Signs of a health issue along I-75

Good afternoon, everyone.

The Weekly Packet will be getting back to regular sailing now that Nesiritide. The Rise and Fall of Scios has passed the final proofing and is on the way to the printer. Please look for the title as above on Amazon, or alternatively search by author: Roger M Mills, MD.

I have also been scrambling to get to a final draft of Clinical Management of Heart Failure, 3rd edition. The co-authors (Jim Young and Javed Butler) and I opted for starting the third edition with a clean slate. As a consequence, I have just made the long drive from our camp in Michigan’s Upper Peninsula to spend a day with Jim at the Cleveland Clinic. Which leads to what’s really on my mind.

On June 7th, JAMA ran an opinion piece titled “Lifespan Weighted Down by Diet” by David S. Ludwig, MD, PhD from the New Balance Foundation Obesity Prevention Center at Boston Children’s Hospital and Harvard Medical School. In response to the recent widely publicized observations of decreasing life expectancy among US counties in the Southeast and Midwest, Ludwig raises the hypothesis that technologic advances may no longer be sufficient to compensate for the adverse health effects of obesity.

He goes on to state, “Direct medical costs associated with obesity among noninstitutionalized adults have been estimated to have reached $190 billion annually in 2005, an amount that does not include losses from lower worker productivity.”

What does this have to do with driving the 495 (Mapquest) miles from Hulbert Lake to the Cleveland Clinic? Everything! With the exception of the very sparsely populated areas in northern Michigan, the trip is a visual festival of high-caloric density food. The woods and fields of the rural Midwest are blotted out by billboards for McDonald’s, Wendy’s, Kentucky Fried and scores of local places like Cops and Donuts (Clare, MI). And the drive thru lanes and parking lots for these places are packed. This observation prompted the following chain of thought.

First, I have read, learned, and written a lot about drug costs and their relationship to overall health care costs. Second, JAMA now publishes an expert from Harvard who tells us that the medical cost of obesity passed $190 billion a year a decade ago! Third, new data suggest that dietary composition may have an impact above and beyond caloric balance alone. Fourth, the fast-food industry is not about production and consumption of “high-quality proteins, fruits and vegetables, legumes, nuts, and other whole foods,” as a basic diet.

Where does this leave me? I cannot avoid the growing suspicion that some large players in the food industry are making profits by making us unhealthy, and driving the overall cost of health care up in the process. This seems at least an order of magnitude more villainous than making profits for discovering and developing new drugs to make us healthier.

One of the core values of writing the Packet was to use data to gain perspective on problems. Over the summer months, I’ll look for more data and a clearer perspective on these and other epidemiologic questions.

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.

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?

Standing at the bedside in Phase 1

Most of the folks who visit this site work in health care, either as medical professionals or in the pharmaceutical development industry. If you have not yet heard, last week a Phase 1 trial in France was complicated by five subjects experiencing very serious adverse events. One subject has died, and four others have had serious neurologic events, reportedly involving deep brain bleeds.

I had the opportunity to serve as a study responsible physician in a Phase 1 trial. The fundamental compound was a human hormone, and we had experience with it using intravenous administration. Nonetheless, we conducted a very careful Phase 1 trial with first-in-human precautions because we were administering it in a novel formulation linked to another molecule.

I went to our clinical pharmacology unit, at a center in Belgium, to be present for the first in human dosing. The setting was hardly dramatic, just a healthy young man lying on a Gurney with an IV, an automatic BP cuff, and ECG telemetry electrodes in place. An experienced study nurse gave the subcutaneous injection, and…nothing happened.

Of course, one of the six subjects in the first series would receive placebo, so on the following morning, we did it all again. Another subject, in the same setting, with another injection and … again, nothing happened. Since the arithmetic demanded that at least one of the two subjects was assigned active drug, one of the two subjects had received the very first dose of this compound ever injected into a human being.

What do you think when you are the “responsible” physician standing at the bedside for such an event? F. Scott Fitzgerald captured the experience perfectly. He wrote, “The test of a first-rate intelligence is the ability to hold two opposed ideas in mind at the same time and still retain the ability to function.” One idea is, “my goodness, we are making such a fuss over something that we know is safe.” The other, not surprisingly, is “I hope and pray that nothing goes wrong, but if it does, I hope I my emergency plan works and he will be all right.”

Our subjects were all right. But the subjects in the Bial trial were not. This is the enormous responsibility that everyone involved in research involving human subjects shoulders. Unexpectedly, despite our best efforts, something goes off the tracks.

Instinctively, we all feel sympathy for the subjects. Let’s also feel sympathy for the researchers who had high hopes for a safe and effective new drug, and were terribly, terribly wrong. We cannot brush bad outcomes under the rug. We need to talk about them, and to make sure that the lay public understands that pharmaceutical research is not a strictly commercial activity. It is a very human, and occasionally very dangerous, effort to make life better.

Technology in the exam room

December 16, 2015

In the interests of full disclosure, I want to state that in my checkered past, I have belonged to a couple of interesting organizations. In my early teens, I belonged to the National Rifle Association. As a geeky kid growing up in the Midwest, I got deeply involved in competitive target shooting through a team at the local YMCA. We shot .22 caliber rimfire bolt-action “target rifles,” at standard targets at 50 feet. I was actually pretty good at it. To do this and compete in various matches, we all joined the NRA. I also avidly read “The American Rifleman,” the NRA monthly magazine and Sports Afield. After a couple of years of looking at pictures of  middle-aged men with rifles posing beside large dead furry animals, I realized that improving one’s proficiency with firearms is ultimately about doing mortal harm to other creatures. In survival situations, if one is hunting for food or part of a military conflict, I am all for proficiency with firearms. Go for it! Otherwise, not so much. My membership lapsed when I was about 14, and I’m not going to re-up now. (Yes, I do admit to some pictures of me with large fish. I am a strictly single-hook, barbless, catch-and-release fly fisherman.)

The American Medical Association is the other organization I’ve belonged to in the past, but with which I have never really come to terms. The AMA has been fairly consistent about opposing rational reform of the American health care system. Based on the historical record, the best thing that I can say for the AMA is that the organization has been even-handed. It has opposed every initiative, whether Republican (yes, both TR and Nixon supported health care reform) or Democratic (FDR, Truman, Ted Kennedy).  I joined some years ago, thinking that more academic physicians should get involved.  That was a naïve idea.

Having ‘fessed up, I hope you will understand that once on the AMA email list, a physician is on it for life. In fact, maybe longer; I can’t say yet.

So, here is a quote from one of yesterday’s (12/14) AMA Morning News stories, titled Some physicians suffering burnout over EHR mandates, “In a 1,200-word story, the Chicago Tribune discussed how the Federal government’s “elaborate – or maddening and onerous – system of electronic health records” is affecting physicians. According to the Tribune, medical associations nationwide are attributing “increasing doctor burnout to the demands of clicking through page after page of records, whether the patient shows up for a physical, a quick follow-up visit, or treatment for chronic disease.” Recently, “Mayo Clinic researchers, working with the American Medical Association, found that more than half of physicians felt emotionally exhausted.” Contributing to that exhaustion are “heavier workloads and ‘increased clerical responsibilities.’”

Now, I hope you do realize that the AMA’s default position on the federal government is not amicable. Nonetheless, I think they may have a valid point here.

The Wall Street Journal of December 14th also had a piece titled, “Is Your Doctor Getting Too Much Screen Time?” by Sumathi Reddy. The report was nicely balanced between patient and physician viewpoints, and covered both some pros and some cons. (For “fair balance,” I had a look at the New York Times, too. They did not have much objective data, but there was a terrific blog piece. 

With the AMA and WSJ articles on my mind, I went to PubMed and did a clinical search for “electronic health records patient satisfaction” and one for “electronic health records physician satisfaction.” In PubMed, overall, the patient-related citations outnumbered the physician-related citations three to one. Given publication bias (the tendency to publish positive results rather than negative findings), I suspect that the researchers make the patients’ somewhat happier with EHRs than they really are, but here are a few take-home observations.

  1. In a “similar articles” search on satisfaction with EHRs, the publications were heavily weighted toward exploring patient satisfaction. I estimate the recent ratio is about 10:1 toward patient rather than physician satisfaction.
  2. Among the few articles that looked at physician satisfaction, the highest rate of “very satisfied” physicians that I found was 38%.
  3. One telling issue was that EHR suppliers felt that their “customers” were hospital managers or practice managers, not the health care professionals using the system.
  4. American patients were concerned about “eye contact.” In contrast, European patients were concerned about data privacy.

I’m not about to jump on the podium and tell you that I know the answer to the problems of implementing EHRs into medical practice. I certainly don’t know the solution to reducing the stresses of being a physician in today’s world. But here are a few thoughts that came to me as I reflected on the data and some of my own recent visits for out-patient health care.

First, the architecture of the space in which patients and providers interact is archaic. The traditional exam room must have originated in the early 20th century. The layout certainly inhibits communication when the provider has to use electronic technology. I don’t mind sitting on an exam table, but when the exam or procedure is over, wouldn’t it be nice to get dressed and sit down beside the doctor (or nurse practitioner) for a quick discussion looking at the data together? When I went to the Cleveland Clinic for my most recent orthopedic check, Viktor Krebs reviewed the films with me on a monitor in the exam room. On a recent visit with Bawa Das, a retinal specialist here in Michigan, he showed me my fluorescein angiogram on a monitor right in the exam room. Both of these physicians are exceptional individuals, and both of them used what I would call “work-around” solutions, but they did work. Think how much easier and more effective these interactions would be if the exam rooms were actually designed with wall-mounted monitors and a work station where the patient and the provider could sit together and look at the screen!

Second, steady improvement in handwriting and voice recognition technology is likely to reduce the future “input burden” for providers, but providers are going to have to complain loudly about the burden to get the managerial classes to continue to invest in technology as it changes.

Third, we should be more concerned about personal privacy. The Europeans have legitimate concerns. (Check the NY Times blog link mentioned above for more on this.)

The bottom line? The technology is not going away, any more than the NRA or the AMA will. But, unlike our relationships with organizations where we don’t fit in, we can’t just drop out of our technologic world and make a reasonable living growing organic crops. We have to develop a reasonable degree of proficiency in using the tools, and we also have to get involved in making the technology work for us. That’s a hint to readers for further discussion…

By the way, if you found the “Hullabaloo about Drug Prices” interesting, you might want to look at “The Folly of Targeting Big Pharma: The biggest driver of rising health-care spending is the cost of labor, not drugs” by Michael Mandel in the Wall Street Journal. (Dec. 10, 2015)