Results tagged “pharma” from Pathophilia

But try explaining that concept to a jury.

The clinical data, and they are imperfect to say the least, suggest that there may be an idiosyncratic link between Accutane use and depression or suicide. But studies (not case reports) do not collectively support a bona fide association between the drug and affective disorders in users.*

It turns out that the same may be true for any posited association between Accutane and inflammatory bowel disease (IBD)—despite the hundreds of personal-injury cases brought against Accutane's former maker, Roche, in mass-tort litigation.**

There are at least 3 compelling case reports (here, here, and here) suggesting that Accutane causes or exacerbates enteritis or colitis and that these flares remit and recur with withdrawal and reuse, respectively, of the drug. And the drug's PI warns against the occurrence of IBD with Accutane use. (The mechanism by which Accutane, a vitamin A analogue, might cause IBD is unknown.) But a recent, population-based study in Canada found no association between Accutane use and the development of IBD. The study, which was not funded by Roche, is evidently the first of its kind to examine any such association, outside of case reports.

By using the Manitoba Health databases, the Canadian authors identified a similar percentage of patients (age cutoff, <40 years) who used Accutane before or after their first diagnosis of IBD (see adapted Table). These data suggest no association, much less a causal link, between Accutane use and the development of IBD. Moreover, Accutane use among matched controls (for age, sex, and residence) without IBD was similar (1.1% and 0.9% for the before and after populations, respectively). And the mean time between the diagnosis of IBD and the last Accutane prescription was lengthy (1048 days or ~2.8 years), suggesting that any cause-effect relationship in the 25 "before" IBD cases is unlikely.

A more recently published, case-control study from UNC largely confirmed the Canadian findings, but the US authors concluded a "strong" association between Accutane use and UC among 24 total cases of IBD (OR for ulcerative colitis = 4.36 [95% CI: 1.97, 9.66]). The risk of UC appeared to increase with Accutane dosage and duration of treatment among the small number of cases (only 0.3% of subjects in the total IBD population had been exposed to Accutane). The US authors concluded, "Although the absolute risk of developing UC after taking [Accutane] is likely quite small, clinicians prescribing [Accutane] as well as prospective patients should be aware of this possible association." 

* Whatever Emory psychiatrist Doug Bremner may say on YouTube in his not-particularly-sophisticated interpretation of his and others' data.

** One of these cases was brought by actor James Marshall of "Twin Peaks" and A Few Good Men fame. Marshall, who is reportedly corralling celebrity witnesses to argue his case, claims that Accutane caused his IBD, which in turn put the kibosh on what would have been a James Dean-like film career (without the violent, early death, presumably). See last week's Bloomberg story.

Photo of Roaccutane, aka Accutane, from Wikipedia.

08/06/10 addendum: Yesterday the New Jersey Superior Court Appellate Division repealed the $10.5 million verdict for the plaintiff in Kendall v Hoffman-La Roche. The appellate court ruled that the Roche was hobbled during trial by restrictions on the presentation of background data for the incidence of IBD. Kendall, who was treated several times with Accutane for nodular acne during adolescence and young adulthood, developed UC at the age of 15 years, which coincided with Accutane retreatment. However, her bowel condition was not uniformly exacerbated by further treatments with Accutane.

Kendall's case hinges on the argument that Roche failed to warn of the risk of IBD, and Roche's warnings are based on risk data known at the time of Kendall's Accutane treatments. Bloomberg covered the story; the appellate decision can be found here.

A similar appellate reversal was made in McCarrell v Hoffman LaRoche, and the retrial resulted in an even bigger verdict for the plaintiff. An appeal on this verdict is reportedly in the works.

The world's largest drug company is advising US physicians who visit its exhibit booth at the ongoing ASCO meeting that they will have to swipe their registration cards if they want a freebie latte, reports Reuters. And oh no, you di'int: MDs from Minnesota and Vermont can't have one at all, thanks to their state laws that prohibit all swag—no matter how trivial.

Moreover, if you do accept a latte from Pfizer, the company may provide your name to US regulators and post the fact that you received caffeinated remuneration at its disclosure website. God knows, you could end up scribbling scores of prescriptions for Aromasin during your 20-minute Pfizer-propagated caffeine buzz.

At least the oversight measures are keeping somebody employed...and amused.

ASCO = American Society of Clinical Oncology.

"angry latte" by Chris Barkeley at Flickr.

06/10/10 addendum: It's hard to keep up, but Vermont recently amended its existing, relevant law to allow the "provision of coffee and other snacks or refreshments at a booth at a conference or seminar." The bill became effective on March 27th (without the governor's signature, according to the FDA Law Blog).

Tossing McClain's case into the OSHA-biosafety mix also does a disservice to those very few scientists who probably did acquire disease in the workplace, like...

• Ru-ching Hsia, a Department of Agriculture scientist who developed coma-inducing hemolytic uremic syndrome after becoming infected in 2003 with laboratory-derived E. coli O157:H7;
• Jeannette Adu-Bobie, who contracted meningococcal septicemia in 2005 while working in a New Zealand vaccine laboratory; and
• Malcolm Casadaban, a U of C researcher who died September 13, 2009, of infection caused by a weakened version of Yersinia pestis.

According to Wikipedia, "[t]he last known case of a scientist dying from a pathogen he was studying was Howard Taylor Ricketts, who died of typhus in 1910."*

* The Rickettsiaceae guy!

OSHA = Occupational Safety Health Administration (which reportedly denied McClain's claim).

Walk correctly assails the authors' methodology, or lack thereof; their inherent bias in only interviewing prevailing whistleblowers; and findings (or "findings") that might be found in any lazy magazine piece—like, "a typical day could be meeting an FBI agent in a parkway rest stop. Sitting in his car with the windows rolled up. Neither heat nor air conditioning."

Neither heat nor air conditioning? Walk's pithy response: "Wow."

Another wry criticism of the authors' findings: Questioning how some whistleblowers "accidentally" "fell into the qui tam process." Walk responds, "As lawyers, we know it’s pretty hard to file a lawsuit accidentally," and "Try that argument at home to excuse some dumb thing you did."

And if it truly, really, verily isn't about the money, as the interviewed whistleblowers would like us to believe, then revamp the whole process. Walk logically concludes,

Then the qui tam system urgently needs revision. We're wasting millions that could be benefiting us as taxpayers. Obviously, these relators didn’t need the millions of dollars they received to motivate them to bring qui tam lawsuits. All that money can go back to the taxpayers or, better yet, our clients, the pharmaceutical companies.

Last Walk snipes at the authors' conclusion that the qui tam system should be revamped on the basis of their interviews.

What a great idea – deciding important public policy questions based only on a few interviews of one of many interested groups. Maybe someone will follow this NEJM-approved "scientific" approach to public policymaking and make serious proposals to reform the nation’s regulation of doctors based solely on 30 to 45 minute interviews of 26 successful medical malpractice plaintiffs.

Image of Saint Sebastian by Guido Reni from Wikipedia.

The 26 interviewed relators, who received a median of $3 million ($100,000-$42 million), were reportedly motivated by their senses of justice, altruism, or integrity, according to the study. In other cases, whistleblowing was viewed as a way to avert possible future accusations of engaging in illegal activity (eg, off-label promotion). They also cited heavy personal and professional costs during the qui tam investigation and litigation.

However, one sentence in the NEJM article, in particular, suggests that whistleblowers are at least initially motivated by the prospect of a financial windfall and don't accurately anticipate the direct and indirect costs of the qui tam process. In a concluding statement to the section, "Settlement and Life Afterward," the authors report the relators' advice to would-be whistleblowers:

Some offered strategic suggestions, such as hiring an experienced personal attorney, and many suggested a need to mentally prepare for a process more protracted, stressful, and conflict-ridden, and less financially rewarding, than prospective whistle-blowers might expect.

The authors also note that if the Justice Department decides to intervene in whistleblowers' qui tam suits, almost all result in settlements or judgments against the pharma defendant. So once the DoJ picks up a case, it's highly unlikely that the whistleblower would decide to back out, whatever the upfront headaches.

* Related to the alleged improper promotion of Vioxx.

Image of Saint Sebastian by Guido Reni from Wikipedia.

Addendum: In a highly revealing statement, one interviewee "likened his large settlement to 'hitting the lottery,'" which, as we all know, has the sole upfront cost of forking over a buck or two for a ticket.

Given the oppressive anti-pharma mood generated by mainstream media and Marcia Angell, it's refreshing to have Gladwell remind us—in a really entertaining way, no less—just how "boinking" hard it is to bring an effective and safe cancer therapy to market.

By using newly released data from Thomson Reuters (for 2010 and 2014) and EvaluatePharma (for 2016), a timeline graphic of the 7 drugs that are expected to remain within the top 10 best sellers is presented. Notably only 1 of the 7, Crestor, is a conventional pill.

Advair (fluticasone/salmeterol; GSK) and Remicade (infliximab; Centocor Ortho Biotech) lose position, while the other drugs are expected to rise on the list. The future top seller, depending on your source, is Humira (adalimumab; Abbott) or Avastin (bevacizumab; Roche).

Last month

Now Allergan, in perhaps a tone-deaf move, is suing Kristen's mom for legal fees, to the tune of $460,000, reports the OC Register. The company is likely sending a harsh message to existing or would-be plaintiffs and their attorneys. Among 14 other pending civil lawsuits against Allergan is that of physician Sharla Helton, who alleges that cosmetic Botox caused a multitude of neurologic problems, presumably due to the migration of toxin (which seems, BTW, highly unlikely at cosmetic dosages). The trial began this week in Oklahoma City. The physician is represented by Ray Chester of the Texas-based firm McGinnis, Lochridge, and Kilgore. Chester also represented Dee Spears.

In the meantime, Allergan's lawyers are consumed with the company's free-speech case against the government (Allergan v the United States of America). A motion hearing was scheduled for April 26; however, today's search of the court calendar reveals nothing on the schedule for the remainder of the year.

In its entirety, the code, currently endorsed by 13 member societies,* addresses charitable contributions, corporate sponsorships, educational grants, exhibits and advertising, licensing, research grants, and editorial standards for society journals. The other 19 member societies, including CMSS President James Scully's American Psychiatric Association, have until the end of the year to sign on.

* American Academy of Family Physicians (AAFP)
  American Academy of Neurology (AAN)
  American Academy of Ophthalmology (AAO)
  American Academy of Pediatrics (AAP)
  American College of Cardiology (ACC)
  Accreditation Council for Continuing Medical Education (ACCME)
  American College of Emergency Physicians (ACEP)
  American College of Obstetricians and Gynecologists (ACOG)
  American College of Physicians (ACP)
  American College of Preventive Medicine (ACPM)
  American College of Radiology (ACR)
  American Society for Radiation Oncology (ASTRO)
  American Society of Clinical Oncology (ASCO)

I don't get it. How does an employee with, by all appearances, an inherited illness prevail in litigation against a company for personal injury? At least the federal judge in the case of McClain v Pfizer threw out the issue of whether a Pfizer-bioengineered virus caused the plaintiff's recurrent paralytic illness.

Nevertheless, a jury awarded nearly $1.4 million to ex-Pfizer scientist Becky McClain, by ruling that the company had violated free-speech and whistle-blower laws. (The judge left the personal-injury issue to workers' compensation litigation.)

Coverage of the jury's decision is provided by the NYT, which also reveals that McClain, 52, suffers from "a potassium deficiency that causes sporadic and temporary paralysis"—in other words, hypokalemic periodic paralysis, a rare, genetically determined* disorder of ion channels in muscle (ie, a channelopathy). Unfortunately news coverage of the trial fails to stress the crucial genetic feature of McClain's reported illness. (They also fail to note that her OSHA complaint was evidently dismissed.)

Approximately 60% of cases of Hypo PP are due to a mutation in CACNA1S (calcium channel) gene; 20% are caused by a mutation in the SCN4A (sodium channel) gene. The remainder are probably due to new dominant mutations, according to information cited in a review by Venance et al. These ion-channel mutations cause the aberrant depolarization of muscle fibers, which renders them inexcitable; the clinical result is periodic paralysis. It's not clear what kind of Hypo PP-related mutation, if known, is harbored by McClain.

The essential features of Hypo PP, beyond its genetically determined nature, are listed:

• Age at onset: 1st or 2nd decade
• Duration of paralytic attacks: hours to days (may be diffuse or focal)
• Usual triggers: rest after exercise, carb loading
• Ictal potassium level: low
• Cardiac arrhythmias or skeletal developmental abnormalities: no (unlike Anderson-Tawil syndrome**)
• Response to potassium: improvement of weakness

Hypo PP is diagnosed on the basis of episodic paralysis, low serum potassium levels during the paralysis, and EMG features (post-exercise features may be particularly helpful). For anybody presenting with Hypo PP-consistent symptoms after the age of 20 years or whose family history is nonexistent, thyroid function should be assessed to exclude thyrotoxic PP.

According to news reports, McClain—who has an MS degree—claims that her paralytic illness was triggered by infection with a genetically engineered lentivirus at Pfizer's Groton, CT, campus. The Connecticut Law Tribune reports that McClain left work in early 2004 after developing her alleged symptoms.

Though her doctor cleared her to resume working a few months later, her attorney instead negotiated with Pfizer over her work conditions. Unable to reach an agreement, McClain was terminated in May 2005; Pfizer said it was because she had abandoned her job.

By then, McClain had filed a complaint with OSHA. It was dismissed when investigators ruled that her complaints were without merit; the OSHA report cited Pfizer for making "substantial efforts" to address McClain's concerns.

Probably smelling the high possibility of litigation from McClain on whatever grounds, it seems reasonable to conclude that Pfizer would have bent over backwards to accommodate McClain and her safety concerns—at least on some kind of sensible level.

According to the Center for Public Awareness in Bioethics web site, McClain has a bachelor's degree from Indiana University and a Master of Science in Public Health from the University of Texas School of Public Health in Houston. She worked for Pfizer as an unspecified scientist from 1996 to 2005 and filed her suit against the company in 2006.

EMG = electromyography; OSHA = Occupational Safety and Health Administration.

* Prevalence is reported at 1 in 100,000. The disorder is inherited in autosomal dominant fashion, with reduced penetrance in women. Also sporadic mutations are reportedly common in Hypo PP.

** The triad of PP, ventricular ectopy, and skeletal anomalies.

Both cardiologists acknowledged historical examples of the marketing influence that pharma and the medical-device industry have had on professional education and, potentially, medical practice. But Harrington painted a more complex picture, in which physicians and medical journal publishers have been complicit in allowing this influence to happen. While Harrington advocated that ongoing relationships with commercial entities are "critical," he urged clear "firewalls" between physicians (particularly academic physicians) and industry and full access to data from industry-funded research. Harrington also correctly stressed that potential conflicts of interest go beyond money; "scientific hubris" is also in the mix.

And speaking of hubris...

Nissen conversely argued that industry funding to sponsors of continuing medical education (CME) and professional medical societies must cease. He cited a Merck-funded CME program at the ACC's Cardiosource web site, "Optimizing Patient Outcomes in Acute Heart Failure Syndromes: Strategies to Preserve Cardiorenal Function," which was sponsored by an accredited* medical-education communications company (Med-IQ) and the ACC.** Without citing specific examples of undue industry influence in the program, Nissen argued that Merck's reason for sponsoring the program was due to the fact that the company had a novel compound, rolofylline, in development that addressed the condition in question. Nissen called the CME program a "market preparation business activity" and an ultimate "misuse of medical information," primarily because the drug died in phase 3 development. But Nissen failed to acknowledge the obvious follow-up question: How could Merck influence cardiac practice with this particular CME program if rolofylline can never be prescribed?

Using an even more tenuous example, Nissen implied that the American Heart Association had backed away from a study that linked soft-drink consumption with cardiac risk factors and an NEJM-advocated soft-drink tax, on the basis of the AHA's alleged marketing relationship with Coca-Cola. As evidence, Nissen offered up the red-dress logo for The Heart Truth educational campaign, which has been prominently displayed on cans of Diet Coke. Nissed charged that the logo comes from the AHA.

However, on this very circumstantial point, Nissen appears to be wrong in his facts. According to MedPage Today, the logo belongs to the National Heart, Lung, and Blood Institute. Moreover, both the AHA and the NHLBI deny that any money has been exchanged between Coca-Cola and their organizations to produce the campaign. The Heart Truth program is solely funded by government entities, according to an NHLBI spokesperson.

Those physicians who argue that ties between industry and medical practice should be severed may have some valid points, but Steve Nissen didn't deliver their perspective in any compelling fashion in this debate. Like in the recent b-ball champ-ship, the hands-down ACC winner here was (the guy from) Duke.

N.B.--Audio portions of the debate are provided by MedPage Today.

* Nissen called the Accreditation Council for CME, the organization that accredits other organizations to sponsor certified CME, "absolutely pathetic" and a "toothless watchdog."

** Notably the program included faculty from Duke (acknowledged by Nissen) and the Cleveland Clinic (not acknowledged by Nissen).

Image of The Heart Truth campaign logo from the NHLBI web site.

Addendum: The AHA sponsors the trademarked Go Red for Women campaign, which is supported by Macy's and Merck, according to the campaign web site. The campaign's logo (left), while incorporating a red dress, is distinct from The Heart Truth's logo. Both red-dress logos are trademarked by the DHHS.

03/19/10 addendum: Christopher Cannon, Harvard cardiologist and Cardiosource Editor-in-Chief, reviewed the Merck-sponsored CME program that was criticized by Dr. Nissen and provided a lengthy comment at MedPage Today. Among 5 talks, according to Cannon, 4 did not mention Merck's (now defunct) drug in development, rolofylline. The talks covered the pathophysiology and epidemiology of the condition in question, possible interventions, and clinical development. Last a case was presented "where the drug is not mentioned." Cannon counted 130 slides in the CME program, 8 (6%) of which concerned the funder's drug in development. Cannon concluded, "This is I believe a fair balanced program and it does not meet the charaterization [sic] stated by Dr. Nissen." 

Dimebon (latrepirdine), the nonselective antihistamine that Pfizer shelled out millions for, failed to improve cognition or global functioning in a placebo-controlled phase 3 study of patients with mild-moderate Alzheimer disease. The disappointing results were distributed today by way of press release from the drug's codevelopers, Medivation and Pfizer.

In a double-blind study of 598 individuals with AD in North America, Europe, or South America, Dimebon 20 mg tid was no better than placebo for improving or delaying declines in cognition (as measured with the ADAS-cog) or global functioning (as measured with the CIBIC-plus) at 6 months. Measures of secondary endpoints (eg, activities of daily living) were, likewise, similar between Dimebon- and placebo-treated patients.

As expected, the most frequently reported adverse events with the antihistamine were somnolence and dry mouth. A 5-mg treatment arm and another, large phase 3 safety study revealed consistent drug tolerability. For what it's worth, the phase 3 safety study showed that the drug can be taken with common AD medications, like cholinesterase inhibitors (eg, Aricept; Pfizer) or memantine (Namenda; Forest).

Results from the phase 3 efficacy study were to be used in conjunction with positive results from a phase 2 Russian study to support FDA approval. But, evidently, no more. 

In 2008, Pfizer agreed to pay Medivation $225 million upfront and another $500 million when the drug was approved. The agreement also conferred licensing rights to Pfizer for use of the drug in Huntington disease. Last month, results from a 90-day safety trial of Dimebon in HD showed that the drug may improve cognition.

The price of Medivation stock dropped nearly 30 points on release of the phase 3 trial results, from $40.12 to $12.88.

ADAS-cog = Alzheimer's Disease Assessment Scale-cognitive subscale; CIBIC-plus = Clinician's Interview-Based Impression of Change Plus Caregiver Input.

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

Given the exclusion of Doug Bremner's plaintiff-funded PET study from Accutane litigation, specifically Palazzolo et al v Hoffman La Roche et al, the Emory psychiatrist (if he is still allowed to testify*) will need to rely on other clinical studies to convince a jury that Accutane causes depression and, in particular, suicidal depression. (For background on the trial's decision, go here and here.)

However, on this point, results from available clinical studies—none of which is well controlled—are mixed. And some data actually suggest an improvement in depression or anxiety with Accutane treatment.

So what are the data? The following is my review, based on several PubMed searches, of published clinical studies that attempted to assess any link between Accutane (or isotretinoin) use and depression or suicide. Overall I found 5 prospective, cohort studies in which patients received Accutane or a comparator treatment (eg, oral antibiotics), 4 prospective studies without comparator treatment, and 1 large retrospective population-based study. (Note: Case reports or case series are not included in this review.)

Prospective, cohort studies (treatments not randomized)

Ng et al, 2002 (University of Melbourne): Patients with acne (N = 215) received Accutane or antibiotic/topical treatments. No treatment-related differences were noted at 6 months in mean depression or quality-of-life scores, and there was no correlation between Accutane dose and depression score. However, 5 Accutane-treated patients (3%) withdrew from the study because of "worsening of mood." Financial support for the study is unclear.

Chia et al, 2005 (St. Louis University): Patients aged 12-19 years with moderate-severe acne (N = 132) received Accutane or conservative therapy (ie, oral or topical antibiotics or topical retinoid). Among the 101 subjects (77%) who completed the study, CES-D scores suggestive of clinically significant depression and rates of new-onset depression at 3 months were comparable in the 2 treatment groups. The authors found that improvement in acne with either treatment was associated with reduced depressive symptoms. Patients who were unavailable for follow-up did not have significantly different baseline depression scores, and dropout rates were comparable in the 2 treatment groups. The authors reported "None" to financial disclosures.

Bremner et al, 2005 (Emory University): Adults aged 18-50 years with "treatment-resistant" acne (N = 28) received Accutane or oral antibiotics. There were no significant increases in Hamilton depression scores at 4 months with either treatment and no significant between-treatment differences in these scores. Changes in "depression related to acne" were also not significantly different between the treatment groups. There was no correlation between baseline metabolism in the orbitofrontal cortex (an area of the brain implicated in depression), as determined by PET, and depression on any measure used in the study. The study was funded by Accutane plaintiffs (Liam Grant, 80%; Accutane-litigation lawyers, 20%).

Cohen et al, 2007 (University of Calgary): Patients aged 14 years or older with acne (N = 200) received Accutane or oral or topical antibiotics. At 2 months, there was no correlation between Accutane treatment and scores indicating the development of depression (CES-D or Zung Depression Status Inventory). The study was funded by the Centre for Advancement of Health, Calgary.

Kaymak et al, 2009 (University of Gazi): Patients with acne (N = 78) received Accutane or topical treatment. At 2 months, quality of life (measured by using the DLQI) was more impaired in the group receiving topical treatment. At 4 months, measures of quality of life, depression, and anxiety (the latter 2 via the BDI and HAD scale) showed improvement with Accutane treatment. Funding for the study is unclear.    

Prospective Accutane studies without comparator treatment

Rubinow et al, 1987: Patients with cystic acne (N = 72) were treated with 1 of 3 dosages of isotretinoin. The authors observed "significant reductions in anxiety." "[M]itigation of anxiety and depression [was] most robust in those patients with the greatest dermatologic improvement." Financial support of the study is unclear.

Strauss et al, 2001 (University of Iowa). Patients with severe recalcitrant nodular acne (N = 600) received either a micronized formulation of Accutane or standard Accutane treatment in double-blind fashion. At 20 weeks, the rates of adverse events were "generally lower" with the micronized formulation—specifically mucocutaneous events (eg, dry nose, dry eyes) and hypertriglyceridemia. Three patients taking the micronized drug and no patient taking the standard drug withdrew from the study because of depression. Psychiatric adverse events (eg, depression, anxiety, panic) were reported in 11 patients (4%) taking the micronized drug and 1 patient (0.3%) taking the standard formulation (who experienced a panic reaction). The study was funded by Roche. (N.B.—To my knowledge, the micronized formulation never made it to market.)

Ferahbas et al, 2004 (University of Ericyes, Turkey): Patients with "severe recalcitrant acne" (N = 45) received Accutane for 16 weeks. Among the 23 patients (51%) who completed the final assessment, the authors noted decreases in depression and anxiety scores (the latter being statistically significant) from baseline. No patient attempted or committed suicide. The abstract (I was not able to obtain a copy of the full article) does not provide information on the subjects who withdrew from the study. Funding for the study is also unclear.

Rehn et al, 2009 (Helsinki City Health Center): Male military conscripts (N = 135) received Accutane for 12 weeks. Among those who completed follow-up (93%), the mean depression score (via the BDI) and the proportion of patients with clinically significant depressive symptoms or suicidal ideation declined with treatment (the former, significantly). The authors, however, note that "one non-depressed patient attempted suicide while intoxicated with alcohol." It is assumed that the study was funded by the Finnish government, given the nature of the subjects.

Retrospective, population-based cohort study

Jick et al, 2000 (Boston Collaborative Drug Surveillance Program): By using the Canadian Saskatchewan Health Database and the UK General Practice Research Database, the authors analyzed computer-recorded histories from patients with acne who took Accutane (n = 7535) or oral antibiotics (n = 14,376). There was no increased risk of newly diagnosed depression or psychosis or attempted or committed suicide with Accutane exposure. This study, which was funded by Roche, has been criticized for its methodological limitations.

======================

Ten imperfect clinical studies, assessing the relationship between Accutane treatment and depression or suicide, were discovered. Two of these studies (the 2 largest) were funded by Roche, 1 study was funded by Accutane plaintiffs, and the other 7 studies were supported by independent or unclear sources. Overall these studies do not support an association between the available formulation of Accutane and depression or suicide; although Ng et al reported that 5 Accutane-treated patients (3%) dropped out of their study because of worsening mood, and 1 small study reported a high dropout rate for unclear reasons (Farahbas et al). Some studies indicate an improvement in mood with Accutane treatment, on the basis of an improvement in acne.

The prescribing information for Accutane, which is no longer sold by Roche in the United States, contains warnings regarding the risks of depression or suicide with treatment; although "[n]o mechanism of action has been established." On the basis of their study, Ng et al concluded that the potential risk of depression with Accutane treatment is "a rare unpredictable idiosyncratic side-effect."

BDI = Beck Depression Inventory; CES-D = Center for Epidemiologic Studies Depression scale; DLQI = Dermatology Life Quality Index; HAD = Hospital Anxiety and Depression; PET = positron emission tomography. 

* In the recent appellate ruling, the judge wrote, "We therefore remand this case to the trial judge to consider whether Dr. Bremner should be permitted to testify as an expert on general causation, without reference to the PET study. We leave to the judge's discretion whether to permit or require any further proceedings prior to issuing a decision on remand. We do not retain jurisdiction."

Photo of Roaccutane, aka Accutane, from Wikipedia.

Recently I wrote

The reflexive "ick" to plaintiff-sponsored research or, more broadly, litigation-driven research is undoubtedly related to the fact that the outcome is intended to support one side of an argument. This inherent bias in litigation-driven research is, therefore, completely contrary to the fundamental tenet of scientific endeavor, which is to investigate the universe with as much objectivity as possible.

By comparison, there is generally less disgust when considering industry-funded, and in particular, pharma-funded, research—although agendas certainly exist among the financial supporters of these clinical studies. The reasons for the relative ease with which we accept pharma-funded research, despite the fact that these studies are designed and performed to sell prescription drugs, are threefold: 1) there is a longtime precedent of reviewing and accepting pharma-funded research; 2) the intended outcome of pharma-funded research is less overt than that of litigation-driven research; and 3) the drug industry is government regulated. Specifically much of the clinical research supported by pharma, including raw data, is subject to the scrutiny of FDA officials (which is why reasons 1 and 2 exist, for the most part).

But law professor William Childs, in a 2006 paper, argues that litigation-driven research should not be dismissed out of hand by the scientific community. Moreover, litigation-driven research may add importantly to the foundation of science by funding studies that would not have been performed otherwise. And the validity of litigation-driven research, especially if it has been published in a peer-reviewed journal, will likely be subjected to a lengthy Daubert hearing—which is used by many courts to determine the admissibility of expert testimony.

This legal scrutiny of scientific research, Childs argues, goes beyond peer review*—the parameters of which are limited and vary widely from journal to journal—to examine researchers' methodologies and, importantly, their raw data. For instance, in the case of Bremner's Accutane-PET study, a lengthy pretrial court hearing revealed that the authors did not follow their methodology as described, and that there were outcome-altering errors in data entry. Without the hearing and the resulting court opinion, these shortcomings of the peer-reviewed study would not have been known.

It therefore goes to reason that researchers who perform litigation-funded research, knowing that their research will likely be subjected to cross-examining attorneys and the scrutiny of opposing expert witnesses, should be sufficiently motivated to perform their research with irreproachable standards. These standards should certainly include avoiding dishonesty or the appearance of it. 

Childs writes that, while "it is highly unusual for a party's retained expert to testify contrary to the party's litigation position,"** checks exist to ensure the integrity of litigation-driven research through the possibility of subpoenas and depositions and any consequent risk to a researcher's reputation—"the coin of the realm in academia." 

* In fact, Daubert hearings reveal the shortcomings of peer review to reliably ferret out scientific fraud.

** And the plaintiffs' retention of an expert "is dependent on whether the results support the plaintiffs' argument." Recently Bremner emphasized that he was retained as an expert witness by the Accutane litigation plaintiffs after the PET study was completed--which means that his retention as an expert witness by the plaintiffs was dependent on the results of his study.

Image of vintage Pepto-Bismol ad from Flickr.

This under-the-radar news of the NDA submission comes as a surprise—not because the fingolimod NDA was submitted (that was actually expected back in December), but because the news was provided so sotto voce.* I merely stumbled across the information while I was looking for more dirt on the company's recent Trileptal plea agreement.

And just in case I missed news of the NDA submission back in December (despite blogging semi-feverishly about the race between Novartis and Merck Serono to market the first-ever disease-modifying pill for multiple sclerosis), I rechecked the Google news archives. Nope, nothing.**

So the question is: Why no big announcement of the Gilenia NDA submission, Novartis? In typical fashion, Merck Serono trumpeted the submission of its NDA for the fast-track approval of oral cladribine in September.

Perhaps the answer has something to do with the FDA's December announcement that it refused to file Merck Serono's cladribine NDA. But I have to admit: I'm kind of flummoxed.

* Not to mention, a month after it happened.

** Although, last week, both Dow Jones and Reuters reported Novartis's NDA submission of fingolimod. I am mentally flaggellating myself for missing these reports.

However...however.

Decisions have apparently been made that Stanford's Pfizer-funded CME will concentrate on diabetes, cardiovascular disease, smoking cessation, and infections, reports the paper. All of these therapeutic areas are of potential interest to the monolithic company.* For example, Pfizer makes Chantix, a smoking-cessation drug; the blockbuster statin Lipitor; and Caduet, a combo calcium-channel blocker/statin.

Now whether bias is inherent in a CME grant that merely specifies a therapeutic area is up for debate. For instance, see the comments here.

And for the historical record:

1. Last year, Pfizer announced that it would no longer directly provide CME grants to medical education communications companies (MECCs), presumably because of the perception of bias in MECC-produced CME.
2. In 2004, Pfizer agreed to pay the government $430 million to settle allegations of promoting Neurontin (gabapentin) off-label. One alleged off-label outlet: Pfizer-funded CME.**

* Implying here that it might be hard to find a therapeutic area that is not of interest to Pfizer.

** Also 2 months ago, it was revealed that the protocol-defined primary endpoints in company-funded trials of Neurontin were often changed.

No. 9: Belimumab Buzz

There were few notable FDA approvals for "new molecular entities" (NMEs) in 2009:

• Urolic (febuxostat; Takeda) is the first new treatment for gout in more than 40 years. (But come on: it's gout.)
• Simponi (galimumab; Centacor/Ortho Biotech) is yet another TNF inhibitor for rheumatoid arthritis.
• Effient (prasugrel; Lilly) is an antiplatelet therapy poised to take market share away from chemically related Plavix (clodigrel; BMS/sanofi-aventis)—but only in the setting of angioplasty and stent placement.
• Sabril (vigabratin; Lundbeck) is the first anticonvulsant approved for the treatment of infantile spasms, a rare and devastating form of pediatric epilepsy.

And there were drugs approved for even rarer disorders: Ilaris (canakinumab; Novartis), for the cryptic cryopyrin-associated periodic syndromes; and Kalbitor (ecallantide; Dyax) for hereditary angioedema. Add to those: approvals for yet another statin, another fluoroquinolone, another antidiabetic agent...and you get the idea of the ho-hum-ness of 2009.

In pharma, expectations currently run low for groundbreaking treatments, whether for rare or common disorders. One exception, however, may be Benlysta (belimumab). The human monoclonal antibody, codeveloped by Human Genome Sciences and GSK, inhibits the activity of B-lymphocyte stimulator (BLys), which otherwise promotes the survival of antibody-producing B cells. The drug's mechanism of action supports its use in autoimmune disorders, like systemic lupus erythematosus (SLE).

To that end, favorable data from 2 phase 3 trials of Benlysta (BLISS-52 and BLISS-76) in patients with SLE were reported in July and November. The positive clinical data are notable, because there hasn't been a new treatment for the 1.5 million Americans with lupus in about 30 years, says the Lupus Foundation of America. Even the almighty Rituxan (rituximab; Genentech/Roche) bit the dust this year in phase 3 studies of patients with SLE. And another great hope for SLE, CellCept (mycophenolate mofetil; Roche), died a death of noninferiority after it performed no better than cyclophosphamide for the induction treatment of lupus nephritis.

Excitement over Benlysta should be tempered, however, by the fact that neither phase 3 study has been published in a peer-reviewed journal—yet. Human Genome Sciences indicates that applications for the approval of Benlysta in the United States and Europe will be submitted during the first half of 2010. 

TNF = tumor necrosis factor.

What do we want? Raw data! When do we want it? Now!

In the midst of the 2009 pandemic influenza epidemic, BMJ editor Fiona Godlee takes Roche to task for not supplying the necessary data to confirm or refute the benefits of oseltamivir (Tamiflu) in otherwise healthy people with influenza. In one of 2 BMJ editorials, Godlee chides Roche for not supplying unconditional access to raw data from a pooled analysis of 10 company-sponsored trials (Kaiser et al; PubMed link here) to Cochrane reviewers Jefferson et al. Consequently the reviewers were "obliged to disregard" the bulk of these data (8 of the 10 trials) and were unable to verify that oseltamivir prevents lower-respiratory-tract complications (eg, pneumonia) due to influenza.

In their previous 2006 Cochrane review, Jefferson et al had concluded that oseltamivir 150 mg daily prevents such complications on the basis of the Kaiser article. However, the authors were criticized through a public feedback mechanism for using the 10-trial analysis without having access to the raw data. Prompted by this criticism, Jefferson et al then conducted another review, published this week in the BMJ, in which they affirmed their critic's perspective:

Data on the effectiveness of oseltamivir against complications of influenza principally came from one study...This was a meta-analysis of 10 trials containing a mixture of published and unpublished data, two of which are reported in this update and the remainder inaccessible to proper scrutiny, so that we are now obliged to disregard them. The remaining data showed no benefit for oseltamivir against complications.

In her editorial, Godlee asks, "Where does this leave oseltamivir, on which governments around the world have spent billions of pounds?" She, moreover, emphasizes that the Cochrane review data apply only to healthy adults with influenza, but they "say nothing about [oseltamivir's] use in patients judged to be at high risk of complications—pregnant women, children under 5, and those with underlying medical conditions." Even the drug's ability to reduce influenza-related symptoms (which Jefferson et al reconfirmed) are doubted, because there are no head-to-head studies with oseltamivir and NSAIDs, for instance.

In another BMJ editorial (with Cochrane director Mike Clarke), Godlee concludes that the latest Cochrane review and a "linked investigation undertaken jointly by the BMJ and Channel 4 News cast doubt not only on the effectiveness and safety of oseltamivir (Tamiflu) but on the system by which drugs are evaluated, regulated, and promoted." In their investigation, Cochrane reviewers became concerned about the actual involvement of listed authors on the Kaiser analysis, the possibility of ghostwriting, the high rates of influenza in the trials, and the low rates of serious adverse events.

Initial responses from Roche employees, who first declined to provide the data and then offered selected files, were less than satisfactory to the reviewers. The latest response from the company: it is "committed to making the 'full study reports' available on a password protected site soon."

On the basis of this experience, Godlee and Clarke conclude that the current system for reporting drug research "isn't working" and offer a number of potential remedies—including government-mandated access to raw data that are used to license and market a drug (eg, something in the spirit of the FDA Amendments Act of 2007).

News sources are all over this story (eg, Bloomberg), and the BMJ offers full-text access to the following relevant articles, including a response from a Roche employee—who chastises Jefferson et al for enlisting the investigative help of a TV news station.**

• Godlee F. We want raw data, now.
• Godlee F, Clarke M. Why don't we have all the evidence on oseltamivir?
• Smith J, on behalf of Roche. Roche replies to the authors of the Cochrane Review on oseltamivir.
• Cohen D. Complications: tracking down the data on oseltamivir.
• Doshi P. Neuraminidase inhibitors--the story behind the Cochrane review.
• Freemantle N, Calvert M. What can we learn from observational studies of oseltamivir to treat influenza in healthy adults?
• Jefferson T, Jones M, Doshi P, Del Mar C. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis.
• Web extra (including the criticism that got the ball rolling).

* And I mean that in the nicest possible way.

** Roche's Smith writes, "It is unclear to us why Dr Jefferson would adopt this approach, particularly given that he was a paid ad hoc consultant to Roche working on flu and oseltamivir between 1997 and 1999. During that period he worked closely with Roche experts, many of whom are still in the company, and he would therefore not have had difficulty in contacting them directly to discuss his requirements."

Photo from Vermin Inc at Flickr.

For what it's worth (perhaps a teeny-tiny indicator of an economic rebound?), pharma's spending on direct-to-consumer (DTC) advertising increased substantially during the third quarter of this year, to about $1.26 billion according to data from TNS Media Intelligence.* Numbers provided directly by the "intelligence" firm indicate that pharma's investment in DTC advertising increased by nearly 16% during July-September of 2009, when compared with DTC expenditures during the same time last year.

The following figures from TNS show that the latest quarterly increase in pharma's DTC ad spend has stabilized the declining trend in DTC investment for the year. (According to the latest data from the Congressional Budget Office, DTC expenditures by pharma totaled $4.7 billion in 2008—which has declined from a peak of $5.4 billion in 2006.)

Television advertising still gets the biggest share of the DTC pie, about 65% of the outlay, according to the data; although investment in TV prescription drug ads dropped slightly (by 3.9%) during the first 2 quarters of 2009. Spending on Internet-based drug advertising (ie, banner ads) increased dramatically during the first half of the year, from about $36 million in 2008 to roughly $116 million (an increase of >200%).

DTC Perspectives,* also referencing data from TNS Media Intelligence, indicates that spending on Internet-based ads more than tripled during the first 9 months of 2009, to $221 million.

Money spent advertising the top 10 promoted drugs to consumers accounted for nearly 40% of DTC expenditures during the first half of 2009. Again, these data are provided directly by TNS Media Intelligence.

* DTC Perspectives, citing TNS Media Intelligence, indicated that pharma's DTC spending for Q3 of 2009 was about $1.16 billion, which is $100 million off from my calculation. DTC Perspectives Q3 calculation was requoted by Pharmalot.

Although the FDA has not publicly addressed its refusal to file Merck Serono's cladribine NDA, the agency's John Jenkins, director of the Office of New Drugs, provides a hint, according to the blog. Yesterday, during the FDA/CMS Summit, Jenkins addressed the agency's refuse-to-file notifications and a primary reason for drawing them up.

Jenkins implicitly chastised pharma for submitting incomplete NDAs and then providing additional information during the drug-review process—which may require an extension owing to the lack of necessary data.** Jenkins reportedly said that pharma execs who delay the submission of an NDA to ensure its completeness will ultimately save themselves time.

NDA = new drug application; PDUFA = Prescription Drug User Free Act.

* Hey, In Vivo Blog, you can quote the flattery.

** And thereby violates the 6-month "PDUFA clock."

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

The crux of their findings:

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

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

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

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

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

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

2. Converted to 2005 USD.

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

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

Image of Plavix box from Wikimedia Commons. 

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

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

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

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

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

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

* Without a darned-good reason.

1. While the estimated, annual spend on DTC advertising for prescription drugs is approximately $4 billion (according to most sources), the DTC spend has actually been decreasing since 2006 (from a peak of $5.4 billion). One pundit predicts that the total dollars dished out for DTC ads this year will shrink by 11%. The prevailing speculation for the trend: general economic constraints. Clearly decreases in DTC spending do not parallel steadily increasing healthcare costs, including costs for prescription drugs (see item 2).
2. While prescription drugs (along with "nondurables") are, in fact, the third most costly aspect of the US healthcare system, they account for only about 12% of the overall healthcare spend (and are arguably one of the most cost-effective aspects of healthcare). In 2006, the spend on outpatient care was $850 billion (~41% of overall costs), and that on inpatient care was $458 billion (~22%), according to the McKinsey Global Institute. From 2003 to 2006, the costs for outpatient care, inpatient care, and drugs grew annually at rates of 7.5%, 6%, and 6.9%, respectively. The rise in prescription drug costs is due "almost equally" to an increase in consumed drug volume and a rise in drug costs. These increases have been offset, however, by "a [small] trend toward a less expensive drug mix."
3. While it is generally quoted that Americans received an average of 12 prescriptions in 2008,* they use approximately 10% fewer drugs (on a per capita basis) than Europeans and Australians—again according to the McKinsey Global Institute. Prescription drug prices in the United States are about 50% higher than those for Europeans. (Notably branded drugs for Americans are about 77% more expensive, but US generic drugs are about 11% cheaper.) The higher cost of prescription drugs for Americans is due to the use of a more expensive "drug mix"** and higher drug prices. It is generally believed that higher US drug prices subsidize pharmaceutical R&D for the world; however, the R&D subsidy does not sufficiently explain the higher costs of branded drugs for Americans.

* Note that this statement does not indicate that Americans consume 12 prescription drugs simultaneously on a regular, daily basis.

** Although there is a small trend among Americans toward a less expensive drug mix (see item 2).

Image of Novartis's now-defunct Digger the Dermatophyte for Lamisil: Not just responsible for toenail fungus, according to NPR.

The recent publication of commercial payments to physicians allows anyone to compare these data with information disclosed by the very same physicians. And that's just what a few orthopedic surgeons systematically did. Their analysis of their colleagues' disclosures, or lack thereof, is available in the latest issue of the NEJM.

The authors compared online reports of payments in 2007 from the 5 major prosthetic-joint companies (Biomet, DePuy, Smith and Nephew, Stryker, and Zimmer)* with payments voluntarily disclosed by physician participants at the annual meeting of the American Academy of Orthopedic Surgeons (AAOS).

Their findings:

• About one quarter of the commercial payments in 2007 (344/1347) were made to physicians who were AAOS meeting presenters, committee members, or board members in 2008.
• 146 (42%) of these payments exceeded $100,000 (each); 135 (39%) ranged from $10,000 to $100,000; and 63 (18%) were less than $10,000. (From Figure 2, it appears that close to 40 payments exceeded $1 million each.)
• In most cases, payments were made directly to physicians (78% of payments) and were directly related to the presentation topic (70% of payments).
• The overall disclosure rate was 71% (245/344 payments)—meaning that nearly 30% of payments to orthopedic surgeons were not voluntarily disclosed, despite the fact that the meeting's disclosure instructions were broad.**
• Compliance with disclosure was somewhat higher for direct payments (79%) and was substantially lower for indirect payments (50%). (An indirect payment is made through another company or organization—for instance, a medical-education communications company, or MECC.)
• The total amount of undisclosed direct payments (n = 43) exceeded $4 million; the total amount of undisclosed indirect payments (n = 16) exceeded $7 million.
• Payments were more likely to be disclosed if they exceeded $10,000, were given to an individual physician, or included in-kind support.
• Reasons for nondisclosure (from those few nondisclosing, surveyed physicians who responded) included 1) the payment was unrelated to the presentation topic; 2) the disclosure requirements were misunderstood; or 3) the disclosure was incorrectly printed.

* The companies' publication of physician payments in 2007 was required as part of a DoJ settlement.

** The meeting participant was directed to make a disclosure "if he or she has received something of value from a commercial company or institution, which relates directly or indirectly to the subject of their presentation."

In its recent "free-speech" complaint for declaratory judgment and injunctive relief against the US government, Allergan proposes its "speech" to healthcare providers about the risk of Botox spread after injections for spasticity—an off-label indication. But the company logically fears that its proposed speech, which would include only truthful, nonmisleading statements about the off-label use of Botox, puts it in criminal and civil jeopardy. (For background on this story and the FDA's safety requirements re Botox risks, go here.)

First Allergan claims that the FDA-approved boxed warning for Botox,* the mandated Dear Health Care Provider letter, and altered Medication Guide provide only general warnings about the distant spread of toxin. These communications do not provide specific guidance for physicians**—for instance, details about patient selection, toxin dose, number of injection sites, frequency of administration, and injection technique—that would tangibly reduce the risk of remote spread when using Botox for spasticity. Allergan also proposes that it would inform physicians about the expected time frame to observe a therapeutic effect with Botox, when used for spasticity.

Allergan acknowledges that its proposed speech would not alter the official labeling for Botox, but the company recognizes that much of its proposed speech would "fall within the FDA's expansive definition of 'labeling'" and could lead to federal misbranding charges. Discussions about the safety of Botox treatment for spasticity may also be interpreted as promoting Botox for spasticity, and such an interpretation could lead to federal charges of distributing an unapproved "new drug" in the eyes of the FDA (meaning, an existing drug for a new indication).

Following the logic a step further, Allergan writes: "Even by filing this complaint and thereby exercising its First Amendment right to petition the Government, Allergan fears that it will run afoul of the FDA's regulatory regime by demonstrating its knowledge that Botox is sold to physicians who use it to treat spasticity and other off-label conditions. On the Government's view, Allergan's possession of this knowledge—and its choice to defend its constitutional rights—violates 21 CFR §201.128 [which relates to the drug maker's knowledge of intended uses] on its face."

Allergan justifies its fear of prosecution for the off-label promotion of Botox by acknowledging that the company is the subject of a DoJ investigation in the Northern District of Georgia.

* Text of boxed warning advising of distant spread of toxin: "Postmarketing reports indicate that the effects of Botox and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children and adults, and in approved indications, cases of spread of effect have occurred at doses comparable to those used to treat cervical dystonia and at lower doses."

** Allergan reports that it "does not seek to engage in direct-to-consumer communications about the off-label use of Botox."

Case in point: Scott Harkonen

The former CEO of InterMune, was found guilty of wire fraud last week in a San Francisco federal court, reported the DoJ in a September 29 statement.* As a result, Harkonen faces up to $250,000 in fines and 20 years in prison. The jury-trial conviction relates primarily to a press release issued by InterMune on August 28, 2002, and reportedly at Harkonen's direction. 

The InterMune press release in question (reprinted here) claimed, in blatant up-front fashion, that the company's drug Actimmune (interferon gamma-1b) improved overall survival in a phase 3 study of patients with mild-moderate idiopathic pulmonary fibrosis (IPF). However, the trial results failed to show a statistical difference in progression-free survival, the trial's primary endpoint, between Actimmune and standard corticosteroid treatment. News of the missed primary endpoint was buried in the first paragraph of InterMune's press release and overshadowed by follow-up praise for the trial results provided by Harkonen and the study's lead investigator, Ganesh Raghu.

In January 2004, Raghu and his scientific colleagues published the results of the same trial in the NEJM. There the peer-reviewed data failed to show that Actimmune significantly improved progression-free survival, pulmonary function, or quality of life. Later that year, the DoJ launched an investigation of InterMune and its promotion of Actimmune for the off-label indication of IPF. The investigation culminated in InterMune paying a $37-million settlement to the government in October of 2006 (for a detailed timeline of InterMune's troubles, go here).** Harkonen was separately indicted by the DoJ in March of last year.

Harkonen resigned from InterMune in June 2003 and is currently President and CEO of Comentis, a San Francisco-based biotech. Notably, in his legal defense, Harkonen claimed that the InterMune press release should be protected by the free-speech clause of the First Amendment. Harkonen argued that he was engaging in "scientific debate"; the judge, however, failed to buy the argument, possibly because she found the press-release statements to be misleading.

* Harkonen was simultaneously acquitted of a misbranding charge.

** In 2007, the clinical investigation of Actimmune in IPF was abandoned by InterMune after interim results of another phase 3 trial showed no survival benefit with drug. InterMune is currently investigating pirfenidone in IPF.

Last week, Allergan, maker of Botox (onabotulinumtoxinA), announced a suit against the US government, seeking "declaratory relief" from such long-time federally mandated off-label speech restrictions.* The complaint, filed in US District Court for the District of Columbia, specifically applies to the sharing of information about Botox Therapeutic (not Botox Cosmetic) and recent requirements of the FDA's Risk Evaluation and Mitigation Strategies (REMS) program. In its complaint, the company is represented by Paul Clement, former Solicitor General and a current partner in the DC law firm of King & Spalding.

Allergan's suit was filed with respect to the FDA's REMS program for botulinum toxin products. The program was instituted this year because of postmarketing reports of toxin spread after injections for off-label conditions—namely, spasticity in children with cerebral palsy and arm spasticity in adults. In the program, the FDA requires manufacturers to create a "communication plan" that provides information to physicians about the risk of the distant spread of botulinum toxin after local injection.

But Allergan argues that the FDA's required communication plan puts the company in a double bind—effectively mandating proactive discussions about the safety of off-label Botox Therapeutic, while simultaneously prohibiting proactive off-label discussions. Allergan claims that it cannot reasonably abide by the FDA's REMS program for Botox Therapeutic (ie, "proactively provide comprehensive information to physicians about these off-label uses [emphasis added]") without fear of prosecution. The company writes, "Allergan seeks a judgment that would permit it to provide currently available and truthful information to doctors for common off-label uses of [Botox]."

In a conference call on Friday, Allergan's General Counsel, Douglas Ingram, provided additional information about the complaint and fielded questions. Ingram stressed that the company's suit applies to the provision of "truthful," "nonmisleading," and "comprehensive" information about the off-label uses of Botox Therapeutic. Ingram would not comment on a recent investigation of the company by the US Attorney's Office for the Northern District of Georgia, which issued a subpoena in March to the California-based firm regarding the alleged off-label promotion of Botox for headache. Both Ingram and Allergan CEO, David Pyott, stressed that the company's current complaint does not relate to alleged past activities. Ingram also declined to comment on Pfizer's recent record-breaking $2.3-billion settlement with the government concerning off-label drug promotion.

* Mandated by the Federal Food, Drug, and Cosmetic Act of 1938. The FDCA dictates that an approved drug is "misbranded," if it is marketed (in interstate commerce) for an unapproved use. The act stipulates that the product's approved label, in this case, does not provide "adequate directions for use."

Back in May, the Japan-based Eisai informed Pfizer that it had a legal right to terminate their copromotion of the drug, in place since 1994, because of Pfizer's anticipated acquisition of Wyeth. But Pfizer understandably bristled at the threat, given that Aricept generated $482 million in sales for the US firm in 2008.

The new agreement, according to Eisai's press release, continues to allow the companies to comarket Aricept in the United States, Japan, and "key markets in Europe" until 2022. However, copromotion in Japan will cease by 2013, with rights there reverting back solely to Eisai (which discovered the drug).*

The new agreement also launches a long-term comarketing deal for Pfizer's blockbuster drug Lyrica (pregabalin), which is approved in the United States for the treatment of neuropathic pain, epilepsy, and the ever-controversial fibromyalgia. An NDA for the drug has reportedly been filed in Japan. According to the AP, Lyrica generated $2.6 billion in worldwide sales last year.

* Eisai says that the basic patent on Aricept expires in 2010.

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.

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.

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.

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. 

* 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.

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.

Yesterday the FDA announced generic (or nonproprietary) name changes for 2 approved versions of injectable botulinum toxin.* Botox (Allergan), formerly botulinum toxin type A, is now onabotulinumtoxinA; and Myobloc (Solstice Neurosciences), formerly botulinum toxin type B, is now rimabotulinumtoxinB. The generic name for the most recently approved version, Dysport (Tercica), remains abobotulinumtoxinA. The names were changed to emphasize the different potencies of the products—the unit dosages of which are not interchangeable.

In the United States, nonproprietary names for drugs are assigned by the US Adopted Names (USAN) Council, a long-time collaboration among the American Medical Association, the US Pharmacopeial Convention, the American Pharmacists Association, and the FDA. The USAN Council works closely with the International Nonproprietary Names Programme of the World Health Organization to provide standardized and consistent drug names for worldwide use.

According to WHO, nonproprietary names "have to be distinctive in sound and spelling, and should not be liable to confusion with other names in common use"—an explanation which clarifies the unwieldy length of some generic drug names and their near unprounounceability. Pharmacologically related drugs should also share a common stem, which explains why all generic names for therapeutic monoclonal antibodies (mAbs) end with the -mab suffix (eg, rituximab, belimumab). For botulinum toxin products, the names are evidently distinguished by a short prefix (ie, ona-, rima-, and abo-) and the tail designator of "A" or "B," which denotes the toxin type.

Clearly pharmaceutical marketers take advantage of cumbersome generic names by assigning catchier and easier-to-pronounce trade names. For instance, who's going to say, "Hand me the syringe of onabotulinumtoxinA"?

* The FDA also announced that the labels of botulinum toxin drugs would now carry a boxed warning, describing the potential spread of the toxin and the attendant, possibly life-threatening effects.

 ...before looking forward.

Pathophilia's Top 10 Medical Stories of 2008: A Recap

10. Gunvalson v. PTC Therapeutics

9. California v. Roozrokh and Cardiac-Death Organ Donation

8. Hand, Foot, and Mouth Disease in China

7. Continuing Backlash Against Pharma

6. Media Obsession With Delayed Results of ENHANCE Trial

5. Investigational Drugs for Alzheimer's Disease Disappoint

4. Milder Rotavirus Season Coincides With Vaccine Uptake

3. USAMRIID Scientist Identified as Sole Perpetrator of "Anthrax Letter Attacks"

2. Resurgence of Measles

1. Intentional Drug and Food Tampering in China

Other notable stories of 2008 that didn't make Pathophilia's totally arbitrary list:

• More cases of progressive multifocal leukoencephalopathy (PML) with Tysabri (natalizumab) use
• Pig-slaughter neuropathy
• US government compensates Poling family for vaccine-related autism
• Ted Kennedy diagnosed with glioblastoma multiforme

The popular and continuing backlash against the pharmaceutical industry and its potential influence on the practice of medicine (and the practice of academic medicine, in particular) led to a number of notable events this year.

The most tangible is legislation dictating pharma and physician conduct—specifically, the Massachusetts Health Code Bill, which bans pharma gifts and meals to Massachusetts physicians and requires them to report pharma payments for their consulting and speaking services. The legislation is in the spirit of the updated PhRMA Interaction Code, which goes into effect January 1 and bans non-educational gifts—like branded pens, notepads, and stress balls—from pharma or medical-device companies to healthcare professionals.

A prime issue informing these actions is whether pharma money biases the treatment recommendations of key opinion leaders in academia. Notable academic psychiatrists specifically* were caught in the crosshairs of anti-pharma bulldog Senator Chuck Grassley, the national press, and interested bloggers, who charged that these influential physicians failed to report the payment of hundreds of thousands of dollars from pharma.

Another important factor is whether pharma currently holds undue influence over the content of continuing medical education (CME) that it supports financially. Some pharma companies (eg, Lilly), without withdrawing CME support altogether, have agreed to publicly disclose their CME funding to outside groups in a show of conscientiousness and in response to a request from Senator Grassley. Others (ie, Pfizer) cut off direct CME grants to medical education communications companies (MECCs), a probable PR move that is based on the perception of (and not so much actual) bias in MECC-produced CME specifically.

And if academic isolation from pharma is not possible (or very smart), then transparency is next to godliness. This year, the web site of The Cleveland Clinic began disclosing information about its physicians' financial ties to industry; although specific dollar amounts and research funding from pharma are not currently provided. In addition, the University of Pennsylvania recently reported that it will create a searchable web site that discloses the industry relationships of its physicians.

Straggling behind in this anti-pharma zeitgeist is the nearly toothless Accreditation Council for CME (ACCME), the accreditor of CME providers and, like many a bureaucracy, an apparent fan of abstruse verbiage. This year, the ACCME promised to enhance its monitoring and surveillance of CME production (by increasing its fees) and proposed harsh limits on CME production that demonstrated little practical forethought.

* Namely Joseph Biederman of Harvard, Alan Schatzberg of Stanford, and Charles Nemeroff of Emory.

The types of potential conflicts to be posted by Penn are not specified; however, the institution has a longstanding reputation for being relatively pristine, providing few (if any) opportunities for its residents and faculty to interact with pharma.* My estimation, if history is any guide, is that there will be little to disclose. Penn already bans its staff from accepting industry gifts, meals, and even drug samples, and the institution does not allow its name to be posted on pharma-supported CME.

Although the Cleveland Clinic discloses pharma-related royalties, equity interest holdings, and speaker or consulting fees (>$5000) received by its physicians, it fails to provide other, potentially relevant information like research grant support or actual dollar amounts received by faculty. For instance, the web page for Steven Nissen—head of cardiology, harsh critic of Vytorin (ezetimibe/simvastatin; Merck/Schering-Plough), and apparent lover of Crestor (rosuvastatin; AstraZeneca)—discloses no "applicable" financial relationships and reports that he donates all honoraria or consulting fees directly to nonprofit organizations. But other sources (eg, here) indicate that Nissen has received research support—life's blood for any academician—from a number of companies, including AstraZeneca.

* From 1986-1991, I never saw a drug rep in the Department of Medicine or Neurology, and I knew of noone who collaborated with industry on research at the time.

While sympathies for anyone with an untreatable and ultimately fatal condition—like Duchenne muscular dystrophy (DMD)—are undeniable, the right for such a person to access an experimental, proprietary therapy is not clear. There's the issue of unproven safety (not to mention efficacy) and the violation of numerous clinical-trial protocols (on which evidence-based medicine rests) that control important variables—like an enrollee's health status, the double-blind process, and randomization of treatment.

Nevertheless, a New Jersey federal judge ruled yesterday that a 16-year-old boy with DMD, Jacob Gunvalson, should have access to PTC124, a drug in clinical-phase development by PTC Therapeutics. According to PTC's web site, a phase 2b trial of the drug is being conducted in ambulatory DMD patients with a nonsense mutation. PTC124 is an orally administered, small molecule that targets this particular mutation type.

It has not been reported if Gunvalson even harbors a DMD nonsense mutation (if not, the use of PTC124 would be, well, nonsense). Also photographs in news reports suggest that the teenager, shown in a wheelchair, is not sufficiently ambulatory at his age to qualify for the PTC trial. Confirmed particulars of the case, expected to be available in the judge's forthcoming written order, should answer these and other issues* that may have implications for anyone seeking access to experimental treatments.

According to the NYT, PTC Therapeutics plans to appeal the decision, and federal regulators must still approve Gunvalson's application to use PTC124.

* For instance, will Gunvalson even be considered an enrollee in the phase 2b trial, should he receive PTC124?

Among the compromises reached by the Massachusetts legislature last week in its health-code bill is the stipulation that drug companies will report any physician gifts exceeding $50 to the state's Department of Public Health. The bill now awaits the signature of Governor Deval Patrick, but 5 trade groups* are attempting to persuade the governor not to sign by way of a full-page ad in The Boston Globe.

In addition, PhRMA senior vice president Ken Johnson wrote yesterday in a press release that the public disclosure of gifts "could chill ongoing clinical research in the commonwealth." Johnson proposes, "Physicians and other healthcare providers who do not want such personal information disclosed may decide to no longer work with the pharmaceutical research companies sponsoring the clinical studies." He adds, "Public disclosure of a pharmaceutical company's arrangements with the principal investigators of its clinical trials also would reveal sensitive, proprietary business information to a company's competitors. This could erode the independent decision-making of companies trying to bring science from research facilities to patient care settings."

However, it seems unlikely that Massachusetts physicians would forego pharma research grants for clinical study given 1) the nature of this particular "gift" and 2) the fact that grant information is already publicly available through the NIH database at clinicaltrials.gov (although the size of the grant, to my knowledge, is not provided).

As far as public disclosure revealing "sensitive, proprietary business information," PhRMA's Julie Corcoran tells Pharmalot that, according to the bill, companies "shall disclose...the value, nature, purpose, and particular recipient of any fee, payment, subsidy or other economic benefit"—which, she argues, is subject to overly broad interpretation. But again, in the case of clinical grants, the nature, purpose, and recipient of the funds are already available through the NIH registry.

* Biotechnology Industry Organization, Massachusetts Biotechnology Council, Associated Industries of Massachusetts, Massachusetts High Technology Council, Cambridge Chamber of Commerce, and PhRMA.

8/11 update: The Boston Globe reports that Governor Patrick signed the bill yesterday.

Yesterday, the Massachusetts House and Senate reached anticipated compromises on a widely discussed pharma-code bill, reports the Boston Globe. The drafted bill, which is expected to be approved and sent to the state governor this weekend, now requires the following:

1. Companies will report any physician gifts exceeding $50 to the state's Department of Public Health, and the DPH should post this information online for public access.
2. The DPH will adopt something like the recently unveiled, voluntary PhRMA code, which bans branded trinkets and out-of-office meals with reps.
3. A $5000 fine will be levied for each violation by pharma or medical-device companies.

According to the Boston Globe, the bill will require that pharma adopt a marketing code of conduct, like the one PhRMA unveiled last week, which eliminates drug-branded tchotchkes, other noneducational gifts, and anything more than pizza or sandwiches during working hours.

Unlike the PhRMA code, however, the Massachusetts bill bans pharma's purchase and use of drug-prescribing information. New Hampshire's attempt to limit the use of these data by drug companies was judged last year to be an unconstitutional violation of commercial free speech. The AMA currently offers an opt-out program to physicians, which contractually obligates pharma from sharing their prescribing information with reps.

July 17 update: The Massachusetts House unanimously approved the watered-down bill, according to today's Boston Globe. But the House voted to delay the effective date of the part of the bill that bars the purchase by pharma of prescription info (to November 2009), while New Hampshire wrestles with the issue of commercial free speech. The differences between the bill passed in the Senate and the bill passed in the House will probably be reconciled before the end of the month, the paper writes.

That's when PhRMA's updated code on industry's interactions with healthcare professionals—which is now banning non-educational gifts like pens, mugs, notepads, and (alas) stress balls—will go into effect.* Drug reps may continue to provide "modest" educational items (costing less than $100) to physicians, like medical textbooks or patient-education anatomical models. But other items, like stethoscopes, pedometers, and DVD players, are not acceptable—even if used for patient education or to promote healthy behavior. The updated code outlines other acceptable interactions in a number of contexts.

Rep visits: Reps may continue to present educational, scientific information to healthcare professionals during their work day, including mealtimes, and reps may provide "occasional, modest" meals like sandwiches or pizza to healthcare attendees. However, these visits are limited to the office or hospital, and no spouses or guests are allowed to attend. The PhRMA code also emphasizes no scavenger-like "dining and dashing."

CME: Drug companies should separate their CME grant-making functions from their sales and marketing departments (a move that most, if not all, companies have already undertaken within the last few years). Funding companies should not advise or guide the content or faculty selection for the CME program, even if asked by the CME provider. Healthcare professionals who attend industry-funded CME should not be reimbursed for their travel, lodging, or other personal expenses. That means no parking validation; so don't even ask.

However, in the brief time provided, Stossel did attempt to consider the unintended and uninvestigated consequences of banning low-ticket pharma gifts (eg, pens, notepads, sandwiches), such as the loss of state business and jobs. It is important to note that there is little-to-no evidence indicating that such gifts negatively affect physician behavior or health care outcomes. Stossel also indicated that the ban may limit pharma funding to state institutions for research.

On the other hand, Daniel Carlat—a proponent of banning all pharma gifts and pharma-funded CME—would have you believe that physicians are incapable of autonomous judgment and should, therefore, be subject to his non-evidence-based gut morality.

Photo: iStockPhoto.

Yesterday, industry chemist Derek Lowe (In the Pipeline) directed attention to a study in the latest issue of Nature Reviews Drug Discovery, which assessed drug-development approval and failure rates. This information relates directly to a recent mini-investigatory post here at the Pathophilia blog describing the success rates of phase 3 drug trials.

The article's authors (from Bear Stearns Health Innoventures [yeesh, hate the portmanteau]) present the FDA-approval and phase-3-failure rates of drugs during a 2-year period (from January 2006 to December 2007) for biotechs, pharma, biotech-pharma alliances, and pharma acquisitions as percentages of the total approvals and failures, respectively.

However, I agree with Lowe and find the numbers more informative when the data are sliced to examine the ratio of FDA approvals to phase 3 failures. Following Lowe's lead, I've manipulated the data a tiny bit further to provide the phase 3 success rates (meaning the percentage of phase 3 trials that lead to FDA approval) by industry type: