lots of people believe that they are much more effective than this, and that once you start an SSRI, you can pretty much expect to get better.”

BMJ

It is little wonder that physicians would think that these drugs are more effective than they actually are; the medical literature is littered with studies showing that SSRIs are “pretty good drugs,” he says, but one study (. 2003;326: 1171 - 1173), based on a compilation of all the studies submitted to the Swedish drug regulatory authority, concludes that “any attempt to recommend a specific selective serotonin reuptake inhibitor from the publicly available data is likely to be based on biased evidence.” Many negative trials are simply never published, he adds.

Off-Label Use

Another problem is off-label use. Among the 246 clinical trials on gabapentin (Neurontin) found on PubMed, almost all show it is an effective agent, but a closer look reveals that most of these trials fit into SPIT. “Gabapentin in published, peer-reviewed data is effective for overactive bladder, neuropathic pain, hiccups, social phobia, hot flashes, migraine headache, narcotic withdrawal, tinnitus, phantom limb pain, etc. What is the biological plausibility of that? How does it happen that we’re giving gabapentin for billions of dollars a year for off-label uses based on evidence like this?” he asks.

Part of the reason for this level of prescribing can be inferred from the $430-billion fine the company paid for illegal promotion of the drug for off-label uses.

Cholinesterase Inhibitors

The cholinesterase inhibitors (ChEIs), including tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne), have become the main approach to symptomatic treatment of Alzheimer’s disease (AD).

J Am Geriatr Soc

The peer-reviewed literature indicates that ChEIs are safe and effective in treating symptoms of AD, says Dr Finucane, pointing out a study that found that use of donepezil for AD results in significant delays in nursing home placement (. 2003;51:937-944).

“This is a very powerful example with which to sell donepezil,” he says. “You might not see an effect, but if you give this drug, the patient’s entry into a nursing home is going to be delayed.”

“We all think that we’re immune to

the drug reps, and the pens, and the bags…most likely we’re not.”

—Thomas E. Finucane, MD

This study was conducted with a flawed design, he says, because it is based on adherence. It “takes everybody who gets on donepezil in any of a series of randomized clinical trials or their open-label follow-up, and compares those who are able to comply with donepezil at least 80% of the time with those assigned to donepezil who don’t take it faithfully.” Dr Finucane says that “analyzing treatment effect based on adherence, however, is an absolutely thoroughly discredited technique.”

Lancet

In the following months, several letters pointed out extreme baseline differences between those who complied with the treatment regimen and those who did not. Dr Finucane believes the difference was “good caregivers” who ensured adherence. He believes there is “no biological plausibility and no evidence to support the claim.” And a subsequent study (. 2004;364:2105-2115), called AD2000, an actual randomized trial, found no significant benefits associated with donepezil compared with placebo on institutionalization or the progression of disability, he points out.

Incontinence Drugs

How about the new drugs for incontinence? What are the data on these new, very expensive drugs for overactive bladder? The effect size for these drugs is to reduce the number of urinations by perhaps 1 per day, compared with placebo, in women with overactive bladder, Dr Finucane stresses.

“In some of the studies, mainly of women, the average is to go to the bathroom and urinate about 12 times a day. If you pay $100 a month you’ll go about 11 times a day. If the average number of incontinent episodes is about 1 per day—it varies in the studies from 1 to 3 per day—what is the reduction in the number of accidents a woman will have when she gets on one of these drugs? About every third day, she’ll skip 1 accident,” he explains.

He adds, “A patient comes in, it’s a problem, you want to do something, and our reflex is to give a drug; but remember that for $100 a month, the effect size is basically trivial.”

Insomnia Medications

Insomnia is a very common complaint that physicians hear from their patients, says Dr Finucane. “They say they’re waking at 3:00 am, and they’re wide awake until 6:00 am. If you look at patients like that in the sleep lab, it turns out that they are awake for 5 or 10 or 15 minutes, and the perception of lying awake at night is extremely uncomfortable to some patients, particularly those who have been whipped up into a lather by the ‘insomnia campaign.’”

The truth is that we don’t know very much about sleep, but if you say that the purpose of sleep is to be awake, vigilant, and able to solve problems the next day—no clinical trial of a sleeping pill has ever shown any patient to have objectively measurable benefits in any of these areas.

“What you do is you render that patient unconscious for a period of time that is suitable to that patient and to you— you don’t give him a good night’s sleep, and you don’t make him more able to perform the next day,” he adds.

If you read the package insert that comes with these drugs, the “boast is that [patients] are no worse off. There’s no next day drowsiness. There’s no hangover. So the best the drug companies can offer is we don’t make them any worse, but you can’t see any benefit. In someone who complains of insomnia, you don’t make them more awake the next day. You knock them out, they quit complaining, and that’s it.”

Medical Letter

The new hypnotics, also called “Z” drugs (eg, zaleplon [Sonata], zolpidem [Ambien]), cost about $100 per month, according to the , and are not all that different from short-acting benzodiazepines, he says. A review of all published data on hypnotics conducted by the National Institute for Clinical Excellence, an arm of the National Health Service of the United Kingdom, stated that physicians should “choose the cheapest one, use it at the lowest dose, and use it for the shortest time possible.”

As an alternative, oxazepam (Serax) costs about $9 per month, so “to a trained eye the choice is obvious. The Z drugs are expensive, have lots of side effects, are ineffective in the important aspect of being better the next day, have lots of toxicity, and there is a credible, cheap alternative when your back is up against the wall. But in general, giving sleeping pills is bad medicine,” he adds.

Dr Finucane suggests one simple thing when reading the medical literature—scan the first and last sentences of the discussion section. “When you read these [studies] quickly, just be alert that there is rhetoric that is completely separated from the scientific findings, and it’s a very serious problem in reading the research literature.”

Another serious problem that is “operating in the background” has to do with the pharmaceutical representatives who visit physicians’ offices bearing gifts that often seem harmless at the time.

“We all think that we’re immune to the drug reps, and the pens, and the bags, and so forth—most likely we’re not,” he says. “A very consistent finding is saying, ‘I cannot be affected by this conflict of interest, but my colleagues, you don’t know what they’re going to do.’ So I think we have to be skeptical. This is an industry, fair enough, but we have to remember that their [drug companies] goal is not doing what is best for the patient. But for us who are trying to do what is best for our patients...we should remain skeptical and vigilant about these drugs, recognizing that they’re being promoted more obviously by the reps, and less obviously by many of the papers in the published peer-reviewed literature.”