Category: Medicine

Harvard neurologist Peter Lansbury argues in the WP that we should end mandatory Phase 3 clinical trials for new pharmaceuticals. Aside from the expense of Phase 3 trials (hundres of millions of dollars) and years of delay he writes that:

There are also scientific reasons to replace Phase 3. The reasoning behind the Phase 3 requirement — that the average efficacy of a drug is relevant to an individual patient — flies in the face of what we now know about drug responsiveness. Very few drugs are effective in all individuals. In fact, most are not effective in large portions of the population, for reasons that we are just beginning to understand.

It’s much easier to get approval for drugs that are marginally effective in, say, half the population than drugs that are very effective in a small fraction of patients. This statistical barrier discourages the pharmaceutical industry from even beginning to attack diseases, such as Parkinson’s, that are likely to have several subtypes, each of which may respond to a different drug. These drugs are the underappreciated casualties of the Phase 3 requirement; they will never be developed because the risk of failure at Phase 3 is simply too great.

Lansbury also recognizes the importance of off-label prescribing and how it flies in the face of FDA power.

Once the FDA has approved a drug based on its effectiveness against one condition, it can be prescribed for any other condition. This practice recognizes that your physician is best equipped to evaluate all the available information and advise whether you could benefit from a particular drug. About 40 to 50 percent of all drug use is for such unapproved, or “off-label,” uses. Some drugs that “failed” in Phase 3 trials for one condition, but were approved for another, are still widely prescribed for the first because physicians agree that the evidence shows they can be effective.

I agree with Lansbury’s analysis and so do a lot of physicians. See my papers Assessing the FDA via the Anomaly of Off-Label Drug Prescriptions and Do Off-Label Drug Practices Argue Against FDA Efficacy Requirements? Testing an Argument by Stuctured Conversations with Experts.

The US is a world leader in sperm exports primarily because sperm banks in the U.S. are run on a for-profit basis. As a result, US sperm is reckoned to be of high quality (we always knew this didn’t we?) particulary because the US version comes with a background on the vitals of the donor. Denmark also exports a lot of sperm because of high standards and demand for that blond, blue-eyed look.

Exports to Canada have increased in recent years because of a scandal involving poorly screened Canadian sperm. Canadians also import a lot of US eggs. The Canadian government, however, is apparently miffed as a new law is being readied that would forbid donations involving a paid donor. The law would not only make paid donation illegal in Canada it would make it illegal to use any paid-for sperm. Canadian couples seeking fertility options will suffer and who will benefit? I cannot think that this law is anything but spiteful and ridiculous. Is paying for sperm an original sin? As with other areas of Canadian medicine (see Tyler’s posts here and here), the rich will now travel to the United States for treatment.

Aside: The Canadian Health Official quoted here is ignorant or disengeneous when she says “We don’t buy or sell blood, or organs or tissues.” In fact, Canada also imports a lot of US blood plasma. Plasma takes longer to donate than straight blood and as a result altruistic donation rates are low and much of the world relies on paid-for US plasma for its life-saving properties. Similarly, donating eggs is not nearly as much fun as donating sperm so altruistic donation of Canadian eggs is unlikely to make-up for restrictions on the import of paid-for US eggs.

Thanks to Eric Crampton for the seminal email.

I don’t aim to be the cynical economist that Tyler writes “might suggest social stigma for suicide, rather than forgiveness” but it is frightening how easy it seems to be to jump to the sad equilibrium. The story of suicide among young boys in Micronesia (I recommend Malcolm Gladwell’s The Tipping Point for a discussion but will cite some online material) illustrates how actions and social attitudes reinforce one another. As the action becomes more common, perhaps reaching a “tipping point”, condemnation declines, and the action increases even further. Here, from one of the researchers who first documented the story, is a chilling description of suicide in Micronesia:

As suicide has gained familiarity among youth, the act itself has become increasingly more acceptable or even expected. Suicides appear to acquire a sort of contagious power. One suicide might serve as the model for successive suicides among friends of the first victim. There has been an apparent increase in suicides among very young children, aged １０-１４. Evidently the idea of suicide has become increasingly commonplace and compelling, and young children are now acquiring this idea at earlier ages.

Another of the earlier researchers writes:

Love songs mention suicide, youths discuss the subject openly among themselves and at times make suicide pacts with one another, and youngsters express admiration of those who have taken their own lives and are mourned so terribly by their families and friends. What is even more shocking, however, is that a number of adults in our communities seem to share the belief that these young people have died altruistic and even heroic deaths. If the majority of Micronesians really believe that suicide is an honorable option, then this paper is thoroughly useless and all of us had better resign ourselves to continuing high rates of suicide in the future. Young people, after all, are very quick in sensing the basic values of their elders. If they get the impression that we ourselves honor suicide, then they will be only too happy to oblige by hanging themselves.

Note that one could tell similar stories in the United States about divorce, having children out of wedlock, welfare dependence etc. (also teenage suicide at a local level).

Here is a graph of suicide rates in Micronesia indicating a massive increase in a few short years in the early 1970s. The tipping theory generates credence when we note that virtually all the suicides take a similar, ritualistic form involving hanging.

Tyler appears to be growing more skeptical of the value of health care spending (see his posts here and here). A simple model explains most of what is going on and why he and another of my very smart colleagues Robin Hanson, are wrong. In the graph below spending on health care is on the X axis, health outcomes are on the Y axis. Spending shows diminishing returns. We are currently at point Q on the graph labeled T1 – note that at this point marginal increases in spending have little effect on output (Tyler asks, What margin has low value? Answer: The marginal dollar). Even fairly large increases or decreases in spending will not change outcomes very much given that we are currently at point Q.

Why are we spending so much as to push us into the flat portion of the production function? One reason is that out-of-pocket expenses for medical care are much lower than true costs – we typically are spending someone else’s money. A second reason is that the marginal utility of wealth is low if you are dead so spending on health care near the end of life has unusually low opportunity cost. A third reason may be that various psychological factors make the desire to avoid regret particulary strong for health care, as Tyler speculated earlier.

Although the marginal dollar has low return the value of improvements in medical technology is enormous. These gains are illustrated by the shift from T1 to T2. It has been estimated, for example, that increases in life expectancy from reductions in mortality due to cardiovascular disease over 1970-1990 has been worth over $30 trillion dollars – yes, 30 trillion dollars (for this research see: book, papers, summary). A conservative estimate is that 1/3rd of these improvements in life expectancy were due to better medical technology. One third of the annual benefits is $500 billion – this is much more than total government spending on medical research (the budget of the entire NIH is around 25 billion).

The low value of medical spending at a particular point in time and the high value of medical research over time suggest that we would be much better off if we cut back on medical care spending and devoted the funds to medical research. We should spend less on Medicaid, Medicare, Prescription drug plans etc. and use the savings to better fund the NIH (or other methods of increasing medical research such as prizes etc.)

My idea of genetic insurance created some controversy with Randall Parker at FuturePundit, Brock Sides at Signifying Nothing, and MR’s guest blogger Lloyd Cohen raising some objections. One of the objections that all three had in common (dealt with in my papers but not in the post) is that adverse selection is still a problem if people lie about having taken a test. This minor problem is easily handled, however. Insurance companies could have a clause in the contract forbidding previous tests. We don’t worry so much about people having a theft and then buying home insurance and the issue here is quite similar. (See my papers for a little more on this issue).

Randall at FuturePundit, however, raises a more serious problem. As the price of genetic tests falls it will soon be economic to sequence a person’s entire genome at birth or even before (see Randall’s posts for some links on costs). In this case, genetic insurance works only if the parents buy the insurance. This is not so implausible (especially not for those who have their child’s DNA sequenced!) but it is a real issue. (We should also remember that genetic insurance will be quite cheap because most people do not have serious genetic defects.) If we have genetic insurance today, however, we can perhaps avoid the adverse selection problem for a couple of decades and that may be good enough for one of two things to happen 1) genetic engineering will reduce the need for insurance (sequencing is much more valuable if there is genetic engineering to correct defects) or 2) genetic insurance could evolve into a more Rawlsian scheme (perhaps involving government at some level) in which payments are made at birth to compensate for Nature’s genetic lottery.

In a previous post I wondered whether additional spending on health care in fact brought greater health. Whether we do controlled experiments, or look at cross-national data, a convincing effect is often hard to find.

Brendan Kennelly of Lehigh referred me to this OECD paper, which examines cross-national data to find a positive health effect from health care spending. The result is much stronger for women than for men.

I asked Robin Hanson what he thought of the piece, here is his response:

When a coefficient is truly zero, about 5% of the studies estimating that
coefficient should show a significant difference at the 5% level. And if
people search for specifications that will give this result because they
believe the coefficient is not zero, you might expect 10-20% (or more) of
the reported results will show a significant non-zero coefficient. So
given the current state of econometric practice, the most you could
reasonably hope for when a coefficient is really zero is for about 90% of
the studies to fail to find a significant effect of the desired sign. This
is the current state of the evidence on the aggregate effects of medicine
on health.

My take: The whole debate still makes may head spin. I wonder how much of health care expenditure is geared toward alleviating anxiety (“we did all we could…”) rather than improving health per se. We may be mismeasuring the relevant output. If we could measure the total costs of illness, what percentage of the total would come in the form of anxiety? Furthermore, health care is not a single thing. The marginal return from some forms of health care (bypass operations?) is certainly high, in other cases the return much lower or perhaps negative. So perhaps the debate should shift away from aggregates, and toward trying to identify which health care expenditures we can do without, or do not need to subsidize at current margins.

…lifting children out of poverty can diminish some psychiatric symptoms…A study published in last week’s issue of The Journal of the American Medical Association looked at children before and after their families rose above the poverty level. Rates of deviant and aggressive behaviors, the study noted, declined as incomes rose.

“This comes closer to pointing to a causal relationship than we can usually get,” said Dr. E. Jane Costello, a psychiatric epidemiologist at Duke who was the lead author.

The study tracked 1420 children, many of whom lived on an Indian reservation. A local casino opening lifted many out of poverty, and also improved their mental health:

…the rate of psychiatric symptoms among the children who had risen from poverty was dropping. As time went on, the children were less inclined to stubbornness, temper tantrums, stealing, bullying and vandalism – all symptoms of conduct and oppositional defiant disorders.

After four years, the rate of such behaviors had dropped to the same levels found among children whose families had never been poor. Children whose families broke the poverty threshold had a 40 percent decrease in behavioral symptoms. But the payments had no effect on children whose families had been unable to rise from poverty or on the children whose families had not been poor to begin with.

Even I, author of a book called In Praise of Commercial Culture (see to the right), am surprised by this result. Supposedly the wealthier parents were now able to spend more time with their children, thus improving their mental health. I wonder whether the key factor instead might have been improved behavior on the part of the parents.

Here is the abstract, plus you can buy a copy of the original research for $12.

Addendum: David Levy, citing Adam Smith, wonders if it isn’t the growth rate of income that makes people better off, rather than the level.

The shortage of human organs for transplant grows worse every year. Better immuno-suppressive drugs and surgical techniques have raised the demand at the same time that better emergency medicine, reduced crime and safer roads have reduced organ supply. As a result, the waiting list for organ transplants is now 82,000 and rising and more than 6000 people will die this year while waiting for a transplant.

The economics of the shortage are so obvious that one popular textbook, Pindyck and Rubinfeld’s Microeconomics, uses the organ shortage to explain the effect of price controls more generally!

Perhaps because the shortage is growing, opposition to financial compensation for cadaveric donation (compensation for live donors is a distinct issue) appears to be lessening. The AMA, the American Society of Transplant Surgeons and the United Network for Organ Sharing have agreed that tests of the idea would be desirable. (A group of clerics, doctors, economists (I am a member) and others has formed to lobby for the idea – see our letter to Congress.) Currently, even tests are illegal but Representative James Greenwood (R, Pa.) has introduced a bill (H.R. 2856) that would create an exception.

Aside from the obvious benefits of saving lives, financial compensation for organ donation would likely save money. Here is a back-of-the-envelope calculation. There are some 285,000 people on dialysis in the US. Transplants are cheaper than dialysis by something like $10-$25,000 per year. About a quarter of those on dialysis are on the waiting list but perhaps as many as half could benefit from a transplant (fewer people are put on the list because of the shortage.) Let’s take the lower numbers. Assume that a quarter of the patients on dialysis could benefit from a transplant and that cost savings are $10,000 a year for five years. Then ending the shortage would save 3.5 billion dollars. Note again that this is a lower estimate. How much would it cost to end the shortage? No one knows for certain but I think a $5000 gift to the estates of organ donors would increase supply enough to greatly alleviate the shortage – that would involve doubling the supply to 12,000 for a paltry cost of $60 million. If this is not enough – raise the gift – anyway you cut it, the savings from dialysis exceed the costs of compensating donors by a large margin.

We should in fact count the value of the lives saved. If we can save 6000 lives and value each life at 3 million dollars (a lower value than what the US government typically uses in its calculations) then that is a further gain of 18 billion dollars.

A Tragedy of the Commons? Economics provides another way of looking at the crisis. Currently we have organ socialism – anyone who needs an organ is allowed access to the organ pool regardless of whether or not they contributed to the upkeep. As with other resources owned in common we get over-exploitation and under-investment. Consider, instead a “no-give, no-take policy” – only those who have previously signed their organ donor cards are allowed access to the pool. Not only is this more moral than the current policy it creates an incentive to sign your organ donor card. Signing your card becomes the ticket to joining a club – the club of people who have agreed to share their organs should they no longer need them. Equivalently signing your organ donor card becomes analogous to buying insurance. I discuss the idea further in Entrepreneurial Economics.

An organ club has in fact been started – I am not just an adviser, I’m also a member! You can join too at www.lifesharers.com.

The NYTimes reports that “introductions of new drugs plummeted last year to 17 from a high of 53 in 1996, despite a near doubling in annual research spending, to $32 billion.” The Times blames lost lab productivity from mergers. Based on close second-hand experience – my wife is a microbiologist who worked at a pharmaceutical firm as it underwent a merger – I can attest to the fact that mergers create havoc. Reaping the potential economies of scale and scope that drive the merger requires that product lines be discontinued and new lines of hierarchy established. But the power struggles involved in the transition are dissipative and disheartening. It’s not uncommon for some research programs to be canceled and then started again as new coalitons form. The uncertainty alone is draining. The best of the researchers have no stomach for this ordeal and jump ship.

The Times gets a number of things wrong, however. It can take a dozen or more years to research, develop and get a new drug approved so it makes no sense to compare this year’s research spending with this year’s output. The fact that research spending is up even though current output is down is a positive signal of potentially better things to come.

The Times also misses the fact the FDA was approving drugs faster in the late 1990’s than for many decades previously. The FDA got burned, however, as Pulitzer prize-winning critics accused it of endangering the public. Sadly, the FDA learned its lesson and slowed down. (See here for more on FDA incentives and why the Pulitzer prize committee did us all a disservice.)

Finally, the Times says nothing about why the mergers are taking place. One reason is the rising cost of pharmaceutical research. It now costs $900 million dollars to bring the average new drug to market. Firms are merging in order to better control these costs and diversify their risks. FDA reform could lower these costs.