November 2009 Archives

Murder, My Sweet

(1944): Hungry for clients, private dick Philip Marlowe (Dick Powell) gets tangled up in two seemingly disconnected investigations. Based on Chandler's Farewell, My Lovely.

You won't find harder-boiled flashback narration. To wit:

I just found out all over again how big this city is. My feet hurt. And my mind felt like a plumber's handkerchief.

I don't get the simile either; but the phrase sounds oh-so-noirishly right.

HT: KTG

It's been implied that direct-to-consumer (DTC) advertising of prescription pharmaceuticals is a major cause of rising healthcare costs generally and of rising expenditures for drugs specifically. For example, in mid-October, NPR's "Morning Edition" ran a piece in which DTC ads were correlated with rising prescription drug use among Americans and associated costs. But the NPR show failed to note that spending on DTC ads has actually decreased since 2006, while drug costs have grown annually at an average rate of about 7% [1].

To more thoroughly examine the possible effect that DTC advertising has on prescription drug use and costs, US and Canadian researchers examined reimbursement for clopidogrel (Plavix; BMS/Sanofi) [2], a blockbuster antiplatelet launched in 1997, in the US Medicaid program before and after the advent of DTC advertising in December 2001. The results of their study are available in the latest issue of the Archives of Internal Medicine.

The crux of their findings:

Clopidogrel use: From 1999 to 2005, the trend [3] of ever-increasing clopidogrel use (units dispensed per 1000 Medicaid enrollees) did not change significantly after the fourth quarter of 2001, when DTC advertising began.

Medicaid reimbursement per clopidogrel unit dispensed: DTC advertising for clopidogrel was associated with a significant one-time bump in Medicaid reimbursement for the drug ($0.40 per unit). However, the slope of the line depicting increasing reimbursement for the drug remained unchanged after this bump.

Total Medicaid reimbursement: Owing almost exclusively to the price bump, the quarterly rate of Medicaid reimbursement increased significantly after the advent of DTC advertising for clopidogrel. Quarterly rate increases in Medicaid reimbursement for clopidogrel use: before DTC advertising, $95.68 per 1000 enrollees; after DTC advertising, $136.26 per 1000 enrollees. The increased total reimbursement rate resulted in an additional $207 million Medicaid dollars spent for clopidogrel use in 27 states after DTC advertising, the authors calculated.

The authors assume that the one-time bump in Medicaid reimbursement for clopidogrel use was due to an increase in the manufacturer's price (which just happened to coincide with the advent of DTC advertising); however, this assumption cannot be confirmed, because pricing data are confidential, they report. BMS/Sanofi's motives for increasing the unit cost of clopidogrel at the time of DTC advertising include an attempt to offset expenses for DTC marketing [4], the anticipation of increased sales, and general conditions of the market.

N.B.--Data after 2005 were not used in this study, because many Medicaid-eligible individuals were transferred to Medicare Part D plans in 2006.

1. According to the McKinsey Global Institute, the rise in prescription drug costs is due "almost equally" to an increased in consumed drug volume and a rise in drug costs. These increases have been offset, however, by "a [small] trend toward a less expensive drug mix."

2. Converted to 2005 USD.

3. In other words, the slope of the line depicting increasing clopidogrel use.

4. According to the authors, total DTC ad costs for clopidogrel in the United States (2001-2005) totaled more than $350 million.

Image of Plavix box from Wikimedia Commons. 

A "potentially significant" mutation of the 2009 H1N1 virus has been detected in 3 severe cases (including 2 fatalities) of pandemic flu in Norway; however, the mutated virus is nothing new, according to the World Health Organization. The spontaneous mutation—which does not confer resistance to the antiviral drugs oseltamivir (Tamiflu; Roche) or zanamivir (Relenza; GSK)—was detected as early as April and has been found sporadically in both severe and mild flu cases in other countries,* reports WHO.

The 2009 H1N1 mutation has not been described or labeled explicitly in news reports. But according to a quoted Norwegian health official, the mutation "makes it possible for the virus to fasten itself or infect deeper into the bronchioles, and therefore provide for a more serious progress of the disease." This description suggests that the mutation lies in the gene encoding the viral binding protein, hemagglutinin.

WHO maintains that the current pandemic flu vaccine does produce immunity against the mutated virus.

* Namely Brazil, China, Japan, the Ukraine, and the United States.

Depiction of H1N1 virus from Wikipedia.

Pygmalion (1938): Leslie Howard is my preferred Henry Higgins in this definitive film version of Bernard Shaw's best-known play. With a screenplay adapted by the writer himself.

Pandemic influenza activity has declined during the last week in the United States, according to today's CDC briefing from Anne Schuchat, MD, Director of the National Center for Immunization and Respiratory Diseases. A total of 43 states are now reporting "widespread" activity, Schuchat said, which is down from 46 states last week.

However, Schuchat advised, flu activity at this time is much greater than activity during the same time last year. She further cautioned that flu activity, particularly during this season, is unpredictable.

In addition, there have been a cumulative 171 laboratory-confirmed pediatric deaths due to pandemic flu; about two thirds of these fatalities were children with underlying conditions (eg, cerebral palsy, muscular dystrophy). But the CDC estimates a far greater number of pediatric deaths due to H1N1. The Center will provide new mortality estimates in the near future.

The supply and distribution of pandemic flu vaccine continues to increase. Schuchat reported that a cumulative number of 54.1 million doses have been made available, which is 11 million more doses than 1 week ago. And 93% of the available supplies have been ordered by states. A total of 94.5 million doses of seasonal flu vaccine, the distribution of which is managed by the private sector, have been disseminated.

Schuchat also provided 4 tips for holiday travel:

1. Travel "well"—meaning, if possible, travel only when you're well.
2. Wash your hands.
3. Cover your coughs.
4. Get vaccinated—particularly if you're in a targeted population.

Statements from the media included comments about "potentially significant" viral mutations discovered in 3 H1N1-related cases (2 fatalities and 1 seriously ill patient) in Norway. Schuchat responded that these mutated viruses, although possibly concerning, have been seen in mild cases as well. 

President Obama has repeatedly proposed information technology (IT)—for example, the use of electronic medical records—to realize overall healthcare efficiency and savings. But the proposal just isn't true, say Harvard researchers. In fact, their study of computerization and administrative costs at US hospitals, published in today's online issue of The American Journal of Medicine, shows that "more wired" hospitals may have higher total costs than their lower-tech counterparts.

In a survey of 4000 US hospitals,* conducted from 2003 to 2007, the total costs of hospitals with higher calculated computerization scores (measured by the use of computer applications) were significantly greater, at least in one analysis. Hospitals that underwent computerization at a relatively rapid pace sustained particularly high administrative costs. And researchers did not discover delayed cost benefits from computerization—meaning, computerization costs in 2003 were not realized in savings 5 years later.

On the other hand, investigators found that a modest improvement in the quality of healthcare (and in particular, the management of acute MI) may correlate with hospital computerization.

Lead author of the study, David Himmelstein, MD, said in a press release: "Our study finds that hospital computerization hasn't saved a dime, nor has it improved administrative efficiency. Claims that health IT will slash costs and help pay for the reforms being debated in Congress are wishful thinking."

The researchers offer 3 reasons for why IT has failed to decrease hospital administrative costs.

• Potential savings are offset by the costs of purchasing, implementing, and maintaining computer systems.
• The current stage of hospital computerization is not advanced enough to realize healthcare savings.
• The available computer systems focus on coding and reimbursement rather than efficient clinical care.

To realize substantial healthcare savings and quality of care from IT, the authors propose a VA model of care—in which a single-payer program eliminates the need for billing and most internal accounting. Himmelstein and his coauthor Steffie Woolhandler, MD, are affiliated with Physicians for a National Health Program, an organization that supports a single-payer system. 

* Data were derived from the Healthcare Information and Management Systems Society (HIMSS) Analytics annual survey, hospital-submitted Medicare Cost Reports, and the 2008 Dartmouth Health Atlas.

Authors of the peer-reviewed phase 2 study of bapineuzumab in patients with Alzheimer disease conclude that the "trial provides insufficient evidence to support or refute a benefit" of the anti-amyloid mAb. The results of the Elan/Wyeth-funded trial, which are now available in an online issue of Neurology, were originally made public in a less-than-candid June 2008 company press release and at the International Conference on Alzheimer's Disease 1 month later.

The major drawback of the multidose study now appears to be related to a change in its primary outcome. The trial was originally designed and powered to assess the safety of bapineuzumab in AD, but the protocol was amended on the basis of phase 1 data. The authors write, "It was recognized that the small cohorts in this study would provide sufficient power to detect only very large treatment differences; however, if successful, the urgency of delivering an effective treatment to patients with AD argued for making the efficacy the primary outcome."

In other words, the investigators changed the primary endpoint of the phase 2 study on the chance that differences in efficacy outcomes might be substantial. In addition, the authors report the results of a modified intent-to-treat (mITT) population (n = 227), which consisted of patients who received at least 1 dose of study drug and underwent 1 or more efficacy evaluations during the study.

Despite these modifications, there were no statistically significant primary-efficacy* differences between placebo- and bapineuzumab-treated patients at 18 months. However, "exploratory analyses" showed "potential treatment differences" in the completer population (ie, patients who completed bapineuzumab treatment and underwent week-78 assessment) and in the subpopulation that did not have an ApoE4 allele.

Reversible vasogenic edema was observed in nearly 10% of bapineuzumab-treated patients and was dose dependent. Vasogenic edema was also more likely in ApoE4 carriers. In August, Elan and Wyeth announced that the highest bapineuzumab dosage, 2.0 mg/kg, would be discontinued in 2 ongoing phase 3 studies of ApoE4 noncarriers (40%-70% of AD patients), because of the risk of vasogenic edema. (Protocols for phase 3 trials of the mAb in ApoE4 carriers remain unchanged; these trials are assessing only 1 bapineuzumab dosage, 0.5 mg/kg.)

During the 18-month phase 2 study, bapineuzumab was given IV every 13 weeks at 1 of 4 doses (0.15, 0.5, 1.0, or 2.0 mg/kg). The smallest dose was added to the study after investigators identified vasogenic edema on some brain MR images of patients receiving 0.5 mg/kg.

An aside: The disclosures of the authors, several of whom are industry employees, consume about 3 columns of small type.

N.B. Bapineuzumab now belongs to JNJ, instead of Elan. Wyeth now belongs to Pfizer.

ADAS-Cog/12 = 12-item Alzheimer's Disease Assessment Scale-Cognitive subscale; DAD = Disability Assessment for Dementia; mAb = monoclonal antibody.

* Measured by using changes in ADAS-Cog/12 and DAD scores. 

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism. 

Investigating medical ghostwriting, Senator Chuck Grassley (IA-R), ranking minority member of the Senate Finance Committee, sent a letter to the deans of 10 medical schools, reported the NYT on Wednesday. The text of the 2-page, single-spaced letter was chosen carefully by one or more members of Grassley's staff and then signed by Grassley.

In the Grassley-signed letter (which can be found here), the medical deans are asked to respond to 6 essay-type questions regarding their schools' policies on ghostwriting and plagiarism. The deans will, no doubt, delegate the writing of the responses to administrative minions and then sign their names to the responses no later than December 8th, as requested.

Photo of Senator Grassley from grassley.senate.gov.

Niacin, the B vitamin, may only provide protective benefits in a select group of patients with atherosclerotic vascular disease. This conclusion is based on the somewhat conflicting results of 2 studies, both of which were presented at the ongoing Scientific Sessions of the American Heart Association.

In a highly anticipated, Abbott-sponsored phase 4 trial (abbreviated ARBITER 6-HALTS), extended-release niacin (Niaspan) outperformed Merck's ezetimibe (Zetia) in 5 of 7 outcomes, including a composite clinical outcome. But the small study population (N = 208) was a selective one, in which high-risk statin-treated adults had already attained target LDL levels (<100 mg/dL) and had moderately low HDL levels. Niacin therapy in such patients would be expected to elevate HDL, and ezetimibe treatment would be expected to further lower total cholesterol and LDL levels—which is what the investigators found.

Change in Outcome*	Extended-Release Niacin 2000 mg/d (n = 97)	Ezetimibe 10 mg/d (n = 111)	Statistical Significance
Mean CIMT, mm (primary outcome)	–0.0142 ± 0.0041	-0.0007 ± 0.0035	P = .01
Mean CIMT at 8 months, mm	–0.0102 ± 0.0030	+0.0014 ± 0.0020	P = .001
LDL, mg/dL	–10.0 ± 24.5	–17.6 ± 20.1	P = .01
HDL, mg/dL	+7.5 ± 9.2	–2.8 ± 5.7	P < .001
Cholesterol, mg/dL	–6.9	–18.8	P = .025
Triglycerides, mg/dL	–36	–9	P = .018
Major CV events	2/160	9/165	P = .04
Adverse events leading to study withdrawal	17/27	3/9	P = .12
Adherence to study medication, %	88 ± 15	95 ± 8	P = .001

In another small study (Abstract 685), this time of 145 statin-treated elderly patients in the Baltimore area, extended-release niacin (1500 mg/d) significantly lowered LDL and raised HDL at 18 months, when compared with placebo. But declines in carotid-wall plaque (as measured by MRI) were comparable in the 2 treatment groups. The investigators concluded that the addition of niacin to statin therapy did not provide "further benefit," despite the lipid panel changes.

The hurdle with using and maintaining high-dose niacin therapy is tolerability of the drug. In ARBITER 6-HALTS, 36% of niacin-treated patients experienced flushing, and adherence to study medication was significantly lower.

According to the Niaspan package insert, therapy must be initiated at 500 mg and given at bedtime to reduce the incidence and severity of side effects. The dosage should not be increased by more than 500 mg in any 4-week period. (Consequently the dosage used in ARBITER 6-HALTS could be attained in 3 months or more.) The most common side effects with Niaspan treatment are flushing, diarrhea, nausea, vomiting, increased cough, and pruritus. 

ARBITER 6-HALTS = ARterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 - HDL and LDL Treatment Strategies in Atherosclerosis; HDL = high-density lipoprotein; LDL = low-density lipoprotein.

N.B.--ARBITER 6-HALTS was terminated early, in June, and stock analysts speculated that the findings favored the addition of niacin to statin monotherapy.

* ARBITER 6-HALTS outcomes were assessed at 14 months, unless otherwise indicated.

News source: HealthDay.

Image of niacin structure from Wikipedia.

On July 6, 2009, for reasons that remain unclear, the Senate Special Committee on Aging sent a letter to Thomas Sullivan, president of Rockpointe Corporation, a private, 18-employee company that produces continuing medical education (CME) programs for physicians. The letter requested "an accounting of funding received by Rockpointe Corporation from pharmaceutical, medical device and biologics companies for three and one-half years from January 1, 2006 to the present."

In his July 20 response to the Committee, Sullivan voluntarily provided the financial information, while requesting that the Committee use "reasonable protection against this information becoming publicly available." Sullivan clarified, "[A]s we have discussed with your Chief of Investigations, Jack Mitchell, the business information provided is proprietary."

Later in his letter, Sullivan expressed confusion about the Senate Committee's specific interest in his private CME company:

It is a concern to us that this letter has been directed to Rockpointe as a result of a group meeting that we initiated with the Aging Committee staff. That initiative was intended to provide information, understanding and insight concerning CME and the proposed Physician Payment[s] Sunshine Act. The meeting, and the required time and preparation, constituted a good faith effort to bring relevant information to the Committee. Our intent was to differentiate accredited CME from promotional marketing. Under the credo of "no good deed goes unpunished," this initiative led directly to your singling us out among the hundreds of similar CME providers to submit confidential business records. We have expended considerable time, expense and professional fees identifying, locating, reviewing and organizing nearly 4 years of business records in order to digest and prepare the accurate summary you requested. An inquiry of his nature will likely discourage other "good Samaritans" from exercising their rights as involved citizens to bring issues of concern to the attention of the committee.

Rockpointe's financial data (and Sullivan's letter) were recently made publicly available through UCSF's Drug Industry Document Archive and reported last week by Alicia Mundy in the WSJ. It is certainly reasonable to conclude that the data were provided to the archive through the Committee (either directly or indirectly), despite Sullivan's request that the confidential information remain confidential.

But I contend that the suspected behavior of the Committee toward Sullivan's company could have been predicted by examining its powerful chief investigator, Jack Mitchell (whom Sullivan mentions in his letter).

John Howard "Jack" Mitchell (who, ironically enough, was a presenter along with Sullivan at the recent National Disclosure Summit in March) is mostly a career government staffer—although he served as an investigative reporter under syndicated columnist Jack Anderson in the late 70s/early 80s and was evidently a CNN correspondent sometime in the mid-90s. But the role that appears to have primarily informed Mitchell's "purpose" (for lack of a better word) is that of Special Assistant for Investigation in the office of FDA commissioner David Kessler. There, during the late 90s, Mitchell worked closely with Kessler on his unsuccessful effort to bring the tobacco industry under FDA control. Mitchell is specifically credited with bringing Jeffrey Wigand, the notorious industry whistleblower and tobacco insider, to the attention of Kessler.* At a symposium of the Association for Medical Ethics in March 2008 at the University of California at Irvine, Mitchell said of his FDA stint, "[T]o some respects, that was one of the best jobs I ever had."

Mitchell's work with Kessler against Big Tobacco can reasonably be expected to inform whatever righteousness he may feel when investigating other industries, including the drug and medical-device industries—which are presently in the sights of the Senate Committee on Aging. (And Mitchell's righteousness as a government reformer could only have been fortified by the recent passage of legislation that now puts tobacco under FDA control.)

However, caution is warranted in dealing with the righteous, particularly crusaders who hold powerful, non-elected government positions. Generally everything's fine if you completely agree with the crusader; however, you're no more likely to convince him that there's more than one side to an issue than you are of persuading Joel Osteen that Jesus was merely a nice Jewish boy. Moreover, if you reveal sufficient differences of opinion to a crusader, and specifically one who happens to be a senior Congressional staffer, you may find yourself the subject of a Senate Committee investigation—as Sullivan discovered.

In language that supports this contention, Mitchell himself displays an authoritarian mindset that merits caution, if not outright distrust. To illustrate, the following are excerpts from Mitchell's speech at the ethics symposium (which can also be viewed here).

When you've done the kind of work I do for so long—as an investigative reporter, a Senate investigator on 2 different occasions, and I've run government investigative offices like Dr. Kessler's—I see that frankly as part of the same thing. Just in different jobs, in different roles. When you do that, you realize that, to some degree, that whether you like it or not, whether you care to admit it to yourself or not, that there's a strong reformist streak within you. And so I tend to seek out people who are like that or see that, and I see that characteristic in them.

And so the most important thing you bring to the table when you try to do effective oversight, you try to change public policy, is you find, you ferret out the people who are capable or who have the courage to do something like that. That's how I found Dr. Jeffrey Wigand and made myself close enough to him that he was willing to come forward to the FDA.

In some cases, Mitchell's language suggests that he thinks he runs the Senate Committee on Aging and is a legislator. For instance, notice his use of "I," "my," and "we," instead of language that would more accurately refer to the Committee or Senator Kohl.

When I did a, when I began our year-long series of hearings last year on conflicts of interest and consultant payments in the medical-device and pharmaceutical industries...

And

So these are all parts of the same things the committee continues to explore as we continue our series of 5 or 6 hearings on these type of conflicts, both in the medical-device and pharmaceutical industries. And we hope to do some more hearings in the fall and into next year in support of a number of pieces of legislation. We're gonna be looking at continuing medical education. We've done a hearing on academic detailing by the pharmaceutical companies. We're going to do some hearings on free drug samples that are given to physicians and medical students and ways to combat that type of influence peddling. And we're going to do some more hearings as necessary on these continuing conflicts in order to deal with them.

And most of that is in support of some legislation you've heard about here...called the Physicians Payment[s] Sunshine Act, which is coauthored by my boss, Senator Herb Kohl of Wisconsin—who is chairman of my committee, the Senate Special Committee on Aging.

And

Now at this point, while we've negotiated this bill very closely with industry and with other parties, it's not clear to me what the fate of the bill will be for this year. We've tried to put it into the Senate Medicare package. We haven't been successful with that to date, and it doesn't appear that's going to happen. We may introduce it as a stand-alone bill with an advisement to industry...

And

One thing you may wonder, for those of you not very familiar with Congressional oversight is, the question of why would we—why would Congress be interested or why would it be any of Congress's business—the type of ethics issues that we're discussing in the medical-device and orthopedic and, as well, pharmaceutical industries. Well the reason is that my committee has jurisdiction over Medicare, and most of the medical-device companies receive a majority of their income from Medicare and Medicaid in many instances—not in all—but many. In fact, many medical-device companies receive the bulk of their income from Medicare reimbursement and Medicaid reimbursement payments. So that provides my committee, at least, with the direct jurisdiction—since we have control of the centers for Medicare and Medicaid in order to make sure and try to be vigilant that our taxpayer dollars, which go into this system—the billions of dollars—are well spent and well protected.

And

We fully intend any legislative efforts that we undertake to include all of those players, not just the large companies. And while it's pretty difficult to establish what I might call a level playing field that is our ultimate goal—we want to establish a regulatory framework that's fair to everybody and includes limits that are not unreasonable for the small companies or for the large companies. And that takes a lot of back and forth and push and shove. And I'm not sure that even the language we have in the legislation now is final or is the final answer to the problems. 

What is also concerning is that Mitchell conveys not-so-veiled threats to companies or organizations that don't cooperate with the Committee.

...[S]hould anyone block the bill's progress...we will come back next year with more oversight hearings and a much more toughly worded bill that we will be much less willing to compromise over or negotiate.

And

I must say that we invited some of the more established surgical professional associations to participate or submit written testimony to our hearing, and they declined. So hopefully, I'm hopeful they will see that the train is leaving the station, and that some of these groups really need to get on board or at least offer some comment and cooperation in terms of the legislative and other proposals which we put forward on the table.

Finally Mitchell discloses that his (or really, the) Senate Committee on Aging is not averse to going after small companies.

The large companies aren't the only players. There are a lot of entrepreneurial small companies who are out there spending a lot of money trying to influence physicians and surgeons and draw them into their sphere of influence. 

* Mitchell is featured prominently in Kessler's book about his anti-tobacco crusade, The Question of Intent.

Thumbnail image of Jack Mitchell from disclosuresummit.com.

On Friday, the WSJ printed a story by Alicia Mundy, "Health-Bill Disclosure Rule Is Resisted," which revealed that a recently passed health-reform bill in the House would require drug companies to disclose payments made to physicians and third parties, such as medical education communications companies, or MECCs. But the idea is nothing new, and reports of such disclosures have been carried extensively by various news sources, including the WSJ and the related WSJ Health Blog.

Given the scrutiny that financial relationships between pharma and physicians have received of late (thanks largely to the Senate Special Committee on Aging and Senate Finance Committee), several drug companies (for example, Eli Lilly and GSK) have voluntarily offered readily accessible information about payments made to physicians for consultant, advisory, or speaking services, as well as educational grants given to MECCs to produce CME programs.

Resisting disclosure, Mundy reported, is John Kamp, executive director of the Coalition for Healthcare Communication. The Coalition, according to the organization's web site, "defends the right of health professionals and consumers to receive truthful information regarding pharmaceuticals and medical products, as safeguarded by the Constitution of the United States. Founded in 1991, the Coalition represents organizations, rather than individuals, dedicated to assuring the free exchange of scientific information without undue government interference." Among the member groups of the Coalition are the American Association of Advertising Agencies and the Association of Medical Media.

Kamp penned his objection to legislated CME disclosure in a July letter to Senator Herb "I'm Richer Than Croesus and God" Kohl (WI-D), who chairs the Special Committee on Aging. In response to an inquiry from the Committee, Kamp wrote, "Many leading drug and device companies have published all their grants for the world to see, and others are following quickly. Given this trend, the Committee should consider elimination of certified CME reporting in all versions of Health Care Reform bills because they are unneeded, redundant and needlessly expensive [boldface sic]." Mundy quoted Kamp, beginning at "should consider..."; she failed to clarify why Kamp resisted legislated disclosure—thereby misleading her readers to believe that Kamp resists disclosure altogether. 

Mundy then segued to Thomas Sullivan, president of a small Maryland-based MECC, Rockpointe, and sole blogger at Policy and Medicine. Although Sullivan reported to Mundy that he's not against legislated CME disclosure from drug companies, he has been openly critical of Senator Kohl's Committee, as well as Senator Chuck Gassley (IA-R), who is the ranking minority member of the Senate Finance Committee. In a September blog post, Sullivan described the efforts of Grassley's investigator, Paul Thacker, into physician-related conflicts of interest with pharma as "witch hunts." (It's a description that Sullivan should have heeded when considering any voluntary cooperation with Senator Kohl's Committee and its chief investigator, Jack Mitchell. But more on Mitchell in a follow-up post.) 

In a move that was off-point from her article's lede but apparently designed to shock or embarrass, Mundy then proceeded to report the amount of educational grant money that Sullivan's private company had received from drug firms during the last 3½ years. Evidently Mundy had obtained this proprietary company data through the UCSF's publicly accessible Drug Industry Document Archive, which had received the information from Kohl's Committee.

In July, the Committee had requested "an accounting of the funding received by Rockpointe Corporation from pharmaceutical, medical device and biologics companies." Why the Committee was spending taxpayer dollars investigating the 18-employee, privately owned MECC is anybody's guess.* In any event, Sullivan volunteered the information, writing, "We have discussed with your Chief of Investigations, Jack Mitchell, the business information provided is proprietary. We would appreciate your use of this information in the aggregate, and reasonable protection against this information becoming publicly available." So much for government courtesy. 

Mundy proceeded to report the cumulative amount of CME grant money that Rockpointe received from the beginning of 2006 to July 2009 (~$23 million), as well as a breakdown of funds the company received from Medtronic ($802,791 or about $100,350 per CME seminar). She added, "Rockpointe's classes typically addressed ailments that the sponsors' products treat"—an observation that should be news to, well, no one. A drug firm is not going to fund a CME program that is outside its therapeutic area of interest.

What Mundy (most egregiously) failed to do was examine (or ask an independent and knowledgeable physician to examine) Rockpointe's CME programs, to determine if any were biased toward the grantor's product. To do so would have required work, and the possible outcome (namely that Rockpointe's CME programs were not biased) would mean that Mundy wouldn't have much of a story. 

But as irresponsible as Mundy's reportage is here, it's nothing compared to the harsh writing of blogger and shrill critic of pharma-funded CME Daniel Carlat—who, curiously enough, posted his arguably libelous rant about Sullivan and his company's finances the day before Mundy's story was published. The timing suggests that Carlat is more than a mere fall-off-a-log quote source for lazy and/or agenda-driven reporters like Mundy.

* In his letter to Senator Kohl (which is available at the UCSF archive), Sullivan wrote, "It is a concern to us that this letter has been directed to Rockpointe as a result of a group meeting that we initiated with the Aging Committee staff. That initiative was intended to provide information, understanding and insight concerning CME and the proposed Physician Payment Sunshine Act. The meeting, and the required time and preparation, constituted a good faith effort to bring relevant information to the Committee. Our intent was to differentiate accredited CME from promotional marketing. Under the credo of "no good deed goes unpunished," this initiative led directly to your singling us out among the hundreds of similar CME providers to submit confidential business records. We have expended considerable time, expense and professional fees identifying, locating, reviewing and organizing nearly 4 years of business records in order to digest and prepare the accurate summary you requested. An inquiry of this nature will likely discourage other concerned "good Samaritans" from exercising their rights as involved citizens to bring issues of concern to the attention of the committee."

Image of Alicia Mundy from the New America Foundation; reproduced through a Creative Commons license.

Using a model to account for the underascertainment of cases, the CDC now estimates that 14-34 million Americans were infected with the pandemic influenza virus between April and October 17, 2009. The Center previously estimated the number of US cases between April and July 23rd of this year at 1.8-5.7 million.

A breakdown by age (years) shows that pandemic flu has preferentially affected younger adults and children. (The graph provides midlevel estimates of cases [horizontal bars] and estimated ranges [vertical bars].)

The same model was used by the CDC to estimate the number of pandemic flu hospitalizations at 63,000-153,000 and related deaths at 2500-6000 between April and October 17th. Again, an age breakdown reveals that disproportionate numbers of younger adults (and to a lesser extent, children) have been affected with severe pandemic flu.

By using the CDC's midlevel estimates, the mortality rate of pandemic flu is 0.018%—which is consistent with the range of mortality rates provided by Harvard epidemiologist Marc Lipstich (0.007%-0.045%).

One of the latest apparent victims of pandemic flu is University of Ottawa chemistry professor Keith Fagnou, 38, an otherwise healthy father of 3 children. Fagnou died of suspected H1N1 disease on November 11, 3 days after being hospitalized.

HT: In the Pipeline.

The Wages of Fear, or Le salaire de la peur (1953): One of 2 signature movies from Henri-Georges Clouzot. (The other is Diabolique.)

Stuck in a South American shit-hole, 4 ex-pats vie for a highly lucrative job of trucking nitroglycerin for an exploitive American oil company. After a very leisurely European start, the pace intensifies as the freelance truckers haul the explosive over roads that are actually worse than the Illinois Tollway system. With Yves Montand.

N.B. William Friedkin directed the not-so-iconic 1977 remake, Sorcerer.

Question: What kind of protection does the seasonal influenza vaccine provide against pandemic influenza?

Brief answer: None.

Longer answer: Recent surveillance data from 356 adults in 8 states indicate that the likelihood of contracting pandemic flu is unaffected by receiving a seasonal flu vaccine. Results of the data analysis are available in the latest issue of MMWR.

After adjusting for age and chronic medical conditions,* the CDC found that the overall effectiveness of the seasonal flu vaccines against contracting pandemic flu was -10%, with a wide 95% confidence interval (CI) straddling zero (-43%, +15%). Data were obtained during the period from May to June of this year.

These epidemiologic data complement known serologic (laboratory) data, which suggest that the trivalent seasonal flu vaccines are unlikely to provide meaningful cross-protection against pandemic flu. Likewise a recent Australian study showed that, in children or adults who received seasonal flu vaccines, cross-reactive antibodies against pandemic flu were not produced. The overall age-adjusted effectiveness of the seasonal flu vaccines against pandemic flu in this study was 3% (CI: -56%, +40%). An unpublished study of high schoolers in New York City also suggests no protective benefit of seasonal flu vaccines against pandemic flu.

However, these data are at odds with those from a recently published Mexican study, which reported a seasonal flu vaccine effectiveness rate of 73% against pandemic flu. But control patients in this study were more likely to have chronic medical conditions—making seasonal flu vaccine coverage more likely in this group. Unpublished data from Canada suggest that "medically attended" pandemic flu may actually be more likely in recipients of the seasonal flu vaccine.

The MMWR editors advise that studies with more rigorous designs and methods are currently under way to evaluate any immunity conferred by seasonal flu vaccines against pandemic flu.

* Which increase the risk of influenza-related complications (eg, heart disease, asthma, diabetes, cancer).

Here's something any perpetrator should catch hell for: changing the primary outcome of a trial.*

In studies of gabapentin (funded by Parke-Davis and later by Pfizer) for neuropathic pain, bipolar disorder, or migraine prevention (all off-label uses), the protocol-defined primary outcome was often changed in the published report. This is just one observation of Johns Hopkins investigators after their analysis of internal documents from 20 industry-sponsored gabapentin studies. Their full report is available in the latest issue of the NEJM.

Among the 20 trials assessed, only 12 (60%) were published (see Table); the results of 9 trials were reported as full-length articles. In 8 (67%) of the 12 trials, the protocol-defined primary outcome differed from the primary outcome in the final report. In 6 (50%) studies, a completely new primary outcome was introduced; and in 5 studies, the new primary outcome favored gabapentin treatment.

Article	Statistical Significance Favoring Gabapentin?
Primary outcomes agreed with protocol
Backonja M et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA. 1998;280:1831-1836.	Yes
Backonja M, Mutisya EM. Review of gabapentin dosing in five placebo-controlled clinical trials for neuropathic pain. Eur J Neurol. 2002;9(suppl 2):191.	No
Serpell MG, Neuropathic Pain Study Group. Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial. Pain. 2002;99:557-566.	Yes
Gomez-Perez FJ et al. Gabapentin for the treatment of painful diabetic neuropathy: dosing to achieve optimal clinical response. Br J Diabetes Vasc Dis. 2004;4:173-178.	Yes
Primary outcomes did not agree with protocol
Mathew NT et al. Efficacy of gabapentin in migraine prophylaxis. Headache. 2001;41:119-128.	Yes
Wang PW et al. Gabapentin augmentation therapy in bipolar depression. Bipolar Disord. 2002;4:296-301.	Yes
Vieta E et al. A double-blind, randomized, placebo-controlled, prophylaxis study of adjunctive gabapentin for bipolar disorder. J Clin Psychiatry. 2006;67:473-477.	Yes
Caraceni A et al. Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol. 2004;22:2909-2917.	Yes
Gorson KC et al. Gabapentin in the treatment of painful diabetic neuropathy: a placebo-controlled, double-blind, cross-over trial. Neurology. 1998;50(suppl 4):A103.	Yes
Wessely P et al. Preliminary results of a double-blind study with the new migraine prophylactic drug gabapentin. Cephalalgia. 1987;7(suppl 6):477-478.	No
Pande AC et al. Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Bipolar Disord. 2000;2:249-255.	No
Gordh TE et al. Gabapentin in traumatic nerve injury pain: a randomized, double-blind, placebo-controlled, cross-over, multi-center study. Pain. 2008;138:255-266.	No

Other scientifically unsound behavior included the failure to differentiate between primary and secondary outcomes (2 trials), the relegation of primary outcomes to secondary outcomes (2 trials), and the failure to report 1 or more protocol-defined primary outcomes (5 trials). The Hopkins investigators found that trials with statistically insignificant primary outcomes were more likely to be partially reported or reported with a changed primary outcome.

The internal documents were made available to the Hopkins researchers as a result of ongoing litigation regarding the improper marketing of gabapentin. The anchor author of the analysis (Kay Dickersin, PhD) has served as a paid expert witness in litigation related to gabapentin clinical trials, and the lead author (S. Swaroop Vedula, MD) has received fees from plaintiffs' lawyers.

A study published earlier this week, in the Annals of Family Medicine, revealed that the primary outcomes of randomized studies published in 5 highly regarded journals (including the NEJM), were often changed from those defined in the trials' registry listings. The original primary outcomes of the gabapentin trials were only known through access to internal documents. Dickersin argued to MedPage Today that public registration of industry-sponsored trials should be mandatory to aid the transparency of these clinical studies.

N.B.--In 2004, Pfizer paid a $430-million fine to the government for the off-label marketing of gabapentin (ie, Neurontin).

* Without a darned-good reason.

Forever brainstorming, Google is now helping Americans find a flu shot (either against seasonal or pandemic influenza) through the company's beloved Maps feature. The new tool (found here) is the product of a collaboration between Google and the US DHSS, the CDC (flu.gov), and the American Lung Assocation.

For example, here's where residents of the White House can possibly get a seasonal (blue) or pandemic (red) flu shot. (To the left of the map would be a list of the locations, ordered by proximity to the entered address and labeled "A" through whatever.)

Keep in mind that the Goggle tool is in its beta stages: locations for many flu shot clinics may be missing, the company advises, and locations currently listed may be out of stock. Nevertheless, it's a starting point for consumers.

For more information about the tool's development, go here.

HT: Mashable by way of attentionusa.com.

A GSK version of the pandemic H1N1 vaccine has now been approved by the FDA, says a company press release dated yesterday. The US DHHS has ordered 7.6 million doses of the vaccine to supplement the approximately 250 million doses of vaccine already obtained by the US government. GSK will produce multidose vials of the vaccine, which are expected to begin shipping in December.

The pandemic flu vaccines of 4 companies—CSL, MedImmune, Novartis, and sanofi pasteur—were approved by the FDA in mid-September. GSK's vaccine was delayed by a US government decision to omit immunity-boosting adjuvant (eg, aluminum salts) from all available pandemic flu vaccines, reports the LA Times. (GSK also announced yesterday that it will be donating 50 million doses of its adjuvant-containing pandemic flu vaccine to WHO for use in developing countries.) 

As of November 4, more than 26 million doses of pandemic flu vaccine have been shipped throughout the United States and its territories, according to the CDC. The top 10 recipients have received about half of the supply.

California	2,953,000
Texas	2,092,700
New York and New York City	1,687,100
Florida	1,495,700
Illinois	1,096,600
Ohio	983,500
Pennsylvania	948,600
Michigan	819,100
New Jersey	795,700
Virginia	781,800
Total	13,653,800

According to the HHS, the latest US government spend on pandemic H1N1 vaccines is $2,255,120,945, or about $8.75 per vaccine dose.

Novartis	$979,144,920
MedImmune	$446,668,000
sanofi pasteur	$395,908,025
GSK	$253,400,000
CSL	$180,000,000
Total	$2,255,120,945

DHHS = Department of Health and Human Services.

N.B.--GSK also makes Relenza (zanamivir), an anti-influenza treatment.

NBA legend Kareem Abdul-Jabbar, 62, has Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia (CML), according to numerous news sources. ABC News reports that Abdul-Jabbar was diagnosed with the disorder in December of last year. What treatment Jabbar has received to date is unclear; although the LA Times states that the disease is managed with "daily oral medication" (probably imatinib [Gleevec; Novartis]) and regular "blood analysis."

Here are some facts about CML and its treatment, according to the NCCN Clinical Practice Guidelines:

• CML accounts for 15% of adult leukemias. This year, an estimated 5050 cases will be diagnosed, and 470 will die of the disease.
• The median age of onset is 67 years.
• The disease is characterized by a translocation between chromosomes 9 and 22, resulting in the formation of the Philadelphia chromosome. The translocation results in a fusion gene, BCR-ABL, which is believed to play an important role in the development of CML. The fusion protein produced by BCR-ABL is an oncogene, with unregulated tyrosine-kinase (TK) activity.
• CML occurs in 3 phases: chronic, accelerated, and blast. CML is usually diagnosed in the chronic phase.
• Untreated CML will progress to advanced disease in 3-5 years.
• First-line treatment for chronic Ph+ CML is imatinib, a selective inhibitor of the TK portion of the bcr-abl fusion protein. 
• Responses to the initial treatment of CML are monitored periodically (eg, every 3 months), by assessing bone marrow cytogenetics (ie, cytogenic response [CyR]) and transcript numbers of the BCR-ABL gene (ie, molecular response).
• Long-term data (median follow-up, 60 months) for first-line imatinib: complete CyR, 87%; overall survival, 89%.
• The most common high-grade toxicities with imatinib: neutropenia and thrombocytopenia. Rare cardiotoxicity has been reported with long-term therapy.
• The most common adverse events with imatinib: GI disturbances, edema, rash, and musculoskeletal complaints.
• Management of disease progression that occurs during imatinib therapy may include increasing the imatinib dosage; the use of an alternative TK inhibitor (dasatinib [Sprycel; BMS] or nilotinib [Tasigna; Novartis]); hematopoietic stem cell transplantation (HSCT), or enrollment in a clinical trial. Traditional chemotherapy regimens may also be considered for blast crisis.

The NCCN guidelines conclude, "The development of imatinib...has revolutionized the treatment of CML." Before the advent of imatinib, CML was treated medically with interferon alpha and low-dose cytarabine. According to ABC, Abdul-Jabbar is a spokesperson for Novartis, the manufacturer of imatinib. 

The FDA approved imatinib for the first-line treatment of CML in December 2002.

NCCN = National Comprehensive Cancer Network.

Image of Abdul-Jabbar in 2007 from Flickr.

I had the fortune (I won't say it was misfortune) of sitting next to a Chicago-based shock jock (possibly former shock jock) at the National Radio Hall of Fame induction ceremony on Saturday. In what I can only assume was his on-air "on" mode,* the deejay announced that the Fort Hood shootings were an act of terrorism and that we (assuming "we" meant the FBI, not the ceremony attendees) should interrogate every Muslim in the US military as a consequence.

Perhaps the guy's comments were merely a knee-jerk way to get the table talking (or, in a different context, the phone lines blinking). But there was no indication that he didn't believe what he said—which is concerning. It is, moreover, troubling that the man could spout off these unmeasured words to a large radio audience, words that could reasonably be expected to foment religious- or ethnic-based hate. (I am aware, at least in the abstract, that radio is a bastion for freewheeling types, especially freewheeling conservatives; but this kind of thoughtlessness is more acutely felt when it's sitting next to you. Changing the station wasn't an option.)

Most of us know that, even if interrogation of every one of the thousands of Muslims in the US military were a smart use of resources in the investigation of the Fort Hood shootings (and it isn't), it cannot be done. The act, providing that you could even determine who's Muslim and who's not, would be blatantly discriminatory. The objection is obvious to anyone who's watched a "Law & Order" episode—or any legal TV show, for that matter.

The potentially stickier question is whether the Fort Hood shootings were an act of terrorism. The answer to this question depends on the definition of terrorism, which is in a perpetual state of flux. Defining terrorism is like defining pornography, in that visceral input seems necessary.

But words of law must, nevertheless, try to be explicit. In the US Federal code, terrorism (whether international or domestic) comprises the following: 

1. Violent acts or acts dangerous to human life that are a violation of the criminal laws of the United States.
2. Acts that are intended (as in, appear to be intended) to intimidate or coerce a civilian population or to influence government policy or conduct.

In the case of the Fort Hood shootings, the definition of terrorism hinges on the second component and particularly on knowing, to the extent it is ever possible, the intent of the suspect, Major Nidal Malik Hasan. Did Hasan intend to intimidate or coerce a civilian population? Given the location of the shootings, it certainly doesn't appear so—at least not directly. If anything, Hasan was attempting to influence a military population, if he was attempting to influence anyone at all. The issue of whether Hasan was attempting to influence government policy or conduct seems even more abstruse. The thoughts of the irrational are, by definition, difficult to fathom. Perhaps, in his unbalanced way, Hasan was simply trying to eliminate as many military personnel as possible—personnel that could be deployed to Afghanistan or Iraq.

A profile of Hasan suggests a deeply troubled psychiatrist, who buried himself in his Islamic faith after the deaths of his parents in 1998 and 2001. Also a highly sensitive individual, Hasan may have been particularly vulnerable to any anti-Muslim sentiment or harrassment that he encountered in the US military. An anti-Muslim environment, if it existed, may have pushed Hasan to Islamic extremes. It is reported that Hasan was unable to reconcile his growing fundamentalism with his military duties. Moreover he falsely believed that he could not escape his military service. The personal bind could have led to Thursday's desperation. From the profile, we can reasonably conclude that Islamic fundamentalism informed Hasan's behavior; but an act of violence by an Islamic fundamentalist is not necessarily terrorism. At least I don't think so.

An unwritten component in the definition of terrorism rests on the issue of conspiracy. Specifically was Hasan inflenced by another to shoot up the Fort Hood processing center?** Investigation to date suggests that Hasan's act was not conspiratorial in nature—meaning: he acted alone. Despite the probability that Hasan was influenced by Islamic extremism, there is no evidence (at least to date) that he was urged or supported by another individual to harm anyone generally or enlisted men and women specifically. In this way, Hasan, a native American, appears similar to our growing list of lone mass murderers: from Charles Whitman to Seung-Hui Cho.***  

* I hope, for the sake of his wife, he's got an off mode.

** It is assumed that terrorists want to clarify that their acts are terrorism. Otherwise what's the point?

*** Who coincidentally, like Hasan, attended Virginia Tech.

Harvard Beats Yale 29-29

(2008): A simplistic, but still engaging, account of a(n) historic football game between the unbeaten teams of Harvard and Yale in 1968.

Spearheaded almost exclusively (or at least apparently almost exclusively) by Harvard grad Kevin Rafferty (The Atomic Cafe), the documentary cuts simply between quaint archival game footage and current head-shot interviews of the seminal players—nearly all of whom are sufficiently articulate and suitably reflective. They are Ivy League grads, after all. Moreover, they attended school when proper emphasis could be placed on the components of "student-athlete."

A surprising exception is actor Tommy Lee Jones, former Harvard offensive tackle, who is something short of reticent in his interviews. But one of the most entertaining participants, perhaps inadvertently so, is former Yale linebacker Mike Bouscaren, who evidently likes to remember himself as the team enforcer. Bouscaren's amusing attempt to take credit for inuring Ray Hornblower, Harvard's star halfback, reminds us: Before you brag, know what's on film.

Earlier this week, the WSJ Health Blog reported on a newly published study by Boston researchers Zinner et al (Participation of academic scientists in relationships with industry. Health Aff (Millwood). 2009;28:1814-1825), who assessed the extent to which academic physicians and other scientists have financial ties with the drug or device industry. The story was also predictably picked up by Ed Silverman at Pharmalot.

The blogs' respective ledes highlighted the finding that about 53% of academic researchers have some kind of financial relationship with industry—an observation plucked from the article's abstract. But if one reads the article, the most face-slapping result, IMNSHO, was the horrifying uniformity of the surveyed respondents: 72% were male, and 77% were white. The ethnic/racial diversity, or obvious lack thereof, is flabbergasting. The only minority represented to any notable extent was "Asian."* Among the 2168 respondents** from clinical or nonclinical "life-science" departments, 22 described themselves as black or African American. That's one percent.

Ethnicity/Race	No.	%
White	1705	77
Asian	314	14
Hispanic, any race	56	3
Declined to report	57	3
Other	47	2
Black or African American	22	1
Total	2201*	100

And it's not as if the survey candidates were cherry picked. The authors selected a random sample of faculty from the life-science departments at the 50 US universities that received the most NIH funding in 2004. Survey responses were collected between December 2006 and March 2007. The findings are, therefore, one hell of an indictment of those making contemporary academic appointments in the life sciences at our top programs.

Unfortunately the authors (who include my favorite, sociologist Eric Campbell) did not address the homogeneity of their survey population; perhaps they believed it to be off point. But such a stunning revelation demands examination.

* The ethnic/race breakdown was similar for clinical and nonclinical faculty. The authors did not break down race by professorship level (full, associate, and assistant). The findings are probably even more disheartening.

* It's assumed, although not clarified by the authors, that 34 respondents selected more than one ethnicity/race in the survey.

IMNSHO = in my not-so-humble opinion.

The acute awareness of pandemic influenza (2009 H1N1) has led to an unprecedented demand for, and subsequent shortage of, vaccines for seasonal influenza. According to today's NYT, the shortage of seasonal flu vaccines is so severe that the NYC health department has asked doctors to refrain from vaccinating healthy adults younger than 65 years of age.

The number of doses of seasonal flu vaccine that were manufactured for this year, 114 million, is slightly higher than the number made last year, and about 90 million doses have been shipped so far, reports the NYT. But the shipped supply has nearly been consumed, with an estimated 85 million shots administered to date (which is about 24 million more than the number given out by this time last year). Manufacturers cannot make more seasonal flu vaccine, because they are committed to producing the pandemic flu vaccine.

Among the 5 FDA-approved vaccines for seasonal flu, a total of 248 lots have been released. (But how many packages or doses in a lot is unclear. The numbers may also vary, depending on the manufacturer or distributor. If lot numbers are uniform, then 1 lot represents about 46,000 doses [114 million divided by 248].)

Vaccine and Manufacturer	No. Lots Released	Package	National Drug Code (NDC)
Afluria; CSL Ltd	52	10 single-dose prefilled syringes	33332-009-01
		10-dose vial	33332-109-10
Fluarix; GSK	16	5 single-dose prefilled syringes	58160-876-46
Flulaval; ID Biomedical Corp of Quebec (distributed by GSK)	19	10-dose vial	19515-886-07
FluMist; MedImmune	36	10 single-dose prefilled sprayers	66019-107-01
Fluvirin; Novartis	39	10 single-dose prefilled sprayers	66521-112-02
		10-dose vial	66521-112-10
Fluzone; sanofi-pasteur	86	10 single-dose prefilled syringes (0.25 mL)	49281-009-25
		10 single-dose prefilled syringes (0.5 mL)	49281-009-50
		Single-dose vial	49281-009-50
		10-dose vial	49281-384-15

1 dose = 0.5 mL, unless otherwise indicated.

Except in the case of Flumist,* the seasonal flu vaccines contain the following inactivated viruses:

• A/South Dakota/6/2007 (H1N1) (an A/Brisbane/59/2007-like virus)
• A/Uruguay/716/2007 (H3N2) (an A/Brisbane/10/2007-like virus)
• B/Brisbane/60/2008

* Flumist contains the attenuated viruses.

N.B.--The NDC contains an initial 5-digit labeler code, which is assigned by the FDA, and a 3- or 4-digit product code, which is assigned by the drug firm.

In 2007, the Vaccine Injury Compensation Program ruled that the family of Hannah Poling, a girl who developed an autistic condition after receiving a concentrated series of vaccinations, was entitled to compensation. The prevailing explanation for Poling's brain dysfunction: Vaccine-induced immune responses exacerbated an underlying mitochondrial disorder.*

The issue of whether children with inborn errors of metabolism (IEM), like mitochondrial disorders, are more susceptible to vaccine-related adverse events was explored by combing data from the vast Northern California Kaiser Permanente electronic medical-record system. Results of the investigation were presented Friday by Kaiser physician Nicola Klein at the annual meeting of the Infectious Diseases Society of America ("Evaluating immunization rates and safety among children with inborn errors of metabolism." Abstract 187).

Klein and her colleagues found no difference in the up-to-date vaccination rates of 79 infants who had IEM and those of 1580 matched, healthy infants.** In addition, vaccination was not delayed during the first year among infants with IEM.

By using data from 322 children with IEM who received any vaccine, Klein et al also found no difference between the rates of ER visits and hospitalizations during the 30 days after vaccination and the same rates on postvax days 31-60. The rationale for the comparison was clarified by Klein at MedPage Today: "If the vaccine was causing any problems, we would expect to see them emerge right around the time of vaccination, not a month later."

MedPage Today also indicated that "children with [IEM] were not more likely than normal children to visit emergency rooms or need hospital care after vaccination"; however, this important finding (if correctly reported) was not included in the meeting abstract, nor was it elaborated by the medical news source.

* Although Poling's mother has implied that the vaccines caused the girl's mitochondrial disorder, a belief that contradicts a general understanding of inborn errors of metabolism and her neurologist father's explanation.

** Up-to-date vaccination rates were assessed at 2 years of age. Subjects were members of the Kaiser system from birth to the age of 3 years during the time period from 1990 to 2007.

HT: MedPage Today.

Update: In an e-mail, Dr. Klein confirms that her study compared ER visits and hospitalizations for the 2 time periods (within 30 days postvax and from 31 to 60 days postvax) only among children with IEM. She further advises that a comparison of ER visits and hospitalizations between healthy children and children with IEM is not appropriate, because the 2 populations are too dissimilar. Children with IEM would be expected to have "higher background rates of ER visits and hospitalizations" than healthy children.

For spam: opt-out policy → bad.

For HIV testing: opt-out policy → good.

A nationwide policy that would allow a person to opt out of routine HIV testing would prolong thousands of American lives, according to a study presented Saturday by Michael April, a Harvard medical student, at the annual meeting of the Infectious Diseases Society of America (IDSA) in Philadelphia. April estimated that such a policy would save 610,000 life-years,* provided that US infection rates remain stable.

Since 2006, the CDC has recommended routine HIV testing of all adults, adolescents, and pregnant women in healthcare settings—unless the patient declines, or opts out of, testing. Knowledge of an individual's HIV status has important implications for reducing transmission of the virus and prolonging life with medical treatment.

Current policies for opting into or out of HIV testing are dependent on the state. April reported that New York and Florida, for instance, maintain antiquated opt-in policies for HIV testing, in which a person must consent to HIV testing instead of decline routine testing. Both states have comparatively high rates of HIV infection. 

April calculated the rates of HIV diagnosis within opt-in and opt-out states at about 20% and 25%, respectively.** The difference in detection rates amounted to 681,000 undiagnosed HIV infections over time and an average loss of 9.1 months for each infected patient in an opt-in state.

According to the National HIV/AIDS Clinicians' Consultation Center, the following 18 states have opt-out policies for HIV testing or regulations that are compatible or consistent with those of the CDC, as of January 2009. However, in many cases, explicit provisions for HIV testing were not found, or the wording of the policy synopsis is confusing (eg, "Consent is required; oral or written not specified but must be documented. Opt-out process implied. Compatible with CDC Recommendations.").

Alabama
Arizona
Arkansas
California
Colorado
Connecticut
Hawaii
Illinois
Iowa
Kentucky
Louisiana
Maine
Mississippi
New Hampshire
North Carolina
Ohio
Rhode Island
Virginia

The Kaiser Family Foundation (KFF) indicates that 22 states have opt-out policies for the HIV testing of pregnant women.

AIDS = acquired immune deficiency syndrome; HIV = human immunodeficiency virus; opt-out testing = patient consent is inferred, unless patient declines; opt-in testing: patient must explicity consent to testing, often in writing.

N.B.--In the United States, HIV testing is mandatory for blood or organ donors; military personnel and applicants; prison inmates (in certain circumstances); newborns (in some states); and immigrants.

* The abstract reports 549,437 life-years saved.

** An estimated 21% of all HIV-infected Americans are unaware of their infection.

HT: MedPage Today.

Additional sources: April MD et al. The survival cost of opt-in consent for HIV testing. IDSA 2009. Abstract 1254; KFF.

Image of MiraCare Rapid HIV Antibody Test, one FDA-approved laboratory test.

There is a particular irritation to be found in the criticism of continuing medical education (CME) by a nonphysician. There is even more irritation to be found in the criticism of CME by a purveyor of sociology. There may be practical benefits of the so-called science, but its merits have eluded me in a life that's had its fill of academia.

In the latest issue of JAMA—a journal becoming known for its overbearing editorials—sociologist Eric Campbell, PhD, and health economist Meredith Rosenthal, PhD, condemn the current state of physician CME by applying general critiques from the landmark Flexner Report of 1910. They also advocate investment in something they call "physician human capital," a term adapted from economists to convey the medical knowledge and skills that are required to provide "high-quality, efficient, and cost-effective care."

By using the Flexner Report, Campbell and Rosenthal attempt to draw parallels between the heterogenous state of early American medical education and the quality of today's CME, which they allege is equally scattershot. The comparison is meant to empower their criticism of CME, but the comparison is invalid.

In the early twentieth century, educator Abraham Flexner visited more than 100 US medical schools at the behest of the Carnegie Foundation for the Advancement of Teaching, which conducted its survey at the behest of the AMA's Council on Medical Education. The 2 major reforms for graduate medical education that were promoted (and ultimately realized) by the AMA Council were 1) the standardization of the preliminary requirements for entry into medical school and 2) the implementation of a nationally recognized curriculum of 2 years of basic sciences and 2 years of clinical instruction in a teaching hospital.

Among Flexner's findings in 1910 was, as suspected, the fact that medical curricula varied widely from school to school. But Campbell and Rosenthal wrongly apply Flexner's observation to today's CME by maligning physicians' autonomy when selecting from the varied number of certified CME activities. They argue, "While the diversity of CME offerings provides benefits to physicians, it also deprives CME of representing the mastery of an essential core set of knowledge and competencies."

The problem with the authors' criticism is that, for practicing physicians, the foundation or "essential core" of medical education has already been established, thanks to the Flexner-inspired curriculum of accredited medical schools and postgraduate clinical-training programs. Perhaps if Campbell and Rosenthal had undergone medical education themselves, this blatant fact would not have been so stunningly overlooked. 

It is also entirely reasonable to assume that individual physicians are in the best positions to select the CME activities that may be most beneficial to their practices. Moreover, as Campbell and Rosenthal indicate, the mastery of an essential core set of knowledge and skills is already periodically reinforced by the required maintenance-of-certification examinations through the American Board of Medical Specialties (ABMS). It hardly seems necessary, or even desirable, that participation in specific CME activities should be dictated to practicing physicians beyond the state-mandated requirement of so many certified hours per year. I would be no more inclined to require that Dr. Campbell read certain sociology journals.

Flexner also lambasted the for-profit medical schools of his time, largely because of their substandard curricula. Campbell and Rosenthal proceed to make a very loose correlate between Flexner's observation and the "excessive commercialization" of current CME activities. They cite the ACCME's 2007 report, which indicated that 58% of the income of accredited CME providers came from industry. (The 2008 report indicates that about 44% of total income came from industry, a drop of nearly 25%.) However, there are no objective data to show that commercially supported CME is inferior or less effective at improving medical practice or patient outcomes than CME activities funded by other sources. In fact, Campbell and Rosenthal acknowledge, "[T]here is scant evidence that CME actually improves patient outcomes." In this statement, Campbell and Rosenthal do not distinguish between commercially and noncommercially supported CME. The inferiority of industry-funded CME is merely assumed by the authors, apparently because it has been argued or assumed by others.

Campbell and Rosenthal also maintain that CME relies too heavily on the lecture format, a criticism that Flexner threw at unregulated medical schools 100 years ago. By extension of their argument, the authors claim that CME "is not adequately focused on improving patient outcomes." However, later in their editorial, while advocating CME reform the authors anticipate a transition to CME that is provided by hospitals. But already overburdened hospitals are unlikely to pioneer innovative formats for CME activities.

To realize their "new model of CME" and to ensure physician human capital, Campbell and Rosenthal conclude by advocating 3 lofty reforms. They might as well advocate a tilt of the Earth's axis without proving why it's really better or specifying how to bring it about. Two of their reforms require monumental changes to US medical practice: 1) physician-payment reform to motivate practice quality and efficiency (as if physicians aren't sufficiently motivated to achieve these ends at present) and 2) the use of "sophisticated health information technology" to facilitate on-the-job learning. In addition, the authors propose specialty certification as a requirement for state licensure—an admittedly nice idea that will never happen.

"Boston Ivy" from Flickr.

Results of an Australian study—which were used by the Institute of Medicine and the CDC to recommend fitted N95 respirators to prevent influenza among healthcare workers—have been retracted. The retraction was made in a surprise announcement over the weekend, reported MedPage Today, at the annual meeting of the Infectious Diseases Society of America in Philadelphia.

A reanalysis of the Australian study was prompted by initial criticism of the study's design, which did not use randomly selected hospitals as a control group. Follow-up statistical adjustments, to compensate for "clustering" and "multiple testing," revealed nonsignificant differences between infection rates with N95 respirators and those with surgical face masks, reported the authors at the meeting. The reanalysis triggered a retraction of the original conclusions, which had favored the preferential use of N95 respirators. The new, nonsignificant findings are consistent with results of a recent Canadian study, which showed no added, protective benefit from N95 respirators among hospital nurses.

By advocating the more expensive N95 respirator, the originally reported Australian study had considerable cost implications. To provide a rough idea of the price differential between the 2 mask options: At labsafety.com, a 20-pack of 3M N95 respirator/surgical masks costs $24.90 ($1.25/mask), and a 50-pack of run-of-the-mill surgical masks will set you back $9.70 ($0.20/mask).

Another phase 3 trial of belimumab (Benlysta; Human Genome Sciences/GSK) in patients with systemic lupus erythematosus (SLE) has met its primary endpoint, according to a company press release. These data complement results of a previous phase 3 study, BLISS-52, in which the mAb (when compared with placebo) significantly improved disease activity* at 1 year.

Combined trial data will undoubtedly be used to support a biologics license application (BLA) to the FDA. Neither phase 3 study, however, has been published in a peer-reviewed journal.

In the placebo-controlled BLISS-76, belimumab 10 mg/kg significantly improved the SLE Responder Index** at 52 weeks (43.2% vs 33.8% with placebo; P = .021). However, the 1-mg/kg dose was not associated with statistically significant improvement. Outcomes of several secondary endpoints (eg, Physician's Global Assessment, reduction of corticosteroid dosage, SF-36 Physical Component Summary) also did not reach statistical significance.

Serious or severe infections were observed in 7.2% of patients who received belimumab and 8.0% of patients who received placebo. Rates of serious or severe infusion reactions were 1.1% with belimumab and 0.7% with placebo. Rates of discontinuation due to adverse events were 7.2% with belimumab and 7.6% with placebo. A handful of malignancies and deaths were also reported.

A comparison of the BLISS-52 and BLISS-76 results is provided here:

Outcome	BLISS-52	BLISS-76
Primary endpoint (52 weeks)	√ (1 and 10 mg/kg)	√ (10 mg/kg only)
Belimumab 10 mg/kg, %	57.6	43.2
Belimumab 1 mg/kg, %	51.7	40.6 (NS)
Placebo, %	43.6	33.8
Secondary endpoints
Reduction of SELENA SLEDAI score	√ (1 and 10 mg/kg)	√ (10 mg/kg only)
Belimumab 10 mg/kg, %	58.3	46.9
Belimumab 1 mg/kg, %	53.1	42.8 (NS)
Placebo, %	46.0	35.6
Improvement in PGA	√ (10 mg/kg only)	NS
Reduction of corticosteroid dosage (≥25% to ≤7.5 mg/d)	√ (1 and 10 mg/kg)	NS
SF-36 Physical Component Summary	NS	NS
Adverse events
Serious infections
Belimumab, %	6.1	7.2
Placebo, %	5.9	8.0
Infusion reactions
Belimumab, %	N/A	1.1
Placebo, %	N/A	0.7
Discontinuation
Belimumab, %	N/A	7.2
Placebo, %	N/A	7.6

Per protocol, BLISS-76 will continue for another 24 weeks, and according to the CEO of HGS, a BLA will likely be submitted to the FDA in the first half of next year.

Belimumab is a human mAb that inhibits the activity of B-lymphocyte stimulator (BLyS), which promotes the survival of (auto)antibody-producing B cells. The drug was discovered by HGS, which entered into a codevelopment and comarketing agreement with GSK in 2006. Other anti-B-cell therapies in clinical development for SLE include epratuzumab (Immunomedics) and ocrelizumab (Genentech, Biogen), aka Son of Rituxan.

A recent great hope for SLE, mycophenolate mofetil (CellCept; Roche) died a death of noninferiority after it performed no better than cyclophosphamide in the induction treatment of lupus nephritis. Rituximab (Rituxan) also flopped in a recent phase 3 study of lupus nephritis.

According to the Lupus Foundation of America, roughly 1.5 million Americans and more than 5 million people worldwide have lupus.

mAb = monoclonal antibody; N/A = not available; NS = not significant.

* Measured by using a combination of 4 recognized scales: a reduction of the SELENA SLEDAI score by at least 4 points from baseline; no worsening per the Physician's Global Assessment (PGA); no new BILAG-A organ domain score; and no more than 1 new BILAG-B organ domain score.

** The SLE Responder Index defines patient response as an improvement in the SELENA SLEDAI score by at least 4 points and no clinically significant decline per the BILAG score or PGA.