Saturday, May 28, 2011

You read it here first (or, overcoming climate change avoidance)

I was glad to see that both Climate Progress and Grist are finally drawing attention to the fact that cancer is now the leading cause of death in China.  Perhaps now people will start paying attention to the health consequences of pollution.

I've been pretty flummoxed lately by the abundant attention being given by the press to asthma and respiratory disorders as sequelae of air pollution. Yes, asthma is a problem—it kills eleven people each day in the U.S.—but at least it is treatable and usually controllable, unlike the cancer, birth defects, and neurological diseases arising from toxic pollutants in China (and undoubtedly elsewhere). With all the talk about saving the planet "for our children/grandchildren" and the perils (such as mass migrations and wars over water) that “may” face us “this century” “if we don’t act soon,” I've begun to think that even those of us concerned about the environment have protective mechanisms we're unaware of: without being climate change deniers, we can be climate change
avoiders, preferring to think about the distant impacts of our (in)action rather than the very clear and present dangers we face now, and, indeed, have been facing for decades.

In any case, the Grist article provides more background than my post on the topic
. Though it does hint that the West bears some culpability for the problem (wanting to buy cheap goods made in China), it doesn't go as far as I did (namely, suggesting that our manufacturing plants in Asia are likely polluting the rivers just as much as any other plants there).

Saturday, May 21, 2011

Recommendation: "The Filter Bubble: What the Internet is Hiding from You"

Eli Pariser, of fame, has just come out with a book about how the internet filters information for us—even when we don't know it, and don't want it to. Pariser takes the experience I touched on in The Trouble with Choice, pursues it to its roots, and explains it better than I ever could.

The consequences of this kind of filtering for our political and social life are enormous. Democracy is hard enough when we share the same facts; it is impossible if we are being shunted into parallel universes. 

In March, the TED conference invited him to preview his call for an ethical, open internet. With Bill Gates and Google executives in the audience (!), he made a powerful case: here's a 9-minute video of his talk. It's truly eye-opening.

Pariser's work, interestingly enough, confirms my recent experience of doing internet research for this past week's series on drug shortages.  I found out about the shortages initially through a subscription medical journal, but when I googled to find more widely available reports, I got hardly any useful hits. I found this puzzling, but was even more perplexed when I would perform the same searches again a day later, then the day after that, and so on, and each time get more and more relevant hits that had clearly been there all along. If you've ever noticed this pattern yourself, you've got to watch the video.

And if you haven't noticed this happening, then you really have to watch the video.

Friday, May 20, 2011

Speaking of the connection between human and environmental health...

The Amazonian rainforest 

Frrom the department of perfect timing: as I was finishing the previous post, I received an email alert from an organization called Amazon Watch.  They have a video that is an "open letter" (so to speak) to the citizens of the United States of America from 30,000 Ecuadoran plaintiffs in the recently decided Chevron v. Aguinda environmental lawsuit. Chevron lost the suit but has sworn that they will never pay to remediate the region they have contaminated beyond habitability. Please take a look at the not-quite-three-minute video and sign the letter if you are so moved, as I hope you will be.

Lessons from the shrinking supply & burgeoning demand for vincristine

This is the fifth post in a series on the current drug shortages. I've been interested in peering beneath the surface of the industry reports to look at what this crisis might tell us about how the pharmaceutical industry operates and why our reliance on drugs seems to increase with time. The case of vincristine brings these issues to a head and illustrates why we cannot atomize our societal problems into neat little packages.

Vincristine, one of many drugs currently in scarce supply, is used primarily to treat non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, acute lymphoblastic leukemia, childhood leukemias, and nephroblastoma. Vincristine is derived from the periwinkle plant (Catharanthus roseus), which has long been used in pre-scientific medical practice to treat diabetes and regulate menses. It is now endangered—slash and burn agriculture has decimated its native habitats—but it is widely cultivated. Only two companies produce the drug: Teva says that they have had manufacturing delays, while Hospira says they can't keep up with increased demand. 

A word, then, about increased demand. 

Over the past two decades, the incidence of leukemias and lymphomas, the diseases vincristine treats, has risen dramatically; the rate of non-Hodgkin’s lymphoma alone has doubled [1]. These blood cancers are among the most common malignancies in humans, and the most common in children. Chemicals and agricultural pesticide exposure, hair dyes, and radiation are all well-established risk factors, as are chronic antigenic stimulation and autoimmunity (the incidence of both of which are also on the rise) [2]. The Houston city government’s State of Health report from 2007 offers these shocking statistics: cases of leukemia and lymphoma are twice as high among children living within two miles of the Houston Ship Channel, an area heavily contaminated by petrochemical plants, as those living outside the two-mile radius, and exposure to air pollution in the Ship Channel increases overall cancer risk by a factor of 1000 [3].

The National Cancer Institute states that every hour, an estimated 150 Americans is diagnosed with some form of cancer. That’s one in four Americans.

And we’re not even the ones at greatest risk. Not by a longshot.

A sewage pipe feeding directly into the sea.
In China, 80% of the residents of a small town called Shangba, one of the notorious "cancer villages," have died of some form of malignancy in the past twenty-five years, many in their first few decades of life. Surviving villagers are plagued by kidney stones and skin diseases. Why?  Extraordinary levels of pollution. The village is located near chemical plants whose frequent "accidents" contaminate the rivers that supply water to the town. 

Serious environmental “accidents”— I use quotation marks because somehow the word just doesen't seem to capture the recklessness, greed and sheer stupidity that cause a continual stream of these events—happened, on average, once every three days in China in 2007. In 2009, Dr. Hu Yali, a geneticist at Nanjing University, said he believed environmental pollution was responsible for a tenth of all physical defects in Chinese infants—and birth defects at that point had risen by 40% since 2001. The incidence of neurological and neurodevelopmental disorders is also sky-rocketing. These diseases are not curable. They aren't treatable. And even if the cancers can be treated, it is no use sending people back to live in toxic environments.

It's easier to catch fish when they're already dead.
Needless to say, these diseases are merely the most readily apparent effects of pollution on humans—currently. I suspect that these prevalence and incidence rates are under-reported in China (it would be bad publicity for the totalitarian state), but more to the point, we have neither the ability nor the inclination to track the effects of pollution on animals, wild or domestic. We do know there is a tremendous amount of waste in industrial farming, i.e., unhealthy animals cannot be sold for human consumption—though our standards for what constitutes healthy-enough-to-be-edible are pretty low—but no one does autopsies on most of these animals, and in any case we know that whole species are disappearing around us each day.

If you think that what happens in China is entirely China's problem, think again. Many U.S. pharmaceutical and chemical companies have manufacturing operations in China and India, another country facing dire environmental problems. I cannot help but wonder how many contaminating events involve companies with U.S. ties.

It is one of the bitter ironies of our age that to treat cancer we engage in processes that produce it.

And could contaminated chemicals be contributing to all the "manufacturing difficulties" being reported, along with shortages of plant and animal substrates for the chemical processes?

It's hard to tell, because the drug companies don't specify the nature of their difficulties.  Asymchem Laboratories, a North Carolina-based custom manufacturer of pharmaceutical ingredients with laboratories, pilot plants, and large-scale manufacturing operations in northeastern China, has said that small producers of basic intermediate compounds are disappearing because they cannot meet tougher environmental standards now being promulgated by the Chinese government in response to their enormous health crisis. In their sympathy for small companies, I think Asymchem misses the larger point.

Let's be clear: almost any standard in China would be tough to meet, considering their record. China has been the world’s largest polluter. In the first six months of 2007, the last year for which I could find statistics, the number of environmental accidents increased 98%, along with demand for energy and minerals. It remains cheaper for Chinese plants to employ inefficient processes that waste fuel than to improve manufacturing. (Surely the price of energy is not nearly high enough.) Yet each year, there are articles that repeat the same question asked by this piece from Time Magazine last July:
While the country's [China's] economic boom has always been dogged by environmental and safety hazards, the frequency of disasters this summer has raised new questions about whether the country can maintain its pace of expansion without doing catastrophic harm to its people and the environment.
"Without doing catastrophic harm"? The catastrophes have been occurring regularly for decades. How many years can we witness these disasters and think that they “raise new questions”? How much evidence must accumulate before we stop using “but more studies are needed” as an excuse to keep our head in the sand? The Time article mentions all the outrage expressed over the BP oil rig explosion in the Gulf—but even here in the States, where journalists aren't being jailed for reporting the truth, the consequences of the hemorrhage into the Gulf have dropped off the national radar screen. 

It is worth pointing out the limits of scientific inquiry in assessing damages in situations like these. We have little information on the ecosystems affected by environmental accidents. Before the Exxon Valdez oil spill, for example, there were no baseline data on the abundant species thriving in Prince William Sound. We know some species have disappeared from the area, others are still in very low numbers. But without a baseline, it will always be possible for corporations to argue about the sequelae of an event and debate the numbers. The quest for certainty becomes a distraction.

What does seem certain is that we cannot solve our problems by doing more of the same: using chemicals to counteract other chemicals to counteract others, taking antibiotics to treat the infection we got from eating meat from an animal who itself was given antibiotics.  As treehugger reported just this week, China's watermelons are "exploding like landmines" because the fruit is injected with chemicals to make it grow faster and ripen more quickly. Unsure whether the melons can be safely consumed by humans, they're chopping them up and feeding them to their farm animals.

What's next? A chemical to prevent the explosion of fruit injected with explosion-inducing chemicals?

In philosophy, this is known as infinite regress. 

Industry calls it guaranteed profits. 

Naïveté calls it progress.

Swimming in India

[1] See, for example, Fisher SG and Fisher, RI: The emerging concept of antigen-driven lymphomas: epidemiology and treatment implications, Curr Opin Oncol. 2006 Sep;18(5):417-24.
[2]  Fisher SG and Fisher, RI:The epidemiology of non-Hodgkin's lymphoma, Oncogene 2004 Aug 23;23(38):6524-34.
[4] The Asthma and Allergy Foundation of America; additional statistics here.

Thursday, May 19, 2011

Old treatments, new patents, big money: the case of colchicine

(This is Part 4 of a series examining the current drug shortages and what they might indicate about our approach to health and healthcare. Part 1 described the shortages; part 2 the response of the healthcare industry; part 3 examined one case in which the demand for a drug, oxytocin, seemed to be excessive, and asked how much of our reliance on chemical tinkering actually manifests cultural preoccupations with control over nature and self-improvement.)

The New England Journal of Medicine published a pointed article in 2010 on incentives for drug development. I excerpt it here; if you have access, you can read the full article [1].
In July 2009, the Food and Drug Administration (FDA) officially announced what physicians have long known — that the drug colchicine can effectively treat acute flares of gouty arthritis. The plant from which colchicine is derived was first used as a therapeutic agent for gout more than 3000 years ago in ancient Greece, and the tablet form has been widely available as a generic prescription drug in the United States since the 19th century. On the basis of evidence that had built up over the years, numerous consensus guidelines recommended colchicine as an effective second-line treatment for gout — for example, in patients who had adverse effects from nonsteroidal anti-inflammatory drugs.
It came as a surprise to many patients and physicians that the FDA not only approved the new version of colchicine (Colcrys) but also granted the manufacturer, Philadelphia-based URL Pharma, 3 years of market exclusivity for this ancient drug. The possibility of such an exclusivity period arose because colchicine, despite its longevity, had never been officially approved by the FDA for a particular indication. The 1938 Food, Drug, and Cosmetic Act required that all new drugs be approved by the FDA for safety before being introduced on the market, but it allowed drugs that were already on the market to remain available...
In 2007, URL Pharma organized pharmacokinetic studies testing its version of colchicine in healthy volunteers and a randomized, controlled trial involving 185 patients with acute gout. The combined findings of these studies confirmed the drug's safety and efficacy.... On the basis of this new trial, combined with the previously published evidence, the FDA approved Colcrys for treatment of acute gout. Because this was technically a new indication for the drug, the Waxman–Hatch Act authorized the FDA to award the company 3 years of market exclusivity — an incentive that the agency believes could encourage voluntary compliance with the drug-approval process.
At the same time, under the Orphan Drug Act, the manufacturer also received 7 years of market exclusivity for the use of Colcrys in the treatment of familial Mediterranean fever (FMF), a genetic inflammatory disorder that affects only about 100,000 patients worldwide. The Orphan Drug Act provides federal grant funding and tax credits for clinical trial costs, as well as market exclusivity, to encourage research into rare diseases. The orphan-drug incentive is not restricted to new products: currently available drugs that are approved for a new orphan indication can also be granted exclusivity. For example, thalidomide, a drug designed as an antiemetic agent that fell out of favor in the 1960s after it was linked to birth defects, was approved in 1998 as an orphan product for the treatment of leprosy and in 2006 for the treatment of multiple myeloma. In the case of FMF, the usefulness of colchicine in helping to control debilitating attacks of fever and abdominal pain was already established, and the orphan indication for Colcrys was approved on the basis of a review of previously collected data, along with additional limited safety information from the pharmacokinetic trials.
...After the FDA approved Colcrys, the manufacturer brought a lawsuit seeking to remove any other versions of colchicine from the market and raised the price by a factor of more than 50, from $0.09 per pill to $4.85 per pill. These increased prices directly affect the availability of the drug to patients with gout or FMF who have long been using colchicine safely in an evidence-based manner. Exclusivity can also affect health care delivery more broadly. According to the Centers for Medicare and Medicaid Services, state Medicaid programs filled about 100,000 prescriptions of colchicine in 2007 and paid approximately $1 million for the drug. Use of the new brand-name colchicine could add as much as $50 million per year to these insurance programs' budgets....
Drug companies regularly complain that the costs of R&D are so high they are simply forced to charge more for drugs. There are several problems with this claim. First, many drugs, like colchicine, have been in use for centuries: not a lot of research investment needed in these cases, and no one is offering  patent royalties to native tribes. Second, the vast majority of drugs are “me-too” compounds that differ remarkably little from their predecessors. Again, not much research investment required. Third, the figure bandied about by the industry, a little under $1 billion to develop a new drug, remains vastly inflated even if we limit it to cases in which all the research is undertaken by the company (which is hardly ever the case, since most basic discoveries are made in academic medical centers, where research is funded largely by the NIH). As Marcia Angell, MD, Editor of the New England Journal of Medicine for twenty years, explains
A group of economists—mainly funded by the drug companies—came up with the widely quoted figure on this. They said that it cost $802 million to bring a drug out. They, however, were looking at the most expensive drugs to develop: new chemical compounds developed entirely in house. Most new drugs aren't that at all. Most are what people call "me too" drugs, which are slight variations of older drugs already being sold.
According to these economists, the real cost of bringing out those rare original drugs is actually around $403 million. But they doubled it by factoring in how much money the companies might have earned if they'd invested that $403 million. Moreover, the economists did not figure into their total the many generous tax breaks these companies receive for doing research and development. This is a highly inflated figure.
The fact is that for the last two decades the drug companies have been hugely profitable. Last year there was a little wiggle downward, but in 2002, the 10 biggest American drug companies had a median profit of 17 percent of sales compared to a median of 3 percent for the other Fortune 500 companies. In the 1990's, profits ran between 19 and 25 percent. Prices are high to keep profits high.
Dr. Angell is actually a little off on one point. She implies that drug companies have enjoyed chubby profit margins for only the past two decades or so. In fact, as economist Alek Rozental wrote fifty years ago in “The Strange Ethics of the Ethical Drug Industry” (Harper’s Magazine, May 1960):
Insulation from the cold wind of pure competition is provided by our patent system which actually encourages "limited islands of monopoly." Our laws are, in fact, more lenient than in most industrial countries, especially as they apply to drugs. [...]
Today whether measured as a proportion of sales or of return on invested capital, the net profit after taxes of ethical drug makers are double those of manufacturing as a whole. In 1958, a comparatively poor year, Smith Kline & French netted nearly 17 per cent after taxes, G. D. Searle, over 20 per cent. In the same year American auto makers got less than 4 per cent. The Wall Street Journal commented: "The 1958 performance showed no signs that drug makers were affected by the recession that had other industries stumbling."
The drug industry's favorite defense of its high returns is the fact that it spends more than three times as much on research, in proportion to sales, as does American industry as a whole. But in fact for every pharmaceutical dollar spent on research four are spent on promotion and selling. Moreover, much of this research money goes into "development," which consists chiefly in devising new dosage forms and combinations of ingredients.
So 17-20% in the recession of '58, a median of 17% in the recession of the 2000's: the industry has  consistently enjoyed the same extraordinary profit margins and dominated American industry by the same ratio for over 50 years. Remember this when you hear that it’s not profitable to continue producing drugs once they’re off patent.  And remember colchicine when you’re told that the pharmaceutical industry should not be regulated, because the “free market” and “competition” ensure the best quality for the best price.

Finally, as an addendum to my previous post, which asked whether the availability of a drug didn’t create a need for it as much as the other way around, Prof. Rozental has this to say:
The story of the tranquilizers illustrates the relaxed attitude toward "ethics" of even the most respected firms. To the manufacturers, tranquilizers were much more than an important adjunct in the treatment of severe psychotics in mental hospitals. Sales could be pushed into doctors' offices and into private homes, providing a unique opportunity to reap a harvest. More than half of the $200 million worth of tranquilizers sold annually are bought by normal people who, whatever their inner tensions, lead humdrum useful lives. Reserpine derivatives, based on Indian snake root, are promoted not only for the severely disturbed but also for the "nervous, the tense, the emotionally unstable." Roerig lists twenty-five situations where Atarax is indicated, including apprehension over weddings, depression at funerals, and anxiety over examinations. Meprobamate (under the trade names of Miltown and Equanil) has become a household word and in the space of less than two years fourth among all drugs sold. Smith Kline & French's tranquilizers are said to account for over half of the firm's total profits. No one can deny that tranquilizers have helped the mentally ill and even made it possible to buy commercial insurance against psychiatric ailments.[!] But many of the more potent tranquilizers have dangerous side effects...Others have very debatable therapeutic value or, in the dosage suitable for office patients, are little better than older sedatives at one-twentieth the cost.
In promoting tranquilizers to physicians, one firm spent $100,000 on a single mailing. In elaborate, multi-colored spreads, the industry combines quasi-scientific information with emotional, often subconscious symbols. Atarax ads, for instance, are said to favor blue on the advice of "motivational" specialists. Thorazine for menopausal upsets [!] is illustrated by a heart-rending picture of a woman anxiously watched by her daughter. Doctors are reached by the frequent repetition of "O.K." words such as "synergistic," "potentiating," "sure-fire", and "low toxicity." Little presents are often sent along with the literature and samples.... Wallace Laboratories sent physicians a record with an Oistrakh violin solo on one side and a product plug on the other.
Thorazine, by the way, was and is used to treat schizophrenia and other psychotic states. And you wondered whether  Mad Men was exaggerating the misogyny and manipulation of Madison Avenue....

The next(and final) post of this pharmaceutical series, Part 5, explores a link between the burgeoning demand for a cancer drug, its limited supply, and our environmental problems.

As a treat for having made it through such a lengthy post, check out this page to see Thorazine advertised as a treatment for anxiety, arthritis, asthma, alcoholism, burns, cancer, cancer-phobia, hiccups, ulcers, menopause, busy hospital wards, disturbed patients, nondisturbed patients, former patients, vomiting, radiation sickness, and, yes, schizophrenia.


[1] “Incentives for Drug Development — The Curious Case of Colchicine,” Aaron S. Kesselheim, M.D., J.D., and Daniel H. Solomon, M.D., M.P.H. N Engl J Med 2010; 362:2045-2047June 3, 2010

Our demand for drugs: the case of oxytocin

In the first two posts of this series, I outlined the current prescription drug crisis and the responses of physicians, the managed health sector (PHA) and the pharmaceutical industry (PhRMA). I believe these drug shortages reveal the unsustainability of certain healthcare industry practices as well as fundamental flaws in how we think about health, technology, and progress. To build the foundation for this argument, I will sketch brief case histories of three drugs over the next few posts, beginning here with oxytocin.

The January 2000 British Medical Journal report I referred to in Part 1 of this series noted that in October 1999, the Harvard-affiliated Brigham and Women’s Hospital abruptly found itself unable to procure oxytocin, which it used “in almost every one of its 10,000 annual deliveries.”  Speeding along in my first reading, I suddenly stopped short. Oxytocin was used in nearly every delivery?

As most of you know, oxytocin is administered to induce labor. The hormone actually serves many purposes; all of us produce it naturally, men as well as women, and it has been touted as “the social bonding factor.” It was discovered by accident in 1909 when Sir Henry Dale noticed that pituitary gland extract induced uterine contractions in a pregnant cat; as early as 1911 pituitary extract was being used to stimulate labor [1]. In 1953, oxytocin became the first peptide hormone to be synthesized in a lab. Both Dale, who discovered the hormone, and Vincent de Vigneaud, who synthesized it, went on to win Nobel Prizes.

By 1998, about 16% of labors were induced, by oxytocin, an additional 16% that began naturally were augmented with oxytocin, and the drug was also used post-partum to prevent hemorrhage [1]. Oxytocin use peaked in the late ‘90s and early 2000’s before greater caution set in, as much from an increasing cultural preference in the West for ‘natural’ childbirth as from evidence that exogenous oxytocin could have adverse effects on the infant [2].

The BMJ noted that Brigham and Women’s Hospital did not find that the oxytocin shortage compromised care or the results of labor and delivery. Why, then, was it used in almost every delivery in the Boston hospital? Perhaps self-selection was involved: BWH is a renowned, high-tech hospital that likely draws more women with high-risk pregnancies (or women who are anxious about their pregnancies, or who are technologically inclined). A medical article published in 1999 sheds some light on the attitude of physicians at this time:
In an ideal world, all pregnancies would go to term, and labor would begin spontaneously. In reality, it is often best to deliver the infant before the onset of natural labor... In the past decade, our knowledge of the mechanisms of labor has increased tremendously. In addition, the ability to detect and manage antepartum maternal and fetal complications has greatly improved. As a result, labor can be induced in an increasingly rational and successful manner.
The authors clearly have a strong conception of what an “ideal world” looks like and the kinds of “rational management” that can lead us there. These ideas deserve consideration, but for now, let me just note that last April, a study conducted by Iraqi physicians from 2004 to 2006 concluded that acupuncture largely eliminated the need for oxytocin in women who had undergone ceasarean deliveries [3]. (Persistent shortages of oxytocin had compelled physicians to seek alternatives.)

Along the same lines, a 2004 paper published in Hospital Pharmacy evaluated the results of an antibiotic shortage on patient outcomes and costs and found that the alternative antibiotics they substituted for piperacillin/tazobactam (P/T) reduced the average hospital length of stay by about one day and slightly reduced costs, without adverse effects on patients. This is not to say that drug shortages never have ill effects—they increase the risk of errors, for one thing—but this question has not been formally addressed in most cases. Given that experts consider only about two to four dozen compounds to be the core of our pharmacopia, with the remainder being "me-too" drugs, it is possible that lack of a particular drug poses a problem less because of the drug's unique characteristics than because of the structural consequences of the scarcity (secondary shortages, time spent locating alternatives, etc.).

The oxytocin story does raise other questions, however. How much of our reliance on drugs is necessary, or even beneficial, to our long-term health? And how much does the availability of a drug create our "need" for it? How different is our desire to control events like labor and delivery from our desire to control events like erections? (Have Viagra and Cialis ever been scarce?) And how does the desire for control shade into the wish to enhance abilities like pitching a fast ball, or concentrating in school, or simply feeling happier? Where does treating illness cross over into self-improvement or simply extend our strong cultural tendency to want to dominate nature, subdue our bodies, control our wayward physiology?

The next post will concern the curious case of colchicine.


[2] See, for example, Oscarsson, ME et al., Outcome in obstetric care related to oxytocin use. A population-based study.  Acta Obstet Gynecol Scand. 2006;85(9):1094-8.


Wednesday, May 18, 2011

Supply or Demand?

(This is part 2 of a series on pharmaceutical drug shortages, which began with Not what the doctor ordered. A brief recap: over the past decade we've experienced more numerous and more severe shortages of prescription drugs. Currently over 240 drugs are unavailable, and another 400+ are back-ordered. Roughly half of the unavailable drugs are "sterile injectibles" used for chemotherapy and sedation. Consequences to patients and practitioners abound.)

The web sites of the FDA and the ASHP (American Society of Health-System Pharmacists) list drugs that are in short supply and the reasons for their scarcity. The three general reasons are: “manufacturing difficulties,” “increased demand,” and “no explanation given.” I assume the last arises when a company decides to stop making a low-profit-margin drug but doesn’t want to take the public relations hit that would come from stating the case so baldly.

ow shortages develop: the perspective of managed care organizations

The Premier Healthcare Alliance (PHA) report I mentioned in the
 first post
of this series offers the following reasons for the shortages (the categorization is my own, for the sake of clarity):
Interruptions in supply: “lack of active pharmaceutical ingredients”
Quality control: “Roughly half of the shortages of injectable drugs in 2010 were due to product quality situations such as presence of particulates, microbial contamination, newly identified impurities, and stability changes.”
Consolidation of drug manufacturers (i.e., takeovers and mergers): "Where we used to have two and three [companies] providing drugs in some cases, we now have one.” 
Financial motives, i.e., companies make less profit from generics so they stop making them: "Manufacturers are delaying or discontinuing investments, thereby impacting product availability."
Fear-based financial motives: “Pressures are mounting to offset profit reductions resulting from patent expirations, healthcare reform, and investments related to FDA regulatory compliance for older products." 
The FDA: “The agency requires manufacturers to abide by what are known as good manufacturing processes (GMPs) or else face regulatory action.”
Hm. These last two reasons bear closer examination. It is true that several hugely profitable patents are set to expire in rapid succession, and without new blockbusters in the pipeline the companies are justifiably nervous. But the situation feels dire only because the industry has enjoyed such fat profit margins (at least several times that of the oil industry) for so many decades; the guy with a billion dollars in the bank blanches at the thought of losing a hundred million, but it won't actually make him poor. We should bear this in mind.

Moreover, healthcare reform was actually a boon to the pharmaceutical industry, since it ensured an increase in the number of insured and thus an increase in drug consumption—long-term stability they gladly traded for short-term discounts to insurance—and, astonishingly, guaranteed twelve years of exclusivity rights to branded biologics, far longer than the usual five years given to small molecule drugs. The industry thus maintains its "islands of monopoly" (see discussion in part 4: Old treatments, new patents, big money).

Finally, let's consider the complaint about FDA insisting on Good Manufacturing Practices. How, exactly, are quality controls supposed to contribute to the shortages? Recall that half of the shortages were caused by contamination of one sort or another. I suppose the industry would have preferred to be able to sell the contaminated drugs—at a discount, of course. After all, one aspect of Premier Healthcare Alliance’s mission is to “operate at costs in the lowest quarter of the healthcare system while providing quality in the highest quarter.” Given the subsidized monopolies that healthcare and drug companies enjoy, I assume that ‘quality’ refers to return on investor shares and ‘highest quarter’ means the penthouse suite.

The PHA report elsewhere concedes that safety is a good thing, but then they hedge:

"While the FDA's vigilance of [GMPs] and actions against unapproved drugs help keep medications safe and effective for the public, new regulations may have a downstream impact on the entire marketplace," the report authors said.
I’d say that if the regulations requiring manufacturers to adhere to quality standards didn’t have a “downstream impact on the entire marketplace” there would be no use for them. But you have to give the PHA credit for their subliminal messaging about "new" regulations that "may...impact"; there are no new regulations affecting production that I could unearth, but the phrase conjures an ominous sense of Government Interference looming just around the corner. 

The pharmaceutical industry’s response

Here is the statement issued by the Pharmaceutical Research and Manufacturers of America (PhRMA) in response to PHA’s survey:
"According to the Food and Drug Administration (FDA) and other experts, drug shortages can occur for any number of reasons, including natural disasters; shifts in clinical practices; wholesaler and pharmacy inventory practices; raw material shortages; changes in hospital and pharmacy contractual relationships with suppliers and wholesalers that can cause fluctuations in the availability of certain products; adherence to FDA-mandated distribution protocols, which can impact patients' timely access to medicines; individual company decisions to discontinue specific medicines; and manufacturing challenges," said PhRMA Senior Assistant General Counsel Maya J. Bermingham.
PhRMA has not taken a position on Klobuchar's drug shortage legislation.
The tone of this statement is instructional, as if PhRMA is patiently teaching a class on drug shortages. "Experts say that there are eight reasons for..." It's also slick: you’ve got to admire the way PhRMA doffs its hat to the FDA at the beginning to set up a more convincing accusation later. Unsurprisingly, Big Pharma wants to spread the blame around. First there are the “acts of God”: natural disasters and raw material shortages. Then there are faults with healthcare providers themselves: “shifts in clinical practice,” “inventory practices,” “changes in hospital and pharmacy contractual relationships with suppliers” (a.k.a. drug companies; anyone see any circularity here?). Then, of course, there is the the FDA, which wields the stick of “mandated distribution protocols” (so that hospitals get, say, flu vaccines before retail pharmacies).

To their credit, PhRMA does not complain about having to adhere to the FDA's Good Manufacturing Processes. But notice that they assiduously avoid mentioning their own significant contribution to the problem, industry consolidation. They also fail to cite manufacturing difficulties, which I find curious.

What's missing

The one explanation that is missing from both the PHA report and the PhRMA response is increased demand. It's the elephant in the room no one wants to acknowledge, because it calls into question everything we've been taught to believe about health, technology, the "free market," and progress. I'll take up these implications one by one in the next few posts.

Tuesday, May 17, 2011

Not what the doctor ordered

After decades of gleeful consumption, we seem to be finally coming up against the reality of limits. We may not know the details [1], which in any case are impossible to pin down with certainty, but the gist is familiar: the pie is shrinking, there are more of us trying to get a piece of it, and the two trajectories are on a collision course. Oil and water supplies, rainforests, and animal species have been decimated by our wasteful, anthropocentric ways, and the most we seem to be able to manage in global response is a collective shrug.

To top it all off, we are now facing a serious shortage of . . . prescription drugs.

I had my own brush with a drug shortage two years ago, when I could no longer procure the thyroid medication that works best for me, but I had no idea of the scope of the problem. Leave aside for a moment the first question that pops into any reasonable person’s mind, namely, how on earth we have become so sick that the mighty pharmaceutical industry can’t keep up. What's actually happening?

In the late 90's . . .
Drug shortages apparently started attracting attention in medical publications in the late 90’s. The British Medical Journal reported in their January 20, 2000 issue that afew years ago a hospital might run short of one or two critical drugs a year, whereas in the past year the number has run to as many as two dozen drugs.” The report gave three examples, one of which was the following:
      . . . Brigham and Women's Hospital in Boston found itself unable to buy sufficient supplies of oxytocin, which is used in almost every one of its 10,000 annual deliveries. Doctors therefore had to cut back on their use of the drug. Fortunately no patient suffered, said Dr David Acker, the hospital's chief of obstetrics.
The BMJ article offered three explanations for the shortages: manufacturing difficulties, “just in time” inventories (keeping minimal supplies on hand to save outlays and storage space), and “price inflation in the ‘grey’ market for drugs, under which small drug wholesale distributors obtain drugs and resell them at large markups to hospitals unable to obtain them from regular suppliers.” According to the BMJ, the grey market accounted for about 1% of total sales of prescriptions drugs in 1999 (~ $1 Billion). Although only the manufacturing difficulties would account for an actual reduction in supply, distribution practices presented a significant problem. In 1999, the American Society of Health System Pharmacists protested to then-secretary of Health and Human Services, Donna Shalala, that hospitals weren't receiving their orders for flu vaccine yet the vaccine was shipping regularly to supermarkets and other retail outlets. In response, the US Food and Drug Administration set up a website to serve as a central repository of information on scarce drugs:

. . . and now.
As of May 2011 there are over 240 drugs in such scarce supply that no one knows when they’ll become available; another 400+ are on backorder (you can see the list of drugs here). Most of these drugs are used in the hospital setting for sedation, emergency care and chemotherapy, but antibiotics and other meds are also affected. 

Over the past few months, dozens of journalists have been riffing on a survey performed last year by a “performance improvement alliance” of 2,500 U.S. hospitals, the Premier Healthcare Alliance (PHA), which asked 311 “pharmacy experts” at hospitals, surgery centers, and long-term care facilities about their experience with shortages during a six-month period in 2010.[2]  Among the survey respondents:
53% said treatment-plan-changing shortages had occurred more than six times during the six-month period 
80% experienced shortages that caused delay or cancellation of patient care (surgeries and oncology treatments in particular); 34% reported such a shortage occurred more than 6 times in the six-month period
89% experienced shortages that “may have caused” a medication safety issue or error in patient care. Eight out of 10 times a shortage occurred, the patient’s care was delayed or the medication intervention was canceled.
98% experienced shortages that led to increased costs. Drug shortages are estimated to cost U.S. hospitals “$200 million a year, in part because providers pay an average of 11% more for shortage products.” 
What is the fallout from a drug shortage?
The unavailability of a favored drug can disrupt healthcare—providing or receiving it—at multiple levels. Most obviously, there are the logistical imperatives of scarcity: because pharmacists and physicians often don’t find out until the day the drug is needed that it is not going to be available, scrambling about for a substitute requires time and tactical adjustments that can only add tension to a system already stretched thin.

In some cases, there isn’t a good substitute. A related drug might be less effective for a particular use, in a particular patient, or less well tolerated. It might also be much more costly. A brand-name cancer drug called Fusilev (levofolinate) contains similar active ingredients as the now-scarce $7.41/dose leucovorin, but at $177 per dose it costs nearly 24 times as much. (It’s noteworthy that most of the supply problems affect inexpensive generics and off-patent drugs.) The two drugs also have different treatment profiles, and no one knows how Fusilev interacts with other compounds in the chemotherapy cocktails that used to contain leucovorin. Even if an effective substitute is available, greater demand for that substitute is likely to create a secondary shortage. Sudden interruptions in supply also create headaches for clinical trials.

Most problematically, scarcity sets the stage for dangerous mistakes. Drugs in the same family can differ greatly in dosing requirements: two patients died after receiving hydromorphone at the same dose as its chemical kin, morphine. A September survey by the nonprofit Institute for Safe Medication Practices documented more than a thousand errors, near-misses, and adverse patient outcomes directly attributable to drug shortages.

Senators Amy Klobuchar (D-MN) and Bob Casey (D-PA) recently sponsored a bill that would require pharmaceutical companies to notify the FDA when they expect a shortage of a particular drug or plan to discontinue it. Even though the proposal is merely an early-warning system, and a toothless one at that, the pharmaceutical industry has not yet decided whether it supports the legislation, which just might be able to grow teeth in the future. (Currently, drug companies are not required by law to alert the FDA when they expect a shortage, even though in about a dozen cases when the FDA received early word of a supply problem they were able to avert a crisis.) 

In the meanwhile, physicians, nurses and pharmacists are devising heroic workarounds, sharing resources, forming networks with other providers, strategizing for the near future. Perhaps their effectiveness, all the more remarkable considering the other pressures they labor under, is why more of the public is not aware of the problem.

In the next post, I'll analyze the way the shortages are being understood by the industry itself.


1.  Some of these statistics are estimates, but they're unlikely to be too pessimistic:
Non-Opec nations passed peak oil production in 2010
Potable water has already caused bloodier conflicts than petroleum, including the Rwandan genocide
Rainforests once covered 14% of the earth’s surface, now cover less than 6%, and the rest could be consumed in the next forty years
About 137 species disappear every day because of deforestation
Half of all ocean species have vanished in the past fifty years
2. The AHP mission and vision statements deserve an analysis on their own (and will receive one in due course).