September 2009 Archives

Elan may well be the Lindsay Lohan of pharma. The long-troubled, press-worthy company courts controversy and our attention.

So now...It is reported that, on September 24, the US Securities and Exchange Commission subpoenaed the Dublin-based Elan for information regarding 2 announcements from 2008. The SEC subpoena was revealed in Elan's most recent filing with the Commission.

According to the filing, the SEC is investigating Elan's July 29, 2008, announcement of phase 2 data for bapineuzumab and the company's July 31, 2008, announcement of 2 Tysabri-related cases of progressive multifocal encephalopathy (PML). Elan currently comarkets the monoclonal antibody Tysabri (natalizumab) with Biogen Idec for the treatment of multiple sclerosis and is codeveloping the anti-amyloid monoclonal antibody bapineuzumab with Wyeth for the treatment of Alzheimer disease (AD).

The July 29 filing ("Elan and Wyeth Present Encouraging Results from Phase 2 Clinical Trial of Bapineuzumab at International Conference on Alzheimer's Disease"), which parrots an Elan press release of the same date, optimistically described the phase 2 results of bapineuzumab in patients with mild-moderate AD. The study results were used to promote the drug's ongoing clinical development, despite the fact that a statistically significant difference between the mAb and placebo for the primary endpoint was not observed. Dose-dependent vasogenic brain edema was also reported with bapineuzumab, especially in patients with the ApoE4 allele.

The phase 2 bapineuzumab data were first publicized by Elan in a July 17, 2008, press release (discussed here)—in which the missed primary endpoint was buried in the second paragraph and favorable post-hoc results were highlighted. Initial news of the study results was associated with substantial increases in Elan's and Wyeth's share prices (10.6% and 4.8% bumps, respectively) and generally favorable Wall Street buzz. However, after the same data were presented in the sober context of the International Conference, the companies' respective share prices dropped 19.6% and 11.2% (see "Bapineuzumab and Share Prices of Elan/Wyeth: What a Difference Some Undefined Thing Makes").

It seems reasonable to speculate that the SEC is investigating Elan's presentation of the bapineuzumab data in conjunction with a pump-and-dump-like scheme.

Reasons for the SEC's investigation of Elan's report of the PML cases are less obvious. The filing of July 31, 2008, described 2 European patients with multiple sclerosis who developed the potentially fatal, opportunistic infection after prolonged Tysabri monotherapy (14 and 17 months). To date, 11 cases of Tysabri-related PML have been reported since the drug's reintroduction into the marketplace in 2006. The risk of PML with the drug increases substantially with prolonged therapy (>12 months).

Two short weeks ago, JNJ closed its highly publicized buyout deal with Elan, in which JNJ acquires the rights to Elan's AD immunotherapy program. The program includes the development of bapineuzumab. The major sticking point of negotiations between the 2 companies became JNJ's potential access to Tysabri. Tysabri comarketer Biogen cried breach of contract with Elan over the initially proposed buyout, and a federal judge agreed. The newly cemented JNJ-Elan deal (for $100 million less than the original offer of $1.5 billion) omits the mAb.

While film director Roman Polanski fights extradition to the United States, time is taken here to remember Quaalude—the drug that a 43-year-old Polanski allegedly gave to a 13-year-old girl before he had sex with her in 1977.*

Quaalude is the trade name for methaqualone, a chemical developed in the 1950s in India as an antimalarial compound. Contemporaneous data also indicated that the drug provided "good hypnotic activity" and had "low toxicity" when compared with widely used barbiturate sedatives. Consequently, during the 1960s, the drug became a popular prescription alternative to potentially addictive agents like secobarbital (Seconal; Eli Lilly) for the treatment of insomnia.

In the United States, the drug was first sold by Pennsylvania-based William H. Rorer, Inc, which applied the trademark Quaalude to its tablets in 1965. The company incorporated the double-a into the brand name as a way of capitalizing on the success of its antiacid product, Maalox (which is now owned by Novartis Consumer Health). The recommended therapeutic dosage for Quaalude was 150 or 300 mg.

Reports of physiologic addiction to and overdose of methaqualone were published repeatedly in the medical literature, beginning in the late 1960s (for example, here and here). Among Americans, abuse of Quaalude exploded during the 1970s, especially among young adults and teens—who often combined the drug with alcohol for a really soporific buzz. The activity was known as "luding out." The drug also gained a word-of-mouth reputation as an aphrodisiac and enhancer of sexual pleasure (eg, "The Love Drug" or "Heroin for Lovers"); although these effects were overstated, if not outrightly made up. As one young user described her Quaalude experience to the Washington Post in 1978: "I fell asleep."

With the rise of its legitimate and recreational popularity, the unpatented methaqualone was also legally manufactured in the United States by Anar-Stone Laboratories, which called its capsule Sopor (in 75-, 150-, and 300-mg doses). Other American manufacturers of methaqualone compounds included Parke-Davis (Parest) and Wallace (Optimil).

A 1972 Chicago Tribune report ("A Sedative Gains in Drug Culture") indicated that the street cost of methaqualone was 25 or 50 cents per pill. Slang names for the drug included "Rorers" and "seven-fourteens." These terms were derived from the stamp on the branded Quaalude tablet, "Rorer 714." In her grand jury testimony, Polanski's 13-year-old victim reported that the director gave her part of a tablet (dose unknown) that had "Rorer 714" on it.**

According to a 2006 "Frontline" report, high methaqualone demand in the United States was supplied not only by drug firms, but through rogue domestic labs and counterfeit South American operations. In 1981, recreational use of methaqualone was so widespread that it ranked second to marijuana in popularity. The DEA estimated that 80%-90% of the world's methaqualone production was diverted to the illegal drug business. (The DoJ cites the emergence of "stress clinics" in New York, New Jersey, and Florida—essentially B&M equivalents of today's dubious online pharmacies—for the boost of methaqualone abuse in the early 1980s.) 

"Frontline" credits the DEA's Gene Haislip with shutting down the illicit methaqualone business in the United States. Haislip successfully convinced foreign manufacturers of the methaqualone powder and their resident countries to stop production. And without the powder, South American producers, like those in Colombia, could no longer pound out pills for export. Simultaneously US physicians began prescribing other hypnotics as sleep aids, and law enforcement shut down the stress clinics. Then in 1984, federal legislation banned the domestic production and sale of methaqualone; in other words, the compound was designated a Schedule I drug.

South Africa is the current hotbed of methaqualone abuse. There the drug is consumed in the form of Mandrax (which combines 250 mg of methaqualone with 25 mg of diphenhydramine). The tablet is typically crushed and snorted or smoked with cannibis.

* Polanski also allegedly plied the girl with champagne. For relevant court records, including Polanski's contemporaneous guilty plea to having sex with a minor, start at thesmokinggun.com.

** Rorer 714 t-shirts were a popular counterculture item.

Image of methaqualone pills attributed to Indiana Prevention Resource Center.

And no state remains unaffected.

The CDC advises, however, that heightened H1N1 activity does not reflect the severity of disease. At least 99% of all subtyped influenza virus samples (n = 1402) are the 2009 H1N1 virus.

Also according to CDC data, the in-hospital death ratio associated with influenza-like illness (ILI), as of September 19, was 0.093 (mortality rate, 9.3%). US deaths include 49 children.

Multiplying the US hospitalization ratio for April 15 to July 24 (0.114) by the CDC's latest in-hospital death ratio for ILI provides a case-fatality ratio of 0.0106 (mortality rate, ~1%). However, a Harvard epidemiologist recently estimated the H1N1 death rate to be considerably lower—from 0.007% to 0.045%.

Vaccines for the 2009 H1N1 virus are expected to be available next month (that is, in a few days), with the nasal-spray vaccine preceding the shot vaccine in the US marketplace. Candidates for the nasal vaccine are nonpregnant persons 2-49 years of age.

Newly released results from a national survey (N = 1678), performed by the University of Michigan in August, revealed that a minority of parents plan to have their children vaccinated against the pandemic H1N1 virus. (The CDC currently recommends that all individuals from 6 months to 24 years of age undergo H1N1 [swine flu] vaccination.) Surveyed parents reported that they are more likely to have their children receive the seasonal influenza vaccination.

Vaccine	Likelihood, % of Parents
	Definitely/ Probably Yes	Unsure	Definitely/ Probably Not
Seasonal flu	54	19	27
2009 H1N1	40	31	29
Hispanics	52	23	25
Whites	38	32	30
Blacks	30	35	35

Parents' perception of the risks associated with H1N1 flu were closely linked to the likelihood of opting for the vaccine. Notably Hispanic parents were more likely to report their intention of having their children undergo vaccination—possibly because they perceive a higher threat from the disease than non-Hispanic parents. For instance, Hispanic parents may be more aware of the recent history of H1N1 disease in Mexico.

The Well

(1951): A black girl's disappearance ignites a race war when a white man (Henry Morgan) is suspected of kidnapping her. The movie, however, returns quickly (and naively) to racial harmony, when it's discovered that the girl has fallen 60 feet down a forgotten well. Her suspected kidnapper then plays a major role in her attempted rescue.

Although the primary-speaking roles belong to white actors, the film is notable for employing a considerable number of black actors—including Maidie Norman—who didn't have to pretend they were domestic help for a change.

Major HT to KTG.

Probably.

Laura Manuelidis and her colleagues at Yale continue to chip away at the idea that prions—proteinaceous infectious particles—cause transmissible spongiform encephalopathies (TSEs) all by themselves. (For background on this story, start here.) Her group's latest work to undermine the prion hypothesis, for which Stanley Prusiner received the Nobel Prize in 1997, was somewhat stealthily published in the August 11th issue of PNAS.

According to the prion hypothesis of disease, the normal, endogenous form of prion protein (PrP) misfolds to become infectious. (This abnormal, disease-associated form of PrP, which is resistant to degradation, is denoted PrP-res.) PrP misfolding may occur spontaneously, through genetically encoded triggers, or by the inoculation or ingestion of misfolded PrP from infected tissues. The last method is apparently how kuru, sheep scrapie, and variant Cretuzfeld-Jacob disease (or vCJD, from bovine spongiform encephalopathy [BSE]) are propagated.

The prion hypothesis also stipulates that conversion of normal PrP into PrP-res is only possible when there is considerable homology between the donor and host PrP. But, as Manuelidis points out, this idea has not been consistently supported by animal experiments. For instance, the vCJD agent has been readily transmitted to normal mice but not to transgenic mice that expressed only human PrP. Data also show that PrP-res Western-blot profiles do not vary with different infectious TSE agents, as would otherwise be expected.

Other problems with the prion hypothesis include the inability to demonstrate the reliable infectivity of purified PrP-res and the fact that tissue samples without PrP-res can transmit infection. Arguably the most heretical aspect of the prion hypothesis is that the infectious agent, unlike bacteria or viruses, does not contain nucleic acid—that is, DNA or RNA. 

For these reasons, it remains difficult for many to wholeheartedly embrace the prion hypothesis, despite its now wide acceptance within the scientific community.

Contradicting the proposal that donor and host PrP must be homologous to transmit TSE, Manuelidis et al showed in PNAS that high levels of murine wild-type PrP did not prevent the transmission of primate kuru to mice. Instead high levels of murine wild-type PrP shortened the incubation time of disease—a phenomenon that would be expected if PrP acts as a viral receptor, she argued. Mouse experiments with the infectious agents for sporadic CJD, BSE, and scrapie also showed incubation times, pathologic features in the brain and spleen, and animal behaviors that were distinct from those of kuru.

Ultimately Manuelidis proposes that host PrP is required for TSE infection, but that it probably acts as a receptor or "scaffold" for the true infectious agent—which is possibly a 25-nm virus-like particle, at least in the case of scrapie.

If given a choice between the injected vaccine and the nasal-spray vaccine for either seasonal influenza or pandemic influenza, you may want to opt for the shot. But only if you're a grown-up.

That's because...

The injected vaccine for seasonal influenza was more effective at inducing immunity than the nasal-spray version in adults, according to a study published yesterday in the NEJM. The results can possibly be applied to vaccine options for pandemic H1N1. (But then again, maybe not. Read on.)

In a randomized, double-blind, placebo-controlled study of 1952 healthy adults (18-49 years of age) during the 2007-2008 influenza season,* the injected vaccine (which contains inactivated virus) reduced the relative risk of laboratory-confirmed influenza by 50%, when compared with the nasal-spray vaccine (which contains live, attenuated virus). The rates of absolute efficacy against influenza A (predominately the H3N2 virus) were 72% and 29% for the shot and spray vaccines, respectively.

Other data indicate, however, that the spray vaccine is more effective for the prevention of flu than the injection in young, vaccine-naive children (2 doses) and in older children (1 dose).

It is speculated that the nasal-spray vaccine is relatively less effective in adults, because preexisting seasonal flu antibodies thwart the vaccine antigens at their entry point in the nasal passages. But because the pandemic H1N1 virus is new to everybody, the nasal-spray vaccine may work comparably in children and adults.

* According to the CDC, circulating viruses during this season in the United States were influenza A (71%) and influenza B (29%). Early in the season, influenza A H1N1 viruses predominated, followed by an increase in circulating H3N2 viruses. Influenza B viruses were more common during the tail of the season. Circulating H3N2 viruses were most common overall.

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And on a related note...

A high-profile anecdote of confirmed illness with the pandemic H1N1 virus was provided yesterday by CNN's Sanjay Gupta. Gupta's prominent symptoms were similar to those of seasonal flu: a hacking cough, fever, nausea, and body aches. Although Gupta reported, "[T]his was the sickest I have ever been," he recuperated after a couple of days of symptomatic treatment and bed rest. He evidently did not receive antiviral therapy (eg, oseltamivir [Tamiflu]).

The FDA wasted little time in exercising its new authority over the tobacco market. (Although the federal action is more show than substance [see below].)

Candy-, fruit-, and clove-flavored cigarettes* are now banned in the United States, reported the agency yesterday. The legal ban is authorized by the recently enacted Family Smoking Prevention and Tobacco Control Act, which allows the FDA to regulate tobacco products. The corresponding bill was introduced into Congress in March and signed into law by President Obama on June 22nd. If only healthcare reform worked that fast.

The FDA's rationale for targeting flavored tobacco products is their appeal to young and first-time smokers**—an appeal that may lead to a lifelong smoking habit and its costly health-related consequences. The agency states that 3600 "young people" start smoking every day.

Citing a recent study by Klein et al, the FDA reports that 17-year-old smokers are 3 times as likely to use flavored cigarettes as older smokers (≥25 years of age). Data from 2 national surveys indicated that the rates of use of Camel Exotic Blends, Kool Smooth Fusion, or Salem Silver Label cigarette brands during 2004-2005 were 22.8% among 17-year-olds, 21.7% among 18-19-year-olds, and 6.7% among smokers aged 25 years or older. The cigarettes came in tasty-sounding flavors like "Mandarin Mint" and "Mocha Taboo."

In an agreement with the attorneys general of 40 states, RJ Reynolds, the manufacturer of the cigarette brands, agreed to stop selling candy-, fruit-, and alcohol-flavored cigarettes in the United States in 2006.

The FDA also reports that it's reviewing the regulation of menthol cigarettes and other flavored tobacco products.

In the meantime, the flavored-cigarette tins, some of which remain sealed, can be found on ebay.

* So stage actors will have to use the real deal during performances that require smoking.

** Despite the fact that Gawker thinks they're wussies for smoking flavored cigarettes in the first place.

11/07/09 update: On November 2nd and 3rd, the FDA sent warning letters to 14 companies that continue to sell flavored cigarettes through their web sites. The letters were the result of Internet searches performed by the FDA's Office of Enforcement and the Center for Tobacco Products. Failure to comply with the recent US ban on flavored cigarettes may result in regulatory actions like seizure or injunction, the agency stated. The specific warning letters can be found here. The location of several of these companies appears to be unknown. 

In an attempt to reduce the understandable confusion (hell, I'm confused) about who should receive what influenza vaccine, information from the CDC and news sources is condensed here for reference. But the reader is urged to consult the relevant CDC web pages (for example, here) and a treating physician for authoritative recommendations. Notably guidelines for the pandemic H1N1 vaccine are developing actively and rapidly.

Seasonal Influenza Vaccine (available now)

Who should receive the seasonal influenza vaccine?

• Individuals from 6 months to 19 years of age and individuals 50 years of age or older
• Pregnant women
• Persons with certain chronic medical conditions
• Individuals living in nursing-home or long-term care facilities
• Persons living or working with others who are at risk for influenza-related complications (eg, healthcare workers, daycare employees).

Who is a candidate for the intranasal spray vaccine, which contains 3 live, attenuated seasonal influenza viruses?

Healthy, nonpregnant persons 2-49 years of age.

Who is a candidate for the intramuscular vaccine, which contains 3 inactivated seasonal influenza viruses?

Children 6-35 months of age (dose, 0.25 mL) and individuals 3 years of age or older (dose, 0.5 mL).

Who should receive 2 doses of the seasonal influenza vaccine (each separated by 4 weeks)?

Children younger than 9 years of age who 1) are receiving the seasonal influenza vaccine for the first time or 2) received the vaccine for the first time during the previous influenza season and received only 1 dose.

Pandemic H1N1 (Swine Flu) Vaccine (expected in October)

Who should receive the swine flu vaccine?

• Pregnant women
• Persons who live with or care for infants younger than 6 months of age
• Healthcare and emergency medical personnel
• Persons aged from 6 months to 24 years
• Individuals aged 25-64 years who are at risk for influenza-related complications (eg, persons with asthma, diabetes, hypertension, HIV). 

Who is a candidate for the intranasal spray vaccine, which contains the live, attenuated pandemic H1N1 virus?

The same individuals who are candidates for the intranasal seasonal influenza vaccine: healthy, nonpregnant persons 2-49 years of age.

Who is a candidate for the intramuscular vaccine, which contains the inactivated pandemic H1N1 virus?

All individuals who are priority candidates for the pandemic H1N1 vaccine.*

Who should receive 2 doses of the swine flu vaccine (each separated by 3-4 weeks)?

Late-breaking data suggest that 1 vaccine dose will be sufficient to induce a protective immune response in persons 10 years of age or older. Children from 6 months to 9 years of age, however, will likely require 2 doses of vaccine.

* I suspect that doses, like those for the seasonal influenza vaccine, are cut by half for children 6-35 months of age; however, I have not yet confirmed this information.

**********************

The US Department of Health and Human Services (HHS) recently ordered 56 million more doses of the pandemic H1N1 vaccine from MedImmune and sanofi pasteur for an additional $438,143,025. The total US government spend on the pandemic H1N1 vaccine is now $2,255,120,945, which amounts to $8.98 per vaccine dose.

Novartis	$979,144,920
GSK	$253,400,000
sanofi pasteur	$395,908,025
CSL Biotherapies	$180,000,000
MedImmune	$446,668,000

Medical-education communications companies (MECCs) must brace for more retrenchment.

GlaxoSmithKline announced today that it will no longer provide continuing medical education (CME) grants to MECCs, according to Reuters. The drug company's decision, which is part of a new grant policy, is effective immediately. GSK joins Pfizer, which announced its decision to cut off educational grants to MECCs more than a year ago.

GSK also reports that it will fund fewer CME programs and "invite grant applications from approximately 20 medical education providers with a documented track record of developing and delivering high quality medical education programs that have a measurable impact on improved patient health." Invited applicants are limited to unnamed, accredited academic medical centers and national physicians' organizations.

It's been argued here that the move by drug firms to deny grants to MECCs is based on the perception of bias, not actual bias, in MECC-generated CME. In any event, it's bad news for companies like CE Alliance ($225,000), Discovery Communications* ($426,500), Physicians' Education Resource Group ($363,700), Pri-Med Institute ($1,024,773), Research to Practice ($530,000), and Vindico Medical Education ($225,338), which received a total of nearly $2.8 million in grants from GSK in the first half of this year. (Values in parentheses indicate GSK funds to the individual company for the first 2 quarters of 2009.)

According to data from the ACCME, total income for "publishing and education companies" (in other words, MECCs) dropped 20% from 2007 to 2008. The income drop is largely due to the loss of grant support from pharma.

Whether CME leads to positive changes in healthcare delivery remains up for debate. A recent Cochrane review concluded that professional educational meetings, particularly when combining didactic and interactive formats, can improve healthcare delivery and patient outcomes. However, the effect is typically small and similar to that of other types of CME activities, like audit and feeback programs. The effectiveness of CME increases when serious outcomes or less complex behaviors are considered.

* Suspected to be the Discovery Institute of Medical Education.

09/23/09 addendum: According to Daniel Carlat, blanket critic of all pharma-supported CME, GSK will still provide CME grants to invited applicants that partner with MECCs. Carlat ignorantly describes the MECC-cosponsor arrangement as adding another layer to a "money laundering operation." The description, which Carlat appears to be in love with, is simply wrong.

Money laundering refers to methods by which illegally obtained income (eg, from drug trafficking, prostitution) is moved around to disguise its source. There are at least 2 very important ways in which "money laundering" fails to describe pharma-funded CME. First and foremost: Providing educational grants to MECCs or any other organization is not illegal (although on Planet Carlat, it would be). Second: The source of the funding is not hidden; the pharma grantor must be disclosed on CME materials to the program participant. This requirement is stipulated by the ACCME.

A Lonely Place (1950): Humphrey Bogart is Dixon Steele, a hot-headed screenwriter suspected of murdering a coat-check girl. The main thread of the story, however, becomes Steele's volatile love affair with his neighbor and alibi (Gloria Grahame).

A movement by editors to eradicate ghostwritten articles in medical journals is featured in today's NYT. The perhaps-too-cute term for the movement, "ghostbusting," was coined by the editors of Blood in January.

The most draconian of proposed steps to thwart ghostwriting—which typically involves an unacknowledged medical writer who is employed (either directly or indirectly) by pharma—include immediate article retraction, lifetime banning of the named author, and a report to the author's institution for investigation. Editors at PLoS Medicine recently described these punishments and their disdain for ghostwriting in firm, albeit clumsy, terms.

Medical journal editors need to decide whether they want to roll over and just join the marketing departments of pharmaceutical companies. Authors who put their names to such papers need to consider whether doing so is more important than having a medical literature that can be believed in.

Ideally the Age of Ghostbusting heralds an era of the medical writer as a contributing author and not the avoidance of the medical writer by the physician author—who generally can't write his way out of a paper bag.

It's all swine flu all the time. Here's the latest from the CDC by way of the MMWR.

• Estimated, cumulative number of pandemic H1N1 infections in the United States between April and June: more than 1 million. (See yesterday's post, for example, for how the estimated case number affects the estimated mortality rate.)
• Peaks of activity: May and June nationwide; late August in the Southeast.
• Confirmed H1N1 hospitalization rate from April to August: generally lower than that for seasonal influenza but higher than usual for the time period.
• In-hospital death rate from mid-April to August 30th: 6.5% (593/9079); proportion of deaths due to pneumonia and influenza "within the bounds" of summertime expectations.
• Circulating virus: 97% pandemic H1N1 that is sensitive to antiviral treatment.
• Antiviral drug sensitivity: 99.4% of 1372 tested samples are susceptible to oseltamivir (Tamiflu; Roche); oseltamivir-resistant viruses still susceptible to zanamivir (Relenza; GSK); all viruses resistant to amantadine and rimantadine.
• Recommendations for persons with influenza-like illness (ILI): after afebrile (untreated), stay home for another 24 hours.
• Antiviral treatment recommendations: early therapy for persons with severe ILI and those individuals with suspected ILI and risk factors for complications (<5 years of age; >64 years of age; or underlying health conditions, including pregnancy).
• Vaccines for seasonal influenza: available now and urged for all children, persons 50 years of age or older, and those at greater risk for influenza-related complications.
• Vaccines for pandemic H1N1: still expected by mid-October; first in line have already been designated by the CDC.

Depiction of H1N1 virus from Wikipedia.

A Harvard epidemiologist, Marc Lipsitch, estimates the mortality rate for disease due to the 2009 H1N1 virus at 0.007%-0.045%, according to Reuters. This estimate is at least an order of magnitude lower than the US mortality rate calculated by using CDC case, hospitalization, and death data (~0.75%*) and even lower than the crude mortality rate according to WHO data (>1%).

Lipsitch proposes that the mortality risk due to the 2009 H1N1 virus is comparable to that of a "moderate" influenza season—less than 0.1%.** The epidemiologist bases his calculation on reports of influenza-like illness throughout the world, as well as reports of hospitalizations and confirmed deaths.

Working backward, one can conclude that Lipsitch estimates the number of people infected so far with the 2009 H1N1 virus worldwide at several million.

* Calculated by multiplying the US hospitalization ratio from April 15 to July 24, or 0.114, by a recent in-hospital death ratio (eg, 0.065) and then multiplying by 100.

** Although CDC data suggest a death rate for seasonal flu that is higher than 0.045%. According to the Centers, 5%-20% of the US population is affected each year by seasonal influenza. The US population is approximately 300 million, so that means 15-60 million are infected annually. About 36,000 people die of seasonal flu, for an annual mortality rate of 0.06%-0.24%. About 200,000 are hospitalized, for a hospitalization rate of 0.3%-1.3%.

Depiction of H1N1 virus from Wikipedia.

Four vaccines against the novel (2009) H1N1 virus are now approved, said the US FDA yesterday. Initial lots of the vaccines—which will be made by CSL Biotherapies, MedImmune, Novartis, and sanofi pasteur—are expected to be available within the next 4 weeks. MedImmune is producing a nasal-mist spray vaccine, while the other companies are churning out the conventional shot vaccine.

Last week's late-breaking data indicated that 1 vaccine dose (15 micrograms), instead of the originally anticipated 2, will be sufficient to induce a "robust" immune response in most adult recipients. The optimal dose in children, however, has not been confirmed.

The vaccines are produced by using the same methods as those for seasonal flu vaccines, including viral cultivation in chicken eggs. (WHO nicely explains the vaccine-manufacturing process here.) Consequently people with "severe or life-threatening" allergies to chicken eggs should not receive the vaccine. Vaccines will also be available in preserved (ie, thimerosal containing) and nonpreserved formulations.

Side effects of the injected and nasal-mist vaccines are anticipated to be similar to those seen with the seasonal flu vaccines.

Five companies contracted with the US Department of Health and Human Services (HHS) to create and manufacture a vaccine against the novel H1N1 virus; only GlaxoSmithKline failed to receive vaccine approval yesterday. Reasons for the delayed or deferred approval of GSK's vaccine were not provided by the FDA or the company.

According to a cached version of the web page detailing HHS's contracting activities, the following government orders for novel H1N1 vaccines were made in May and June.

Novartis	$979,144,920
GSK	$253,400,000
sanofi pasteur	$252,425,000
CSL Biotherapies	$180,000,000
MedImmune	$96,100,800

HHS = Health and Human Services.

Addendum: An updated HHS web page reveals that MedImmune received a total of $151,008,000 in contracts for May and June. The cumulative government spend is therefore $1,815,977,920. With an order of 195 million doses, that's $9.31 per vaccine dose.  

Sometimes even Mark and David Geier can flog only a partial confession out of data.

The father-son duo, along with frequent coauthor Janet Kern, were able to publish yet another study implicating at least some kind of link between mercury (this time from maternal dental fillings) and the severity of childhood autism. But the authors missed on what would generally be construed as the primary endpoint of their study. The negative finding is buried in the latest issue of Acta Neurobiologiae Experimentalis (Warsaw), a journal with an impact factor in the 25th percentile.*

For anyone familiar with the Geiers' previous publications, there is little shock value here. Evidently the authors remain incapable of disinterest. The introduction of the article preferentially cites highly questionable data linking mercury in dental amalgam with various bodily dysfunctions generally and autism spectrum disorder (ASD) specifically. And in consistent form, the Geiers cite their own previously published data to bolster their preformed ideas.**

The study methods are vague and fraught with potential bias: They write, "The present study looked at 100 qualifying participants who were prospectively recruited from patients presenting for outpatient genetic consultations at the Genetic Centers of America." Mark Geier is president of the "Centers," which are evidently located in the basement of his residence in Silver Spring, MD. The study is also described as blinded, although it's not clear who is blinded to what. The subjects, born either from 1990 to 1999 or between 1990 and 1999, were "previously diagnosed" with autism or pervasive development delay (PDD) by a "trained professional." As far as the reader knows, this term could refer to an autism specialist, a general pediatrician, a chiropractor, a naturopath, or a plumber. The study protocol itself is described as being approved by the Institutional Review Board (IRB) of the Institute of Chronic Illnesses, another brainchild of Mark Geier. The makeup and objectivity of this IRB has been called into serious question.

The primary finding of the study was that there was no statistically significant difference between the mean number of maternal dental fillings during pregnancy and the severity of autism. After adjusting for age, sex, race, and geographic residence, mothers of children with autism (defined as "severe") had 4.6 fillings, and mothers of children with ASD (defined as "mild") had 3.1 fillings (P = .0946). (Of course, the arbitrary distinction of severe and mild autism on the basis of the prestudy diagnoses, one of which includes the term "spectrum," is highly problematic.)

Undaunted, Geier et al attempted to define a threshold number of maternal dental fillings that significantly elevated the risk of "severe" autism. After performing a "logistic regression analysis," they concluded that the odds of "severe" (vs "mild") autism more than tripled if the number of maternal dental fillings during pregnancy exceeded 5; however, the risk was only statistically significant with 8 or more fillings. The "threshold" finding is the only conclusion cited in the article's abstract.

The most profound limitation (and there are several...arguably many) of this study is the lack of any data from a control population—namely the mean number of dental fillings in mothers whose children do not have autism.

* For comparison purposes, the NEJM has an impact factor of greater than 99%.

** In the opening paragraph, Geier et al write, "As of mid-2008, the US Food and Drug Administration (FDA) has declined to classify the medical-device safety of amalgams used in dentistry [emphasis added]." Given the article's recent publication date, this statement suggests that Geier et al had been shopping this article around for some time. The FDA issued its final regulation on dental amalgam in July. The mercury component of dental amalgam was reclassified from Class I (low risk) to Class II (moderate risk).

Ghostwriting and honorary authorship—the practice of adding, for example, the name of a laboratory head to lend cachet or credibility to an article—remain common in top medical journals, including the prestigious NEJM and the sanctimonious JAMA. This conclusion is based on recent survey results that were analyzed by JAMA investigators and presented last week at the Sixth International Congress on Peer Review and Biomedical Publication in Vancouver.

After submitting an online survey to the authors of 900 research, review, or editorial articles that were published in the Annals of Internal Medicine, JAMA, The Lancet, Nature Medicine, the NEJM, or PLoS Medicine during 2008, Wislar et al reported the following, preliminary results (author response rate, 70%).

Authorship Type	2008, % of Articles	1996, % of Articles
Honorary	26 (range, 16-39)	19
Ghost	8 (range, 2-11)	11
Both	2	2

When compared with survey results from 1996, these data indicate that the rate of honorary authorship has increased, while the rate of ghost authorship has decreased slightly. (The meeting abstract does not provide data on the statistical significance of these temporal differences.)

The rate of ghostwriting was highest in the NEJM (11%) and lowest in Nature Medicine (2%). The reverse was true for honorary authorship: Nature Medicine, 39%; NEJM, 16%. Ghost authorship was significantly more common with original research articles (12%) than among reviews (6%) or editorials (5%). Honorary authorship was reported frequently with all article types: original research, 31%; reviews, 24%; and editorials, 22%.

The JAMA investigators found no authorship differences between journals that require contribution disclosures and those that do not.

The results of the survey will presumably be published in JAMA at some point in the near future. The anchor author of the abstract, JAMA Editor-in-Chief Catherine DeAngelis, is presumed to be an actual contributing author and not an honorary author.

Duplicity (2009): Who's setting up whommmmm in this lust-love affair between an ex-CIA agent with racehorse legs* (Julia Roberts) and an impossibly hot ex-MI6 agent (Clive Owen)?

Absurdity is the foundation of the ridiculously self-important world of corporate spying between 2 rival conglomerates, each headed up by Paul Giamatti and Tom Wilkinson—and neither of whommmmm gets enough screen time for my taste. Giamatti, in particular, is absolutely flawless when rallying his shareholders.

P.S. Skip the self-congratulatory commentary** with writer/director Tony Gilroy.

* Phrase blatently stolen from somebody.

** Despite the fact that Gilroy denies the commentary is self-congratulatory.

While Elan has another 16 days to rework a buyout deal with JNJ—the new crux of which is the potential rights to the MS drug Tysabri (natalizumab)*—this week's NEJM offers 3 reports on the mAb-associated risk of PML.

Chen et al detected the subclinical reactivation of JC virus (the cause of PML) in 19 patients receiving natalizumab monotherapy. After 12 months of treatment, the prevalence of the virus increased significantly, from 19% to 63%, in urine. After 18 months of treatment, JC virus was detected in 20% (3/15) of plasma samples and in 9 of 15 samples of peripheral mononuclear cells. The shedding of JC virus was associated with a significant drop in the virus-specific cellular response.

Wenning et al describe the rocky, but successful, treatment of natalizumab-associated PML in a 52-year-old woman with MS. After 12 mAb infusions, the patient underwent plasma exchange and immunoadsorption therapy to remove natalizumab. She briefly improved but then developed immune reconstitution syndrome (IRS)—a condition otherwise familiar to HIV docs. Pulsed corticosteroid therapy resulted in clinical stability, followed by improvement.

A similar clinical course is provided by Linda et al, who describe the emergence of PML-consistent symptoms after 14 months of natalizumab treatment. Initially JC virus DNA was not detected in the spinal fluid by means of PCR; however, the virus was detected by quantitative PCR after 16 months of therapy (in association with clinical deterioration). Plasma exchange was performed. Three weeks later, the patient developed IRS; JC virus was no longer detected. Ultimately the patient improved.

The risk of PML with natalizumab therapy appears to depend on the length of therapy—an issue addressed in yesterday's WSJ by Shirley Wang. According to Biogen, the comarketer of Tysabri (along with Elan), there have been 11 cases of PML among 56,500 treated patients since the drug's 2006 reentry into the US market, for a crude, absolute risk of 0.02%.**

But the risk of natalizumab-associated PML appears to increase with prolonged therapy (eg, >12 months)—a fact that necessitates the use of an actuarial calculation (although Biogen disagrees). Wang calculates the actuarial risk of natalizumab-associated PML at about 0.08%. Citing neurologist Robert Fox, she also reports a risk of greater than 0.1% when therapy extends beyond 30 months. 

A quantitative risk-benefit analysis of natalizumab treatment, published last year, indicated that the "actual" risk of PML with the mAb would have to increase more than 7 times to reduce the relative benefit of therapy below that of interferon beta. The authors used an annual PML risk that was based on the published risk estimate of 1 per 1000 patients treated for an average of 17.9 months.

* For the necessary biz background, check out the In Vivo blog and the WSJ blog.

** Biogen actually calculates the absolute risk at about 0.01%, according to the WSJ.

HIV = human immune deficiency virus; mAb = monoclonal antibody; MS = multiple sclerosis; PCR = polymerase chain reaction; PML = progressive multifocal leukoencephalopathy.

NYT science reporter Amy Harmon has neglected to provide important follow-up on Insmed's clinical development of Iplex. In May, Harmon covered the story of Joshua Thompson, a victim of ALS, who was trying to obtain compassionate access to the experimental drug—a synthetic insulin-like growth factor that is linked to a binding protein.

Harmon's unidimensional coverage stressed the cruel fallout of a corporate battle over drug ownership and FDA bureaucracy—both of which, she implied, impeded Thompson's access to Iplex (for important background, go here). And Harmon downplayed the total absence of clinical data (including safety data) to support the use of Iplex in ALS; the promise of the drug lay solely in its theoretical ease of access to the central nervous system and in pumped-up anecdotes found on the World Wide Web. After publication of Harmon's story, Insmed experienced a substantial increase in its share price.

The epilogue of Iplex development, for those who care and remember, can be found by searching Google News and by reading Insmed's press releases. On June 25th, the company reported highly disappointing results from a phase 2 trial of the drug in myotonic dystrophy. Insmed's low-priced stock plunged overnight, from about $2.25 to a dollar.

Then one month later, Insmed announced it would no longer supply Iplex to new patients. The company lost its capability to manufacture the "extremely complicated" drug following the sale of its Boulder, Colorado, facility to Merck (a sale which was announced in March).* Insmed also reported that it would discontinue the drug's clinical development. Specifically a planned phase 2 study of Iplex in ALS would be postponed. (This, after a statement in May, in which Insmed reported that it was "working diligently" with the FDA to "make the necessary preparations" for a US clinical trial of Iplex in ALS.)

Insmed stated that the existing, limited supply of Iplex would be reserved for the 70 currently treated ALS patients (12 in the United States [including Thompson] and the rest in Italy through an expanded access program). The inventory would provide coverage for "no more than 24 months."

In response to the news, the ALS Association issued, in part, the following statement:

The Association encourages the FDA and INSMED to establish partnerships with the ALS community to ensure that the program yields meaningful results that will guide the next steps in determining whether IPLEX is effective and safe for people with ALS.

Based on existing clinical and scientific evidence, The ALS Association cannot encourage or recommend the off-label use of this medication without substantive evidence of its efficacy through a rigorous clinical trial. The ALS Association is continuing to monitor and assess information about IPLEX as it becomes available to provide the public with the most up-to-date reports about its potential for ALS.

Since early August, Insmed can only offer penny stock. The company's pipeline currently consists of 2 molecules, rhIGFBP-3 and INSM-18, which may have antitumor activity. The company hopes to find a corporate partner(s) for their clinical development.

ALS = amyotrophic lateral sclerosis.

* In mid-February, Insmed announced that it was selling its follow-on biologics platform to Merck for $130 million. The money would be used, in part, to finance the clinical development of Iplex. The sale was completed in early April.

The latest WHO update (August 30th) for infections with the novel H1N1 virus indicates more than 254,206 cases globally and at least 2837 deaths, for a crude mortality rate of 1.1%. However, this mortality rate is likely overestimated, because the total number of H1N1 cases is underestimated. Pitfalls in calculating the death rate (or the case-fatality ratio) during the H1N1 pandemic are discussed here.

 

In the United States, there have been 9079 H1N1-related hospitalizations and 593 deaths as of September 3rd, for an in-hospital death ratio of 0.65. Multiplying this value by the hospitalization ratio from April 15 to July 24, 0.114, provides a case-fatality ratio of 0.0075 (or a mortality rate of 0.75%). This case-fatality ratio is unchanged from August 20th.

To Die For

(1995): A very wicked satire from director Gus Van Sant and screenwriter Buck Owens Henry (jeez, what was I thinking?); loosely based on the sad life of Pamela Smart, who recruited her teenage lover to murder her husband in 1990.

Nicole Kidman, as the Smart-ish character, is outstanding in many a truth-y, cringe-worthy scene. Case in point: Her aborted seduction of a cable-access news producer, played by Wayne Knight. But the high school kids—depicted by then-unknowns Joaquin Phoenix, Casey Affleck, and Alison Folland—are the undisputed models of verisimilitude in this flick.

Two days ago, I posted a somewhat snarky response (although this is a blog) to the NYT's expose of Forest's 2004 marketing plan for Lexapro (which was drafted in 2003). Contained within the company's leaked, abridged marketing plan was a proposal to use "reporters" from selected psychiatry journals, including "CNS News"—which was probably meant to be written as "CNS Spectrums"—to cover Lexapro data at major psychiatry meetings. (CNSNews is a conservative, mainstream, online news source.) The reports would be included as supplements in the journal and provide continuing medical education (CME) credit.

CNS Spectrums is a monthly neuropsychiatric journal published by MBL Communications, Inc, which offers some CME-certified articles in conjunction with its accredited partner, the Mount Sinai School of Medicine. The general reputation of the journal among clinicians is that of a "throwaway" publication. To wit, I used to receive unsolicited, free issues of CNS Spectrums by mail; I'd glance at them and then throw them away. Nevertheless the journal, despite its lackluster reputation, is included in the National Library of Medicine's PubMed database.

So as a follow-up exercise (and because I'm slightly nuts), I examined the articles that made it into the supplemental issues of CNS Spectrums during 2004. The objective was to determine to what extent Forest's Lexapro marketers realized their described plan, at least with respect to this particular tactic. My methods consisted of 1) a PubMed search within the confines of the year 2004 and the search term "CNS Spectr"[Journal]; 2) a directed search of the CNS Spectrums web site; and 3) a review of clinical supplements listed at the CNS Spectrums web site.

Here are the results:

At least by my search, there is no evidence that a Forest-sponsored article made it into a supplement of CNS Spectrums during the 2004 calendar year. In 5 cases, however, the supplements could not be accessed by using the search function provided at the publication's web site** or through the PubMed link (when provided). Nevertheless, in these cases, it is unlikely that Forest sponsored the supplements (ostensibly to promote the antidepressant Lexapro), given the designated topics—for instance, Alzheimer disease, antipsychotic use, or bipolar disorder.

There is also no evidence that any of these supplements were certified for CME, given the absence of designated learning objectives and other ACCME-required language. Although in 2 cases, the supplements were supported by an "unrestricted, educational grant" (both from GlaxoSmithKline). Whether any or all of these 2004 articles, all of which have clinician authors, were ghostwritten by "reporters" is just about anybody's guess. 

2004 Supplement	Topic	Sponsor	CME	Faculty Disclosures
February	Rapid-cycling bipolar disorder (panel discussion)	AstraZeneca	No evidence	No
April	Anxiety disorders (panel review)	UCB Pharma	No evidence	Yes
June	Mood and anxiety disorders (4 articles)	GSK	No evidence*	Yes
July	Alzheimer’s disease (5 articles)	No data**	—	—
August	Bipolar disorder in women (1 article)	GSK	No evidence*
August	Antipsychotic-associated hyperprolactinemia (1 article)	No data**	—	—
August	Anxiety disorders (1 article)	No data**	—	—
September	Antipsychotic use (4 articles)	No data**	—	—
October	Psychosis/schizophrenia (4 articles)	No data**	—	—
November	Bipolar disorder (3 articles based on data presented at the 2004 APA meeting)	None indicated	No evidence	No

* Although funded by an "unrestricted, educational grant."
** An "error" occurred when attempting to access the article at the CNS Spectrums web site. The error message advises contacting the web designer, which has the unfortunate name of spinindustry.com.

A review of listed clinical supplements at the CNS Spectrums web site reveals only 1 that was sponsored by Forest: "Bridging the Clinical Gap: Managing Patients with Co-occurring Mood, Anxiety, and Alcohol Use Disorders." Published in April 2008, the supplement consists of 5 articles (including an introduction), none of which appear to offer CME credit. Faculty disclosures are provided with each article, and "editorial assistance" is acknowledged by name (Eileen McGee, Marsha Kellar, and Joyce Waskelo) and company (Hudson Medical Communications, which is described as a promotional firm at the web site of its parent company). The acknowledgement appears to be an attempt at editorial transparency and to undermine accusations of ghostwriting. But given the suspicion that McGee, Kellar, and Waskelo actually drafted the articles, they should have been defined as coauthors.

In the 5 articles, "escitalopram" (ie, Lexapro) is mentioned exactly 4 times in the text bodies and in conjunction with other antidepressants (eg, citalopram [Celexa], fluoxetine [Prozac], and paroxetine [Paxil]).

ACCME = Accreditation Council for CME; APA = American Psychiatric Association.

Just to be different.

Dr. Thomas Frieden of the Centers for Disease Control and Prevention (CDC) conducted this week's broadcasted press conference on the status of the novel H1N1 epidemic in the United States.

Points made.

• The bad news: Novel H1N1 virus is here and spreading, and notably, infection didn't abate during the summer ("very usual"). Expect to see more cases in the coming months.
• The good news: The virus has not mutated, as yet, to become more deadly; and so far, antiviral-resistant strains of H1N1 have not been observed. (See Addendum.)
• The caution: But influenza is unpredictable, and readiness for the worst is imperative.
• The verified data:
  a) There have been 36 pediatric deaths in the United States, details of which are in the latest issue of the MMWR; children with special needs appear to be particularly vulnerable to infectious complications, including death.
  b) Recent experience in the Southern Hemisphere (5 countries) is similar to that in the United States (during the Spring); there have been hospitalization challenges but no increase in the H1N1-related death rate.
  c) The Institute of Medicine (IOM) issued a report today recommending fitted N95 respirators, instead of the typical face mask, for healthcare workers who interact with H1N1-infected patients.*
• The unverified data: A 1-dose vaccine, which was recently approved in China.
• The 2-dose vaccine:
  a) Still expected in mid-October.
  b) To induce effective immunity, 2 doses are anticipated to be necessary.
  c) Recommended groups for vaccination remain the same.
  d) The vaccine itself is free, although administration may not be; the government is in the process of releasing $1.5 billion to enable/facilitate vaccine administration.
  e) Vaccination programs will be run on the local level (eg, state). 
• The upcoming surveillance: For possible adverse events (eg, Guillain-Barre syndrome, miscarriages) associated with vaccination.
• The challenge to safeguard healthcare resources:
  a) Most cases of novel H1N1 infection are mild and don't necessitate laboratory testing or antiviral treatment.
  b) Stay home if you're sick.
  c) Cover your face when coughing or sneezing.
  d) Wash your hands.
  e) Don't go to the doctor unless you're severely ill or have an underlying condition (although it's important to be seen promptly in these cases, so that antiviral therapy can be instituted in a timely fashion [ie, within 48 hours of symptom onset]).
  f) To employers: Don't require a permission note from an employee's doctor before the employee can return to work; in general, telecommuting may be a good idea.

* The IOM was not charged with considering cost, when making its recommendation.

Depiction of H1N1 virus from Wikipedia.

09/05/09 addendum: In its August 12th report, WHO indicated knowledge of 12 cases of disease that is resistant to oseltamivir (Tamiflu; Roche). The mutated virus, however, remains sensitive to zanamivir (Relenza; GSK). Oseltamivir-resistant cases occurred sporadically throughout the world and were apparently not connected. 

Children with underlying medical conditions are particularly vulnerable to complications, including death, due to infection with the novel (2009) H1N1 virus. This conclusion is based on a recent analysis of 36 pediatric deaths that have occurred in the United States due to the virus.* Features of these cases are provided in the latest issue of the CDC's MMWR.

Among the 477 deaths associated with laboratory-confirmed novel H1N1 virus in the United States (as of August 8), 36 (7.5%) have occurred in persons younger than 18 years of age. The age breakdown of the pediatric victims is as follows:

Age	Percentage Affected
0-6 mos	6
6-23 mos	8
24-59 mos	6
5-8 y	14
9-12 y	36
13-17 y	30

Most of the children (67%) had at least 1 "high-risk" medical condition (eg, respiratory, cardiac, or neurologic condition), and 92% of these children had neurodevelopmental conditions (eg, developmental delay, cerebral palsy).

A substantial percentage (43%) with culture or pathologic data (n = 23) had bacterial coinfections; among these 10 children, 6 were 5 years of age or older and had no high-risk comorbidities. Confirmed bacterial pathogens were Staphylococcus aureus (3/5 of which were methicillin resistant), Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus constellatus. All pathogens were community acquired, according to the CDC's Thomas Frieden (at today's broadcasted press conference; see today's follow-up post).

The median duration of illness, from symptom onset to death, was 6 days (range, 1-28 days). One half of pediatric victims were male; one third were Hispanic.

Among 31 children for whom data were available, 19 (61%) received antiviral treatment; but only 4 received treatment within 2 days of symptom onset. Just over half (13/25) of the children had received at least 1 inoculation against the 2008-2009 seasonal H1N1 virus.

The MMWR article also provides pediatric-death data from previous influenza seasons; however, the editors advise caution when comparing seasonal death data because of possible differences in case ascertainment and differing sensitivities of laboratory tests (particularly rapid H1N1 tests). In addition, comparisons of seasonal data are highly limited during an ongoing epidemic/pandemic. 

Influenza Season	US Pediatric Deaths	Percentage With High-Risk Medical Condition
2003-04	153	47
2004-05	47	55
2005-06	46	48
2006-07	73	35
2009 H1N1	36	67

The CDC editors stress the importance of pneumococcal vaccination in children, particularly in very young children with high-risk medical conditions, and the benefit of antiviral treatment in persons who are hospitalized for novel H1N1 infection, even when treatment is started 48 hours after symptom onset. Empiric antibacterial therapy should be directed at S. aureus, S. pneumoniae, and S. pyogenes. 

* The conclusion is not unexpected, given that complications due to seasonal influenza are increased in very young children (<5 years of age) with certain chronic medical conditions.

And gambling occurs in casinos.

Yesterday Gardinar Harris of the NYT revealed that Forest Laboratories, the maker of the antidepressant escitalopram (Lexapro), had a 2004 marketing plan for the drug. Harris's article,* which is made possible by government access to a previously confidential document from Forest, seems intended to generate a considerable amount of righteous indignation. But a review of the abridged plan, which is made available here, reveals nothing more than the usual strategies and tactics by pharma to achieve or maintain a drug's market share—objectives that are, in fact, a company's responsibility to its shareholders. Frankly if Forest's marketing team, circa 2003, is to be publicly chided, it should be for lack of originality.

The not-so-surprising subtext of the marketing document, which contains the expected SWOT analysis (or a version of it), is to obtain the best-of-all-possible fiscal worlds for Lexapro and Forest. One strategy or tactic for doing so (depending on how you define each term) was to "increase med ed efforts," including more sponsorships of continuing medical education (CME).** Proposed CME efforts included plans to sponsor various professional-meeting symposia, summaries of these symposia, and scientific sessions. Nothing outside of the ordinary or, more important, in violation of standards for commercial support of CME (either then or now).

The description of the proposed goal and purpose of CME is similarly banal:

[To] Sponsor the development of continuing medical education activities that will educate physicians and other healthcare providers and assist them in acquiring the most current knowledge in the diagnosis and treatment of depression and other related disorders.

Perhaps the only proposed CME tactic to raise an eyebrow is the use of reporters "from publications like CNS News [probably CNS Spectrums], Psych Times, and the Journal of Clinical Psychiatry...to cover key Lexapro data presented at important medical meetings." The report would then be included in the journal as a CME supplement.

Overt (non-CME) marketing methods in the Forest document included the use of bylined medical articles from thought leaders, some of which could be ghostwritten; the typical speakers' bureau; and drug rep-presented "Lunch and Learn" programs for doctors.

Whether any or all of Forest's 2003 marketing plan for Lexapro came to fruition is not addressed by Harris. It is presumed that at least some of it was realized; but what was and what wasn't funded is probably only known to Forest personnel—at least at present.

* One of Harris's points is to show how Forest promoted (or intended to promote) escitalopram as superior to its other antidepressant citalopram or Celexa, which was going off patent--despite the fact that Lexapro is merely an enantiomer (or chemical mirror image) of Celexa. The tactic of creating an enantiomer of a successful, but soon-to-expire, drug to maintain pharma revenue is nothing new: think omeprazole (Prilosec) and esomeprazole (Nexium), both from AstraZeneca.

** The fact that Forest included CME in its marketing plan 6 years ago may be shocking to some, but it shouldn't be. In the current climate of scrutiny, however, major pharma companies separate their proposed CME and marketing efforts.

A novel antiplatelet drug, ticagrelor, from AstraZeneca delivered a knockout punch to uber-drug clopidogrel (Plavix; BMS/sanofi-aventis) in a phase 3 study of patients with acute coronary syndrome (ACS). Results of the head-to-head trial were presented Sunday at the ongoing congress of the European Society of Cardiology (ESC) in Barcelona. Trial specifics were simultaneously published online in The New England Journal of Medicine.

Both ticagrelor, trade named Brilinta [oy], and clopidogrel belong to the thienopyridine class of oral antiplatelet agents; although ticagrelor, unlike clopidogrel, is a reversible inhibitor of the P2Y12 receptor on platelets. (Read on for the importance of this distinction.)

The international AZ-sponsored trial, abbreviated PLATO, enrolled 18,624 patients with ACS* who received randomly assigned ticagrelor (180-mg loading dose followed by 90 mg bid) or clopidogrel (300-600-mg loading dose followed by 75 mg qd). (Before randomization, the overwhelming majority patients had received aspirin, and about half had received clopidogrel. During the trial, everybody got aspirin, 75-100 mg/d.) The average treatment time was 278 days (range, 6-12 months), and the follow-up rate was phenomenal—better than the purity of Ivory soap: 99.97%.

Rates of the composite primary endpoint—MI, stroke, or cardiovascular death—were 9.8% with ticagrelor and 11.7% with clopidogrel. The outcome amounts to a statistically significant relative-risk reduction of 16% with ticagrelor. Moreover, investigators observed a statistical difference between the 2 drugs at 30 days of treatment. Rate differences for several secondary endpoints, including MI or cardiovascular death, also favored ticagrelor. However, both drugs performed similarly with respect to the isolated outcome of hemorrhagic or ischemic stroke (1.5% vs 1.3%).

The ho-hum stroke outcome may have something to do with the relatively reduced risk of stroke in patients with ACS (vs the stroke risk in patients with a history of stroke). There is also the possibility that some thienopyridines aren't particularly great at preventing stroke, at least in some patients.** For instance, in the mammoth pivotal trial for clopidogrel (published way back in 1996), the drug edged out aspirin with respect to the composite outcome of ischemic stroke, MI, or vascular death in at-risk patients; however, clopidogrel was no better than aspirin in the post-hoc analysis of a stroke-only outcome. Most of the overall protective benefit of clopidogrel in this study was observed in patients with peripheral arterial disease. (Although clopidogrel is still recommended as first-line therapy for preventing recurrent stroke.) 

With respect to overall major bleeding, rates with ticagrelor and clopidogrel in the PLATO trial were similar (11.6% and 11.2%). But major bleeding in a non-CABG context was higher with ticagrelor (4.5% vs 3.8%; P = .026). Dyspnea was also more frequent with ticagrelor (14.2% vs 9.2%) and led to the discontinuation of the drug in 1% of treated patients.

In addition to outperforming clopidogrel on efficacy measures, ticagrelor has the advantage of not being a prodrug—meaning that metabolic conversion is not necessary to achieve antiplatelet activity. Consequently ticagrelor is faster acting than clopidogrel. And because ticagrelor is a reversible inhibitor of platelets, its activity wears off more rapidly than that of clopidogrel. This property enables emergent CABG, should the procedure be necessary in ACS patients who don't respond to coronary stenting. (However, rates of major bleeding during CABG were not significantly different between the 2 drugs [7.4% vs 7.9%] in the PLATO trial). The downside of ticagrelor is its twice-a-day administration. 

In the United States, clopidogrel goes off patent in 2011 (according to the LA Times); there's also a recent history of several foreign generics encroaching the market.

CABG = coronary-artery bypass grafting; PLATO = PLATelet inhibition and patient Outcomes.

* With ST-segment elevation intended for primary percutaneous coronary intervention (PCI) or without ST-segment elevation intended for invasive or medical management.

** Very recent data indicate that clopidogrel's activity is reduced in patients who are poor metabolizers of the drug (ie, those patients with genetically reduced function of CYP2C19, a P450 component). The genetic variant is associated with the reduced inhibition of platelet aggregation and an increased risk of cardiovascular events or death. About 30% of the population have the CYP2C19 variant.