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.

The swim meet


We live on a curving street, and share the back yard area where the lots converge with our next-door neighbors (NDNs) to the north as well as our “back-yard neighbors” (BYNs) to the west. Over the past 4 years, we have gotten to know the BYNs pretty well. The NDNs got their daughter through her first year of college, shouted “hooray,” and decamped for Colorado. (Didn’t take it personally; he’s a fly-fisherman.)

To resume the narrative, the BYNs have two children, a younger girl in middle school and a boy who is now a sophomore in high school. As you might expect in a “suburb” of Ann Arbor (“suburb” meaning a rural haven from the incredibly high tax rates that providing municipal services for the University of Michigan imposes on the town of A2), the schools are filled with bright kids from well-educated families.

Sam, the older boy, made the high school varsity swim team. He also plays bass violin in the orchestra, and does well academically. Yesterday, my wife Katherine joined Sam’s mom to watch a home swim meet. Katherine not only has her own family experience as a reference point, she also has an academic perspective with her master’s degree in psychology/sociology. When she came home, she commented, “I can’t believe the schedules the high school kids keep, and the pressure they’re under.”

As usual, I muttered something about “thinking about it a little more.” After doing just that, here’s what I think. The BYNs are the same age as our kids. Their children are the same age as our grandchildren.

I don’t think it’s the kids who are under the pressure, really. After all, they are kids, and they seem to be having a lot of fun. Sure, they’re busy. But, the parents are providing transportation and food and the financial resources to support all this activity.

I think it’s the parents who are under pressure. They are the ones who are now old enough, mid-40s to early 50s, to see how the world really is and it is not pretty. We have a society that has become divided into “haves” and “have nots” and the middle is vanishing. Income distribution looks more and more like a double-humped Bactrian camel than a bell curve. (OK, bi-phasic distribution if you want. I like the camel better.) This is not news. Today’s parents know that getting into the high-end hump requires a college education, and that requires the sports and cultural activities that the kids are doing, as well as grades and standardized test scores. All that is frightening enough, but most parents are willing to at least discuss it.

Here’s the part they don’t want to talk about. If you start sliding toward the camel’s rear end, you will never get back. Mobility in this world is essentially unidirectional. We are all now old enough to know the uncle who never finished college, started drinking and drugging, and died in his late 30s. Or maybe he didn’t die, but could never hold a job; now his kids have dropped out of high school, and they have kids.

Today’s parents talk to their high school students about the importance of education, and how much the parents want the students to have the opportunity to learn. They don’t talk about life on the back hump. But they have seen what happens to family members and friends who ended up there. They know the game and they know the stakes. That’s pressure.

Sam’s team won the meet.

The “drug cost crisis.”

During my relatively brief tenure on the faculty of the University of Kentucky College of Medicine, I enjoyed the privilege of participating in UK’s first “Certificate in Medical Management” program. The business school faculty ran the course, with some additional input from other faculty. Although I might stumble on some specifics, the major themes of what we learned have stayed with me. I think that explains my fascination with the “drug cost” headlines that are appearing with alarming frequency.

This is a topic that can arouse even the most factually unarmed to foaming fury, so I’ll proceed very carefully. Peter Bernstein, in his wonderful book Against the Gods, documents that various forms of the insurance business have been around since at least 1800 BC. Without getting too technical, today’s insurance practices have benefitted from steady advances in both math, basically statistics, and data handling, so-called “big data.” However, there are some fundamental and intuitive facts that no one can dispute.

First, illness is not equally distributed in the general population. Some individuals have substantially greater health burdens than others. In fact, the National Institute for Health Care Management Foundation analysis of data from the 2012 Medical Expenditure Panel Survey shows that the less expensive 80% of the civilian non-institutionalized US population accounted for 18% of the cumulative total health care spending that year, while the more expensive 20% of the population accounted for the remaining 82% of spending. The “80/20 rule” has some validity!

Second, with the exception of a few dramatic diseases like Ebola, in developed societies the burden of illness is both chronic and costly.

Third, other things being equal, if the goal of insurance is to cover the health care costs (or automobile losses, or shipwreck costs) of a population, a larger the pool of insured individuals will result in a lower cost to each individual.

Given these three basics, the conclusion seems straightforward that the least expensive approach to health insurance is to require that everyone in a large pool, say the US population, have a basic policy.  Does this mean the end of the private health insurance business? It hasn’t in Europe, where private insurance often adds coverage beyond the basics. It’s the kind of approach that says, “At least, everyone should be able to ride a bus or a train. If you want a fancy car instead, that’s up to you.”

Now, just for fun, let’s move on to drugs. I would like to call your attention to a piece by Peter Sullivan posted on a site called “The Hill.” The Center for Medicare Services, or CMS, has collected some interesting data. The spreadsheet is available on line and worth a careful look. The take-home message is that just 40 drugs out of the 3,761 in the Medicare prescription drug program make up a full 33 percent of the total $121.5 billion in yearly costs. That’s even more lopsided than the 80/20 rule. What’s more interesting is that if we focus on the set of indications for those drugs, we will narrow the field even more to hepatitis-C, oncology, and severe forms of mental illness.

Well, cost cutters, one approach would be to deny progress. These expensive drugs are used to treat illness that has not been treated previously. Instead of having patients die from liver failure and metastatic cancers, we are adding to the population of individuals with expensive chronic diseases. Of course the total cost of drugs will go up! One alternative would be not to use these new agents, and let the diseases run their course. Aside from the moral issues, that’s NOT what insurance is about. It’s about spreading the cost across the largest possible pool.

In addition, as we have learned from the EU, national health systems have a lot of leverage in negotiating drug costs.

To summarize what the data really show about the US drug cost “crisis” is that:

  1. The real drivers of health care cost increases are hospital costs and personnel costs.
  2. A large majority of the population accounts for only a small portion of health care costs.
  3. Expansion of the subset of patients with complex chronic disease that can only be managed with expensive new drugs accounts for most of the increase in drug costs.

Are these problems that can be entirely attributed to the pharmaceutical industry? I think not. Rightly or wrongly, the industry has tried to figure out what price the fragmented market will bear. In the rest of our society, that’s a generally accepted practice. On the other hand, we can’t escape the fact that multiple competing interests have repeatedly defeated attempts to develop a more rational health care system.