Monday, October 22, 2018

What Was The FDA's Statutory Authority For Granting Marketing Exclusivity On Colchicine?

Maybe this seems obscure, but it gets to the heart of something I've wondered about for quite some time: how did URL Pharma get a licensing exclusivity on colchicine? Colchicine is a drug made from the autumn crocus, Colchicum autumnale, and has been known since antiquity as a curative for gouty arthritis. From Wikipedia:
An unintended consequence of the 2006 U.S. Food and Drug Administration (FDA) safety program called the Unapproved Drugs Initiative — through which the FDA sought more rigorous testing of efficacy and safety of colchicine and other unapproved drugs[27] — was a price increase of 2000 percent [28] for "a gout remedy so old that the ancient Greeks knew about its effects."[28] Under Unapproved Drugs Initiative small companies like URL Pharma — Philadelphia drugmaker — were rewarded with licenses for testing of medicines like colchicine. In 2009, the FDA reviewed a New Drug Application for colchicine submitted by URL Pharma. URL Pharma did the testing, gained FDA formal approval and was granted rights over colchicine. With this monopoly pricing power, the price of colchicine increased.

In 2012 Asia’s biggest drugmaker — Takeda Pharmaceutical Co. — acquired URL Pharma for $800 million including the rights to colchicine (brand name Colcrys) earning $1.2 billion in revenue by raising the price even more.[28]

Oral colchicine had been used for many years as an unapproved drug with no FDA-approved prescribing information, dosage recommendations, or drug interaction warnings.[29] On July 30, 2009 the FDA approved colchicine as a monotherapy for the treatment of three different indications (familial Mediterranean fever, acute gout flares, and for the prophylaxis of gout flares[29]), and gave URL Pharma a three-year marketing exclusivity agreement[30] in exchange for URL Pharma doing 17 new studies and investing $100 million into the product, of which $45 million went to the FDA for the application fee. URL Pharma raised the price from $0.09 per tablet to $4.85, and the FDA removed the older unapproved colchicine from the market in October 2010, both in oral and intravenous forms, but gave pharmacies the opportunity to buy up the older unapproved colchicine.[31] Colchicine in combination with probenecid has been FDA-approved prior to 1982.[30]

In August 2009, colchicine won FDA approval in the United States as a stand-alone drug for the treatment of acute flares of gout and familial Mediterranean fever.[32][33] It had previously been approved as an ingredient in an FDA-approved combination product for gout. The approval was based on a study in which two doses (1.2 mg and 0.6 mg) an hour apart were as effective as higher doses in combating the acute flare of gout.[11]
 The Unapproved Drugs Initiative page is singularly unhelpful when attempting to decipher where the FDA thought they were entitled to take this action, but the FDA's page on the colchicine enforcement action is, particularly citing Familial Mediterranean Fever as an excuse the justification for attaching "orphan drug" status to it (21 U.S.C. 360bb). This allowed URL Pharma to get marketing exclusivity for the drug, and all the rest. It's not clear that the Wikipedia page entry's blaming of Hatch-Waxman is appropriate.

Credit to @molratty on Twitter for background assistance.

Saturday, October 20, 2018

Justice As An Explicit Roll Of The Dice: How Many Men Are Rapists?

One of the things we heard constantly during the Brett Kavanaugh confirmation hearings was the old saw that false reports of rape amount to "2 to 8%". Some while back, Scott Greenfield some while ago published a fine review of the statistics of false reports, which found a disparity in terminology that left us with this:
True-ish: 35.3%
Definitively False: 5.9%
Inconclusive: 58.8%
But the thing I wanted to look at was the reverse of the "2 to 8%" figure (actually, 2-10% per Greenfield). If we're supposed to "believe" accusers on the basis of a low reported false accusation rape, why isn't it equally valid to decide guilt based on the number of genuinely innocent men? That is, shouldn't also "believe" men who claim innocence, on exactly the same evidentiary grounds? But how innocent? Let's try to figure out the percentage of the male population that are rapists. We start with Uniform Crime Report data. This counts reported rapes since 1960; the data tool provides data to 2014. So, using the "Legacy Rape" data*,
  • Sum the number of reported rapes from 1960-2014: 4,002,079
  • Divide by the 2014 population (318,857,056): 1.26%
  • Multiply by 2 (because men are half the population):  2.51%
  • Adjust for the RAINN estimated 69% non-reporting rate: 3.64%
The above assumes a 1:1 ratio of rapes to rapists, which contradicts the repeat offender theory of David Lisak and others. It also assumes that the number of rapists is not in part diminishing, because the oldest rapes in that count includes some that might have been committed by men now dead. This is important, because it artificially raises the male rapist percentage. Nonetheless, if we were to say that the number of false rape reports is a reason to "believe" the accusers, the even smaller percentage of male rapists in the general male population (versus the high end of false accusers at 8% or 10%) is an even stronger reason to acquit.

Of course, both of these are stupid; we don't roll the dice to determine guilt or innocence, but look at the individual circumstances of the charges and the presented evidence. N.b., I also didn't investigate actual convictions, because the Bureau of Justice Statistics website is presently broken.


*"Legacy rape" corresponds well to men raping women; the "Revised Rape" tallies include "penetration, no matter how slight, of the vagina or anus with any body part or object, or oral penetration by a sex organ of another person, without the consent of the victim", which would obviously include prison rape.

Saturday, September 15, 2018

The Death Of Science In Academia

It's been a bad couple weeks for anyone concerned about the state of actual science in academia, and Quillette has been all over it. Jeffrey Flier outlines a disturbing scene in which Lisa Littman's work on gender dysphoria was quietly disappeared by Brown University (emboldening mine):
Brown University deleted its initial promotional reference to Dr Littman’s work from the university’s website—then replaced it with a note explaining how Dr Littman’s work might harm members of the transgender community—presents a cautionary tale.
There were also said to be unidentified voices within the Brown community who expressed “concerns” about the paper. But when Brown responded to these concerns by removing a promotional story about Dr Littman research from the Brown website, a backlash resulted, followed by a web petition expressing alarm at the school’s actions. The dean of the School of Public Health, Bess Marcus, eventually issued a public letter explaining why the removal of the article from news distribution was “the most responsible course of action.”
In her letter, Dean Marcus cites fears that “conclusions of the study could be used to discredit the efforts to support transgender youth and invalidate perspectives of members of the transgender community” (my italics). Why the concerns of these unidentified individuals should be accorded weight in the evaluation of an academic work is left unexplained.
 Why, indeed. The real and obvious reason is that the anti-empirical, anti-science, anti-art, anti-men, anti-heterosexual, anti-European Enlightenment politics saturating the academy has enough political muscle to silence anything it doesn't want to hear. They have functionally turned Charles Murray into a non-person, repeatedly getting him uninvited to speaking dates or literally shouting him down, and scalped Larry Summers outright. Its secular wing got James Damore canned from Google for daring to question the party line on diversity. So it was scarcely a surprise when Theodore P. Hill found a published paper he authored on the Greater Male Variability Hypothesis had been disappeared, not once but twice, following complaints from the usual suspects. (Steve Stewart-Williams posted a good synopsis on Twitter.) His paper, co-authored by Sergei Tabachnikov, was accepted for the first issue of Mathematical Intelligencer.
No sooner had Sergei posted a preprint of our accepted article on his website than we began to encounter problems. On August 16, a representative of the Women In Mathematics (WIM) chapter in his department at Penn State contacted him to warn that the paper might be damaging to the aspirations of impressionable young women. “As a matter of principle,” she wrote, “I support people discussing controversial matters openly … At the same time, I think it’s good to be aware of the effects.” While she was obviously able to debate the merits of our paper, she worried that other, presumably less sophisticated, readers “will just see someone wielding the authority of mathematics to support a very controversial, and potentially sexist, set of ideas…”

A few days later, she again contacted Sergei on behalf of WIM and invited him to attend a lunch that had been organized for a “frank and open discussion” about our paper. ...

The next paragraph offers unwavering support for “studying and supporting the health and well-being of sexual and gender minority populations,” as well as “unshakable” support for the “full diversity of gender and sexual identity.” These statements of support are entirely appropriate. But in contrast to the material contained in the prior paragraph on academic freedom and inquiry, there appear in this section no caveats or clarifications. One cannot avoid the conclusion that the author sought to communicate a hierarchy of principles, with diversity on top, academic freedom underneath.
Oh, but it gets better: the National Science Foundation wrote to Tabachnikov "requesting that acknowledgment of NSF funding be removed from our paper with immediate effect".
...[A] Freedom of Information request subsequently revealed that Penn State WIM administrator Diane Henderson (“Professor and Chair of the Climate and Diversity Committee”) and Nate Brown (“Professor and Associate Head for Diversity and Equity”) had secretly co-signed a letter to the NSF that same morning. “Our concern,” they explained, “is that [this] paper appears to promote pseudoscientific ideas that are detrimental to the advancement of women in science, and at odds with the values of the NSF.”
Mathematical Intelligencer then rescinded its publication notice, claiming "publication would provoke 'extremely strong reactions' and there existed a 'very real possibility that the right-wing media may pick this up and hype it internationally.'" Imagine that. (Someone needs to tell these people about the Streisand Effect.)

Hill resubmitted the paper (minus Tabachnikov's co-authorship, to suppress political problems for him) to the New York Journal of Mathematics, which agreed to publish a revised version... right until it, too, was disappeared again.
Three days later, however, the paper had vanished. And a few days after that, a completely different paper by different authors appeared at exactly the same page of the same volume (NYJM Volume 23, p 1641+) where mine had once been. As it turned out, Amie Wilkinson [who was instrumental in censoring the paper at Mathematical Intelligencer] is married to Benson Farb, a member of the NYJM editorial board. Upon discovering that the journal had published my paper, Professor Farb had written a furious email to Steinberger demanding that it be deleted at once. “Rivin,” he complained, “is well-known as a person with extremist views who likes to pick fights with people via inflammatory statements.” Farb’s “father-in law…a famous statistician,” he went on, had “already poked many holes in the ridiculous paper.” My paper was “politically charged” and “pseudoscience” and “a piece of crap” and, by encouraging the NYJM to accept it, Rivin had “violat[ed] a scientific duty for purely political ends.”
 The author, a Vietnam War veteran and former U.S. Army Ranger, has not stepped away from the controversy, and has since published at ArXiv. (Reason's Robby Soave has also got a useful summary.) Amie Wilkinson published a statement regarding the affair that mentions the "unfounded allegations" Hill made against her that doesn't exactly refute them (many of the charges are leveled at her Facebook comments, wherein she attacked the authors and the paper). This can be easily resolved by an email trail; the charges of behind-the-scenes coercion for political ends are all too believable.

Update 2018-09-16: Farb has his own statement, which is just as unimpressive as Wilkinson's. Having the paper disappeared by the NYJM and replaced with some random paper is hardly normal practice. It is not an explanation, but a confession.

Update 2018-09-19: A semi-complete inventory of germane emails at Retraction Watch (headline intro here). Notably, none actually rebut Hill's claims that his paper was un-published, which is to say, they amount to a confession rather than an explanation. Andrew Gelman penned a long-form piece in which he claims that such revocations are commonplace, without any citations (supposedly had happened to him frequently). This comment from Gelman is a particular howler:
There are no saints here. Just people trying to do their jobs and making mistakes along the way. Based on everything I’ve heard about this case, it’s my impression that everyone in the story, including Hill, Tabachnikov, Wilkinson, Farb, Peterson, Pinker, and all the journal editors involved, all support free and open discussion. I don’t think that supporting free and open discussion makes anyone into a saint. All the people in this story did things that I wouldn’t have done in their place. And I’m no saint either.
Hannah Arendt, pick up your white courtesy phone!

Update 2018-09-23: Added the link to the Lisa Littman story. 

Sunday, September 9, 2018

Nike's Cynical Kaepernick Calculation

Let us take as a given that Colin Kaepernick's national anthem protests are legitimate.
  1. Without an actual organization, with concrete aims, to capitalize on the attention this is giving to the issue of young black men being killed by police, it is highly unlikely the situation will change.
  2. This actually benefits Nike, in the same way that legalized abortion benefits anti-abortion crusaders on the right. Just as the latter can campaign on ending abortion without delivering, so can the former keep selling sneakers (and keep the public's eyes away from their Asian sweatshops) without moving the bar toward less deadly police encounters.
Whatever Kaepernick might have intended to change is now more entrenched, not less, with an even murkier path toward redemption.

Thursday, September 6, 2018

Shooting The Messenger On Part-Time Female Physicians

Tell the truth these days (or come close to it) and your assured destruction at the hands of the feminist lynch mob will soon ensue. Take Dr. Gary Tigges, M.D., P.A., who recently said of the alleged gender gap in pay among physicians,
Yes, there is a pay gap. Female physicians do not work as hard and do not see as many patients as male physicians. This is because they choose to, or they simply don’t want to be rushed, or they don’t want to work the long hours. Most of the time, their priority is something else … family, social, whatever.

Nothing needs to be “done” about this unless female physicians actually want to work harder and put in the hours. If not, they should be paid less. That is fair.
Of course, this yielded a pointless apology from him, a dumb parody piece (uncharacteristically) from Gomerblog — and the usual horrified objections disconnected from any actual rebuttal. Take this one from the American Council of Science and Health, by Jamie Wells, M.D. Mostly indignant offense-taking, she finally settles down to marshal something resembling an argument. And by "resembling", I mean just that, because it isn't much of one. For instance:
Dr. Tigges' misguided statements, out of step with more than a decade of data that disputes his biased assertions demonstrating that female physicians are not only as good as their male counterparts but in many instances provide higher quality care with better outcomes, are commonly held beliefs throughout the healthcare system, particularly by those in management and administrative roles (see here and here).
But wasn't the issue compensation due to time spent in patient care, not administrators and managers? Okay, let's keep going. Maybe she provides something of substance anon.
Another example that is standard fare for those subscribing to the Tigges way of thinking is that more women physicians work part-time. The reasons for this are often mischaracterized as "their choice." This is often not the case. Practices don't have to cover benefits or pay as much for part-time, so they offer it instead which uniformly results in full-time work for part-time pay. Changing jobs or accepting the reality of seeing more for less until something better comes is a mainstay dilemma for countless women.
This word salad rebuts not at all Tigges' assertion that women see fewer patients. Perhaps it is not their fault. But so what? Earlier, she complains of "the perverse payment incentives of the RVU (relative value unit) system here which values low quality, high volume patient mill type medical practice." All these things may be true. But, again, they do not form a counterargument.  At last, she drags out the big guns, from something called Equity Quotient. There, we learn
  • Of 446 major U.S. occupations, physicians have largest median gender-based pay gaps; in some subspecialties, as much as $90k (Wall Street Journal 2016)
  • Over $9,000 per physician/per year is spent by healthcare organizations due to gender inequality — cost accrued from attrition, burnout and litigation (discrimination/sexual harassment).
  • Total cost of recruitment, on-boarding, lost revenue, about $400k (up to $600k) for a single hospitalist
At last, an on-point citation with numbers! Unfortunately for Equity Quotient and Dr. Wells, the underlying 2016 Wall Street Journal story buttresses Dr. Tigges' assertion, not hers. The devil is in the details (paywall, emboldening mine):
The biggest gaps in many white-collar professions don’t easily lend themselves to legislative remedies. In fact, the Journal’s findings belie policy makers’ hope that the most-educated women would lead the way in shrinking the gap. Currently, more women than men graduate from college.

Wage transparency—requiring employers to report salary data—is “just not going to move the needle much,” says Claudia Goldin, a Harvard University economics professor and one of the country’s foremost scholars on gender and pay. Prof. Goldin found in a 2010 paper that men and women earned almost the same salaries right after receiving University of Chicago M.B.A.s. At least a decade after graduating, the women earned 57% of their male classmates.

The main factor, she and her co-authors concluded: Women became mothers, interrupted their careers and eschewed lengthy hours that generated higher paychecks. “These particular occupations,” Prof. Goldin says, “are not very forgiving of taking time off and having kids.”

The Journal’s analysis of Census Bureau data for the five years through 2014 found male doctors working full time earned about $210,000 annually on average. Female physicians made 64% of that, about $135,000 a year. Among personal financial advisers, men took in about $100,000 while women made about $62,000.

Many white-collar jobs give substantially larger financial rewards to those logging the longest hours and who job-hop often, phenomena that limit white-collar women who pull back for child-rearing. Researchers on the topic say ingrained workplace cultures also impede women’s earnings.
What those "workplace cultures" are, the unnamed researchers don't say later in the article, but one suspects it has to do with the expectation of long hours, among other things. As with the overall and principally bogus "pay gap", hours, continuity, and specialization produce higher returns. A multivariate analysis based on specialty, time spent on the job, and continuity of employment would be useful. Too bad we don't appear to have it.

Previously: The Crisis of Part-Time Physicians

Monday, September 3, 2018

The Sad, Futile, Career-Ending Gesture Of Colin Kaepernick

Everywhere today blared the news that Nike continued to pay Colin Kaepernick since his banishment from football.
 Kaepernick, born of a white mother and a black father, and raised in California's Central Valley by white adoptive parents,  protested a number of controversial police shootings of blacks on social media, calling Alton Sterling's death a "lynching". In protest, he famously took a knee rather than stand for the national anthem, an act copied by many other players. And yet, if you were to look at his foundation and try to estimate what their aims were, you would find yourself stymied to make any sort of connection to ending senseless police shootings of young black men, besides the most tenuous ones. "Know Your Rights Camp" takes as its mission statement "to raise awareness on higher education, self empowerment, and instruction to properly interact with law enforcement in various scenarios." Aside from my universal banishment of all charities whose principal aim is "awareness", does this not seem like weak tea, the product of a meeting with lawyers and public relations types? If you were going to immolate your career for something, shouldn't it be more concrete and take direct action — such as political activism aimed to demilitarize the police (say)? As phrased, this sounds like "how to avoid being lynched" lessons.

Update 2018-09-04: Nike shares are down 4% following the news. This announcement may well prove disastrous to the sneaker manufacturer:
"The fallout was no surprise but Nike may be betting that the upside of a Kaepernick endorsement is worth angering conservative Americans and supporters of President Donald Trump," writes Bloomberg.

That might prove to be a bad bet, however. As Bleacher Report notes, a recent NBC News/WSJ poll found that a majority of voters (54%) thought Kaepernick's protest movement was "inappropriate," while just 43% said it was "appropriate."

Thursday, August 30, 2018

Raising The Curtain On Peggy McIntosh

I have mentioned elsewhere Peggy McIntosh's seminal rant-disguised-as-an-academic-exercise, "White Privilege: Unpacking the Invisible KnapsackPeggy McIntosh" (PDF). It has received an unusual number of citations (3,895 by Google Scholar's count), i.e. more than one, and with good reason: it is foundational to the enterprise of intersectional politics, i.e. the scaffolding supporting the entire parasitic operation. Yet not enough attention has been paid to the woman herself, an oversight happily rectified today by William Ray at Quillette. McIntosh, it turns out, benefited mightily from wealthy parents and deep, aristocratic connections:

So central has this doctrine [of intersectionalism] become to progressive politics, pedagogy, and activism, that to even question its validity is to invite the inquisitorial wrath of ‘social justice’ radicals. But it is for this very reason that it is important to subject McIntosh’s ideas to scrutiny.

Peggy McIntosh was born Elisabeth Vance Means in 1934. She grew up in Summit, New Jersey where the median income is quadruple the American national average—that is to say that half the incomes there are more than four times the national average, some of them substantially so. McIntosh’s father was Winthrop J. Means, the head of Bell Laboratories electronic switching department during the late 1950s. ...

Elizabeth Vance Means then attended Radcliffe, a renowned finishing school for the daughters of America’s patrician elites, and continued her private education at the University of London (ranked in the top 50 by the Times Higher Education World University Rankings), before completing her English Doctorate at Harvard. Her engagement to Dr. Kenneth McIntosh was announced in the New York Times‘s social register on the same page as the wedding of Chicago’s Mayor Daley. McIntosh’s father, Dr. Rustin McIntosh, was Professor Emeritus of Pediatrics at Columbia University. His mother was President Emeritus of Barnard College, an institution in the opulent Morningside Heights district of Manhattan, famous since 1889 for providing the daughters of the wealthiest Americans with liberal arts degrees. This was once the stomping ground of American cultural luminaries like F. Scott Fitzgerald, Cecil B. DeMille, and several Supreme Court Justices. Kenneth McIntosh was himself a graduate of the Phillips Exeter Academy, which boasted alumni including Daniel Webster, the sons of Presidents Lincoln and Grant, and a number of Rockefeller scions. He later completed his elite education at Harvard College and the Harvard Medical School. By the time of his marriage to Elizabeth, Kenneth McIntosh was a senior resident at the prestigious Brigham Hospital in Boston, founded by millionaire Peter Bent.

In other words, Peggy McIntosh was born into the very cream of America’s aristocratic elite, and has remained ensconced there ever since. Her ‘experiential’ list enumerating the ways in which she benefits from being born with white skin simply confuses racial privilege with the financial advantages she has always been fortunate enough to enjoy.
"One is left to wonder why," Ray continues, "given her stated conviction that she has unfairly benefited from her skin color, there seems to be no record of her involvement in any charity or civil rights work." If you are your movement's Moses, your reputation is already secure.