A bit more about drug shortages

Critical shortages of essential drugs continue to plague American medicine. My email inbox includes a daily update from the FDA with, among other things, the latest status reports on drugs in short supply. There were 24 on today’s list. The cancer drugs Doxil and methotrexate were not described; you may have seen that the FDA recently announced some stopgap measures to permit importation of substitutes for those drugs.
For people with cancer, that was a bit of welcome news, but sometimes a substitute won’t do. Pinch-hitting for Doxil, for example, is a drug called LipoDox, which is similar but not the same thing. The differences could be important for patient outcomes—especially for patients in clinical trials using Doxil. Those trials are on hold; the possibly different results with a substitute could make a whole trial uninterpretable.
Most of the drugs in short supply are, in fact, generic, and they generally are not pills but drugs that have to be provided and administered under sterile conditions, by vein. That makes them challenging to produce, and one hiccup in a pharmaceutical plant can ruin their whole day—or a few weeks or months while they shut down and fix things. That has happened to big producers like BenVenue and Teva.
The clearest ethical issue is the appearance of gray markets, consisting of some distributors who exploit shortages to charge larcenous prices. Investigations into these gray markets are ongoing. For example, an outfit called the Premier healthcare alliance has published reports in the last few months. (They don’t publish the names of the reportedly price-gouging vendors.) Drug manufacturers on one end, and hospitals on the other, are on the lookout for these gray market operators, and they say they are aggressively trying to avoid them. Price is not the only issue—drug counterfeits may be involved, as well.
Some weeks ago, a post on this blog raised the ethical issues of allocating scarce resources with regard to these drug shortages. That is, of course, salient, yet less interesting to me. Why? Because, as M.D. Anderson Cancer Center’s Dr. Hagop Kantarjian has put it, drug shortages are “a preventable human disaster.” We should be able to fix this problem.
How? Condemning the gray marketeers is generally agreed upon. But some would go further and say that enforcing price controls is the principal answer. In fact, relaxing those controls may be a better choice. Medicare and Medicaid pay “average wholesale price” plus 6% for these drugs, which are generally cheap. Professor Awi Federgruen of Columbia Business School recently argued in the Wall Street Journal that allowing producers to charge a bit more for these effective drugs would increase the incentive for more suppliers to make them and make the investments needed to be sure their plants avoid shutdowns.
Also, while there’s no lack of finger pointing toward manufacturers (who need to get their act together) or the FDA (for, supposedly, over-regulating), and while some regulatory adjustments may help, Prof. Federgruen has another suggestion: hire (or contract) more reviewers to reduce a 12-month backlog of applications for new generic drug manufacturing plants and processes. Does anyone else want to join me in saying “Duh?”
Maybe the best approach is less one of moral reflection or enforcement than practical problem-solving, in this case.

Contraception, Conscience, and the Language of War

Outcry over the HHS contraception mandate is not going away—and it shouldn’t. (See Steve Phillips’s excellent February 1 post on this blog.) Now, the press is horrified that social conservatives are being heard with a new vigor in our political discussions. “Can’t we just get along?”
Well. Last fall, the sitting Secretary of HHS told supporters of the National Abortion Rights Action League that “we are in a war.” Here’s a link to a report of that: http://www.ncregister.com/daily-news/sebelius-war-lands-her-in-court/. So, several months before the actual promulgation of the regulation, our government officials—at least as high as the Cabinet, if not higher—openly declared war on religious freedom. When the government—with the power of the sword—says that, it is not unreasonable to assume it means it.
The President’s “accommodation” is, of course, a distinction without a difference. It was pronounced “unacceptable” in a letter announced on February 10; the pdf available online shows today’s date, February 21, and can be linked here: http://www.becketfund.org/unacceptable/ In response to the complaint, “Where are the women?” one might note the women who have signed the letter, including CBHD’s Executive Director, Paige Cunningham.
To be sure, as unavoidable as the language of war is in the policy arguments, it may be a bit harsh on the individual level. I don’t talk nearly as much as I ought with people who disagree on social issues, and some of the venues (e.g., the workplace) are sensitive at best, but I have to remind myself to try to tone it down if I can. (Those who know me know I can come across as pretty arrogant.) I think the main discussion point is that the issue is how much control the government ought to have, NOT the supposed health benefits or general availability of the Pill to those who find its use morally acceptable and want to use it. The even more critical point—touchier to discuss, essential to practice—is the full, rich, cosmic significance of marriage in God’s creation design (cf. Genesis 2:18-25) and His redemptive plan (cf. Ephesians 5:31-33). As many have commented, the two big shots the family has taken below the waterline in my lifetime are the Pill and no-fault divorce—abetting the notion that marriage is principally a contractual arrangement for the benefit of adults.
Still, make no mistake—it’s 1534, and the king wants a divorce. (And, while you’re at it, think also of Russell Hittinger’s argument that, in the French Revolution, the Catholic Church drew its battle line at government control over marriage and the family.) We must be stout and wise in this one.

Is(n’t) Kalydeco Worth It?

You may have seen the news last week that the FDA approved Vertex Pharmaceutical’s Kalydeco™ (ivacaftor), a drug used to treat people with cystic fibrosis (CF) who have a specific mutation of a gene called CFTR. CF is a miserable, inherited disease that afflicts about 30,000 people in the US. It causes stick mucous, making breathing labored, infections frequent, digestive problems the norm, and early death (around age 37) a patient’s destiny. About 4 percent of those have the mutation targeted by Kalydeco, meaning that it will be useful for only about 1,200 people—a true orphan drug. From the data summary in the drug label, and anecdotal reports in the general press, this group of patients improves—sometimes a lot. They feel better, their lungs work better, they get fewer infections, they gain weight. They have to take the drug—a pill—twice daily, continuously. If resistance to the drug has emerged, I am not aware of it—but I’m not an expert in CF.
The drug had been in development since the late 1990’s, first by a venture-backed company, Aurora Biosciences, then by Vertex after an acquisition in 2001. The pivotal clinical trials included 213 of the 1,200 potentially eligible patients—a remarkable effort by the company, the doctors treating the disease, and the patients participating. Clinical trials are not finished; the FDA will require Vertex to do a (small) clinical study to address the potential for certain drug interactions, but that’s not a big hurdle. Also, data are not yet available to show the drug is safe and effective in children under age 6.
The FDA approved it in 3 months after getting the data for review—a true fast track.
Oh, and it will cost $294,000 a year per patient.
On its website, the company advertises a financial assistance program it says (press release dated 1/31/12) includes free drug for people with no insurance and an annual household income of $150,000 or less, and co-payment/co-insurance support for “up to 30% of the list price of the medication,” after “a minimal out-of-pocket obligation,” for people of any income who have insurance. Since insurance co-pays for specialty drugs like this commonly are a quarter to a third of the total price, this sounds like, in effect, secondary insurance from the manufacturer to help people afford it.
I think it’s a good deal. I can’t guess at the details of Vertex’s financial calculations based on the publicly available information I can find. They told the SEC that they had about $1.4 billion in revenue last year, almost all from its approved hepatitis C drug and other payments in their hepatitis C work, and about $190 million in profit. They expect to spend roughly $750 million in the next year on R+D all told. I don’t know how much they spent developing Kalydeco. The San Diego Union-Tribune said “millions of dollars of [Vertex’s] own money.” The Cystic Fibrosis Foundation, which will get royalties from Kalydeco sales, contributed $75 million to the drug’s development.
So, although I can’t fully defend the pricing, it sounds like this drug is worth the price. In thinking about these “expensive drug” questions, I suggest: 1) Realize that drug companies are medically-oriented businesses, not an arm of the medical profession, and therefore subject more to business than medical ethics when it comes to financials; 2) Challenge the too-simple notion that “making all drug companies non-profit” will reduce costs or be beneficial to society, since the issues of financing expensive development and recouping costs do not go away, and non-profits’ operations can be distorted by the actions of sinful/fallen actors; 3) Judge each case on its own, separate merits—Kalydeco sounds to me like a much better value proposition than, say, Avastin for breast cancer did; 4) Resist the Manichean “drug-companies: evil” grunt; 5) Affirm that there is a societal obligation to make effective but expensive drugs available for those who need it. That means that, whatever set of payment arrangements we adopt, I’m all for my tax dollars or insurance premiums being used to get this drug to a stranger who would benefit from it.
I realize that doesn’t magically solve the issues raised by expensive new drugs, but I submit it provides a framework for proceeding.

Getting the Doctors to be the Doctors

Physician readers of this blog probably saw the two-page “viewpoint” piece by Dr. Ezekiel Emanuel in the January 4, 2012 edition of JAMA, under the title, “Where Are the Health Care Cost Savings?” The upshot: “First, physicians must be the leaders and must stop looking to drug companies, insurers, or someone else to initiate and achieve cost savings.” (When I read “someone else,” I think, “government.”) I think there is a lot to this—it’s not just an example of asking physicians to answer to society rather than care for patients, a charge with which Dr. Emanuel is undoubtedly familiar. Consider his reasoning:
• Slowing the growth of health costs means “going where the money is” by identifying approaches that can cut costs by at least $26 billion a year, or 1% of current expenditures.
• That implies improving care of people with chronic conditions like coronary artery disease, diabetes, congestive heart failure, and others. About 10% of the population currently requires about 64% of the costs, and most of the 10% are people with a few chronic conditions like coronary artery disease, diabetes, and the like. These patients would be better served, at lower cost, by concerted efforts to reduce avoidable complications, improve patient monitoring, increase medication compliance, use specialists more efficiently (read: selectively), and use technology and currently-less-reimbursed activities (home visits, lifestyle and transportation services) to achieve these.
• Many popular suggestions for reducing cost would have a low “bang for the buck:”
o Malpractice reform might save $11 billion, or 0.5%, per year;
o Reducing insurance company profits means cutting into an amount that, in 2010, totaled $11.7 billion for the 5 largest insurers;
o Drug reimportation might save $2.6 billion;
o Replacing all brand name drugs with generics would save Medicare Part D less than $1 billion;
o Rationing end-of-life care is similarly misguided—in 2010, only 255 patients nationwide had care costing over $1 million each, and while those with bills over $250,000 add up to 6.5% of health costs, they cannot be identified in advance, so planning good but cheaper care for them prospectively is impossible. Besides that, people would “raise the charge of ‘death panels’”—something else he’s heard before. (Insert the emoticon of your choice here.)
Physician leadership principally means, for Dr. Emanuel, that they must work together to redesign care delivery for chronic illness—a challenge, but “only effective physician leadership can ensure successful redesign.” It also means, however, that physicians should not just accept that they will have to be paid differently (bundled payments rather than fee-for-service), they should take the lead in proposing how that deal would look.
I know, I know—Dr. Emanuel is famously a proponent of the “IPAB,” and the notion that doctors will magically see their way to enlightened new ways to pay them is pretty facile. But I cite this piece to suggest that the core point—the doctors have to be the doctors—is the critical one. It is for the doctors to tell the rest of us—not for us to tell them—how they can best care for us, collectively as well as individually, and to identify and implement best practices for that. It seems to me that, whether the challenge is avoiding unnecessary complications or critically asking whether that expensive, marginally effective new cancer drug is really good for a patient, that we should encourage the medical profession to be out in front here. The challenges are immense, and not new, but can’t strong societal leadership by doctors, in the name of caring for their patients better, be part of a vigorous revived Hippocratism?

The state of PGD—an update from ASH

At the 53rd meeting of the American Society of Hematology (ASH), held from December 10-13 in San Diego, there was an “education spotlight” session entitled, “Preimplantation Genetics: The Science, The Medicine, The Bioethics.” The speakers were Joyce Harper, PhD, from the University College London Centre for Preimplantation Genetics and Diagnosis (PGD), and Mark Hughes, MD, PhD, from Genesis Genetics Institute in Detroit. I’m hardly a PGD expert, so I attended to hear perspectives from people who are practicing it. The session was long on science and medicine but too short on the discussion of ethics. This was a shame because the speakers clearly have ethical worries, even though they are clearly not congruent with the concerns of most TIU bioethicists. Still, I found the session thoughtful and informative.
There was far too much for a brief blog post, but here are some highlights, first on the medical/scientific side:
1) PGD can be made on a single cell (typically 1-5), taken at any of several stages of early embryonic development. Dr. Hughes showed how he takes a single cell at the blastocyst stage (5-6 days after fertilization). Results in 24 hours, with a stated diagnostic error rate of 0.7%, and an attendant 1% post-PGD risk of a genetic-recessive disease (compared with 25% by standard Mendelian genetics).
2) PGD is most commonly used by fertile couples to try to avoid a severe genetic disease after a first affected birth or known risk based on parental genetics.
3) Genetic analysis is moving toward genome-wide arrays that can read the entire genome quickly, and at ever lower cost (currently about $2500 per genome). Dr. Hughes: “The technology now has no limitations [diagnostically]…so the question is not ‘can we?’ but ‘should we?’” [diagnose].
4) Biopsied embryos generally—but not always—do well, so the success rate of the (necessary) IVF pregnancies is reduced. The number of implantations is also reduced—e.g., 12 eggs to get 10 fertilizations, 8 embryos biopsied, 7 successfully diagnosed, 5 abnormal and 2 normal, one of those two judged viable for implantation.
5) Dr. Hughes said there were 47,164 PGD babies in the US in 2010. I thought he said born in 2010 but that number sounds high for a single year. Still, it’s a lot.
6) The most prominent “savior sibling” examples are for a disease that is curable with bone marrow transplant (BMT), e.g., sickle cell anemia (SCA). The PGD baby’s umbilical cord blood (UCB) becomes the donor blood. An example is sickle cell anemia (SCA). Dr. Hughes told the story of the family of NBA player Carlos Boozer, whose first child was cured of SCA after receiving a UCB transplant after the birth of his baby brother. Dr. Hughes is working to take this approach to SCA to West Africa at low cost.
7) For a Mendelian-recessive disease, one needs an unaffected embryo that is also an HLA (immunologic) match, with the probabilities being ¾ x ¼=3/16. In other words, 16 embryos to get 3 genetically appropriate “saviors.”
As I said, the ethical discussion was compressed, and must also be here. Clearly one worries about all the other embryos created in this process—and at least one questioner at ASH raised this by mentioning the value of all people despite disease or disability. As someone who considers himself a strong pro-lifer, I do find PGD for the most severe genetic disorders a “hard case,” and I have to admit that I am reluctant to condemn the Boozers. The speakers were most concerned about how to limit the use of PGD, medically. They are clearly uncomfortable with drawing premature conclusions or taking action on the often-uninterpretable results of a genome-wide analysis. They also raised hard cases of using PGD for otherwise treatable disease (e.g., polycystic kidney, or to obtain UCB to transplant a sibling with leukemia), using PGD to get an Rh-negative baby when mom has sensitized to Rh in a prior pregnancy, or using PGD to eliminate a cancer-susceptibility gene like BRCA-1 from the family tree (Dr. Hughes would accept, but he had debated Francis Collins, who would not permit this). Bottom line: these two professionals do seem to agree that defending the “therapeutic boundary” is important. If I read that correctly, I find it at least a bit reassuring and perhaps a contact point for engagement.
Space does not permit more here. I’m happy to try to field questions or carry on discussion through comments.

A Dispatch from A Front

I just attended the Advancing Ethical Research Conference of the group, Public Responsibility in Medicine & Research (“PRIM+R,” or “PRIMER,” because they make the “and” symbol look like a rounded “E”). Saturday’s plenary address was by Jonathan Haidt, Professor of Evolutionary Psychology at the University of Virginia. His topic: “The Intuitive Foundations of Morality (Or, Why some Research is Offensive to Some People).” Key points:
1) His introducer noted Dr. Haidt’s forthcoming book, The Righteous Mind, with the comment that Dr. Haidt research had discovered that all people are deeply flawed, morally. (I made a mental note that he should be congratulated for “discovering” original sin.)
2) Dr. Haidt described himself as an intuitionist but definitely not a cognitivist, having been thoroughly convinced by David Hume that “reason is the slave of the passions.” He described reason as the “rider” on the back of an “elephant” (emotions). (Essay assignment: compare and contrast with Plato’s chariot allegory in the Phaedrus.)
3) He identified 6 basic moral values: care (vs harm), fairness (vs cheating), liberty (vs oppression), loyalty (vs betrayal), authority (vs subversion), and sanctity (vs degradation). These, to him, are analogous to flavors, and the ability to regard them, in the moral sense, is analogous to different taste regions on the tongue. He spent considerable effort applying this to contemporary American politics. Liberals, he argues, value care far above all else, with fairness and liberty a strong but distinct second and third. Conservatives esteem care highly, but less than fairness and liberty. However the other three—loyalty, authority, and sanctity—are also highly valued by conservatives, but disregarded by self-described liberals. This leaves the liberal “moral sense” akin to being able to taste only sugar.
4) Esteem for sanctity, more than self-described conservatism, correlates in his research with some people’s “repugnance” at things that [allow me to interject] ought to be repugnant (though I don’t think he’d go that far).
5) Although the received wisdom is that contemporary bioethics is “autonomy on steroids” (my phrase, not his), as it were, IRB’s actually Invert the priority of the Belmont principles by making beneficience paramount. Top of the list of the IRB’s charge is to ensure that research risks to subjects are minimized and reasonable compared to the likely benefits. Informed consent is critical but comes after that. (Justice, in the form of equitable selection of subjects, may be third but is charging hard on the outside.) Note that there are no Belmont counterparts to loyalty, authority, or sanctity.
6) By a show of hands, about 40% of his audience was “liberal” and about a third of that number “conservative”—“the most conservative audience” he has spoken to.
It seems to me that Dr. Haidt really wants to be a moral realist and not an emotivist. But he appears not to allow that pre-rational commitments might be anything other than emotional. I am reminded of J. Budziszewski’s rejoinder that “naturalist” natural law fails; I prefer his appeal to “deep conscience” as the source of our moral intuitions (if I read him correctly). Also, Haidt’s “scientific” approach seems artificial to me (think: Postman’s Technopoly) and his categories thin alongside the biblical language of sin, righteousness, etc. (I couldn’t help also thinking of Paul Ricoeur’s The Symbolism of Evil.) But I want to read The Righteous Mind and I hope Dr. Haidt will have the chance to engage some conservative audiences.