The pharmaceutical industry is incredibly lucrative. You know that. What you may not realize is that Big Pharma is far more profitable than other large companies that don’t sell drugs (JAMA, March 3, 2020). What is more troubling, though, is how little you get for your money. Drug companies have a secret strategy for convincing physicians and patients that their medicines are far better than they really are.
Why Don’t Drugs Work Better?
People count on things to work. Be honest! When you turn on your laptop computer, tablet or smart phone you expect it to work every time, right? Cars are supposed to start on the first try. If a coffee maker, microwave or vacuum cleaner doesn’t work perfectly, you return or replace it.
In other words, we expect most of the devices in our lives to do their jobs 100 percent of the time. We have little patience for failure.
The same cannot be said of our medications. Most people have no idea how effective their blood pressure pill, antidepressant or flu shot might be. That’s because analyzing clinical trial data to determine effectiveness requires statistics.
Drug companies know that most of us are dummies when it comes to number crunching. Very few of us have mastered statistical concepts. That’s why drug companies rarely state the actual effectiveness of their medicines.
If a medication only works for 1 out of 50 patients, it doesn’t sound very impressive. Pharmaceutical manufacturers have come up with a secret strategy to mislead you into thinking their drugs work way better than they really do.
The FDA Should Know Better!
The head of the Food and Drug Administration recently made a grievous error in describing the purported effectiveness of a treatment for COVID-19. Dr. Stephen Hahn made a rookie mistake when he explained the benefits of convalescent plasma against COVID-19.
He claimed that 35 patients out of 100 would have had their lives saved if they had received blood plasma from a person who had recovered from a severe coronavirus infection.
That sounds impressive. Who wouldn’t want such a powerful treatment? A lot of people would likely ask for convalescent plasma based on Dr. Hahn’s numbers. Sadly, his explanation of effectiveness was totally misleading.
The Secret Strategy: Relative Risk Reduction:
Dr. Hahn was citing something called relative risk reduction. It almost always makes something seem far more effective than it really is. Dr. Hahn fell into a trap that most first-year medical students should avoid. Not surprisingly, he took a tremendous amount of criticism for this blunder.
Dr. Eric Topol has been a frequent guest on The People’s Pharmacy radio show. He is a renowned cardiologist. Dr. Topol is Director and Founder of the Scripps Research Translational Institute and is Editor-in-Chief of Medscape. Here is a link to our latest interview with Dr. Topol:
Show 1184: How Technology Could Make Medicine More Humane
Medicine is heavy on technology but often lacking in empathy. How could technology be coupled with listening to make medicine more humane?
“I can’t remember a mistake by FDA or the commissioner as serious as this one. Serious mistakes undermine your credibility.”
Dr. Hahn downplayed his mistake by saying:
“What I should have said better is that the data show a relative risk reduction not an absolute risk reduction.”
What Really Happened?
It turns out that the message that 35 lives would be saved out of every 100 patients treated was totally deceiving. The study Dr. Hahn was referring to did not have a placebo arm. Everyone in the study with COVID-19 received convalescent plasma.
One group of patients got the plasma within three days of being hospitalized. The other group received their intravenous plasma later. Mortality was assessed after a week and again after 30 days. The death rate for the early plasma recipients was 9% after seven days compared to 12% in the delayed plasma group. At one month, 22% of the early plasma recipients had died compared to 27% in the delayed group.
The absolute risk reduction of death was somewhere between 3 and 5 percent. That doesn’t sound nearly as impressive as the 35% Dr. Hahn originally cited.
How Big Pharma’s Secret Strategy Relies on Relative Risk:
Drug companies have long recognized that small reductions in absolute risk will not get doctors to prescribe pricey meds. That’s why relative risk reductions are used in advertisements to make a medication seem highly effective.
The Famous Lipitor Ad:
One classic example is a decades-old ad for the popular cholesterol-lowering drug atorvastatin (Lipitor). When the manufacturer boasted that its drug lowered the risk of heart attacks by 36 percent, it put an asterisk next to that number.
If you followed the asterisk, here is what you found:
“That means in a large clinical study, 3 percent of patients taking a sugar pill or placebo had a heart attack compared to 2 percent of patients taking Lipitor.”
This is the absolute risk reduction. In other words, if 100 people took Lipitor for several years, two of them would have a heart attack. In comparison, out of 100 people on placebo during the same amount of time, three people could be expected to have a heart attack. So one person taking atorvastatin got the benefit.
How did the company turn that 1 out of 100 into a 36 percent lower risk? What they did is divide that one person by the three people who had heart attacks in the placebo group. That leads to a 33 percent reduction. In reality there were thousands of people in the study, which is how the company actually ended up with a 36 percent relative risk reduction. Such a number sounds much more convincing than the absolute risk reduction of 1 out of 100.
What Does It Take to Get FDA Approval?
All a drug company has to do to get FDA approval is prove that a medicine works better than placebo at a statistically significant level. As a result, a drug like Lipitor might prevent a heart attack in 1 person out of 100 and still pass the FDA’s sniff test.
Many people have a hard time measuring drug effectiveness. Antidepressants have been shown to work just a little bit better than placebos in large, randomized controlled trials (JAMA, Jan. 6, 2010). Studies have shown that many people improve on sugar pills. That is why double-blind, placebo-controlled trials are so essential. Here is a link to an in-depth article we have written on this topic.
Billion Dollar Drugs Are Dramatically Disappointing
How effective is your medicine? This simple question is surprisingly complex. In many cases benefits of these billion dollar drugs are barely detectable.
The FDA often allows drug companies to describe benefits in terms of relative risk reduction. In other words, drug companies can use their secret strategy to make doctors think their products are highly effective. We have been disappointed that the FDA does not always require absolute risk reduction information in a prominent place in the prescribing information. Ditto for medical journals. Even prestigious publications like the New England Journal of Medicine and JAMA do not always require authors to include the absolute risk reduction or the NNT in a prominent place. More about the NNT below!
Patients rarely have access to clinical data themselves. Many health professionals do not volunteer information about outcome data that matters to patients. That’s why the NNT is so important.
The Number Needed to Treat (NNT):
Here is why we like the concept of the number needed to treat or NNT. It is a simple way to analyze a medication’s effectiveness. Boiled down to its essence, the NNT tells you how many people need to take Drug X for one person to get a measurable benefit. Here is a link to a website (the NNT) that explains this in far more detail.
An Example Provides Insight:
PPIs vs. Stress Ulcers:
When people are admitted to hospitals in bad shape they often end up in the ICU (intensive care unit). These patients are thought to be at very high risk for bleeding stomach ulcers or “stress ulcers.” Doctors believe that if they give powerful acid-suppressing drugs like esomeprazole (Nexium) or lansoprazole (Prilosec) prophylactically, they can prevent stress ulcers.
A report on The NNT describes their analysis. The reviewers looked at data from 57 trials involving 7,293 critically ill adult patients.
• “1 in 63 were helped (clinically important gastrointestinal bleeding was prevented) when compared to placebo
• No one was helped (no death was prevented) when compared to placebo”
They also described the benefit in percentages (absolute risk reduction):
• “1.6% lower risk of clinically important gastrointestinal bleeding (compared to placebo)”
A more recent review in the BMJ (Jan. 6, 2020) reached these conclusions:
“PPIs and H2RAs [histamine antagonists like cimetidine or famotidine] might increase the risk of pneumonia (low certainty). They probably do not have an effect on mortality (moderate certainty), length of hospital stay, or any other important outcomes. PPIs probably reduce the risk of bleeding more than H2RAs (moderate certainty).”
That is hardly reassuring. But wait, there’s more:
“In most critically ill patients, the reduction in clinically important gastrointestinal bleeding from gastric acid suppressants is closely balanced with the possibility of pneumonia. Clinicians should consider individual patient values, risk of bleeding, and other factors such as medication availability when deciding whether to use gastrointestinal bleeding prophylaxis.”
Do you think a critically ill patient who is in the ICU can tell the clinician her values? We sincerely doubt it. And will the doctor explain that PPIs are not likely to reduce the risk of death or “any other important outcomes.” But they could increase the risk for pneumonia. What a dilemma for a critically ill patient.
If we held medications to the same standards we use for dishwashers, smartphones or automobiles, they would likely be a lot less popular. If your toaster only worked once out of 15 times, you would get a new toaster. And yet many of our medicines only work for one out of 15 patients. Some drugs are far less effective than that and yet they remain on the market and are prescribed in huge quantities.
Do not let drug companies get away with their secret strategy to inflate effectiveness by using relative risk reduction. Always ask your doctor what the true effectiveness is of any medicine you take. To do that, you will need an outcome that matters to you.
Lowering a number on a lab test is just the first step. It is called a “surrogate marker.” What you really want to know is something you care about.
If you have diabetes, lowering your blood glucose is relatively meaningless unless the drug also reduces the risk of having a heart attack or a stroke. You would ideally like the drug to also lower your odds of developing visual problems or nerve disorders like neuropathy.
The next time you get a new prescription ask these questions:
- How likely am I to get benefit from this drug? Numbers please!
- What is the absolute risk reduction for my health problem?
- What is the number needed to treat (NNT)?
- What is the number needed to harm (NNH)? What are the most common side effects and the most serious adverse reactions?
- What symptoms should I be on the lookout for?
- Are there any symptoms that require emergency action?
- How can I contact you promptly if I develop one of those serious side effects?