Ethics: March 2008 Archives

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.

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.

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

———Frank Lloyd Wright (attributed)

The Pathophilia blog lost its most recent breakfast, lunch, and dinner after reading today's NYT article on the rejection of vaccination by some terribly misguided parents, who happen to live in (shock of shocks) California. Probably most disconcerting is the photo accompanying the story, in which San Diego vaccine rejectionists Linda Palmer, Julie Chiariello, and Sybil Carlson look so damn shiny, happy, and casually Californian while putting their and other children at risk for potentially deadly infectious diseases.

To America's misfortune, these clueless women have bred (why yes, I am a harsh bitch, but justifiably so) and have elected to eschew vaccinations for their kids on the basis of a "personal-belief exemption" to California law that otherwise requires routine inoculations. This is an exemption that is separate from, more or less, a religious exemption to vaccination. Electing to take the personal-belief exemption—which is surprisingly easy in some states—is often based on the not-just-unfounded, but disproven, idea that vaccination increases the risk of autism.

The problem with the terribly misguided public policy of allowing personal-belief exemptions is that, not only are the vaccination-exempt children susceptible to illness, they pose an infectious risk to children too young to receive vaccines and to those children who have already been vaccinated. The NYT article points out that the measles vaccine, as an example, is not 100% effective at preventing the disease.

This fact was recently illustrated when 2 measles-vaccinated college students in Texas contracted the disease from a traveling sales rep who acquired the infection from a Japanese player at last year's Little League World Series in Pennsylvania. In 1989 and 1990, a measles outbreak in San Diego affected hundreds of children and caused 3 deaths; all of the children who became ill were either unvaccinated or too young to be inoculated. The San Diego outbreak is a sober reminder that measles is not necessarily a benign childhood illness.

According to the Johns Hopkins Institute for Vaccine Safety, 48 states allow religious exemptions to vaccination (Mississippi and West Virginia do not, and I'll never say anything bad about either state again), and 21 states allow for personal-belief exemptions as of January 2007 (the parade of state shame is provided below and, sadly, doesn't merely include our loopy western states). The distinction between religious and personal-belief exemptions is downright murky, as the latter can include "religious, philosophical, and any other unspecified nonmedical exemption." Also a religious exemption to vaccination can be taken on the basis of a personal belief that is not necessarily religiously founded, as in Maryland.

States That Allow Personal-Belief Exemptions to Vaccination: Arkansas, Arizona, California, Colorado, Idaho, Louisiana, Maine, Michigan, Minnesota, New Hampshire, New Mexico, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Texas, Utah, Vermont, Washington, and Wisconsin.

The ease with which a personal-belief exemption can be taken varies widely from state to state. According to a 2006 JAMA study, a California parent simply has to sign a prewritten statement on the school immunization form, and signing this form is much easier than filling out the immunization record, which typically requires the assistance of a health care professional. In other states, taking the personal-belief exemption is more difficult and requires "a signature from a local health department official, annual renewal, notarization, or a personally written letter from the parents explaining the reasons for vaccine refusal."

Not surprising, the rates of nonmedical exemptions are higher in states that permit personal-belief exemptions and higher still in those states that easily grant the exemptions. The danger of providing personal-belief exemptions and their easy access is demonstrated in the JAMA study, which found that the incidence of pertussis* (ie, whooping cough) in states allowing personal-belief exemptions is more than 2 times the incidence in states allowing only religious exemptions. The incidence of pertussis in states granting easy access to a personal-belief exemption is 90% higher than that in states with more difficult procedures to become exempt. The study defines the following states as providing easy access to exemption (but these states do not all provide personal-belief exemptions): Alaska, Arizona, California, Hawaii, Idaho, Maryland, Michigan, Missouri, Oklahoma, Oregon, Pennsylvania, Rhode Island, Vermont, Washington, and Wisconsin.

Other horrifying information from the NYT article is the hosting of disease parties by anti-vax parents, where their unvaccinated children are exposed to viruses like varicella or measles (presumably from an already sick child in attendance) in an effort to develop natural immunity. I have no idea why this activity doesn't constitute child endangerment. To justify the parties, Linda Palmer gives the following eye-rolling quote to the NYT, which was no doubt delivered with all the insensible calm that befits it: "It is a very common thing in the natural-health oriented world." (So is mumps orchitis, but try explaining that to your boy.) Palmer, however, decided against sending her son to a measles party, with the excuse that she feared her son would be ostracized if he became ill, not that she feared her son would become ill.

Even more disturbing is the tolerance of an anti-vaccination attitude by some physicians. The NYT interviewed San Clemente pediatrician Robert W. Sears, who admitted that vaccination should not be mandated. He acknowledged that approximately 20% of his patients are not vaccinated and that another 20% are only partially vaccinated. With statistics like those, it behooves Sears to post infectious-disease warnings in his waiting room.

One issue not addressed in the NYT article is that of liability, should a vaccinated child or a child too young to receive vaccination acquire a preventable infection from a child who has not been vaccinated on the basis of a personal-belief exemption.

*If only I could mandate that Linda Palmer, Julie Chiariello, Sybil Carlson, and like-minded parents watch this video on a loop until they come to their senses.

Yesterday, San Luis Obispo Superior Court Judge Martin Tangemen dismissed 2 charges against transplant surgeon Hootan Roozrokh in the failed attempt to harvest Ruben Navarro's organs in Februay 2006, according to the San Luis Obispo Tribune. Roozrokh will stand trial by jury for dependent-adult abuse at a time yet to be determined.

According to the news report, Tangemen ruled that there was insufficient evidence to proceed with the charge of administering a harmful substance, Betadine, and that the unlawful prescription of controlled substances did not apply in this case. The former dismissed charge was the gravest, with a maximum penalty of 8 years in prison. The maximum penalty for dependent-adult abuse is 4 years in prison.

Roozrokh's defense attorney, M. Gerald Schwartzbach contended in court that his client "could not have violated the standard of care to merit the dependent adult abuse charge...because no such standard applies to the extraordinary circumstances of this case," according to the news report. "This is a situation where the entire system failed," Schwartzbach declared, as quoted by the paper.

The judge's ruling (found here) provides a number of interesting points:

• Ruben Navarro most likely had developed a considerable tolerance to morphine. Navarro received an intrathecal pump in 2005 to deliver morphine and the antispastic agent baclofen. During Navarro's previous hospitalization, attending physician Eric Schultz had prescribed morphine and Ativan (lorazepam) for the patient at dosages up to 10 mg every 15 minutes prn.
• Accounts from witnesses in the OR at the time of the attempted cardiac-death donation could not be reconciled with respect to the amount or timing of the medications given. No one recorded the administration of medications in the OR, and the vital-sign records for this time period were lost.
• "There was no credible evidence that Dr. Roozrokh ordered the administration of Betadine," according to the ruling. The testifying nurses could not identify whether Roozrokh or transplant surgeon Arturo Martinez delivered the Betadine to Navarro; although, Martinez denied ever touching Navarro "in this manner." The judge adds, however, that Martinez's claims are suspect given his "natural interest in avoiding civil and criminal liability despite his obvious presence and superior experience [to that of Roozrokh]." A footnote adds that detective Crawford found some of Martinez's statements "lacking in credibility." In addition, the amount or concentration of Betadine given to Navarro is unknown, thereby precluding a determination as to whether the Betadine was harmful. Finally the judge relied on the wording of the relevant statute to determine that it did not apply in the context of a medical procedure.
• The judge made his best guess, based primarily on the testimony of nurse Diane Stevens, as to how much and when morphine and Ativan were administered to Navarro. In the ICU (between 10:05 and 10:30 pm), Navarro received a total of 20 mg of morphine and 4 mg of Ativan, each in 2 separate doses. In the OR (between approximately midnight and 1 am), Navarro received a total of 180 mg of morphine and 80 mg of Ativan, each in 4 separate doses.
• The judge ruled that an unlawful prescription of controlled substances did not apply in this case, because the relevant statute indicates that "[a]n order for controlled substances for use by a patient in a...licensed hospital shall be exempt..."

Yesterday, the DoJ indicted W. Scott Harkonen, MD, former CEO of InterMune, for wire fraud and the misleading promotion of Actimmune (interferon γ-1b) for idiopathic pulmonary fibrosis (IPF). At the center of the case appears to be whether Actimmune, which was and is not FDA approved for IPF, was promoted by Harkonen for the treatment of the fatal condition on the basis of insufficient data. If convicted, Harkonen could face up to 20 years in prison.

 

In a press release yesterday, Harkonen's defense counsel* claimed that Actimmune "was supported by persuasive science as a new potential treatment for [IPF]," and that "the government is trying to criminalize an important potentially life-saving scientific debate." Harkonen was CEO of InterMune from February 1998 through June 30, 2003, and a member of the company's board of directors from February 1998 through September 2003. He is currently president and CEO of CoMentis, a small biotech operation in San Francisco.

 

According to the indictment, Harkonen directed the promotion of Actimmune for IPF and established sales goals toward that purpose in 2000, after a small, open-label trial of the drug indicated improved lung function in patients with glucocorticoid-refractory disease. The trial results were published in the NEJM in October 1999.

 

It is also alleged that Harkonen then fostered the company's public misrepresentation of results from a 2002 placebo-controlled, phase 3 trial of Actimmune in medically refractory IPF, GIPF-001. The trial results, according to the indictment, were negative; however, Harkonen then allegedly directed a post-hoc subgroup analysis of the trial data, which produced a statistical trend toward improved survival with Actimmune in patients with mild-moderate disease.

 

The indictment goes on to allege that Harkonen was instrumental in crafting the following press release, which was filed with the SEC, to promote the manipulated results of GIPF-001. (The Pathophilia blog has not been able to find a peer-reviewed report of the trial's results. Update: The GIPF-001 trial results were published in the NEJM in 2004 [Raghu G et al]. Actimmune, when compared with corticosteroids, did not significantly improve progression-free survival [the primary endpoint], pulmonary function, or quality of life.) 

 

INTERMUNE ANNOUNCES PHASE III DATA DEMONSTRATING SURVIVAL BENEFIT OF ACTIMMUNE IN IPF

—Reduces Mortality by 70% in Patients with Mild to Moderate Disease—

 

BRISBANE, Calif., August 28, 2002—InterMune, Inc. (Nasdaq: ITMN) announced today that preliminary data from its Phase III clinical trial of Actimmune® (Interferon gamma-1b) injection for the treatment of idiopathic pulmonary fibrosis (IPF), a debilitating and usually fatal disease for which there are no effective treatment options, demonstrate a significant survival benefit in patients with mild to moderate disease randomly assigned to Actimmune versus control treatment (p = 0.004). These data confirm the survival benefit seen in the Phase II trial presented earlier this year at the 98^th Annual Conference of the American Thoracic Society. There was also approximately a 10% relative reduction in the rate of progression-free survival associated with Actimmune versus placebo, the trial's primary endpoint, but this was not a statistically significant difference.

 

"We are extremely pleased with these results, which indicate Actimmune may extend the lives of patients suffering from this debilitating disease," said W. Scott Harkonen, MD, President and CEO of InterMune. "Actimmune is the only available treatment demonstrated to have clinical benefit in IPF, with improved survival data in two controlled clinical trials. We believe these results will support use of Actimmune and lead to peak sales in the range of $400-$500 million per year, enabling us to achieve profitability in 2004 as planned."

 

"The mortality benefit is very compelling and represents a major breakthrough in this difficult disease," said Ganesh Raghu, MD, Professor of Medicine, University of Washington in Seattle, and the Phase III study's lead principal investigator. "Interferon gamma-1b is the first treatment ever to show any meaningful clinical impact in this disease in rigorous clinical trials, and these results would indicate that Actimmune should be used early in the course of this disease in order to realize the most favorable long-term survival benefit."

 

The indictment further alleges that an e-mail containing instructions for presenting the GIPF-001 trial results was distributed to the InterMune sales force, and that InterMune hired a marketing research firm to determine whether the GIPF-001 press release would affect the prescribing habits of pulmonologists (the results: it would). The indictment also charges that Harkonen acted to disseminate "false and misleading" information through letters delivered to patients with their Actimmune medication and through letters that were fax-blasted to doctors, both of which were distributed by a Florida specialty pharmacy.

 

It is especially noteworthy that another phase 3 study of Actimmune, the INSPIRE trial, which began enrolling patients with mild-moderate IPF in December 2003, was terminated for lack of efficacy in March 2007. From 2000 to 2003, Actimmune sales were 90%-100% of InterMune's total sales, according to the indictment, and the "vast majority" of Actimmune sales were for IPF treatment, claims the DoJ. The estimated costs of 1 year's supply of Actimmune for one patient is $50,000.

 

A press release provided yesterday by InterMune establishes considerable distance between the company and its former leader. In October 2006, InterMune entered into a deferred prosecution agreement and will pay nearly $37 million "to resolve criminal charges and civil liability in connection with the illegal promotion and marketing of its drug Actimmune," reports the DoJ. InterMune is also evidently a party to a 5-year Corporate Integrity Agreement with the OIG.

 

A couple of more interesting quotes on the Harkonen indictment by government authorities, specifically with respect to individual culpability in the pharma industry and effects on government agencies, like the VA:

 

"Pharmaceutical executives who promote drugs using false and misleading information should not be allowed to hide behind a corporate shield," said Kim Rice, Special Agent in Charge of FDA's Office of Criminal Investigations, Washington Field Office. "Pharmaceutical companies do not run themselves, and those who engage in criminal conduct will be held personally accountable."

 

"The results of this criminal investigation show our commitment to protect the Veteran Administration’s healthcare system from deceptive and fraudulent practices by pharmaceutical companies," said Special Agent in Charge Douglas J. Carver of the US Department of Veterans Affairs, OIG.

 

*James J. Brosnahan. Check out the California firm's interesting domain name: "mofo."

 

Note: Yellow highlighting has been added by the Pathophilia blog.

 

Photo: www.7x7sf.com

The NYT is reporting that the heparin-like molecule found in batches of Baxter's recalled heparin is probably an over-sulfated version of chondroitin sulfate. Chondroitin sulfate, an essential component of animal cartilage that is marketed as a nutritional supplement for joint pain, was intentionally altered with additional sulfate groups to confer anticoagulant properties to the molecule. How, when, or where the ersatz heparin was mixed into Baxter's product and whether the altered chondroitin sulfate is reponsible for the reported allergic reactions remain unknown.

Chemical structures of heparin (left) and chondroitin sulfate (right) are shown (source: Wikimedia Commons).

Lilly wasted no time in drafting a formal response to the NYT's Friday article, "Lilly E-Mail Discussed Off-Label Use," which stated that CEO-to-be John C. Lechleiter sent a 2003 internal e-mail that advised the off-label promotion of Zyprexa (olanzapine) for children. The Pathophilia blog also wasted no time in questioning the intelligence of a high-level pharma executive who would draft such an e-mail. According to the NYT, the contents of Lechleiter's e-mail were revealed during the ongoing proceedings of the state of Alaska v. Eli Lilly, in which Alaska seeks reimbursement from the drug company for Medicaid costs related to Zyprexa-related diabetes.

In its response, Lilly called the NYT's assertions "flat out wrong" and claimed that the paper "mischaracterized Lechleiter's e-mail, which the court deemed inadmissible." However, Lilly neglected to mention that the e-mail was deemed inadmissible because the claims seeking damages due to off-label promotion were dismissed by the judge, not because of any misrepresentation made by the prosecution (or others) about the e-mail.

Lilly also advised that, during 2003, Lechleiter oversaw the development of new products and late-stage clinical programs; he was not in a position to "oversee or direct promotional or marketing activities." With its statement, Lilly evidently meant to defend Lechleiter's intention to provide medical guidance for off-label questions, given his clinical position; however, Lechleiter's non-marketing position coupled with his e-mail that addressed marketing issues could just as easily be used to indict Lechleiter's intentions, rather than defend them.

Lilly also implied that Lechleiter's e-mail was merely a response to pleas from the medical community on how to care for "special patient populations." "Dr. Lechleiter's email was nothing more than a call to action to ensure Lilly's development organization placed a high priority on conducting clinical trials to address these important medical questions," Lilly wrote. Take that explanation for what you will. But until the full e-mail is made publicly available (perhaps by another state seeking reimbursement for the off-label promotion of Zyprexa), Lechleiter's intentions can only be interpreted from disclosed e-mail excerpts and Lilly's PR department.

Perhaps trying to justify how it spent the last 5 months, the AP follows up its throw-up-your-hands-to-the-skies "exposé" of trace-trace-trace pharmaceuticals in drinking water by reporting the reactions to its story. "Test it, study it, figure out how to clean it—but still drink it," is how the AP begins its follow-up. Did the AP—perhaps now substituting alcohol for all of its drinking water—expect that we would or should avoid consuming water on the basis of its arguably useless report?

 

"There is no wisdom in avoidance," advised one Washington-based environmental lawyer as quoted by the AP. No freekin' shit, Sherlock. Whatever risks may be posed by drinking infinitesimal amounts of pharmaceuticals—and nobody knows if there are any—lack of water will kill in no time. Trust me. They teach that stuff in medical school.

 

The AP water story reminds me of those ridiculous signs in California hotels that warn of the dangers of breathing the building's air. What in a supreme being's name am I supposed to do with that information? Not breathe? Run outside, where the air's even filthier?

 

Next thing you know the AP's going to tell me that saliva causes cancer, but only if swallowed in small quantities over an extended period of time. No wait. Chevy Chase already reported that information on SNL in nineteen-dickety-two. It's the cycle of news to parody, back to news again.

 

Photo: www.saturday-night-live.com

In the ongoing proceedings of the state of Alaska v. Eli Lilly,* it was revealed that Lilly CEO-to-be John C. Lechleiter wrote a company e-mail in 2003 that encouraged the off-label promotion of Zyprexa (olanzapine) to pediatricians and child psychiatrists, according to a late-breaking report from the NYT. 

Now it is not news that pharma clandestinely markets its drugs for off-label use, but for a company executive to urge off-label promotion in an e-mail is colossally stupid. Lechleiter's allegedly proposed off-label marketing strategy, according to the NYT, was to discuss the potential use of olanzapine in children (for whom the drug is not FDA approved), when reps were already promoting Strattera (atomoxetine) for attention-deficit disorder. The NYT also reports that, in the e-mail, Lechleiter encouraged the off-label promotion of olanzapine to neurologists for pain.

In a feeble shot at damage control, a Lilly spokesperson indicated that Lechleiter "was not advocating off-label promotion in his note but simply wanted the company to respond to physicians’ requests for information," wrote the NYT. Drug reps can respond to unsolicited requests from physicians for off-label information. 

The Lechleiter e-mail will not be presented to jurors in the Alaska trial, because the claim seeking damages for off-label olanzapine promotion was dismissed.

In related news, former olanzapine rep Shamram Ahari testified before the Senate Aging Committee about Lilly's alleged sales practices. If this PharmedOut video is any indication, Ahari's probably a very compelling witness.

*Alaska wants Lilly to reimburse its state Medicaid costs for individuals who developed diabetes while taking olanzapine. 

Remarking to CNN on the Eliot Spitzer prostitution scandel, both attorney Alan Dershowitz and former NYC major Ed Koch stated that they found "nothing wrong" with prostitution. In fact, Dershowitz claimed that prostitution should be legalized in the United States, and he made the often-repeated, but illogical, assertion that prostitution is a victimless crime.

Easy for a non-hooker* to say.

*And I mean literally a person who is not a prostitute: that is, a person who does not sell her body for sex. Not someone who figuratively prostitutes himself.

Concluding testimony was provided Friday in the preliminary hearing for transplant surgeon Hootan Roozrokh, reports Sarah Arnquist of the San Luis Obispo Tribune.

• Pulmonologist Eric Schultz, MD, Ruben Navarro's attending physician,* testified that he did not think Navarro was a good candidate for cardiac-death donation, because "he would not stop breathing for hours to days" once off mechanical ventilation. Schultz also stated that the doses of morphine and lorazepam given to Navarro were "way over the top." During cross-examination, Schultz conceded that he only wrote in Navarro's medical chart that the patient would not die immediately after extubation; Schultz did not define a time frame for the patient's death. Schultz also admitted to Roozrokh's defense attorney that the medication may have spared Navarro some suffering, given that he died 8 hours after the attempted cardiac-death donation.
• San Luis Obispo police officer Charles Riedel testified that both Sierra Vista OR nurse Jennifer Endsley and technician Celeste Tracy^† witnessed a transplant surgeon inject Betadine into Navarro’s feeding tube in the OR, but they couldn't specify whether the surgeon was Roozrokh or Arturo Martinez.

Next week, opposing counsel will submit written arguments to the San Luis Obispo Superior Court judge, and oral arguments will be presented in court on March 19th to determine if there is sufficient evidence to proceed with a jury trial against Roozrokh. 

Establishing which surgeon gave Betadine to Navarro is crucial, because the related criminal charge—administering a harmful substance—carries the gravest punishment among the charges that Roozrokh faces.

*On the night of February 3, 2006, Navarro's care was provided by covering physician Laura Lubarsky.

†The reports do not define what type of technician Celeste Tracy is; it is presumed she is an OR technician.

ICU nurse Diana Stevens testified yesterday that transplant nurse Carla Albright and transplant surgeon Hootan Roozrokh ordered morphine for potential organ donor Ruben Navarro on the night of February 3, 2006. Stevens has been granted immunity from prosecution in the criminal case against Roozrokh. The following items are based on Stevens's testimony, as reported today in the San Luis Obispo Tribune:

• Albright, despite the fact that she cannot legally prescribe controlled substances, ordered Stevens to administer 20 mg of morphine to Navarro while he was in the ICU (before he was transported to the OR for the cardiac-death donation procedure). Stevens evidently complied.
• Stevens also gave Albright 20 mg of morphine before the procedure. It is unclear when or whether this dose was administered to Navarro. According to Stevens, all of the morphine vials "were empty and accounted for" after the attempted cardiac-death donation.
• Roozrokh gave 3 orders that night to Stevens, who testified that she administered a total of 180 mg of morphine and 80 mg of lorazepam (Ativan) to Navarro in the OR. Today's Tribune report does not break down the relationship between Roozrokh's orders and the medication amounts or times.
• The attempted cardiac-death donation was terminated by Roozrokh just before 1 am on February 4, 2006.

More (and somewhat different) details of the events of February 3, 2006, at the Sierra Vista Medical Center are described in a Tribune article from October 14, 2007.

9:30 am: Albright arrives at Sierra Vista to coordinate the donation. She speaks with Navarro's doctors, examines Navarro, and books the OR for the donation process. Albright claims that, despite having reviewed Navarro's chart, she never saw a note from the patient's physician (not Laura Lubarsky) claiming that Navarro was not a good candidate for cardiac-death donation.

7:00 pm: Stevens starts her ICU shift. She reviews paperwork describing the donation procedure and administers "small" doses of morphine and lorazepam to Navarro, allegedly for comfort. 

9:00 pm: Fog delays the arrival of transplant surgeons Roozrakh and Arturo Martinez from San Francisco.

10:30 pm: Roozrokh and Martinez arrive at Sierra Vista and examine Navarro in the ICU (against transplant state law and protocol). Roozrokh asks Stevens to bring morphine and lorazepam to the OR. Stevens brings 100 mg of morphine and 40 mg of lorazapam.

~11:00 pm and later: After Navarro is transported to the OR, Roozrokh and Martinez surgically prep the patient for organ harvesting. The surgeons then remain in the OR, again against protocol, and no one asks them to leave. Immediately after a respiratory therapist removes Navarro from ventilatory assistance (another report indicates that Roozrokh gave this order, with Lubarsky tacitly approving), Roozrokh tells Stevens to give Navarro 50 mg of morphine and 20 mg of lorazepam. Navarro is breathing spontaneously, and after a few minutes, Roozrokh asks Stevens to administer another 50 mg of morphine and 20 mg of lorazepam.

At this point, an OR nurse, Jennifer Endsley, allegedly asks Stevens what she is giving to Navarro, and reports later that her question is ignored. She also claims that she asks Albright at this time, "Do you think this goes against God?" After several more minutes, Navarro continues to breathe spontaneously, and Roozrokh orders Stevens to administer more "candy." However, Stevens has no more morphine or lorazepam left and calls a nursing supervisor for another 100 mg of morphine and 40 mg of lorazepam.

The supervisor tells nurse Suzanne McDougal to bring the requested medication to Stevens in the OR. McDougal confirms the medication amounts with Stevens by phone and, although McDougal is uncomfortable with collecting so much morphine and lorazepam, she nevertheless finds a total of 30 vials in 2 hospital areas and delivers them to Stevens. Stevens then reportedly fills syringes with the medications and administers them to Navarro (it is assumed here that this third administration of medication in the OR provides 100 mg of morphine and 40 mg of lorazepam). Navarro continues to breathe spontaneously after a total of 40 minutes have elapsed in the OR, and Roozrokh cancels the donation procedure. Endsley, Stevens, and Martinez transport Navarro from the OR to the ICU. (In this particular Tribune article, it is not stated when Roozrokh allegedly injected Betadine into Navarro's feeding tube.)

Back in the ICU: Stevens retrieves all 20 empty morphine vials and 40 empty lorazepam vials and counts them with another (unnamed) nurse. (Basic arithmetic indicates that a total of 20, 10-mg morphine vials and 40, 2-mg lorazepam vials were used.)

Endsley evidently reports the events to hospital administrators a few days later (presumably on Monday, February 6, 2006). She has been described as the whistleblower in this case.

By way of the WSJ Law Blog from the NYT: A Los Angeles city attorney filed criminal charges yesterday against executives from 2 LA-based importers of Chinese-made toothpaste that was tainted with diethylene glycol. According to the NYT report, most of the toothpaste was brought into the United States through Long Beach, CA, and ~78,000 tubes were sold and distributed by at least one importer between December 2005 and May 2007 to prisons, luxury hotels, hospitals, and discount stores. The importers' predictable response: We didn't know the toothpaste was contaminated.

On January 16, 2008, NBC aired episode 397 ("Bottomless") of "Law and Order," in which a murder investigation leads to the discovery of diethylene-glycol-tainted Chinese-made toothpaste sold by a Wal-Mart-like corporation. The discovery led to criminal charges in the show.

God knows what I'd do without Sarah Arnquist and her coverage of the Roozrokh case for the San Luis Obispo Tribune.

Today's report of the ongoing preliminary hearing reveals that the California Transplant Donor Network did not require physicians or nurses to undergo specific training in cardiac-death donation until 1 year after the attempted harvesting of Ruben Navarro's organs on February 3, 2006. In fact, the criminal investigation of that night's events are reportedly what prompted national standards for the organ-donation procedure to be adopted.

Also continuing testimony from county coroner investigator Stephen Crawford reveals that, before the night in question, transplant nurse Carla Albright had seen only one cardiac-death donation, and transplant surgeon Hootan Roozrokh had assisted only one such procedure. Crawford also testified that 4 witnessess in the OR that evening recounted differing amounts of medication allegedly prescribed by Roozrokh and how often he prescribed it, wrote Arnquist.

More testimony from the preliminary hearing in the criminal case against transplant surgeon Hootan Roozrakh indicates conflicting accounts of the attempt to harvest Ruben Navarro's organs on the night of February 3, 2006. According to the San Luis Obispo Tribune, county coroner investigator Stephen Crawford testified that he could not reconcile information provided by Navarro's attending physician Laura Lubarsky and that from transplant nurse coordinator Carla Albright. Lubarsky allegedly claimed that she was not informed of her role in Navarro's cardiac-death donation that evening by the transplant team, but Albright stated that she had "told Lubarsky to direct Navarro's care."

Also expert witness and Santa Barbara neurologist David Frecker, MD, testified yesterday that the massive doses of morphine and lorazepam (Ativan) given to Navarro would only be intended to suppress respiration. Frecker reportedly stated that he was surprised that the medication did not kill Navarro.

Cross-examination of Frecker by Roozrokh's attorney, M. Gerald Schwartzbach, provides two interesting bits of information. Schwartzbach indicated that 1) a nurse recommended the high dose of morphine for Navarro, because of the patient's alleged tolerance, and 2) the medical records for the time during which Navarro's organs were to be harvested were lost.

In the criminal proceedings against transplant surgeon Hootan Roozrokh, MD, Sarah Arnquist of the San Luis Obispo Tribune provides continuing coverage of the ongoing preliminary hearing and specifically reports on Friday's potentially damning testimony from prosecution expert witness Clarence Foster, III, MD, director of the kidney and pancreas transplantation program at the University of California, Irvine.

According to the latest Tribune report, Foster clarified that "a transplant surgeon should never assume care for a potential organ donor," and that he had "never seen a transplant surgeon order medication to alleviate pain in the transplant process." Moreover, Foster stated that the "only reason to give morphine and Ativan [lorazepam] to potential donors after they are removed from life support would be to hasten their death."

According to the news report, Foster also implied exceptional ignorance on the part of the patient's attending physician, Laura Lubarsky, by stating that he never knew an attending physician to misunderstand his or her protective role toward the patient during cardiac-death donation.

During cross-examination, Roozrokh’s attorney M. Gerald Schwartzbach predictably attempted to undermine Foster's credibility but also provided some insight into the potential strategy of the defense. Schwartzbach highlighted the lack of accepted medical protocols for cardiac-death donation specifically at the time of the patient's death. He also implied that the accepted act of removing ventilatory assistance, which is undeniably intended to hasten death, is really no different than administering morphine or lorazepam, which is also intended to accelerate death.

The rebuttal to this argument, of course, lies in the nature of the act: the removal of ventilatory assistance is the withdrawal of extraordinary medical care, which is ultimately intended to lead to a passive death; the administration of massive doses of analgesic or sedating medication constitutes an intent to actively produce death.