The Theranos evidence, waiting for a story

WFM – Undercover investigative reporter

Spoiler alert! If you already believe that you can learn more by analyzing failure than by admiring success, you can skip the rest of the post.

Because I decided to apply to medical school late in my junior year at college, in the summer of 1963, I took organic chemistry as a summer school course at Penn. I was also rowing with my life-long friend, Bernie Witholt, in a double scull at Vesper Boat Club. When the chemistry course ended, in order to keep up the rowing I needed a job and a place to live. Those very basic needs drove me to wandering through the labs in the basement of Penn’s medical school, looking for a temporary job as a lab assistant. Dr. Rita Wetton, an academic pediatrician working on hyaline membrane disease, had just said “good-bye” to her two summer assistants, and she hired me on the spot.

The next morning, I showed up in the lab, put on a white coat, and headed down Hamilton Walk to a small gate in the wall that separated the medical school from the vast grounds of the Philadelphia General Hospital. Going through, the PGH autopsy building was on my right, a non-descript squat stone outbuilding. I was there to collect fresh human lung specimens for the lab.

The dieners (autopsy assistants) seemed totally unsurprised that a college kid in a sport shirt with a white coat over it had wandered in to pick up some lungs. (At the time, I didn’t know that Dr. Wetton had a formal research agreement with the PGH pathology department.) I think they knew that they had a critical, if very basic, role in medical education. They asked if I wanted to stay and watch the autopsy that would yield the specimens. I did. So the process of looking objectively for the clues to what went wrong literally started on my very first day at medical school, months before the acceptance letter came.

As I write this, my desk is a mess. For a couple of weeks, I’ve been holding on to interesting material from the media in the hope that if I look at it carefully, objectively, maybe I can understand what happened to Theranos, the lab testing company that just a couple of years ago achieved a “value” of some $9 billion. How did Elizabeth Holmes, a Stanford drop-out with no formal medical credentials, build a corporate house of cards that is now slowly crashing under financial and regulatory scrutiny? David Crow, writing in The Financial Times magazine on April 18th, presented the facts in a very thoroughly researched article. But looking at the facts is like looking at individual organs at an autopsy, after the diener has washed them, weighed them, and put them in clean pans. What we need now is the pathologist to come in, and with knowledge and experience, he or she will tell the story that puts the facts together into a coherent narrative. At some point, the narrative may well make an instructive case study.

For now, here are just a few thoughts. A laboratory, any lab, is an attempt to reduce what information theory calls “noise.” A clinical study is a the concept of a lab built out to work in the real world. The idea of the lab is to eliminate or control variables. These can include changes in temperature, humidity, light, seismic vibration (read Black Hole Blues!), or by using inclusion/exclusion criteria and randomization, differences between groups of patients, whatever is on your list. In any lab work, reproducibility of results and documentation of methods is absolutely critical. Even so, experiments will fail; things will go wrong. That’s often when you learn that a week in the library is worth a month in the lab. It’s a painful lesson.

With her extraordinary intelligence and charm, Elizabeth Holmes seems to have believed that reproducibility and transparent documentation of methods, the fundamental steps common to both laboratory and clinical research, could be finessed. The Greeks gave that error a name; they called it hubris.

Those principles have tripped up John Darsee, William Summerlin, and many others.     But at the Theranos scale, the error has gone beyond the personal. Board members have sustained tarnished credibility, and financial supporters have lost substantial sums. And behind it all is a sad story; they didn’t do their homework. They didn’t ask to see the nuts and bolts,to subject the data to critical peer review.

The Theranos story is far from over, but it holds important lessons for all of us. We should continue to follow it closely.

“Just the facts, Ma’am.” More discussion on drug prices

As many readers know, I’m currently working on a new edition of Clinical Management of Heart Failure. This is the third edition in the series, and the first update in about 10 years. I’ve just finished a completely new chapter devoted to the management of heart failure patients with major co-morbid conditions. I haven’t seen anything quite like it, and I thought it would add something of real value to the book.

The conditions that I chose to focus on include Type 2 diabetes (T2DM), chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), and cancer. In the course of doing my homework (Yes, Virginia, there is ALWAYS homework!), I’ve documented that the “average” heart failure patient has up to a half-dozen other important medical problems. About half of the heart failure patients have T2DM; one in every four or five has COPD, and about 4 in 10 have Stage III or higher CKD.

In addition, dramatic improvements in cancer management of the past two decades have given rise to a whole new specialty called “cardio-oncology.” Cardio-oncologists are cardiologists with special expertise in managing the various novel forms of heart injury associated with both chemotherapy and radiation treatments for cancer.

Now, what does this have to do with drug costs? Let me suggest that you have a look at an interesting article in the Wall Street Journal that involves a discussion between senior individuals in pharma, insurance, and AARP. Read it carefully! The interesting part is what isn’t there. These leaders all actively press their own agendas, and represent their own perceived constituencies. Not one of them raises the concern that disease is not evenly distributed in the population. The concern about the rising costs of prescription drugs for medically managed chronic applies to fewer than 20% of the population. This subset tends to be older, to have multiple co-morbidities, and to take multiple prescription drugs. (The prevalence of obesity, substance abuse, firearms, and traffic accidents means that a substantial subset of the US population is not “healthy,” but that (approximately) third of the population does not qualify as having a medically managed chronic disease.)

The currently favored buzzwords for dealing with the drug cost “problem” are “transparancy” and “empowerment.”  Let me ask you a serious question. Do you think that your 83 year old Aunt Margaret, who has high blood pressure, diabetes, a chronic cough from 50 years of a pack of Chesterfields a day, and is getting a bit forgetful, is going to carefully analyze her drug costs and discuss the issues with her doctor and her pharmacist? I’m skeptical.

As the WSJ piece makes clear, drug costs for such patients are already vigorously negotiated. “Doing something” about the cost of chronic illness is going to require either limiting care, which most of us find unacceptable, or improving the efficiency of care. Can we do that with improved access to nurse practitioners who can prescribe generic fixed-dose combinations? Sure. But only if we are willing to accept the concepts that the pharmaceutical costs of managing older patients with multiple chronic diseases are the costs of success, not failure. These patients are living longer, with more complicated problems, than ever before. Their drug costs are relatively small.

We can’t let the headlines about an occasional rogue company raising the cost of drugs for relatively rare conditions (e.g., Daraprim for toxoplasmosis) make us lose sight of the real issue here. The large, ethical, research-based pharmaceutical companies have contributed enormously to improvements in quality of life; they have to be able to continue to fund drug research and to generate reasonable profits for their shareholders. Yes, there are some practices in the pharmaceutical industry, particularly direct-to-consumer advertising of specific drugs, that should be curtailed. But let’s not confuse poor judgement with malice, and let’s try to stick to the facts when we think through our health care options.









Lessons from a slow start?

I’ve been saving a folded section of newspaper with Elisabeth Rosenthal’s New York Times article from February 28 on my crowded desk ( New York Times article). In it, she points out that the health care industry spent $14 billion on advertising in 2014.

Only the US and New Zealand allow direct to consumer (DTC) advertising for drugs, and I suspect (admittedly without data) that the problem is much greater in the US. You know that this is a major problem when the AMA recommends a ban on DTC ads.

Interestingly, pharmaceutical companies are not the only players in the field. Hospital advertising has increased 38% from 2011 thru 2014, to $2.3 billion a year.

Now, my industry experience has taught me that the people who decide to spend this kind of money are NOT stupid! Even if we don’t agree with their use of resources, we ought to respectfully ask, “Why are you doing this?” A hint of an answer surfaced in an unreferenced statement by Boston Globe correspondent Katherine Whittemore, who wrote that some 87% of patients who saw a drug advertised and requested a prescription for it actually received the prescription

Additional confirmation for the concept comes from an interview on NPR. “Something like a third of consumers who’ve seen a drug ad have talked to their doctor about it,” Julie Donohue, a professor of public health at the University of Pittsburgh, told NPR. “About two-thirds of those have asked for a prescription. And the majority of people who ask for a prescription have that request honored.”

The answer to “Why advertise?” seems clear. “It works.” Or, at least, it has worked so far.

Now comes the really difficult question, “Is this a wise and constructive use of resources?”

Some serious thinkers believe that the era of blockbuster drugs is coming to an end. Could the dollars that have poured into advertising be re-channeled into more useful and productive activities?

I’ve just come back from the American College of Cardiology meeting in Chicago, and I think the launch of a major new heart failure compound, sacubitril/valsartan branded as Entresto, may hold some clues. Entresto had very positive phase III trial results for the management of chronic heart failure patients with impaired contractile function, and it has an engaging DTC television ad campaign, yet it has been a slow-starter. I did an entirely informal, non-randomized set of talks with colleagues to try to understand why. Two reasons emerged. First, with more and more physicians employed by large organizations, there’s pressure to hold back on “early adoption” of new agents until “the guidelines” clarify their status. Guidelines have become a huge issue. Second, generics dominate the chronic heart failure market, and because the sponsor has pegged the cost of the drug in the $400/month range there are substantial financial constraints on switching to it.

Perhaps, just perhaps, we are seeing something new and important here. Based on the available clinical trial data, I think Entresto is an important advance in heart failure treatment. But “ask your doctor about it” is not working as well as it has in the past. Maybe those advertising dollars would be better spent on another trial or two, and some physician education?