bmartin: April 2008 Archives
The US Food and Drug Administration wants to hire more than 1300 people during fiscal year 2008, according to today's press release. That's nearly 3 times the number of people who were hired during the previous 3 years, reports the agency.
Critically needed are medical and science professionals to fill new and existing positions throughout the FDA's various divisions to implement the FDA Amendments Act of 2007, the Food Protection Plan, and the Import Safety Action Plan. The FDA also writes that qualified candidates could be on the job in as little as 3 weeks at any number of locations, including in the DC headquarters area, across the country, or overseas.
FDA job fairs will begin mid-May and continue through September at various conferences throughout the country, including those in DC, Dallas, Boston, Denver, Seattle, San Diego, New Orleans, Columbus (OH), and Philadelphia. An overseas job fair in May will be held in Bonn, Germany. The FDA also makes it easy to apply online by submitting a CV and cover letter to JOINOURTEAM@FDA.GOV. Good luck.
Hyperlipidemia appears to provide an important survival benefit in amyotrophic lateral sclerosis (ALS), according to a French study published in the March 25 print issue of Neurology and online January 16. (I know, ancient history in the blogosphere, but to paraphrase former SNL news anchor Norm Macdonald, it's news to me). Specifically ALS patients with a high LDL:HDL ratio lived approximately 1 year longer than those patients with a low ratio (median survival: 49.2 ± 4.2 vs 36.7 ± 2.7 months)—a remarkable difference. For comparison purposes, riluzole (Rilutek; sanofi-aventis), the only FDA approved medication for ALS, has been shown to prolong survival by 2-3 months.
The study also confirmed that a substantial percentage of individuals with ALS exhibit findings consistent with hyperlipidemia. As a group, the ALS patients examined by the French investigators demonstrated significantly higher levels of total and LDL cholesterol and a significantly higher LDL:HDL ratio than age- and sex-matched controls.
Given their findings, the study authors advise against the use of lipid-lowering medications in ALS patients and strongly recommend that nutritional status should be made a priority in affected individuals. A letter in response to the French study reminded readers of a 2007 report in Drug Safety, which suggested that statin therapy may increase the risk of ALS or an ALS-like condition.
More detailed coverage of the French study and related information can be found in the April 17 issue of Neurology Today (however, online access is typically delayed several weeks and may require a subscription).
The monoclonal antibody Rituxan (rituximab) is not clinically effective in patients with systemic lupus erythematosus (SLE) who do not have lupus nephritis, according to data from a 52-week phase 2/3 study. The results were announced today by the drug's US comarketers, Genentech and Biogen Idec. A phase 3 study of Rituxan in lupus nephritis, which affects approximately one third of SLE patients, is currently recruiting subjects.
In today's reported study, 257 patients with moderate-to-severe SLE received 2 infusions (15 days apart) of randomized Rituxan or placebo in a double-blind fashion, in addition to background prednisone therapy. Patients were retreated at 6 months and evaluated every 4 weeks. At 1 year, the proportions of patients who reached the primary endpoint—a major or partial clinical response per the BILAG index score—were not statistically different between the 2 treatment groups. (Percentages were not provided in the companies' press release.) The assessment of 6 secondary endpoints also failed to show statistical treatment differences.
Current long-time therapies for SLE, which may affect more than 1.5 million Americans according to the Lupus Foundation of America, include corticosteroids; the corticosteroid-sparing agents methotrexate, cyclophosphamide, and azathioprine; and the anti-organ-rejection agent mycophenolate mofetil (CellCept; Roche). Given the potential roles of B cells in the pathogenesis of SLE, including antigen presentation and the production of autoantibodies, the investigation of anti-B-cell therapies like Rituxan in SLE is mechanistically founded. Another B-cell targeted therapy, which is entering phase 3 development in SLE, is belimumab (LymphoStat B)—a fully human monoclonal antibody that inhibits the cytokine B-lymphocyte stimulator (BLyS).
BILAG = British Isles Lupus Assessment Group.
Damn, kids. Just say "no" to free tuna hoagies.
That's the recommendation from a task force created by the Association of American Medical Colleges. The report proposes that any gifts from pharma—including food, medical instruments, or ghostwriting services*—should be banned from all US medical schools. And because a large chunk of medical-school education takes place within affiliated hospitals, the proposal would logically extend to these training sites as well.
The task force included representatives from medical academia and organizations concerned with medial education (the AMA and ACCME), but pharma input was also represented by Pfizer CEO Jeff Kindler, Amgen CEO Kevin Sharer, and former Lilly CEO Sidney Taurel. The task force was chaired by P. Roy Vagelos, MD, a former Merck exec.
While seemingly happy agreements were achieved on most of the task force's recommendations, Kindler and Taurel specifically objected to the report's proposal that faculty be discouraged from participating in industry-sponsored speakers' bureaus. These programs typically involve the "training" of scores of key opinion leaders (a term often loosely applied) to give talks to their regional collegues by using industry-supplied slide decks. Robert Alpern, MD, dean at Yale, likened the practice (and the Pathophilia blog agrees with him) to "ghost talking," according to today's NYT. The practice creates a conflict of interest much more egregious than whatever comes with hoovering a free sandwich on the fly.
*Gifts thoroughly enjoyed by preceding generations of medical trainees and/or their faculty.
I'm not sure how to classify Louis Malle's directorial debut, Ascenseur pour l'echafaud (literally, Elevator for the Scaffold). Possibly French new wave/noir, although some may object to Malle being lumped in with the new wavists. In any case, Jeanne Moreau and Maurice Ronet look terrific in this absurdist crime thriller, and the Miles Davis score is beautifully, excrutiatingly sad.
Poster image from Wikimedia and reprinted under fair use law.
Trachoma* remains the leading infectious cause of blindness in the developing world, affecting more than 40 million people, reports UNC epidemiologist James Cook in this week's NEJM. Three million are visually impaired because of this entirely treatable disease, and 500 million remain at risk. Current endemic areas include much of Africa, southeast Asia, Australia, and Brazil.
An initiative to eradicate the disease, the Alliance for the Global Elimination of Blinding Trachoma by the Year 2020, has been established by WHO, and the associated World Health Assembly supports the use of single-dose azithromycin (20 mg/kg for children; 1g/kg for adults) for secondary prevention. Consequently Pfizer, which manufactures azithromycin under the trade name Zithromax, has donated the drug for the eradication initiative and, with the Edna McConnell Clark Foundation, has created the International Trachoma Initiative. (Gasp. A pharma company's doing something commendable.)
The efforts of the WHO initiative and others have been at least partly successful, according to Cook. The estimated number of infected individuals worldwide dropped from 100 million in 1996 to 43 million this year. Fifteen countries have national control programs, and approximately 74 million people have been treated through initiatives since 1998. Trachoma has evidently been eliminated in Morocco. (Cook writes that WHO is currently defining trachoma-elimination criteria.)
Success has also been achieved in Tanzania, according to correspondence in the same issue of the NEJM. UK investigators write that 1 or 2 rounds of mass treatment with azithromycin may be sufficient to eliminate trachoma in areas where infection levels are moderate, such as in Tanzania. (WHO currently recommends 3 annual treatments in areas with moderate infection levels.)
Despite the promising outlook, Cook raises a number of concerns with respect to trachoma-eradication programs, including the possible emergence of bacterial resistance with mass treatment. However, he believes that the eradication of trachoma-related blindness is entirely possible by 2020.
*Chronic keratoconjunctivitis due to infection with serovars A, B, Ba, or C of Chlamydia trachomatis.
Image of trachomatous conjunctival scarring from WHO trachoma grading cards.
The contaminant identified in recalled lots of heparin, an oversulfated chrondroitin sulfate with a tetrasulfated disaccharide repeat, has not been isolated to date from animal tissues, according to data published online yesterday in Nature Biotechnology. Investigators suggest that the contaminant was, therefore, intentionally introduced into the product.
Other important information from the article:
- Synthetic tetrasulfated disaccaride repeat units of chondroitin sulfate exhibit antithrombin activity, which probably explains how the contaminated heparin passed an activity screen, such as a whole-blood coagulation test.
- The contaminant is structurally identical to Arteparon,* an intramuscular drug that was marketed in Europe for the treatment of individuals with degenerative joint disease. Arteparon has been shown to induce an allergic-type response and was withdrawn from the market because of patient deaths, most likely due to thromboembolic complications.
The contaminant in recalled heparin lots appears to trigger hypotension and other adverse reactions by activating the kinin-kallikrein pathway and generating anaphylactoid complement proteins. Testing of the isolated contaminant, oversulfated chondroitin sulfate, and a synthetically generated version on human plasma and in pigs was reported in today's NEJM.
Among the most intriguing findings was the fact that not all animals treated with the contaminated heparin developed adverse clinical signs; however, all treated animals demonstrated activation of kallikrein. On the basis of this observation, the authors speculate that some patients who received the tainted heparin, such as those undergoing dialysis, may have been more vulnerable to the contaminant's contact-system-induced hypotensive effects, because of concurrent exposure to the dialysis membrane (which also activates the contact system) or treatment with ACE inhibitors (which block bradykinin degradation).
The authors conclude that a simple in vitro bioassay that assesses kallikrein activity, in addition to more sophisticated analytic tests, will aid the screening of heparin lots for oversulfated chondroitin sulfate and other polysulfated contaminants.*
*Dermatan sulfate, a known heparin impurity, was found in most of the contaminated lots; however, the compound's presence was not associated with kallikrein activity.
UK researchers indicate that minimal progress has been made in treatment of prion diseases, such as sporadic Creutzfeld-Jakob disease (sCJD) or the human variant of bovine spongiform encephalopathy (vCJD), during the last 30 years. Their literature review, published in the April 8 issue of Neurology, identified only 1 randomized, placebo-controlled trial of therapy since 1971. The investigators describe many of the examined studies as "flawed" or "poorly reported."
In total, the authors found 33 studies (including case reports) that evaluated a total of 14 interventions (N = 149); 10 of the reports included fewer than 4 patients. Most of the studies evaluated patients with sporadic or unspecified CJD. Examined therapies included analgesic, anticoagulant, anticonvulsant, antidepressant, and antimicrobial drugs.
Therapies studied in the greatest (relative) detail:
Amantadine: The authors identified 2 "questionable" comparative studies (n = 17) and 6 case reports (n = 7), most of which were published during the 1970s. Transient, symptomatic benefits were described for some patients in 1 of the comparative studies and in 3 of the case reports.
Pentosan polysulfate: Disease progression may have been slowed by the anticoagulant in some patients, according to 3 published cases of vCJD and cursory descriptions of another 23 patients.
Quinacrine: In 1 comparative study (N = 32), there were no obvious differences in clinical status or survival between treated patients and "matched concurrent controls." Case studies (N = 50) inconsistently reported symptomatic benefit, and drug-related toxicity (ie, liver dysfunction) was described in 10 studies.
Flupirtine: In the "only reliable reported randomized trial," the analgesic may have slowed cognitive decline, as measured by the cognitive portion of the ADAS-cog. Enrolled patients either had sCJD (n = 26) or genetically determined CJD (n = 2).
Given the rarity of prion diseases (quoted incidence of sCJD = 1 in a million), adequately powered trials will require national and, probably more likely, international collaboration, as the authors indicate. Also logical choices for tested therapies will necessitate a better understanding of how prion diseases are initiated and a more universal consensus of their cause (for an examination of the contentious, opposing views on the prion theory, click here).
From the AP by way of the WSJ: A junior high school student in Kentucky was arrested and charged with felony wanton endangerment after planting crumbs from a peanut-butter cookie in an allergic classmate's lunchbox.
The Pathophilia blog believes that this kind of bullying would happen less often if "peanut" didn't sound so funny.
Executives at managed care companies anticipate fewer prescriptions for Vytorin (ezetimibe/simvastatin) and Zetia (ezetimibe) but no immediate changes in coverage for these medications. These conclusions are based on data generated by Cognet-X, a healthcare market research firm, after negative results from Merck's and Schering-Plough's overly scrutinized ENHANCE study were presented at the annual meeting of the American College of Cardiology in March.
According to a Cognet-X press release, more than 75% of pharmacy and medical executives surveyed earlier this month expect prescriptions to shift from Vytorin to generic simvastatin and, to a lesser extent, AstraZeneca's Crestor (rosuvastatin) and Pfizer's Lipitor (atorvastatin). But approximately two thirds expect few changes in coverage for Vytorin or Zetia because of formulary rules already in place, like tier placement and step therapy.
According to the AP, the FDA said yesterday that there is a "solid link" between the hundreds of allergic reactions and now 81 deaths associated with Baxter's recalled heparin and a contaminant, identified as oversulfated chondroitin sulfate. The FDA statement is a response to a Chinese official's claim that the contaminant could not be the source of the adverse reactions, because some batches of the implicated heparin did not contain it. The FDA also responded that this claim is based on false assumptions.
Baxter's heparin supplier, Wisconsin-based Scientific Protein Labs, said in related news, "It is now clear that the suspect contaminant was introduced earlier in the supply chain in China and was widespread throughout the unrelated Chinese supply chains of many companies." SPL owns a Changzhou plant, which buys its crude material from Chinese heparin "workshops." The plant was cited by the FDA in February for a number of "significant deviations" from good manufacturing processes.
The FDA publicly released its warning letter to SPL's Changzhou facility yesterday, which included the following admonishments:
- There is no assurance that processing steps used to manufacture heparin sodium, USP are capable of effectively removing impurities.
- You fail to have adequate systems for evaluating the suppliers of heparin crude materials, and the crude materials, themselves, to ensure that these materials are acceptable for use.
- Equipment used to manufacture heparin sodium USP is unsuitable for its intended use.
The antidepressant fluoxetine (Prozac) restores neuronal plasticity in the rat visual cortex, according to a series of animal experiments published in last week's issue of Science. The results could have implications for the use of selective serotonin-reuptake inhibitors in the treatment of human amblyopia and other neurologic disorders.
Investigators in Italy and Finland conducted a series of monocular-deprivation studies in rats on the basis of the reported relationships between the long-term administration of antidepressants in the animals, the promotion of neurogenesis and synaptogenesis in the hippocampus, and the expression of neurotrophin brain-derived neurotrophic factor (BDNF) and its primary receptor.
When compared with control animals, adult rats (postnatal day 70) treated with fluoxetine (0.2 mg/mL for 4 weeks) demonstrated a type of neuronal plasticity that is typically restricted to the early stages of rat brain development (up to postnatal day 55). Specifically fluoxetine-treated rats showed accommodating changes in cortical dominance* as a result of the deprivation of monocular sight and its subsequent restoration. The neuronal recordings seen with fluoxetine treatment mirrored those observed after the intracortical infusion of BDNF and were inhibited by the infusion of diazepam (a potentiator of the inhibitory neurotransmitter GABA).
The study was supported by grants from the Ministero dell'Universita e della Ricerca, Programmi di Ricerca di Rilevante Interesse Nazionale, Fondo Integrativo Speciale per la Ricerca, the Sigrid Juselius Foundation, and the Academy of Finland and Center of Excellence in Molecular Neurosciences.
GABA = gamma-aminobutyric acid.
*Assessed by using the contralateral-to-ipsilateral ratio of the visual evoked potential (VEP).
A Chinese health official* said today that the oversulfated chondroitin sulfate found in batches of Baxter's recalled heparin could not have caused the reported allergic reactions and deaths, because only some of the implicated batches contained the contaminant. In a weird turnaround, Chinese health officials state that they will visit Baxter's plant in New Jersey, presumably for inspection purposes. Baxter has numerous manufacturing facilities worldwide, including one in Cherry Hill, NJ.
Update: The Philly Inquirer reports that, in February, the FDA inspected Baxter's 372,000-square-foot facility in Cherry Hill, NJ, and observed no infractions.
*Jin Shaohong, deputy director-general of the China National Institute for the Control of Pharmaceutical and Biological Products.
The president of the American Medical Writers Association (to which I belong) has written to its members (below) regarding the practice of medical ghostwriting, and AMWA's response to the NYT article about Merck's use of guest authoring and ghostwriting has been printed. I agree with AMWA's assessment.
Hello, AMWA colleagues,
As many of you have been discussing, the articles in this week's JAMA about alleged misuse of medical writing resources by Merck in publications about Vioxx garnered a lot of press coverage. As is often the case, the JAMA articles and the associated press coverage tend to blur the distinction between "guest authorship" (putting an author's name on an article he/she did not help to write) and the unacknowledged use of medical writers (ghostwriting, a term AMWA tries to avoid). A number of people have asked whether AMWA should do something.
Several of us saw this as an opportunity to assert AMWA's leadership in promoting ethical practices in medical writing. Accordingly, we have submitted letters to the editors of the NY Times, Philadelphia Inquirer, and Chronicle of Higher Education, all of which carried stories about the JAMA articles. All letters are signed by me as AMWA president.
Key points in all the letters:
- While ghostwriting (the undisclosed contribution of a medical writer) is unethical in scientific publications, the use of professional medical writers may be appropriate and ethical.
- Using their skills in communicating complex data, professional writers help researchers report their findings effectively, making contributions comparable to those of professional statisticians who analyze data or artists who create illustrations.
- The 5500-member American Medical Writers Association promotes ethical practices in scientific publication, including acknowledgment of medical writers' roles, adherence to applicable guidelines (eg, authorship rules of the International Committee of Medical Journal Editors), and full disclosure of potential conflicts of interest, including financial support.
- Transparent disclosure of the roles of all contributors avoids ghostwriting and allows readers to evaluate the credibility of research reports.
We're also drafting a response to JAMA. We'll keep you posted to let you know if these letters are published. In addition, Lori Alexander will include an editorial in the summer issue of the [AMWA] Journal, bringing these issues to members' attention.
A prospective study of 5 large cohorts (N > 1 million), presented Wednesday at the annual meeting of the American Academy of Neurology, showed that the relative risk of amyotrophic lateral sclerosis (n = 633) increased significantly with the duration of smoking and the number of cigarettes smoked per day (AAN abstract P04.076). Investigators reported that the multivariate-adjusted RR increased from 1.2 for 1-19 pack-years to 1.4 for ≥20 pack-years (P = .03), and that the risk did not vary by sex.
Investigators also reported the risk of ALS mortality as a function of chemical exposure in more than 1 million participants in the Cancer Prevention Study II (AAN abstract S25.005). From 1989 to 2002, the risk of death due to ALS (n = 937) was not associated with regular exposure (self-reported) to pesticides or herbicides (RR = 1.1). However, regular exposure to formaldehyde did increase the risk of ALS-related mortality (RR = 1.5), and this risk increased with more years of exposure.
Formaldehyde Exposure, y
The investigators advised that this finding is unlikely the result of bias, because of the longitudinal design of the study. (It is important to remember that increased relative risks do not indicate cause-and-effect relationships.)
According to OSHA, formaldehyde exposure occurs most often by means of gas inhalation, but absorption of formaldehyde liquid through the skin is also possible. High-risk exposure is observed most commonly in the health care professions (particularly pathology and histology), in mortuary work (duh), and among students or teachers who handle preserved specimens.
Another passenger on American Airlines flight #293 from New Delhi to Chicago in mid-December has tested positive for tuberculosis, according to the CDC. The passenger was sitting near an actively coughing woman with drug-resistant TB, who was hospitalized 1 week later in California for active disease. However, it is unknown if the newly identified infected passenger, who is not considered a health threat, acquired TB from the index case or in India, where TB is endemic.
According to Fox News, WHO guidelines indicate that 44 passengers sitting within 2 rows of the index case were considered at risk for infection, and the CDC oversaw the testing of 27 passengers. The remaining passengers were TB carriers already or had returned to their home countries before they could be tested.
The infected California woman (who is a native Nepalese) was hospitalized for more than 2 months in isolation and is now confined to her home for several more weeks, while treatment is ongoing. To eradicate the disease, 2 more years of medical therapy may be required, according to a quoted health official.
Fox News reports that doctors have no way to determine if the TB strains of the 2 passengers match. This conclusion is presumably due to the fact that the newly infected passenger does not have active disease, and therefore, this passenger's TB strain cannot be cultured and typed for comparison purposes.
The NIH's National Institute of Child Health and Human Development is offering a calculator to estimate the outcomes for very preterm infants, reports the NYT. The calculated outcomes are based on gestational age (22-25 weeks), birth weight (401-1000 g), sex (girls inexplicably fare better than boys), singleton or multiple birth status, and the mother's receipt of antenatal corticosteroids within 7 days of delivery (to boost infant-lung development). Outcomes are provided for all infants and those who receive mechanical ventilation and include chances of survival with various grades of anticipated neurologic impairment.
The calculator is based on a study of nearly 4500 very preterm infants at a network of hospitals and is intended to aid the decisions of healthcare workers and families regarding levels of care.
From the NEJM: after sickle-cell anemia, α- and β-thalassemias, and G6PD deficiency.
New details regarding a progressive inflammatory neuropathy (PIN) in pork-slaughterhouse workers were revealed yesterday at the annual meeting of the American Academy of Neurology. The illness, according to lead investigator Daniel Lachance, MD, is a new disorder affecting primarily the sensory peripheral nerves and spinal nerve roots and is believed to result from an autoimmune reaction to inhaled, aerosolized pig brain. (For background info on "blowing brains" at the "head table," click here).
The specific immune trigger for the illness has not been identified, although a previously unrecognized IgG autoantibody has been detected in all of the affected workers, according to Lachance. To date, PIN has been diagnosed in 18 workers in Minnesota, 5 in Indiana, and 1 in Nebraska. None of the affected workers (most of whom are Hispanic) has completely recovered, but some have experienced clinical improvement or stability.
I'm referring to the already-heavily-blogged-about case study in today's issue of JAMA, which examined Merck's use of academic guest authors or contract ghostwriters. The study's authors were consultants for the personal-injury attorneys in the Vioxx-related litigation against Merck and therefore had access to the drugmaker's internal documents (which are now publicly available here).*
A primary conclusion of the case study is that Vioxx clinical-trial manuscripts were initially authored by Merck scientists, but that first authorship was later attributed to recruited, university-affiliated physicians—presumably to lend academic credibility or cache to the published studies. The numbers are difficult to pin down, but the JAMA case study identified 24 clinical-trial articles from 1999 on (which are referenced in a detailed table) and highlighted a few studies in the text, including an Alzheimer's trial that was not listed in the table (Thal LJ et al. Neuropsychopharmacology. 2005;30:1204-1215). Elsewhere, the authors identify 16 of 20 clinical-trial articles that were initially drafted by a Merck employee but were then published with an academically affiliated first author. In these cases, the Merck author was typically bumped to an anchor position.
The study authors also described documents revealing the outside contracting of a ghostwriter for one Merck study, "A randomized, placebo-controlled, parallel-group, double-blind study to evaluate the safety and efficacy of rofecoxib 25 mg and celecoxib 200 mg in patients with osteoarthritis of the knee or hip." However, a citation for the published article is not found. (The JAMA case study suggests that medical ghostwriting is, not surprising, more prevalent when creating review pieces.)
Although the intentions of the case-study authors may be well placed, it is troubling that they did not seek direct responses from Merck scientists or the cited academic authors before JAMA's publication of the piece—which is really more of a journalistic-type exposé than any report of scientific merit. (A few of the implicated academics have taken their umbrage to the NYT and other press outlets.) Also, in the full spirit of disclosure, the authors should have revealed their compensation as a result of the Vioxx litigation. If financial relationships with relevant drug manufacturers should be disclosed, then so should financial relationships with relevant plaintiffs' firms.
*Evidently at the insistence of JAMA's chief editors, if DeAngelis and Fontanarosa are to be believed.
Forehead-slapping insights like these explain why Andrew von Eschenbach's head of the FDA and you're not.
A retrospective analysis reveals that 32 of 41 (78%) children with autistic spectrum disorders have defective function of oxidative-phosphorylation enzymes in their skeletal muscle. The data were presented by investigators from Medical Neurogenetics, a genetic-testing facility in Atlanta, at the annual meeting of the American Academy of Neurology on Sunday.
The lead investigator, John Shoffner, MD, told Medscape Neurology & Neurosurgery that, although patients with mitochondrial disorders commonly exhibit autistic features, it is unknown how common mitochondrial disease is in autism. The US government recently decided to award compensation to the parents of Hannah Poling, after it was concluded that a concentrated series of vaccinations aggravated an underlying mitochondrial disorder, which manifested clinically as autism.
The autistic children tested by Shoffner, aged 2-16 years, were referred because of potential indicators of mitochondrial dysfunction, such as increased lactate, pyruvate, or alanine levels. By analyzing mitochondrial-enzyme activity in biopsies of skeletal muscle, defects in representative proteins from 5 mitochondrial-enzyme complexes were found. Further investigation revealed that selected proteins involved in oxidative phosphorylation were abnormal.
Among 40 children, the mitochondrial DNA (mtDNA) sequences of 10 (25%) were found to be abnormal: 2 children demonstrated heteroplasmic mutations, and abnormalities in 8 remain under investigation. Shoffner concludes that nuclear DNA mutations are, therefore, the most likely cause of the observed mitochondrial defects.
Four courses of the monoclonal antibody Rituxan (rituximab) did not delay the time to confirmed disease progression in primary progressive multiple sclerosis, according to a 96-week, placebo-controlled phase 2/3 study. The results were announced yesterday by the drug's US marketers, Genentech and Biogen Idec. A senior scientist at Genetech, however, indicated that the drug exhibited "some evidence of biologic activity" in this uncommon and difficult-to-treat form of MS.
The results are not scheduled for presentation at the ongoing annual meeting of the American Academy of Neurology in Chicago, but safety and pharmacologic data from a 72-week phase 1 study (Bar-Or et al. S12.004) and pharmacologic data from a 48-week phase 2 study (Bar-Or et al. S22.002) of rituximab in relapsing-remitting MS will be presented today and tomorrow at the meeting. Phase 3 development of the drug in relapsing-remitting MS is stalled, because of a protracted dispute between Genentech and Biogen. The development dispute is currently in arbitration.
Did Schering-Plough use data-quality problems as an excuse to forestall publication of ENHANCE's negative outcome, or did the company do a yeoman's job of cleaning up suboptimal data from John Kastelein's imaging lab? That's the latest question raised by the protracted coverage of the study.
According to statements made by John Stein, University of Wisconsin imaging expert, to Forbes, there are substantial differences in the quality of the carotid-imaging data presented by SP at the independent review of the ENHANCE study data in November 2007 and those revealed publicly last month, which looked "quite good" according to the doctor. Forbes reports today that the independent-review panelists saw only 75 of the approximately 40,000 images taken during the study. On the basis of these selected images, Stein had concluded that the ENHANCE data were "not acceptable."
However, Stein's view of the data quality changed considerably when he (and everyone else) viewed the ENHANCE results at the recent ACC meeting and in the NEJM. Stein is now quoted by Forbes: "For anyone to say the data in the study are bad, they either need to say that John Kastelein [ENHANCE primary investigator] is a liar, which I'm certain he is not, or they need to talk to the [SP] statisticians for the study and ask them if there are any problems with the data." SP's ENHANCE study director, Enrico Veltri, MD, argued to Forbes that the reason the public data look so good is because SP put so much effort into their cleanup.
Regardless of what you believe about the data quality in ENHANCE, it's important to remember that image cleanup would not remedy the very sizeable problem of missing data, which affected approximately 75% of the subjects in the trial.
From an April 11 report at Connecticut's TheDay.com:
- Hesketh is currently being held at a Rhode Island detention center after being arrested by Federal agents on March 26 for possessing, receiving, and distributing child pornography. According to Federal agents, Hesketh and a Buffalo, NY, deli worker exchanged 85 pictures, which included infant molestation, during at least one "chat" session. Hesketh reportedly told Federal authorities that he conducted his child-porn activities, under the female persona of "Suzibibaby," at his New London home, at work, and on business trips. During travel, Hesketh allegedly carried more than 1000 child-porn images on 3 compact flash drives.
- Hesketh was hired by Pfizer 6 years ago and was fired as patent director from the company on March 28. Without commenting specifically on Hesketh's case, Pfizer spokesperson, Liz Power, was reported to say that "the company does not allow employees to use computer resources or systems that contain or promote abusive or objectionable language or information that is illegal or obscene." "[A] number of technical controls block objectionable web sites, prevent peer-to-peer file sharing, and remove unapproved software," according to Power, and she indicated that "systems" are scanned several times a year.
- Hesketh, a British citizen, was denied bond after the judge learned that he owned multimillion-dollar properties throughout the world.
- A motion filed April 4 indicates that Hesketh's attorney and the US Attorney's office are negotiating a plea deal. A probable cause hearing that was scheduled for April 10 did not take place.
- According to a spokesperson for the US Attorney's office, most of those convicted in child-porn cases are sent to prisons that have medical hospitals with sex-offender programs; the 2 named were Devens in Ayer, MA, and Butner in North Carolina.
- Hesketh, 61, has been married for 39 years and has 4 adult children and 5 grandchildren. According to Hesketh's wife, the couple are "on the verge of divorce." Reports indicate that she has known little-to-nothing of their finances.
- Before working for Pfizer, Hesketh was an executive at then Glaxo Wellcome in England.
This afternoon's WSJ Health Blog provides access to drafts of after-the-fact "minutes" from the November 2007 meeting of independent reviewers of the ENHANCE study data. The draft documents, which include inserted comments from imaging expert James H. Stein, MD, were originally obtained by a Congressional subcommittee, according to the WSJ blog. Many of Stein's comments relate to the integrity and quality of ENHANCE's image database, which he concluded was "not acceptable." The image database resided at Amsterdam's Core Echo Laboratories (CEL), which is directed by ENHANCE's primary investigator John Kastelein, MD, PhD.
A few excerpted comments from Stein:
The imaging and reading protocols in ENHANCE were suboptimal even relative to methodologies employed at the time the study commenced and relative to procedures in clinical and epidemiological studies conducted in the 1990s.
We did not state the data and analysis "are reportable."
When we looked at images and considered the CIMT [carotid intima-media thickness] values of individual subjects over time, almost all the examples we saw showed measurement errors, biologically implausible measurements, biologically implausible changes in CIMT measurements, and/or failure to adhere to the protocol.
Great concern was expressed that the aggregate values may look reasonable, but that they may not reflect reality.
The concerns about unreported and later updated file segments were serious. I recall that I and other panel member[s] specifically stated that we could not determine if the database was "clean and credible" based on the information presented.
It is my recollection that there also were concerns about data management, such as the existence of data files with measurements that either were not entered into the official measurement database or that reflected more "recent" measurements than those in the measurement database. A statement should be inserted here that reflects concerns about the integrity of the data [which] was part of the reason for convening the expert panel.
It is also revealed in the documents that data for 485 of 640 (~76%) subjects in ENHANCE were missing, and that data for 75 (~12%) subjects were biologically implausible (defined as >0.1-mm CIMT change between baseline and endpoint).* Because the missing data for the common carotid artery were considerably less, either 3% or 8% (depending on which source you take), it was suggested that the primary endpoint might be changed to the CCA measurement.
*The Pathophilia blog has repeatedly expressed its frustration that the volume of missing or implausible data, which would certainly undermine the integrity of and conclusions from the ENHANCE study, had not been revealed.
Moving through this morning's pharma blogosphere is an AP story describing the responses of some drug or medical-device companies to Senator Chuck Grassley's request that they disclose their CME funding to outside groups. The current industry model is that of Eli Lilly, which provides a highly itemized (and therefore, very difficult-to-synthesize) online grants registry report for each financial quarter of 2007.
Among the companies' soup-to-nuts replies to Grassley:
- Medtronic will post payments for professional meetings and patient groups on May 1 (no mention of funds to medical communications companies);
- AstraZeneca will do the same on August 1;
- Merck is "currently in the process of developing an action plan";
- Amgen and Abbott have formed "working groups"; and
- nose-thumbing Schering-Plough reports that it has no plans "at the moment" to publish the requested information.
Today's WSJ Health Blog notes that Grassley's also sponsoring the Physician Payments Sunshine* Act of 2007, which will require quarterly reports from drug or medical-device companies to the DHHS regarding payments made to individual physicians or their employers.
CME = continuing medical education.
*As in, blow sunshine up my...?
The FDA reports today that more than $100,000 worth of nonprescription Chinese "natural supplements" for erectile dysfunction were seized because they contain sildenafil, the active ingredient in Viagra, or a sildenafil analog. The seized products—Shangai Regular, Shangai Ultra, Super Shangai, Naturalë Super Plus, and Lady Shangai—originated in China and were packaged and distributed by a company in Puerto Rico.
Prompted by a consumer complaint, the FDA conducted an inspection of the Puerto Rico distributor in November 2007, at which time the products' active ingredients were discovered; however, the products' labels did not list sildenafil or the sildenafil analog. An FDA press release in December advised consumers not to purchase the drugs, which were embargoed by the Puerto Rico Department of Health before the seizure.
On February 15, The Netherlands Health Care Inspectorate reported its identification of large doses of tadalafil (Cialis), vardenafil (Levitra) and acetildenafil (an analog of sildenafil) in imported Chinese "herbal" impotence pills. Since 2003, the FDA has recalled a number of nonprescription sex-enhancement pills because they contained undeclared tadalafil, vardenafil, sildenafil, or chemical analogs.
Physicians in Leipzig, Germany, identified lead intoxication in 29 regular smokers of marijuana, according to correspondence in the latest issue of the NEJM. Elemental lead was discovered by means of atomic absorptiometry or plain-old eyeball (left) in partially used weed samples from 3 of the affected users. It is believed by authorities that the lead was deliberately cut into the marijuana to increase its weight and therefore the profits from a street product that is sold by the gram. The lead is thought to be easily absorbed through the respiratory tract, once the tainted marijuana is smoked.
Photo: Close-up of partially used dime (euro) bag of marijuana with visible, grayish lead particles from the NEJM.
MedPage Today provides an online video recording of another panel discussion of the ENHANCE study that was held at the recent ACC meeting. The panel was convened "just hours" after the report of the Vytorin-trial results by primary investigator John Kastelein, MD, PhD, on March 30 and the alleged monopoly of a follow-up panel discussion by Yale cardiologist Harlan Krumholz.
In the video recording, Kastelein maligned the day's previous panel discussion, during which a "single individual" conferred a "verdict" on the drug, and no questions were taken from the audience. The day's second, counterpoint panel included not only Kastelein, but also Schering-Plough officers Bob Spiegel, MD, Enrico Veltri, MD, and Tom Musliner, MD, as well as University of Chicago cardiologist Michael Davidson, and the panel was opened for questions from the on-site audience and by phone.
Most of the questions were posed by the media (eg, DocGuide, MedPage Today, ABC News, CBS News) and were disappointingly fixated on previously covered issues, such as the validity of cholesterol lowering as a surrogate marker for atherosclerosis reduction.* Only one questioner, from CBS News, requested more information regarding the delayed release of the trial results (and therefore, alluded to the missing or implausible data). Kastelein fielded the question and gave a passing reference to "data cleaning" during his explanation; however, no other direct explanation of the reasons for or manner of data handling were discussed.
*The panel consensus is that, according to the overwhelming bulk of the data, the lowering of total and LDL cholesterol levels are associated with the significant reduction of atherosclerosis and atherosclerosis-related events.
The FDA has released new information on the number of reported heparin-related deaths and the subset of deaths associated with allergic or hypotensive symptoms since January 2007. According to the FDA, there have been 103 reported deaths since the beginning of 2007, 91 (88%) of which were reported during 2008. Among these deaths, 62 (60%) were associated with one or more allergic or hypotensive reactions—the kinds of reactions that led to the recent recall of Baxter's heparin; 56 of the 62 were reported during 2008. The FDA advises that the presence of allergic or hypotensive symptoms does not necessarily indicate a cause of death.
More concerning than the delayed results of Merck's and Schering-Plough's ENHANCE study are allegations in a recent FDA letter to GlaxoSmithKline that the company failed to report multiple Avandia (rosiglitazone) postmarketing studies. Lapses in annual, required NDA reporting of this information by GSK date as far back as 2001, according to the letter, and include more than 20 studies. At least 2 of the studies, which were requested by European regulatory agencies, were intended to identify cardiac-related or -aggravating adverse events. (The FDA did acknowledge that information from 10 studies had been reported to the agency by other means.)
The lapses in the reporting of the studies were discovered during an extended FDA inspection last year of GSK's corporate headquarters, in the wake of widespread concerns about the cardiac safety of the oral antidiabetic agent. The FDA letter also charged that GSK "lacked appropriate knowledge of the studies associated with Avandia, resulting in the reporting deficiencies noted" and concluded, "Absent a clear explanation of the extent and cause of these deficiences and an adequate plan to correct them, we are concerned that similar deficiencies in the postmarket reporting for your firm's other FDA-approved drugs may exist." GSK markets more than 60 prescription pharmaceuticals, including Flonase (fluticasone), Paxil (paroxetine), and Valtrex (valacyclovir), in the United States.
In a press release today, GSK acknowledged the warning letter and described last year's on-site FDA inspection as "routine." The company also stated that the "observations from the inspection primarily relate to omissions from periodic reports to the FDA regarding Avandia...such as the start and progress of clinical trials, and summaries of final data from some clinical trials [emphasis added]." GSK stressed that the FDA inspection did not result in any citations, despite the fact that the FDA letter threatened "seizure and/or injunction" and the holdup of any pending NDAs or export certificates if the reporting deficiences weren't corrected in a timely manner.
Hat tip to Pharmalot.
Suggesting a twisted version of rock-paper-scissors, 2 recent reports indicate some funky flips in the microscopic food chain.
Last week, investigators at Harvard reported that hundreds of soil bacteria were not only resistant to a range of antibiotics, they could actually subsist on them. The investigators were specifically able to culture clonal bacterial isolates from 11 different soil samples (taken from farms, urban areas, or isolated regions) that could use anywhere from 13 to 17 of the 18 antibiotics tested as their sole carbon source.
These antibiotics included a wide range of compounds—for example, aminoglycosides, penicillins, fluoroquinolones, and sulfonamides. The most accommodating of the antibiotics were chloramphenicol, carbenicillin, penicillin G, vancomycin, ciprofloxicin, and mafenide, which fed bacterial clones from all 11 soil samples. The antibiotic-feeding bacteria were also diverse, with 11 major orders represented; the most common were Burkholderiales (41%), Pseudomonadales (24%), Enterbacteriales (13%), Actinomycetales (7%), Rhizobiales (7%), and Spingobacteriales (6%). Given the diversity of the drug-chewing bacteria and their close relation to some pathogenic organisms, the authors speculate that human pathogens could acquire antibiotic-resistance genes from these wide-ranging, soil-living, über germs.
And yesterday at the meeting of the American Chemical Society in New Orleans, researchers from Arizona State University indicated that certain clay samples can kill or considerably stifle the growth of important pathogenic bacteria—such as MRSA, E. coli, and Salmonella—in culture. The NIH-funded work was inspired by reports of the healing powers of the Côte d'Ivoire's green vocanic mud on Buruli ulcers. WHO currently recommends treatment for these ulcers, which are caused by Mycobacterium ulcerans, with rifampicin and streptomycin/amikacin followed by surgery.
The ASU investigators concentrated their study on volcanic soils (aka bentonite) collected from around the world but also found that samples from Nevada and Oregon were, to their surprise, also bactericidal. However, they report that they do not know the mechanisms by which various clays may hamper bacterial growth and urge against the current use of clay as medicinal therapy. Their next steps are to isolate the potentially active compounds in the clays and perform preclinical testing.
MRSA = methicillin-resistant Staphylococcus aureus.
One of Johns Sayles's best, Lone Star is a cross-generational, cross-cultural murder mystery, which features the terrifically understated Chris Cooper as an ambivalent, small-town Texas sheriff. Shown in flashback sequences are the previous generation's lawmen in the form of one charismatic Matthew McConaughey (what happened, Matt?) and one rattlesnaky Kris Kristofferson.
Mike Huckman at Pharma's Market recently highlighted Pfizer's new, sober-looking DTC print campaign for Lipitor (atorvastatin), which may be taking advantage of Schering-Plough's recent woes with Vytorin (ezetimibe/simvastatin) and the exhaustively covered* ENHANCE study.
The print ad reads, "Unlike Vytorin and Zetia, Lipitor is FDA approved to reduce the risk of heart attack, stroke, and certain kinds of heart surgery in patients with several common risk factors for heart disease."
The head-slapping irony here is that Lipitor, when first FDA approved in 1996, was indicated to reduce LDL cholesterol but had not been shown to prevent clinical vascular events like its 4 existing competitors at the time. Nevertheless, Lipitor quickly became the number-one statin (and an uber-blockbuster) because 1) it reduced LDL cholesterol by a relatively greater percentage than the other statins and 2) clinicians believe (or at least believed) that the LDL cholesterol level is directly related to the risk of vascular events. Lipitor wasn't approved to reduce the risk of vascular events until 2004.
*But not entirely accurately covered.
From Pharmalot by way of The Carlat Psychiatry Blog: Both highlight a relatively recent editorial in Medical Meetings that was written by Donna Beales, librarian and CME coordinator at Lowell General Hospital in Lowell, MA. In the editorial, Beales maligns the current state of industry-funded CME and outlines a provocative "5 Steps to Building Real Firewalls" to separate CME from commercial interests.
My own very blunt view of Beales's editorial is that it comes from a place of ignorance, and I specify some of my objections to her proposals in the comments section of the relevant Pharmalot post.
In response to criticism (mainly in the WSJ) that Harlan Krumholz, MD, unfairly monopolized Sunday's ACC panel discussion of the ENHANCE study, which recommended that Vytorin be relegated to last-resort cholesterol management, the Yale cardiologist fired back yesterday in a blog post to Pharmalot.
"We [the 4-physician panel] were asked to comment on the ENHANCE study and discovered over the course of several weeks of discussion that we had a clear consensus about the recommendations for practice. My comments reflected that consensus," reads an excerpt.
Others on the ACC panel, who have not yet chimed in publicly one way or the other, were Joseph Messer, MD, Rick Nishimura, MD, and Patrick O’Gara, MD, whose selection for discussion of the ENHANCE study at the ACC was questioned by Schering-Plough CEO Fred Hassan. However, criticism of the panel generally and that of Krumholz specifically are not limited to SP insiders like Hassan or chief medical officer Robert Spiegel. A Sanford Bernstein analyst reported to the WSJ that the panel discussion "was essentially not a panel discussion at all, but rather a monologue by Dr. Harlan Krumholz, who was very negative on Vytorin."
Another legitimate criticism from Hassan, a criticism which has nevertheless been cast in a negative light by Pharmalot's Ed Silverman, is the lack of allowed participation by the ACC audience to specifically question the ENHANCE results and the panel. Such an open forum would have (or, at least, should have) raised the issue of the missing or implausible data in the ENHANCE study and their effect on the trial's validity.
Image: The SNL Archives.
Today, the WSJ Health Blog provides access to an entire thread of e-mails sent during July 2007 (~3 months after Carrie Smith Cox sold $28 million worth of SP stock) between the ENHANCE study's primary investigator John Kastelein, MD, PhD, and SP's John Strony, MD (IMPROVE-IT study director), and Enrico Veltri, MD (ENHANCE study director)—all of whom express their various frustrations with the protracted examination of the ENHANCE study data. The thread is the original courtesy of SP, in its attempt to provide balance to the excerpted Kastelein e-mails provided by Senator Grassley. The Pathophilia blog, given its love of chronology (chronophilia?), provides an abridged, interpretive version of the e-mail exchange in temporal sequence. One lesson from the publication of the thread: Be careful who you dis in professional e-mails.
07/06/07, Kastelein to Strony: While on vacation, Kastelein is awfully pissed to learn (presumably from an e-mail sent by Strony) that SP has decided not to present the ENHANCE study results at the upcoming scientific sessions of the AHA in November—especially without consulting Kastelein first. (The deadline for abstract submission was June 1, and that for late-breaking clinical trials was June 29.) Kastelein threatens to terminate his collaboration with the company and to "take appropriate steps" to contact the editors of "major journals" and the FDA—the ultimate, but vague, "Dear John" letter (hey, literally and figuratively) of any academic PI.
07/06/07: Strony responds to Kastelein with a somewhat conciliatory e-mail, indicating his best efforts to contact Kastelein by other means and explaining the decision by SP and Merck execs to hold on the submission of the ENHANCE study results to the AHA. Strony itemizes a number of problems with the processing of the ENHANCE data: The primary, carotid data are undergoing a "query process," and the consolidation of the data into a "commercially available, validated system" from scattered sources (eg, various computers, laptops) chewed up weeks. In addition, the auditing of the image database was stalled, when 150 "extraneous image values" were identified in a particular batch. Strony also advises that SP's standard operating procedures forbid the "locking and relocking" (presumably the unblinding and reblinding) of any database. He concedes that ENHANCE is the "trial from hell."
07/07/07: Still miffed and frustrated, Kastelein responds to Strony and cc's Veltri (aka Rick), indicating that Merck had cleared Kastelein to say publicly that the ENHANCE results would be presented at the AHA. Fearing the perception of colluding with SP to hide or manipulate the ENHANCE data with dilatory tactics, Kastelein writes, "[Y]ou will be seen as a company that tries to hide something and I will be perceived as being in bed with you."
07/09/07: Veltri now writes back, explaining to Kastelein that the decision to delay the presentation of the ENHANCE study results was essentially his (and that of his Merck counterpart, Elizabeth Stoner, MD [who has since left Merck]), so that the quality of the data could be ensured. Veltri reminds Kastelein that they've had a discussion about data-quality issues before and chastises, "I do not see what you are raging about," with respect to Kastelein's threat to contact journal editors and the FDA. Veltri also essentially reinforces Strony's explanation for the delayed processing of the ENHANCE data to ensure integrity: "[W]e must work together to complete the outstanding database cleanup and readings in a rigorous manner and not short cut for the sake of presentation." However, Veltri doesn't discount the possibility of submitting the ENHANCE data, if available, for the AHA meeting, even after the "late-breaker" deadline.
07/13/07: Not entirely appeased, Kastelein responds to Veltri (and cc's Strony) by reiterating his frustration and lack of control over the ENHANCE study. He also expresses dissatisfaction with several study consultants, including Gene Bond (presumably M. Gene Bond, PhD), and adds that he is "constantly under pressure" from Merck (not SP, notably) to plan activities before, during, and after the AHA meeting.
Prompted by continuing coverage of the controversial ENHANCE study—including a recent letter fired off by Senator Chuck Grassley to the CEOs of the study's sponsors, Merck and Schering-Plough—the Pathophilia blog engages in another exercise that illustrates the chronology of SP's stock price, insider transactions, and important events in the ENHANCE study timeline.*
The years preceding 2006 are shown primarily to illustrate what may have been normative insider trading, during a time when the quality of the ENHANCE study data had not been realized. The most intriguing event revealed from this investigation (which may only be news to me, but at least I'm providing semi-colorful graphs) is the inordinately large sale or exercise of stock options taken by 3 SP officers from April 20, 2007, to May 21, 2007—at a time when SP's share price was at an all-time high since 2003, but also when independent contractors were wrestling with the now-recognized data-quality problems of ENHANCE.
According to these insider-transaction data, Carrie Smith Cox, Brent Saunders, and Ron Cheeley sold a little more than $32 million and exercised stock options to the tune of $19 million during this time period. Carrie Smith Cox sold the lion's share of stock for $28 million (as has been previously reported) and exercised $16.5 million in stock options.
CDC = Cholesterol Development Committee, a joint venture of the study sponsors.
*Basic graphs for SP's stock prices were obtained fromMSN Money, and insider transactions were obtained from AOL Stock & Finance.