Tuesday, August 29, 2017
"Blockbuster" drug or slanted reporting: never forget "cui bono"
‘Drug Aimed at Inflammation May Lower Risk of Heart Disease and Cancer’, by Denise Grady in the New York Times, August 27, 2017, reports on a study in the New England Journal of Medicine, ‘Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease’ by Paul M. Ricker, et al. The study, funded by the drug’s manufacturer, Novartis, examined the impact of the use of canakinumab (brand name: Ilaris) on heart attack survivors. The drug is in a class called “monoclonal antibody inhibitors” (as is almost anything ending in “…mab”); in its case, it inhibits antibodies known as “interleukin 1β”. The main effect is anti-inflammatory, which is why it was originally developed for treatment of juvenile rheumatoid arthritis, an inflammatory disease. However, research showing that inflammation plays a major role in coronary artery disease (the cause of heart attacks) stimulated this large multi-center, drug-company sponsored, trial.
So what did the study show? Of the over 10,000 people in the study, those who were treated with canakinumab had lower rates of what the study designers defined as the “primary end point”, the main thing that they were looking for, “nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death.” That is, did patients have another heart attack or stroke, whether they lived or died. The lower rates in the canakinumab groups were statistically significant, with the group that did the best, the middle-dose (they tested 3 different dosages), having 3.86 “events” per 100 person-years, compared to 4.50 for the placebo group. In absolute terms, there were, thus, 0.64 fewer “events” for each 100 person-years (which is a valid concept, one person taking a drug for 100 years, or 100 people for one year, or any combination in between).
There was, however, no significant difference in “all cause” mortality between the treated and untreated groups, mainly because of the increase in deaths from infections in those treated. This is not surprising because the anti-inflammatory effect of canakinumab also decreases the body’s immune response. It is also not surprising that the people most likely to die of infection were those who were oldest and sickest in the first place. Six people developed tuberculosis.
Given that the cost of the drug is about $200,000 a year (think about that!), 100 person-years of treatment would cost $20,000,000. And for this price, 0.64 fewer people have a cardiac “event”, and no fewer people die. And some untold number suffering serious side effects from canakinumab, including the infections that occurred that didn’t kill them (not reported). These could be really serious – long hospitalizations for sepsis or pneumonia or cellulitis, non-fatal but significant events like amputations, etc. No wonder the Times article quotes Dr. David J. Maron, the director of preventive cardiology at Stanford University School of Medicine, as saying “This is fantastic”! Dr. Maron, I imagine, has terrific insurance.
Of course, it didn’t cost Novartis $200,000 a year for the drug for the study; that is the retail price that it plans to charge hospitals, insurers, and patients. We have no idea what the drug actually costs Novartis to manufacture; the price they will charge is based on the highly scientific formula called “what the market will bear”. For their own bizarre reasons (see Elizabeth Rosenthal’s “An American Sickness” and this commentary by Jacob Hacker) insurers may gladly pay for this drug (they get to keep a percent, and a higher price means a higher percent, and they just raise rates). Or they may get a discounted charge. Certainly, many poor and uninsured people are not likely to get it. Maybe – probably – Novartis will have a program for giving the drug for little or no money to poor people. But, given how common coronary heart disease (CHD) is, they are incredibly unlikely to give it for free to every uninsured person who has CHD. Maybe they’ll give them a discount, say 90%. Then the poor person would only have to pay $20,000 a year out of pocket. To reduce their risk of another coronary event by 0.0064 per year. And have no lower likelihood of dying. And a greater likelihood of severe infection. Maybe this is, after all, a boon to the poor and uninsured, as they are unlikely to get this terrific opportunity.
The other amazing thing is the actual story in the Times, and what that says about health journalism. As noted by the insightful Howard A. Rodman, the
· Headline says: "Drug... May Lower Risk of Heart Disease and Cancer"
· The 2nd paragraph tells us it is a "major milestone"
· The 3rd paragraph quotes Dr. Maron saying "This is fantastic."
But then you have to scroll down to find
· In the 5th paragraph, that the drug costs $200,000 per year. It's available only from Novartis, and that Novartis paid for the study.
· And in the 7th paragraph, that the drug suppresses immune response. In the study, the number of deaths from drug-caused infections equaled the number of lives saved.
Lead with the positives, and then let us down later, maybe after those of us scanning the article have stopped reading.
Is the Times trying to mislead us? I don’t think so. I think that they want, however, to get our attention, get us reading, show us blockbusters. Blockbusters are good for getting attention. It is a big article for the New England Journal of Medicine also. This is why there is a built-in prejudice in medical journals for publishing articles with positive results, and why the authors do their best to “spin” results to positive. As if the incredible amount of work they have put in to the study, not to mention the interest of the sponsor, in this case, a pharmaceutical company that makes the drug in question, was not sufficient impetus. After all, getting our attention is what it is all about; it is why reality TV is so big, and why a reality TV star is now POTUS; see Matt Taibbi’s piece “The Media Is the Villain – for Creating a World Dumb Enough for Trump”. He notes that “If a meteor crashes into jello night at the Playboy mansion, it doesn't matter if you send Edward R. Murrow to do the standup. Some things sell themselves.” Maybe a drug that treats a disease that treats heart disease isn’t that big, but it is big; after all, as Grady notes, “Cardiovascular disease is the leading cause of death worldwide and in the United States, where it killed nearly 634,000 people in 2015. Globally, it killed 15 million,” (paragraph 4, if you’re tracking it).
Neither does this mean that published scientific research is unreliable. Some of it is very good science (even this study is generally good science, despite the published report in NEJM and the coverage in the Times being unconscionably skewed to the positive). Some of it actually reports on drugs or other interventions that make a difference. Sadly, however, in addition to the “blockbuster” effect that the media (including medical journals) want to cover, those interventions that will make a lot of money for a company get more publicity. Especially when the company funds the research. Aspirin, by the way, is still cheap, and it is more effective than this drug, recommended by the US Preventive Services Task Force (USPSTF) for prevention of CHD in adults with greater than a 10% 10-year risk.
I tell medical and other health professions students (at all levels) that, although the Introduction and Discussion sections of the article may seem most interesting, the important parts to read are the Methods and Results, which have the meat (or soy, if you’re vegan) and from which you should draw your own conclusions, without the authors’ spin. If you’re not a health professional, and depend on the mass media for coverage, then you better read the whole article and not stop after the fanfare. It is the reporter’s job to provide the necessary information, but your job to read it wisely.
Certainly, health professional or reporter or consumer, look at who is funding the study. It is important information. And think about conflict of interest. And think, of course, about cui bono. It is likely to be the manufacturers, and maybe the researchers, and sometimes those who are wealthy or well-insured enough to get the drug or intervention (when it is of benefit).
And, surprise, it is never likely to be the poor, uninsured, or those most in need.