March 2008 Archives

Despite all the press attention dedicated to the ENHANCE study results, which were finally presented at the ACC's annual meeting and printed in the NEJM yesterday, there's been little-to-no mention of the "missing" or "implausible" ultrasound data that were revealed originally in Schering-Plough's study timeline from January. The effect of these missing or implausible data on the validity of study has now been, in essence, inexplicably ignored. (See previous Pathophilia entries on the ENHANCE study here and here.)

The NEJM article devotes exactly one sentence to the subject:

The exclusion from the statistical analyses of patients with missing data or biologically implausible measures of the carotid-artery intima-media thickness (defined as a difference of >0.1 mm between visits) did not change the primary or secondary outcome results (data not shown).

Ok, the exclusion of these data, the volume of which is not provided, did not change the negative study outcomes. However, if the numbers of patients with missing or implausible data are considerable—and the S-P timeline suggests that they were*—they could very well undermine the validity and/or statistical power of the ENHANCE study and any subgroup analyses that might otherwise reveal significant treatment differences.

The authors do consider that the ultrasound measurement technique that was used to assess arterial intima-media thickness may not accurately reflect changes in atherosclerotic burden; but they dismiss this consideration on the basis of the precision of the measurements, "as exemplified by the high intraclass correlation coefficient and the small standard deviations." However, this explanation only addresses the use of arterial intima-media thickness as a surrogate marker for atherosclerotic burden; it is not relevant to the plausibility of the specific thickness measurements obtained by the ENHANCE study investigators and certainly doesn't address missing data.

In an accompanying NEJM editorial, Drazen et al write, "Only with the full data set and an independent analysis on the scientific record is it possible to properly interpret the trial and formulate follow-up studies to further pursue the intriguing but puzzling results." Amen. But neither of the 2 NEJM editorials that discuss the ENHANCE study mention the missing or implausible data and their potential effect on the trial's results.

Update: In its coverage of the ENHANCE study presentation, heartwire talked to Roger Blumenthal, MD, of Johns Hopkins, who said that 2 limitations "bias ENHANCE toward the null." One is that ENHANCE investigators did not consistently measure carotid intima-media thickness during cardiac contraction (ie, they did not use ECG gating), a method often employed to control the variability of images. The other limitation is that investigators "used single-frame technology instead of putting the images on a cine loop," which would have improved image quality. These comments imply that a sizeable percentage of the ENHANCE study images were, in fact, suboptimal and therefore undermined the validity of the study results.

*These are the data believed to have delayed the publication of the ENHANCE study results in the first place.

Photo: iStockPhoto

According to Fox News, the FBI has shortened its list of suspects who perpetrated the 2001 "anthrax letter attacks" to about 4, and 3 of those suspects are scientists with links to the bioweapons research facility at Fort Detrick, Maryland (USAMRIID). The 3 USAMRIID suspects are described as a former deputy commander, a leading "anthrax" scientist, and a microbiologist, whose writing samples have been obtained by the FBI. The current short list apparently does not include former "person of interest" and USAMRIID scientist Steven Hatfill.

It is presently believed that the attacks were perpetrated by placing a "weaponized" powder version of Bacillus anthracis, which was taken from Fort Detrick, inside the mailed letters. Fox News obtained an e-mail (the date of which was not provided), in which USAMRIID scientists discussed how the B. anthracis powder that was provided by the FBI for analysis was "nearly identical" to that made by a colleague, whose name was deleted from the e-mail.

The B. anthracis strain identified in the 2001 anthrax attacks belongs to the Ames strain, and its genotype (62) indicates that it was originally obtained from a dead cow in Texas in 1981. According to leading B. anthracis investigators, the Ames strain is now apparently rare in nature but is in widespread use in laboratories. Consequently it is believed that the strain of the 2001 anthrax attacks was obtained from a laboratory involved in B. anthracis study.

The big trick in the investigation has been to narrow the attack strain to a single laboratory—a very big trick, since B. anthracis generally and the Ames strain specifically are highly genetically conserved. Just last year, B. anthracis expert Paul Keim and colleagues at Northern Arizona University published their identification of 6 single nucleotide polymorphisms* (SNPs) that merely distinguish the Ames strain from other B. anthracis strains, including close genetic relatives.

However, in a March 18 letter to the Letters in Applied Microbiology, the same investigators reported that they were able to identify 6 distinct genotypes of a single B. anthracis clone (obtained from a 2005 outbreak in South Dakota) by using 4 highly mutable single nucleotide repeat (SNR) markers. SNRs are variable-number tandem repeats in the DNA sequence that exhibit very high mutation rates. The authors concluded, "SNR markers are powerful tools for detailed tracking of natural B. anthracis outbreaks and could also prove useful in forensic investigations."

It seems logical that investigators would be using (or have used) SNR markers in an attempt to subtype various Ames strain isolates from different laboratories.

*Six SNPs were highly specific for the Ames strain: 4 were on the chromosome; 1 was on the pX01 plasmid; and 1 was on the pX02 plasmid.

Like its precedessor All About Eve, 1957's Sweet Smell of Success highlights the negative symbiosis between those who must have publicity and those who must craft it. The fact that Burt Lancaster delivers a historical performance as a Walter Winchell-like gossip columnist, J. J. Hudsucker, is no surprise. But who knew that Tony Curtis could hold his own as the slimy press agent Sidney Falco? The scenes between the two in Hudsucker's hangout, New York's 21 Club, are acting knockouts. Clifford Odets takes part of the screenwriting credit along with Ernest Lehman, who wrote the novella.

What's worse than sexual harassment? Why, child pornography, for one thing.

Blazing through the blogosphere is the news that Pfizer's 61-year-old global patent director, Alan Hesketh, was charged Wednesday with receiving, distributing, and possessing child pornography. Hesketh, a UK citizen and permanent US resident, allegedly did all of this while posing online as a 28-year-old woman ("Suzibibaby") and chatting and trading images with Gregory Nadolski of Buffalo, NY, between June 2006 and May 2007. One Internet address that Hesketh used for these activities, according to news reports, was registered to Pfizer in NYC. Hesketh is reportedly on leave from the company and being held without bond by federal authorities.

From The Boston Globe by way of the WSJ Health Care blog:

In a mildly curious case of media weirdness, the Bay Area's ABC news affiliate recently caught Scott Harkonen, the indicted former InterMune CEO, on tape offering his opinion about which Presidential candidate should receive California's vote. For what it's worth (and can that be much?), Harkonen* thinks pretty strongly that the CA vote should go to the candidate with the most delegates. Well, o-kay.

*If Harkonen's demeanor on camera is any indication, he's taking the indictment with equanimity.

Low-dose lithium may slow the progression of amyotrophic lateral sclerosis (ALS), according to an Italian pilot study published in the February 12 issue of PNAS. The trial results have prompted US investigators to design a multicentered clinical trial of lithium in ALS, according to the latest issue of Neurology Today.

The Italian investigators conducted a parallel-group, randomized trial* of Carbolithium (lithium carbonate) 150 mg bid in 44 patients with nonfamilial ALS (disease duration, <5 years). All patients received Rilutek (riluzole; sanofi-aventis) 50 mg bid (the only agent that is FDA approved for the treatment of ALS). The lithium dosage for those who received the medication was adjusted by an unblinded physician to achieve a plasma level of 0.4-0.8 mEq/L (Therapeutic lithium levels in bipolar disorder have traditionally been 0.8-1.5 mEq/L).

At 15 months, all patients who received lithium (n = 16) were alive, whereas approximately 30% of patients who only received riluzole did not survive. Survival rates between the 2 groups were significantly different at 12 and 15 months. Use of lithium was also associated with the reduced progression of clinical disease, as determined by measures of physical disability and pulmonary function.

Use of lithium in ALS is based on its effects in a mouse model (also described in the study), which showed improved survival, delayed motor dysfunction, and the relative preservation of lumbar motor neurons and their associated interneurons (ie, Renshaw cells). In the mouse model, lithium reduced the motor-neuron changes that are seen in ALS (eg, accumulation of alpha-synuclein, ubiquitin, and SOD1 aggregates and vacuolization due to mitochondrial swelling) and promoted neuroprotective autophagy, which is believed to be deficient in the disease.

SOD1 = superoxide dismutase 1.

*As far as I can tell, the study was not placebo controlled.

From the gray panthers of the AARP by way of Bloomberg by way of PharmaGossip: Nothing new—just drug companies continue to make up for slowing prescriptions and less-than-promosing pipelines by jacking up the costs of their existing meds.

According to the AARP's latest "Rx Watchdog Report," increases in manufacturers' prices of 23 of the top 25 brand-name prescription products during 2007 outpaced the rate of inflation (2.9%) by as much as 25%. Pfizer appears to be one of the biggest offenders with 5.0% increases in the cost of its Lipitor (atorvastatin) products, an 8.7% increase in the cost of Celebrex (celecoxib) 200 mg, and 11.5% increases in the cost of Norvasc (amlodipine) tablets. However, the annual change in the cost of sanofi-aventis's Ambien (zolpidem tartrate), at 27.7%, outpaced that of Norvasc by more than more than 15 percentage points.

Sales Rank	Product	Manufacturer	Change in WAC, %
21	Zocor 20 mg	Merck	0.0
24	Zocor 40 mg	Merck	0.0
2	Plavix 75 mg	BMS	0.5
3	Prevacid 30 mg DR	TAP	5.0
5	Lipitor 20 mg	Pfizer	5.0
6	Lipitor 10 mg	Pfizer	5.0
11	Lipitor 40 mg	Pfizer	5.0
4	Protonix 40 mg	Wyeth	5.2
1	Nexium 40 mg	AZ	5.3
16	Singulair 10 mg	Merck	5.8
15	Namenda 10 mg	Forest	5.9
8	Fosamax 70 mg	Merck	6.2
18	Zetia 10 mg	Merck/SP	6.5
19	Lexapro 10 mg	Forest	6.9
7	Aricept 10 mg	Eisai	7.0
25	Avandia 4 mg	GSK	7.5
12	Actonel 35 mg	P&G	8.1
14	Celebrex 200 mg	Pfizer	8.7
10	Advair Diskus 250-50	GSK	8.8
23	Seroquel 200 mg	AZ	9.1
20	Lantus 100/mL	sanofi-aventis	9.4
17	Flomax 0.4 mg	BI	11.2
9	Norvasc 10 mg	Pfizer	11.5
13	Norvasc 5 mg	Pfizer	11.5
22	Ambien 10 mg	sanofi-aventis	27.7

In fact, the cumulative percentage increase in the cost of Ambien, from 2002 to 2007, was nearly 160%. Less dramatic, but still impressive, cost increases during this time period were those for GSK's Advair Diskus (53.0%), Merck's Fosfamax (39.9%), Eisai's Aricept (37.1%), AstraZeneca's Nexium (33.0%), and Pfizer's Lipitor (32.2%).

P.S. Dumbledore is dead...and may have been gay. 

WAC = wholesale acquisition cost.

While watching "Dancing With the Stars" (yes, color me bust-ed), the Pathophilia blog came to wonder why it is that Priscilla Presley doesn't or can't smile. Is the King's ex-wife that demure by nature? Or did the woman—whose current face (and I mean this in the nicest possible way) looks like it was molded by a new hire at Madame Tussauds—actually get Botox injected into her nasolabial folds? Possible...

But further inquiry leads to medical resource TMZ (read here and here), where it is revealed that Argentinian doctor Daniel Serrano scammed a whole slew of Hollywood celebs not too long ago, including Presley, by offering them facial injections of an "all-natural" anti-wrinkle "serum" that was touted to be better than Botox. 

Unfortunately none of the women, who must have been unbelievably desperate to achieve and/or maintain faux youth, bothered to determine if the doc was licensed in the United States or what the so-called serum actually was. Turns out that what Serrano (who, BTW, was never was licensed to practice in the US) injected into their faces was an industrial-grade lubricant silicone, according to the gossip website. In some cases, TMZ reports, Serrano's injections caused lumps, paralysis, and "holes."*

But even further investigation by the P blog reveals that all of this information is really old news (and may have nothing to do with how Presley's face looks now). Reports from way back in 2004 revealed that Diane Richie (then estranged wife of Lionel) was charged in November of that year with aiding and abetting Serrano, while he used her Beverly Hills home at various times from July to December of 2003 to administer costly injections of what he claimed was the European-approved collagen filler Artecoll,^† but what was really (in some cases) the aforementioned silicone. Serrano was charged with 4 counts in connection with the repeated administration of these injections.

A 2006 Los Angeles CBS news report reveals that Serrano was subsequently sentenced to 18 months in federal prison on charges related to the illegal injections, after he pleaded guilty in 2005 to conspiracy, receipt of illegally imported merchandise, and receipt of an adulterated device in interstate commerce. According to a San Francisco Chronicle article, Serrano, as part of a plea agreement, admitted to giving the illegal injections from 2001 until November 2004 and earning more than $1.6 million for his efforts, according to court papers. (TMZ writes that the guy only accepted lump sums of cold, hard cash from his gullible victims.) 

Serrano's "clients" included Diane Richie, Lionel Richie, and Shawn King (Larry King's wife). King, who also hosted "injection parties" for Serrano (although she was evidently not charged like Ms. Richie), claimed that she developed a "lump" in her lip from the injections, and Beverly Hills resident Ellen Levinthal is the unfortunate woman who experienced the reported facial "holes," according to the report. Presley, very notably, was not mentioned in these contemporary news reports.

*Hey, facial lumps and paralysis I could deal with, but holes?

†Artecoll, aka ArteFill, is an 80-20 mixture of purified bovine collagen and polymethylmethacrylate (PMMA) microspheres (aka Plexiglass beads). ArteFill was not approved by the FDA until October 27, 2006—well after Serrano's alleged use in the United States. The product is indicated for the correction of nasolabial folds.

Photo: "Dancing With the Stars"

Prompted by the DoJ's indictment of former InterMune CEO Scott Harkonen, the Pathophilia blog correlates the chronology of events in the company's history with the firm's volatile share price. Specifically Pathophilia highlights the period from 2002 to 2006 (see graph below, in which numbered circles correspond to events in the provided chronology), when shareholders' highs and lows were informed respectively by InterMune's initial spin of Actimmune's survival data in idiopathic pulmonary fibrosis (IPF) and the follow-up peer review of the same data.

The exercise provides several lessons:

• First, if at all possible, a drug company's financial welfare should not rest solely on the sale of one product.
• Second, if at all possible, a drug company's financial welfare should not rest solely on the sale of one product for an off-label use. 
• Third, if at all possible, a drug company's financial welfare should not rest solely on the sale of one product for an off-label use, for which the data are preliminary or insufficient. 
• Fourth, the favorable spin of a phase 3 trial that fails to meet its primary endpoint cannot be sustained—particularly in the current press climate.
• Fifth, leading academic investigators can get fully sucked into a company's press spin.
• Sixth, when high-level execs abruptly leave a company to "pursue other opportunities," get the hell out (of the company and/or your investment in it).
• Last, we're all a bunch of schnooks who invest in markets that are likely routinely manipulated by inside information.

InterMune Chronology

February 1998: Wesley Scott Harkonen, MD,* founds InterMune, a spin-off of biotech firm Connetics, in California. Harkonen will serve as president and CEO of the company, which will market and sell Actimmune (interferon γ-1b) through a licensing agreement with Genentech. Actimmune was FDA approved in 1991 for the treatment of chronic granulomatous disease.

August 1999: InterMune submits a biologic license application (BLA) to the FDA for the fast-track approval of Actimmune for osteopetrosis.

October 1999: The NEJM publishes a 12-month, open, randomized trial of Actimmune vs prednisolone alone in 18 patients with medically refractory IPF. Use of Actimmune is associated with improved pulmonary function (eg, increased total lung capacity, pO2) in the 9 patients who received it, suggesting that further study is warranted.

November 1999: Harvard Business School grad Timothy P. Lynch is hired as CFO of InterMune.

January 2000: Harkonen is named Chairman of the Board of InterMune.

February 2000: Actimmune is approved by the FDA to delay the time to disease progression in patients with severe, malignant osteopetrosis. David Cory joins InterMune as VP of sales.

March 2000: InterMune is incorporated in Delaware in conjunction with its IPO, at which time InterMune share price rises 25% from the initial offer of $20.

April 2000: GIPF-001, a randomized, double-blind phase 3 study of Actimmune vs placebo in 330 patients with corticosteroid-refractory IPF, is initiated.

December 2000: The share price of InterMune has risen 136% since its March IPO. InterMune's only revenue comes from sales of Actimmune, which amounted to $11 million for the year 2000. The "vast majority" (>90%) of Actimmune sales are for the off-label treatment of IPF.

August 2001: Shares of InterMune are up 12% from the previous year and up 50% during the last 6 months.

December 2001: Revenues from the sale of Actimmune for the year 2001 total $36 million and make up 91% of InterMune's total revenues. Joan Gallagher joins InterMune as a sales rep.

January 2002: Biotech stocks fall sharply, including InterMune's share price. The WSJ blames the free fall on profit taking after the previous month's gains. David Cory is promoted to senior VP of sales.

May 2002: CFO Lynch resigns for reasons unexplained in the press (1). Sharon Surrey-Barbari, a former Gilead exec, is hired as InterMune's new CFO.

08/16/02: Initial results from the GIPF-001 trial indicate that Actimmune fails to improve progression-free survival (the primary endpoint) in patients with IPF. Harkonen directs a post-hoc subgroup analysis of the GIPF-001 data, which produces a statistical trend toward a survival benefit in those patients with mild-moderate disease.

08/27/02: Harkonen and other InterMune employees meet with the FDA's medical review staff, who advise that the current Actimmune data are insufficient to garner approval of the drug for IPF.

08/28/02: InterMune releases a press document touting the results of GIPF-001 (2): "InterMune Announces Phase III Data Demonstrating Survival Benefit of Actimmune in IPF." The subtitle reads, "Reduces Mortality by 70% in Patients with Mild to Moderate Disease." Lead investigator Ganesh Raghu, MD, of the University of Washington, is quoted in the press release, "The mortality benefit is very compelling and represents a major breakthrough..."

08/29/02: The WSJ questions the validity of InterMune's data dredging of GIPF-001. Harkonen projects $100 million in annual sales of Actimmune.

10/24/02: During the Q3 earnings call, InterMune's head of medical affairs indicates that the phase 3 data from GIPF-001 will be submitted for peer review "within the next 4 to 8 weeks."

11/05/02: Follow-up data from the small NEJM study, presented at the annual CHEST conference, suggest that Actimmune favorably affects long-term survival. However, the presentation of the GIPF-001 data at the same meeting is "ambiguous and difficult to interpret," according to a later quote from Harkonen, and the reaction to the presentation is "largely mixed," according to a follow-up Wachovia Securities analyst report (3). 

December 2002: Revenue from the sale of Actimmune for the year 2002 totals $106 million and makes up 94% of InterMune's total revenue.

01/02/03: InterMune releases follow-up data from the GIPF-001 trial, which now show that the relative survival benefit with Actimmune is less apparent than initially presented (4). InterMune initiates the INSPIRE trial, a randomized, double-blind, placebo-controlled trial of Actimmune in patients with mild-moderate IPF. 

01/30/03: David Cory, who was largely responsible for pushing the sales of Actimmune, abruptly resigns from InterMune to "pursue other opportunities," writes Adam Feuerstein of thestreet.com.

04/01/03: Four case reports of acute respiratory failure are associated with Actimmune treatment of IPF in the American Journal of Respiratory and Critical Care Medicine. An editorial accompanying the report, "A dark side of interferon-gamma in the treatment of idiopathic pulmonary fibrosis?" questions the safety of the agent (5).

04/27/03: The NYT prints "Talking up a Drug for This (and That)," which highlights the off-label sales of Actimmune, the controversy surrounding the drug's efficacy for IPF, and the annual cost of the drug (~$50,000) for an individual patient (5). In the article, Harkonen denies that InterMune markets the drug for IPF.

06/11/03: InterMune issues a revenue warning owing to lower-than-expected sales of Actimmune (6).

06/12/03: In response to the revenue warning, Adam Feuerstein writes "Credibility Crisis at InterMune," which reveals that InterMune "admits that demand for Actimmune is flat because doctors have concerns about the equivocal nature of the data supporting Actimmune use in IPF patients." In addition, it is revealed that "InterMune has done a lousy job of managing Actimmune inventory" (6).

06/13/03: Gallagher is fired from InterMune (6).

06/30/03: Harkonen resigns as president and CEO of InterMune (6). William Ringo takes over as interim CEO.

09/25/03: Daniel Welch is named new CEO of InterMune (7). Harkonen resigns from the Board.

01/08/04: The NEJM publishes the results of GIPF-001, in which Actimmune did not significantly affect progression-free survival, pulmonary function, or quality of life, when compared with placebo (8). Ganesh Raghu, who was quoted in the August 2002 InterMune press release, is the lead author of the article.

01/22/04: James Pennington, MD, executive VP of medical and scientific affairs leaves InterMune to "pursue other opportunities." CEO Welch acts as head of R&D until a replacement can be found.

03/12/04: Ex-rep Gallagher files a wrongful-termination suit against InterMune, former CEO Harkonen, James Shaffer (national sales director), and Chad Patton (regional sales director). Gallagher alleges that she was fired after refusing to promote Actimmune off label (9).

08/23/04: Shareholders file a class-action lawsuit against InterMune, former CEO Harkonen, and CFO Surrey-Barbari, who "knowingly, or with deliberately reckless ignorance, made false and misleading statements regarding...Actimmune." Consequently it is alleged that the share price of InterMune stock was artificially inflated during the class-action period. 

11/09/04: InterMune receives a DoJ subpoena to investigate the promotion and marketing of Actimmune (10).

12/31/05: For the year, Actimmune accounts for 100% of the company's product revenue.

05/09/05: InterMune reaches a preliminary settlement with shareholders for $10.4 million (11).

04/18/06: InterMune completes enrollment of the phase 3 INSPIRE trial of Actimmune in mild-moderate IPF.

10/01/06: InterMune pays $37 million to the government to settle the probe of its promotional activities related to Actimmune (12). The wrongful-termination suit filed by Gallagher is settled for an undisclosed amount.

03/09/07: InterMune terminates the INSPIRE trial, after an interim analysis shows no survival benefit with Actimmune. Further clinical study of Actimmune in IPF is abandoned. 

*From September 1995 to April 1999, Harkonen served as senior VP of product development and operations at Connetics. Harkonen graduated from the University of Minnesota medical school in 1977 and has held a valid California medical license since June 1981. According to the AMA web site, Harkonen has received board certifications in internal medicine and allergy and immunology. He is also reported to have received an MBA from the Haas School of Business at the University of California at Berkeley. Harkonen is currently president and CEO of CoMentis.

Based on Ambrose Bierce's short story of a condemned Rebel soldier, An Occurrence at Owl Creek Bridge is a film-school staple, demonstrating the masterful manipulation of time in storytelling.

They turned the country up on its side, and everything loose fell into California.

———Frank Lloyd Wright (attributed)