September 2008 Archives

There is a huge difference between a drug aggravating an existing disease and a drug increasing the risk of a disease.

Earlier this year, French investigators reported a profound survival benefit of hyperlipidemia in amyotrophic lateral sclerosis (ALS) and consequently advised against the use of lipid-lowering drugs (eg, statins) in patients with ALS. The French study followed a WHO pilot investigation, which suggested that the use of statins may be associated with the development of an "ALS-like syndrome."

Now the FDA is weighing in on the subject with a report in yesterday's online issue of Pharmacoepidemiology and Drug Safety. The agency's study was prompted by a disproportionate number of ALS reports associated with statin use in its Adverse Events Reporting System.

By analyzing 41 placebo-controlled statin* trials of a least 6 months' duration, the FDA calculated an ALS incidence of 5.0 cases per 100,000 patient-years with statin use and a comparable 4.2 cases per 100,000 patients-years with placebo treatment. Prevalence rates of the disease were similar in both treatment groups: 9 cases in 64,602 statin-treated patients and 10 in 56,362 placebo-treated patients.

The rate of ALS in the general population is between 1 and 2 per 100,000, but the likelihood of disease increases with age, as does the likelihood of statin treatment. Approximately 80% of statin prescriptions are dispensed to Americans older than 50 years of age. The FDA investigators also note that the incidence of ALS in the United States has remained stable during the last 20 years, but that statin use has increased 30-fold during this time period—facts that make an association between the incidence of the disease and the drug class unlikely.

Nevertheless, results of an ongoing case-control study of the relationship between ALS and statin use, anticipated in 6-9 months, should further clarify the issue.

* Atorvastatin (Lipitor; Pfizer), cerivastatin (Baycol; Bayer), fluvastatin (Lescol: Novartis), lovastatin (Mevacor; Merck), pravastatin (Pravachol; BMS), rosuvastatin (Crestor; AstraZeneca), and simvastatin (Zocor; Merck).

Update: In a study presented last week at the annual meeting of the American Neurological Association, statin-associated pain and weakness were more frequent prediagnostically in patients with sporadic ALS (sALS) who had received multiple statins or who were diabetic or hypothyroid than in patients who developed other motor neuron diseases (eg, familial ALS). The study investigators suggested that myopathic symptoms during statin treatment may herald the clinical onset of sALS in predisposed individuals. However, the statin-treated populations in this review study were small (eg, 31/164 patients with sALS), and only 3 of the sALS patients had received more than one statin. 

HT for update: Medscape Medical News

The latest in the investigation of melamine in Chinese milk and milk-containing products is the revelation that Cadbury chocolates may contain the contaminant. According to the AP, the British candy maker is recalling 11 of its products made at a Beijing plant, which were distributed in Taiwan, Hong Kong, and Australia.

The Xinhua News Agency reports that 22 people in Hebei Province—including managers of pastures, breeding farms, and milk-purchasing stations—have been detained under the suspicion of making or selling melamine and putting the contaminant into milk. Police seized nearly 500 pounds of the toxin in connected raids.

Last year, melamine (along with cyanuric acid) caused renal dysfunction or failure in unknown numbers of domestic cats and dogs as a result of pet food made with contaminated Chinese wheat gluten. In the September 1 issue of the Journal of the American Veterinary Medical Association, investigators reported their findings in 70 cats from a single, commercial cattery* that were inadvertently fed tainted pet food.

Forty-three cats developed clinical signs of disease, including lethargy, poor eating, vomiting, polydipsia, and polyuria. More than half of the cats (38 of 68) that were biochemically analyzed developed azotemia, and 1 cat died. Among the 13 cats that were euthanized, kidney specimens revealed crystal-associated tubular necrosis and perivascular inflammation.

Cyanuric acid, which is produced by the hydrolysis of melamine, forms insoluble (or poorly soluble) crystals when combined with melamine. According to the FDA, cyanuric acid may be generated in the production of melamine or by its degradation. 

There are no news reports, as yet, regarding the content of cyanuric acid in the currently tainted Chinese milk products.

* Cats were used to assess the "routine palatability and acceptability" of commercial cat foods.

Photomicrograph of cat renal tubule containing gold-brown circular crystals of melamine and cyanuric acid (arrow); bar = 50 microns. Source: Ciancolo RE et al. J Am Vet Med Assoc. 2008;233:729-737.

Trouble in Paradise

(1932): All's fair in love and con artistry when two thieving soulmates, Gaston and Lily, pair up to scam a perfume heiress, Madame Colet. There's plenty of naughty repartee in this early talkie, before the MPAA production code was duly enforced.

Gaston: Madame Colet, if I were your father, which fortunately I am not, and you made any attempt to handle your own business affairs, I would give you a good spanking, in a business way, of course.
Madame Colet: What would you do if you were my secretary?
Gaston: The same thing.
Madame Colet: You're hired.

Although the movie is considered an Ernst Lubitsch classic, just about anybody could imagine a Coen Brothers remake with George Clooney.

Poster image from Wikipedia and reproduced under fair-use law.

Stroke is not a fait accompli. In a landmark trial, the NINDS study group showed that the thrombolytic agent alteplase (aka tissue plasminogen activator, aka tPA), if given within the first 3 hours after stroke onset, significantly reduces the risk of disability at 3 months.

These data were published more than 10 years ago, but the use of alteplase in acute stroke remains shockingly low. Only about 4% of eligible stroke patients—meaning those patients with ischemic stroke who show up for medical care within a 3-hour time frame—receive the drug. Clearly healthcare performs a face plant when it comes to the treatment of stroke.

Now the window of time for alteplase therapy has been increased to 4.5 hours, given the results of a new study published in this week's NEJM. In a multicenter, placebo-controlled, double-blind European trial (N = 821), patients with ischemic stroke who received alteplase (0.9 mg/kg IV) between 3 and 4.5 hours were significantly more likely to experience a favorable outcome (modified Rankin score, 0 or 1) at 90 days (alteplase, 52.4%; placebo, 45.2%).

The rate of intracranial hemorrhage was significantly higher with alteplase than placebo (27.0% vs 17.6%), as was the rate of symptomatic hemorrhage (2.4% vs 0.2%). However, mortality rates were comparable: alteplase 7.7%; placebo, 8.4%.

In an accompanying editorial, neurologist Patrick Lyden stresses that these new results importantly extend the window of time for alteplase treatment in acute ischemic stroke, but he also urges that they are not a license to delay brain-saving therapy.

The blogging Drug and Device lawyers are now directly involved in the case of Gunvalson v. PTC Therapeutics, in which a teenager with muscular dystrophy is pursuing access to the biotech's experimental drug PTC124. Consequently they won't be commenting further on the case, but they will provide milestone legal docs, like PTC's opening brief in its appeal to Judge Martini's opinion (read background posts here and here).

PTC's brief is useful to the interested public, because it provides answers to several, previously unanswered questions about particulars in the case and specifically about the illness of the teenager, Jacob Gunvalson (which is now an open book, given the Gunvalson's suit against PTC).

For instance:

• Jacob has muscular dystrophy that is indeed characterized by a nonsense mutation (which causes a premature stop codon) in the gene encoding for dystrophin. Therefore the use of PTC124, which overrides the translation of stop codons, makes theoretical sense in the proposed treatment of Jacob's disease.
• Jacob's mother is a registered nurse.
• One outcome of PTC's 28-day phase 2a trial of PTC124 was the expression of dystrophin. Because patients with Becker muscular dystrophy (BMD) make limited amounts of dystrophin (unlike patients with Duchenne muscular dystrophy [DMD], who do not produce dystrophin), individuals with BMD were excluded from this trial.
• Jacob's Minnesota pediatrician, John Parkin, apparently requested access to PTC124 on behalf of Jacob. PTC's chief medical officer, Langdon Miller, evidently denied this request in a letter dated April 2006, "stating that no [emphasis in brief] access would be given outside of clinical trials until an appropriate time." Therefore Jacob's attempt to access PTC124 antedates his attempt to enroll in PTC's phase 2a trial of the drug (see below).
• Richard Finkel, CHOP neurologist and a principal investigator of the phase 2a trial, reviewed Jacob's medical records in late 2006 to determine the teenager's eligibility for enrollment. Jacob's records, as documented by his pediatrician (presumably Parkin), revealed an 8-year diagnosis of BMD, along with renal dysfunction and a "racing heart" (ie, tachycardia). Finkel evidently reviewed a "muscle biopsy," which was compatible with the diagnosis of BMD (It is not clear if the biopsy report or the actual biopsy specimen was reviewed by Finkel). Jacob was denied enrollment in the phase 2a trial, not only on the basis of his BMD diagnosis, but also as a result of his renal impairment and cardiac condition. Therefore Jacob and his parents did not forgo enrollment in the phase 2a trial on the advice of PTC vice president Claudia Hirawat, as previously indicated; Jacob was ineligible for trial enrollment.
• Jacob's mother sent e-mails to Hirawat on January 30, 2007, expressing deflation at Finkel's decision and indicating that she knew Jacob produced dystrophin, which precluded his phase 2a trial enrollment. Also in December 2006, Jacob's mother sent an e-mail to Hirawat expressing concern that Jacob might receive placebo should he be enrolled in another PTC124 trial (the phase 2a trial was not placebo controlled).
• Jacob became nonambulatory in March 2007, a condition that precluded enrollment in PTC's phase 2b trial of PTC124.
• In May 2007, Cincinnati child neurologist and principal investigator Brenda Wong concluded that Jacob had DMD after a "comprehensive medical evaluation." Her examination, which presumably included a review of Jacob's medical records, also confirmed his history of tachycardia (although there is no mention in the brief of her acknowledgement of his previously noted renal impairment). The timing of Wong's review is interesting, because it suggests that Jacob may still have been attempting to enroll in the phase 2a trial of PTC124 (via Wong) after being rejected for enrollment by Finkel. Addendum: Jacob's recent confinement to a wheelchair probably contributed to Wong's opinion that Jacob had the more severe diagnosis of DMD, in contradistinction to the previous diagnosis of BMD.

The strong subtext of the PTC brief is that Jacob's mother, in understandable desperation, likely heard what she wanted to hear from a number of PTC employees regarding her son's potential access to PTC124. What is evident is that she was concerned about (and wanted to avoid) the possibility that Jacob might receive placebo in a controlled trial of the agent. The brief also implies that Jacob's pediatrician, Parkin, possibly boosted the Gunvalson's unfounded hopes for access to PTC124.

It's a disheartening case all around, but so is every case portending a premature death.

And as the brief argues, Jacob's access to PTC124 would be "monumentally unfair" to those children in PTC's phase 2b trial, who risk the chance of receiving placebo for the sake of advancing medical science.

Yesterday a couple of Brown University journalists showed up the mainstream press by writing a comparatively well researched and cogent article on a controversial 2001 paroxetine (Paxil; GSK) study in adolescent depression. The study's lead author, Brown psychiatry professor Martin Keller, is at the center of the controversy and the focus of charges from Australian psychiatrist Jon Jureidini that data in the GSK-funded study were manipulated to favor the antidepressant and downplay any related suicide risks.

However, what's missing* in this coverage (and the coverage of the coverage) is whether subsequent clinical trials support the use of paroxetine in adolescent depression. In other words, are the findings of Keller et al reproducible (notwithstanding allegations of data manipulation)?

Paroxetine is not indicated for the treatment of depression in adolescents and, in fact, its prescribing information (like that of other antidepressants) carries a black-box warning, which advises of the risks of suicidal ideation or acts in treated adolescents with psychiatric disorders.

A search of the PubMed database reveals 5 controlled clinical trials, in addition to the Keller study, that examined the use of paroxetine in adolescent depression. Three of these studies, like the Keller trial, compared paroxetine with placebo, and 2 of these studies (here and here) concluded that the antidepressant was no better than placebo, according to the Children's Depression Rating Scale-Revised or the Montgomery-Asberg Depression Rating Scale (MADRS), for the short-term (8- or 12-week) treatment of major depressive disorder in adolescents.

A post-hoc analysis of one of these studies found no difference between paroxetine- and placebo-treated patients in the rates of suicidal behavior or ideation. The second study found low rates of suicidal behavior or ideation with either treatment: paroxetine, 1.92% (2/104); placebo, 0.98% (1/102). (The third placebo-controlled paroxetine study, authored by investigators in Nova Scotia and a GSK employee, was conducted to assess the validity of the Kutcher Adolescent Depression Scale as a clinical-trial outcome measure.) 

A clomipramine-controlled study, performed by the DEROXADO Study Group in France, found no significant efficacy differences between the 2 drugs at 8 weeks (primary outcome measures, Clinical Global Impression scale [CGI] and MADRS); however, side effects, particularly anticholinergic side effects, were significantly more frequent with clomipramine. The rates of "suicidal acts" with either drug were comparable: clomipramine, 12.1% (7/58); paroxetine, 12.7% (8/63).

Last, a study published this year in JAMA assessed the efficacy of switching to 1 of 3 SSRIs (paroxetine, citalopram [Celexa; Forest], or fluoxetine [Prozac; Eli Lilly]) or the SNRI venlafaxine (Effexor; Wyeth), with or without cognitive behavioral therapy (CBT) in 334 adolescents whose depression was refractory to a 2-month trial of an SSRI alone. At 12 weeks, responses rates (per the CGI-I) were relatively higher with either medication (SSRI or SNRI) when combined with CBT. The authors found no treatment differences in the rates of suicidal ideation or "harm-related" adverse events.

Consequently data regarding the clinical efficacy of paroxetine in adolescent depression are mixed (if you believe that they haven't been manipulated in their entirety), given the handful of studies that show either the drug's comparable efficacy to placebo or its comparable efficacy to other antidepressants (which may or may not depend on the outcome measure used). The data assessing the suicide risk (either ideation or act) with the use of paroxetine specifically are less murky, with little-to-no differences between the drug and placebo or other antidepressants.

CGI-I = Clinical Global Impression-Improvement scale; SNRI = serotonin-norepinephrine-reuptake inhibitor; SSRI = selective serotonin-reuptake inhibitor.

* Let's not even discuss whether it's more or less preferable to align your medical career with pharma, as in the case of Keller, or personal-injury lawyers, as in the case of Jureidini.

The media failed to educate the public about persistent vegetative state (PVS) in its coverage of the Theresa Schiavo case. This is the conclusion of neurologists who reviewed more than 1000 relevant articles published in the NYT, The Washington Post, or 2 local Florida papers during a 15-year time span. The results of their examination were published in this week's Neurology.

The investigators examined 1141 articles, most of which (75%) were journalistic reports, printed from 1990 to 2005 and found statements denying Schiavo's PVS diagnosis in 71 articles. Other articles falsely claimed brain death (12) or minimal consciousness (10), both inconsistent with PVS. Also some descriptions of Schiavo's behavior (typically obtained from Schiavo's parents or sympathetic individuals)—such as responding, reacting, or communicating—are inconsistent with PVS.

Nearly 30% of articles contained statements that Schiavo "might improve" or "might recover," virtually nonexistent possibilities after spending 15 years in a PVS.* A lower percentage of articles (26%) included statements that Schiavo would not improve or recover. The neurologists, overall, found that "explanations of the basic concept of PVS...were rare."

In an accompanying editorial, neurologist James Bernat—who testified before the United States Senate Health, Education, Labor, and Pension Committee on April 6, 2005, to discuss Schiavo's case—chides the media for "squandering the opportunity to educate the public about disorders of consciousness and end-of-life care." He notes that, instead, coverage fixated on the dispute between Schiavo's husband and her parents and the politicization of the case by ultra-right-wing conservatives in a kind of pro-life stance.

Bernat also reproaches TV media for repeatedly showing an edited videotape of Schiavo, provided by her parents, which was likely to suggest consciousness to an uneducated public. Perhaps most important, the media failed to clarify that Schiavo's desire not to have a feeding tube (at the center of the dispute between Schiavo's husband and her parents) was concluded after "exhaustive hearings," which were based on the testimony of numerous friends and relatives.

On March 31, 2005, Schiavo died 13 days after the court-approved removal of her feeding tube and 15 years after sustaining hypoxic-ischemic brain injury during cardiac arrest (presumed to be due to, ironically enough, hypokalemia as a result of an eating disorder).

The American Academy of Neurology provides criteria for the diagnosis of PVS or, more accurately in the case of Theresa Schiavo, permanent vegetative state.

* Recovery from PVS (due to nontraumatic brain injury) after 3 months is rare.

CT image of normal brain (left) and of Schiavo's brain (right) in 2002, showing marked atrophy with hydrocephalus (presumably ex vacuo). Reprinted, from Wikipedia, under fair-use law.

The Federal Trade Commission has sued 5 companies, alleging their deceptive advertising of bogus cancer cures, according to a government press release on Thursday. The suits are the culmination of an extended investigation,* in concert with the US FDA and the Competition Bureau Canada, to crack down on the online sale of unproven and potentially harmful products that are intended for the prevention, treatment, and/or cure of cancer. (See here for additional background.)

The 5 defendant companies (and associated individuals) are the following.

Alexander Heckman doing business as (d/b/a) Omega Supply and Eric Del Rio (San Diego, CA) through the website laetrilesupply.com: In addition to bogusly marketing cyanide-containing laetrile (aka "amygdalin" aka "vitamin B17") as a cancer cure, Heckman and Del Rio are charged with making false claims regarding the benefits of hydrazine sulphate (a potential carcinogen) and cloracesium (aka cesium chloride).

Mark J. and Marianne Hershiser d/b/a Native Essence Herb Company (El Prado, NM) through various websites: The FTC cites the company's marketing of the chaparral shrub (associated with "acute toxic hepatitis" per the FDA), various herbal concoctions, and maitake mushroom extracts.

James Feijo d/b/a Daniel Chapter One (Portsmith, RI) through the website danielchapterone.com: The company sells shark cartilage and herbal formulations. According to the FTC, Feijo claims that one of his formulations mitigates the adverse effects of radiation and chemotherapy.

William H. Iseley, owner of Gemtronics, Inc (Franklin, NC): Iseley's company markets Chrysobalanus icaco (aka the Florida evergreen shrub cocoplum) and Agaricus, the most widely consumed genus of mushroom.

Mary T. Spohn d/b/a Herbs for Cancer (Surprise, AZ): Spohn markets a whole slew of Chinese herbal teas, according to the FTC's complaint, which are advertised to treat at least 16 types of cancer.

The 5 suits will be litigated before administrative law judges at the FTC. The FTC also reports complaints against 6 other companies that have been settled. The proposed settlements stipulate that the cited individuals and/or companies will pay sizable judgments (in some cases, several hundred thousand dollars) and will be barred from representing their products as preventing, treating, or curing cancer without the support of "reliable scientific evidence." The settlements, however, do not constitute an admission of guilt by the defendants.

* Between August 2007 and January 2008, the FTC sent warning letters via e-mail to 112 websites. Among these, nearly 30% closed their sites or removed cancer-treatment claims.

Martin Scorsese's After Hours (1985) is a wonderfully goofy, bad-dream homage to The Wizard of Oz and every anxious feeling I've ever had about Manhattan. Main-guy foil Griffin Dunne is great casting as a nerdish word processor (an obsolete job!) who ventures into SoHo to meet then it-girl Rosanna Arquette—followed by a whole string of women nut jobs.

The script dialogue, written by Joseph Minion, is still knee- and/or forehead-slapping funny.

Marcy (Arquette): My husband was a movie freak. Actually he was particularly obsessed with one movie, The Wizard of Oz. He talked about it constantly. I thought it was cute at first. On our wedding night, I was a virgin. When we made love—You've seen the movie haven't you?

Paul (Dunne): The Wizard of Oz? Yeah.

There's no reason to assess the removal of a substance when there's no evidence that the substance causes the disease in question.

That's pretty much the thought process of the NIMH, when it decided Wednesday to suspend a planned phase 2 study to assess mercury chelation in autism spectrum disorders (ASD). The study would have assessed the efficacy of DMSA, an oral chelating agent, or placebo to alleviate ASD symptoms in children aged 4-10 years during a 12-week period, despite the fact that mercury (from vaccines or otherwise) has not been associated epidemiologically with autism.

Also chelation is not without its hazards, owing to its ability to remove essential minerals, in addition to toxic heavy metals like mercury and lead, from the body. Moreover, in a study published last year, DMSA in rats that were not exposed to lead "produced lasting and pervasive cognitive and affective dysfunction," which was comparable to that seen with high lead exposure. Enrollees in the NIMH study would have had detectable, but not toxic, levels of mercury and lead.

HT: AP

Melamine-tainted infant formula is now linked to more than 6240 cases of renal stones as of Wednesday, reports WHO. Melamine has been found in products of at least 22 dairy manufacturers in China, with levels ranging from 0.09 to 2.560 mg/kg.

There is also a concern that melamine may turn up in other dairy products, like ice cream. The possible extent of the contamination has caused a nationwide panic among parents, reports the Chinese news agency Xinhua. Today's report also increases the number of melamine-related deaths to 4.

WHO reports that Sanlu, an original source of the tainted formula, received a complaint of illness as early as March of this year and, according to Forbes, Sanlu was urged in early August by its majority owner, New Zealand's Fonterra Cooperative Group, to initiate a product recall. However, Sanlu (in possible collusion with Chinese government officials) delayed the recall to avoid a PR scandal during the upcoming Olympic Games in Beijing. 

Sanlu claims that one of its raw milk suppliers used melamine to artificially boost the product's protein content, wrote Scientific American on Tuesday.

Depiction of melamine chemical structure from Wikipedia.

9/22/08 update: Melamine-tainted infant formula has now sickened 52,857 Chinese children and resulted in the hospitalization of 12,892, reports the AP. More than 80% of those hospitalized were or are 2 years of age or younger, and 104 were or are in serious condition. The latest news report also confirms 4 related deaths. The uptick in ill children may be due to the review of earlier hospital records, from May through August. In addition, the head of the Chinese agency that monitors food and product safety, who had held the position since 2001, resigned.  

In a public letter dated September 16, Oxford statistician Richard Peto wrote heated responses to questions from US Representatives John Dingell (D-MI) and Bart Stupak (D-MI) about the clinical investigation of Vytorin (ezetimibe/simvastatin; Merck/Schering-Plough). The congressmen's questions, many of which imply professional collusion between Peto and Merck/Schering-Plough, were originally submitted to the drugmakers in letters dated August 21 and September 2.

In his response, Peto seemed to be particularly vexed by the request that the companies "make Dr. Peto available for a staff interview as soon as possible." In reply, Peto advised that "the companies have no control over him." However, Peto did offer his assistance as an epidemiologist and statistician to help the congressmen and their subcommittee (of Oversight and Investigations) understand "statistically appropriate ways of interpreting the hypothesis-generating and hypothesis-testing data sets from trials."

Peto is referring specifically to his and others' recent analysis of cancer data from the ongoing Vytorin studies SHARP and IMPROVE-IT. The analysis was conducted in response to an observed association between the drug and cancer rates in the completed SEAS trial (background here). The conclusion of the analysis of Peto et al, which was recently published in the NEJM, is that there is "no credible evidence" that Vytorin (and in particular, ezetimibe) affects cancer rates.

The debate generated from the NEJM analysis rests on whether data from the 3 studies should have been combined to assess the potential cancer risk with Vytorin, as advocated by US cardiologist Steven Nissen, or whether it is inappropriate to lump data from the hypothesis-generating trial (SEAS) with data from the hypothesis-testing trials (SHARP and IMPROVE-IT), as urged by Peto and "any competent trial statistician."

In response to several questions regarding the NEJM analysis, Peto advised the congressmen, more or less, to read the article. Peto further declared that the analysis was undertaken independently of the drug companies and was coordinated by his Oxford colleague Rory Collins, in agreement with the various chairs of the Data Monitoring and Steering Committees of SHARP and IMPROVE-IT.

Other requests from the congressmen were answered with sharp rebukes, including a request for all correspondence between Peto's department, the Clinical Trial Service Unit (CTSU) at Oxford, and Merck or Schering-Plough. Peto replied that this request seems "to constitute inappropriate harassment," given that CTSU has conducted 4 major independent trials of Merck's cholesterol-modifying drugs for more than 10 years. Peto also denied the existence of a "secret" FDA report of his cancer analysis; nor did he send any advance drafts of the study results to Merck or Schering-Plough.

In a curious postscript, Peto requested that the subcommittee declare its own potential conflicts of interest, suggesting that Dingell, in particular, may hold a personal grudge against Peto and the CTSU. In 1997, Peto and others published an article in Controlled Clinical Trials, in which they described the procedures of the subcommittee in its investigation of the National Surgical Adjuvant Breast and Bowel Project (NSABP) as "inappropriate" and Dingell's statements as prosecutorial.

IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; SEAS = Simvastatin and Ezetimibe in Aortic Stenosis; SHARP = Study of Heart and Renal Protection.

Photograph of Richard Peto from CTSU website.

A novel, experimental molecule, AZD3480, did not significantly change cognition (per the ADAS-cog) at 12 weeks in a randomized, placebo-controlled, dose-finding study of 567 European or Canadian patients with mild-moderate Alzheimer's disease. Early results of the phase 2b study were revealed Monday by the molecule's codevelopers, Targacept and AstraZeneca.

In addition, the approved AD drug donepezil (Aricept; Eisai/Pfizer) did not significantly change the mean ADAS-cog score at 12 weeks. (The dosage of donepezil studied was not provided in the companies' press release.) Disappointing outcomes with AZD3480, a selective agonist of a neuronal nicotinic receptor subtype (α4β2), and donepezil, an AChE inhibitor, were due to unexpected cognitive improvement in those patients who received placebo, wrote the companies.

Patients who received 2 of 3 tested doses of AZD3480 did show modest cognitive improvement per secondary outcome measures, as did patients who received donepezil. AZD3480 appeared to be better tolerated than donepezil, with fewer episodes of diarrhea, nausea, or vomiting.

The companies indicate that analysis of the trial results is ongoing, and trial data will be presented in a scientific setting at some unspecified time and place. A decision regarding the continued development of the AD drug candidate is expected at the end of this calendar year. AZD3480 is also being evaluated for the treatment of cognitive dysfunction in schizophrenia (trial results are expected at the end of 2008) and adult attention deficit/hyperactivity disorder.

AChE = acetylcholinesterase; ADAS-cog = Alzheimer's Disease Assessment Scale-cognitive subscale.

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

Approximately one third of individuals with schizophrenia will develop so-called positive psychiatric symptoms (eg, auditory hallucinations, delusional thinking) before the age of 18 years. The prognosis of early-onset disease is typically poorer than that of adult-onset schizophrenia, and studies suggest that adults with earlier-onset symptoms are less responsive to first-generation antipsychotics (FGAs).

The rationale for using atypical, or second-generation, antipsychotics (SGAs) in teenage patients with schizophrenia is based primarily on adult data, given the efficacy of SGAs to reduce positive and negative psychiatric symptoms and the relatively lower risks of extrapyramidal side effects and irreversible tardive dyskinesia with SGAs. Of the few studies that have compared an SGA with an FGA in early-onset schizophrenia (EOS), most (if not all) have used haloperidol (Haldol) as the comparator FGA. These studies have also been of relatively brief duration (6-8 weeks).

Now come results of another short (8-week), double-blind study, which was funded by the NIMH and published online yesterday in the American Journal of Psychiatry. A total of 116 individuals with EOS or early-onset schizoaffective disorder (age range, 8-19 years) received at least one dose of randomly assigned olanzapine (Eli Lilly's Zyprexa—the biggest weight-gain and metabolic offender of the SGAs); risperidone (JNJ's Risperdal—another SGA with a not-inconsequential risk of weight gain); or the FGA molindone (Moban—which has been associated with weight loss in adults; see Allison DB et al. Am J Psychiatry. 1999;156:1686-1696). Molindone was administered with benztropine 1 mg/d, to reduce the risk of FGA-associated extrapyramidal effects.

On the basis of the Clinical Global Impression (CGI) scale and the Positive and Negative Syndrome Scale (PANSS), psychiatric improvement was noted in 50%, 46%, and 34% of molindone-, risperidone-, and olanzapine-treated children, respectively, at 8 weeks. These improvement rates were not statistically significantly different. However, responses were seen earlier (at 2 weeks) with olanzapine and risperidone than with molindone (at 3 weeks).

Subjects receiving olanzapine or risperidone, not surprisingly, experienced significant weight gain, while those taking molindone did not gain weight. In addition, olanzapine-treated patients demonstrated significantly increased fasting levels of cholesterol, LDL, insulin, and hepatic transaminases.

Given that these study results are not particularly surprising (see another EOS study of olanzapine, risperidone, and haloperidol by the same lead author, Sikich, for example), a more useful study would have compared an FGA with SGAs that are less likely to be associated with significant weight gain (eg, aripiprazole [Abilify*; BMS]). Also longer-term studies are warranted in EOS to evaluate, not only the risk of FGA-associated movement disorders, but also sexual maturity in the setting of antipsychotic-induced hyperprolactinemia.

Randomish side note: Katrina Megget, over at PharmaTimes, reported that shares of Eli Lilly and JNJ dropped more than 1% yesterday on the news of the NIMH study results—which is relatively terrific, because THE DOW DROPPED BELOW ELEVEN-FREAKING-THOUSAND yesterday, Katrina.

* Which has to be one of the dumbest drug trade names ever. Think George W. Bush saying, "We're going to abilify our troops in Iraq." 

With the options of 1) pushing its inane "expose" of trace pharmaceuticals in drinking water and 2) letting its dumb story slip quietly into the ether, the AP makes the wrong decision.

On Friday, writer Martha Mendoza stubbornly updated the AP's idiotic article from March, by reporting that at least 46 million Americans are now exposed to parts per billion or trillion of a scattered number of prescription drugs, like so much fairy dust, in the nation's tap water. Wow. That's 5 million more, likely unaffected individuals to add to the original 41 million, likely unaffected individuals who must drink water to maintain existence. All thanks to the unnecessary testing prompted by the AP's unthinking reportage.*

Despite pressure to examine city water supplies by the AP's moronic investigation, some environmental officials remain rational, including those at NYC's Department of Environmental Protection, who refuse to test for the presence of drugs at infinitesimal levels—probably given, at least in part, the fact that serious macroscopic vermin issues deserve ongoing attention.

* And are measurements of drugs even accurate at that level?

Addendum: Just to get an idea of the dilution we're talking about here, the value of 1 part per billion (ppb) is 10^–9, which is equivalent to 1 microgram (µg) per liter (L) of water or 1 g diluted in 1 million L of water. One part per trillion is 10^–12 or 1 nanogram per L of water or 1 g diluted in 1 billion L of water (400 Olympic-size swimming pools, per Wikipedia). The EPA's action levels for lead and mercury (which are not FDA approved for consumption) in water are 15 and 2 ppb (15 and 2 µg/L), respectively.

Who knew that f#%k-spewing David Mamet could pull off English period drama?

The Winslow Boy (1999)—a thinly veiled love letter from director Mamet to his wife, Rebecca Pidgeon—is the story of seemingly lost causes: the acquittal of the titular boy in a case of theft, women's suffrage, and a chauvinist's love for a feminist. The cast features many a rock-solid English actor, including Nigel Hawthorne and the splendiferous Gemma Jones.

Melamine is back. This time, the suspected renal toxin has been found in Chinese-made infant formula, alerts the FDA. The agency is working to inform Asian and ethnic markets in the United States that illegally imported Chinese formula may be contaminated with the fake protein additive. But the FDA is also reassuring consumers that infant formula approved for sale in the United States, which is not made with Chinese ingredients, is safe.

The Xinhua news agency reports an ongoing police investigation into the contamination of Sanlu brand powdered formula in Shijiazhuang, China, where the product was manufactured. The investigation was prompted by reports of kidney dysfunction in at least 50 Chinese infants who consumed the product. One infant reportedly died as a consequence.

Melamine was found last year in Chinese-imported wheat gluten, which was used to produce domestic pet food. Melamine in the contaminated pet food, along with another contaminant, cyanuric acid, are believed to have led to innumerable cases of renal dysfunction or failure in American pets. The event led to the largest recall of pet food in the United States.

In February, the federal government indicted Sally Qing Miller and her husband Stephen S. Miller, from the Las Vegas-based ChemNutra, for importing 800 metric tons of tainted Chinese wheat gluten into the United States, while conspiring to bypass mandatory Chinese inspections.

Primary news source: USA Today

Depiction of melamine chemical structure from Wikipedia.

Update: In a press release, the FDA reports that the following manufacturers have met the necessary FDA requirements for marketing milk-based infant formulas in the United States—Abbott Nutritionals, Mead Johnson Nutritionals, Nestle USA, PBM Nutritionals, and Solus Products LLC. An English-based manufacturer, SHS/Nutricia, sells an amino-acid-based, nondiary infant formula.

9/15/08 update: The AP reports that 2 brothers, who ran a "milk-collection center" (whatever that is) in Hebei province, were arrested on suspicion of adding melamine to the infant formula. The AP also indicates that Chinese officials were slow to initiate a formula recall, after being alerted to the contamination by Fonterra, a New Zealand dairy farmers' cooperative that owns 43% of Sanlu, the manufacturer of the tainted formula. Complaints were reportedly received by Sanlu as early as March, and company tests of formula revealed the presence of the contaminant in August. The AP story does not reveal how the milk-collection center is connected to Sanlu. The latest casualty numbers: 1253 infants possibly sickened, 340 currently hospitalized (53 in "severe" condition), 2 dead.

9/17/08 update: According to the AP, melamine-tainted baby formula has now sickened 6244 Chinese infants, with 1327 hospitalized and 158 experiencing acute renal failure. Three children are now dead as a result. Four milk suppliers have been arrested in China, and the general manager of Sanlu, the manufacturer of the tainted formula, was detained by Chinese police yesterday, wrote the news service. At the center of the investigation is whether Sanlu or the company's local government stalled a public recall of the tainted formula in August. Other Chinese dairy companies are recalling their possibly tainted products, including 2 Chinese exporters, which have sent formula to parts of Asia and Africa. 

Over at The Carlat Psychiatry Blog, Daniel Carlat finally takes a look at the latest proposal by the ACCME to restrict those writers or physicians who engage in industry-funded promotional efforts (eg, speakers' bureaus) from also producing independent CME. While, to some, this proposal seems to encroach on First Amendment issues, Carlat pooh-poohs the argument. Quel surprise.

Among the various specious arguments I've heard against this policy, the most astonishing is the censorship argument. By forbidding doctors on company speakers bureaus from writing accredited CME, so the argument goes, ACCME is "censoring" them. At Policy and Medicine, for example, Tom Sullivan, president of the MECC Rockpointe, says that "banning certain authors from writing books and giving talks doesn't seem to accord with freedom of speech, but that is exactly what the ACCME is proposing."

Come on folks. Let's get real. ACCME is not preventing anybody from saying or writing anything they want, anywhere, at any time. They are simply witholding[sic] a lucrative seal of approval from speech that does not meet their requirements. When Good Housekeeping Magazine witholds[sic] its seal of approval from a shoddy product, they are not preventing the company from making it. The shoddy product can still be sold; the company just can't use the seal to market the product.

Similarly, ACCME is saying that medical communication produced by people who take marketing money from drug companies no longer meets its standards for high quality CME, and it will no longer accredit such communication. MECCs are still free to provide it, print it, circulate it in conferences, but it won't be accredited information. How is this "censorship?"

Here's potentially how. As I understand it (although I'm certainly not a legal scholar), freedom of speech comes into play at the juncture of government and the public. To my knowledge, all state governments require that physicians acquire so many credit hours per year of certified CME to maintain their licensure. The ACCME is the only organization (again to my knowledge) that accredits educational groups (medical associations, academic CME offices, MECCs) to provide certified CME to physicians. Therefore the ACCME is proposing limitations on who can produce or deliver government-required CME—what can be reasonably argued as a restriction on free speech.

In any event, the ACCME's proposal sure feels like it encroaches on First Amendment rights (Dr. Carlat's opinion excepted), in which case some legally informed somebody should figure out why (if the above is not accurate). Also the ACCME would be wise to seek legal counsel before proposing such restrictions.

Comments to the ACCME's latest proposal can be submitted here, through tomorrow (9/12/08).

ACCME = Accreditation Council for Continuing Medical Education; CME = continuing medical education; MECC = medical education communications company.

Autism's False Prophets: Bad Science, Risky Medicine, and the Search for a Cure

By Paul A. Offit

328 pages

If anybody thinks Paul Offit, infectious-disease specialist at one of the nation's best pediatric hospitals, overstates the physical threats he gets from antivaccinationists, here's a sobering rebuttal: There will be no book tour for Autism's False Prophets, Offit's plain-speaking chronicle of how vaccinations have been erroneously implicated in the rise of autism. The security risk is just too high says the book's publisher, Columbia University Press.

Paul Offit has become the medical equivalent of Salman Rushdie (who went into hiding after the publication of The Satanic Verses, which prompted a fatwa from the Ayatollah Khomeini). And it's not a bad analogy, given the blind faith practiced by those who thoughtlessly adhere to and profit from, against all credible scientific evidence, the idea that vaccines are somehow responsible for a neuropsychiatric condition that is so poorly understood.

In the book's prologue, Offit—who holds a patent on a rotavirus vaccine and who vocally advocates for vaccinations in general—reveals that he gets a lot of hate mail, some of it with religious overtones. One correspondent asked, "Why did you sell your soul to the devil?" and another prays "that the love of Christ will one day flood [his] darkened heart." Offit has also received gruesome death threats ("I will hang you by your neck until you are dead!") and non-too-subtle threats toward his children. But Offit's book, most importantly, is not about Offit.

Autism's False Prophets is a systematic unpacking of the relatively short history of autism, its identification 70 years ago, its rise in frequency (which is primarily, if not exclusively, due to increased recognition), and its broad manifestations, which have driven some parents of severely affected children to the unthinkable. Other parents, desperate for treatment, have been sucked into trying one or more bogus therapies (for instance, facilitated communication), which have been hawked by one or more charlatans willing to fill the therapeutic void in allopathic medicine.

As Offit writes, some of these false prophets are credentialed; some have no medical training whatsoever. Many have been either implicitly or outrightly endorsed by the media and political figures, with no consequences for those who sow the unfounded and dangerous idea that vaccines cause autism. One of the most prominent false prophets, according to Offit, is English gastroenterologist Andrew Wakefield, who attempted to implicate the MMR vaccine as a cause of autism in the late 1990s. Wakefield's work, which received tremendous media attention, was largely funded by a personal-injury lawyer, reveals Offit, and was later discredited on charges of fraud. However, Wakefield's ideas on the dangers of the MMR vaccine contributed to England's recent measles epidemic, and astoundingly, the doctor still has his rabid supporters.

There is also the father-son duo of Mark and David Geier, who (along with others) implicate the vaccine preservative thimerosal as a cause of autism through work performed in their home-basement laboratory in Maryland. The Geiers, in particular, have migrated into shocking territory by advocating dangerous chelation therapy and chemical castration with leuprolide (Lupron; TAP) for autistic children. Offit writes how librarian and tenacious blogger Kathleen Seidel, whose child was diagnosed with a form of autism, has nearly single-handedly revealed the highly questionable nature of the Geiers' work.

Parents of autistic children, like Seidel, who refuse to neglect science or waste their time, energy, and money on unproven and far-fetched treatments, are the poorly credited heroes of the autism story. Offit reveals that he wrote Autism's False Prophets for them. However, the noise from opportunists has been cranked up by ignorant, but highly influential (and arguably financially conflicted), political figures—specifically US Congressman Dan Burton, whose grandchild was diagnosed with autism, and tort lawyer Robert F. Kennedy, Jr., a vocal proponent of the idea that thimerosal causes autism. Public figures like Burton and Kennedy have essentially ignored the series of epidemiologic studies that have exonerated vaccines as the cause of autism, mindlessly asserting that the issue should be settled in the public, instead of scientific, arena. Consequently they divert attention and funding away from credible research into the causes of autism and its treatment.

At play in this mess, Offit soundly argues, is the media's undying hunger for controversy. The idea that vaccines don't cause autism, although true and of vital public interest, isn't particularly provocative. The story's would-be title would mimic a banal headline from the parody newspaper The Onion. Moreover, science itself, which many consumers find terribly dry, isn't easily conveyed in sound bites. Case in point is the appearance of IOM president Harvey Fineberg on "Meet the Press," when he found himself contending on air (in a show of journalistic "balance") with media-savvy writer David Kirby, author of the vaccine-maligning Evidence of Harm. And if "Meet the Press" can't be counted on to provide sound information, little can be expected of Oprah.

For readers who don't believe that science is a yelling contest, the events in Autism's False Prophets—events in which self-interested figures ride roughshod all over medical evidence—will anger. Nevertheless, it is this justifiable anger that can mobilize investigations away from life-saving vaccines and onto the very elusive causes of autism.

Vitamin B12 deficiency (typically defined as a serum level <150 pmol/L, but usually much lower) is a well-documented cause of nervous system injury, traditionally in the form of subacute combined degeneration. Whether low-normal serum levels of B12 pose a risk for milder forms of CNS dysfunction, like cognitive impairment, is less clear.

In this week's Neurology, physicians from the Oxford Project to Investigate Memory and Aging (OPTIMA) report a statistical association between low-normal B12 levels (ie, <308 pmol/L) and brain atrophy in 107 elderly, cognitively intact,* community-dwelling volunteers during a 5-year period.

By using annual, serial MRI studies, investigators assessed the potential associations between brain atrophy (the percentage of whole brain-volume loss per year) and known markers of vitamin B12 status: plasma B12, transcobalamin (TC), holotranscolbalamin (holoTC), methymalonic acid (MMA), and total homocysteine (tHcy). The mean B12 level at baseline was 363 pmol/L, and no subject had a B12 level below 150. Approximately 6% of subjects were receiving oral or injectable B12 supplementation. It is important to note that associations between B12 markers and cognitive function were not examined in this study.

After adjustment for a number of factors (age, sex, creatinine, education, initial brain volume, etc), reduced brain volume was significantly more likely in those subjects with lower B12 and holoTC levels at baseline. Also subjects with B12, holoTC, or TC saturation levels in the bottom third were significantly more likely to demonstrate brain atrophy (but note that confidence intervals for odds ratios were very wide; see Table). While MMA and tHcy are believed to be more sensitive indicators of B12 deficiency, high levels of these metabolites were not associated with loss of brain volume in this study.

B12 Variable	OR, Adjusted (95% CI)	P Value
B12, pmol/L
>386	1.00 (ref)
308-386	4.39 (1.01, 19.03)	.048
<308	6.17 (1.25, 30.47)	.026
HoloTC, pmol/L
>78	1.00 (ref)
54-78	2.63 (0.63, 10.92)	.184
<54	5.99 (1.21, 29.81)	.029
TC saturation, %
>8.4	1.00 (ref)
5.7-8.4	6.64 (1.31, 33.73)	.022
<5.7	6.63 (1.22, 36.05)	.029

The authors appropriately caution that their findings must be confirmed by larger studies in different populations, and that cognitive impairment is yet to be correlated with B12-associated brain atrophy. Also the utility of early B12 supplementation to prevent observed brain loss merits study.  

* Cambridge Cognitive Assessment (CAMCOG) score >80; Mini-Mental State Examination (MMSE) score >24.

$725 million is a lot of money for an old Russian antihistamine.

But that's what Pfizer agreed to give Medivation last week for the worldwide marketing rights to Dimebon (dimebolin), a defunct, nonselective histamine blocker that is now in phase 3 clinical development for Alzheimer's disease: $225 million upfront and another $500 million when (or if) the drug is approved by the FDA.

The agreement—which splits development costs and profits on a 60-40 basis (Pfizer assumes the larger share)—also confers licensing rights to Pfizer for use of the drug in Huntingdon's Huntington's disease. (Dimebon is currently in phase 1/2 development for this condition.)

Pfizer is evidently betting on the chance that the 3-times-per-day Dimebon will sail through clinical development, given recent phase 2 results published in The Lancet. In a randomized, double-blind, placebo-controlled, multicenter study (N = 183) that was conducted entirely within Russia and funded by Medivation, patients with mild-moderate AD who received Dimebon* demonstrated significantly less cognitive decline at 6 months, as measured by the ADAS-cog (mean score difference, 4.0; P < .0001).

Specifically the mean ADAS-cog score of those who received Dimebon improved by approximately 2 points and the mean score of placebo-treated patients declined by more than 2 points. Secondary outcome measures (eg, MMSE) supported these findings. In a blinded, 26-week extension phase, the difference in the mean ADAS-cog score between patients who originally received Dimebon and those who originally received placebo increased further (6.9; P < .0001). The most common adverse effects observed with Dimebon treatment in this phase 2 study were dry mouth and depression.

By comparison, the mean ADAS-cog score difference between the once-daily blockbuster Aricept (donepezil; Eisai/Pfizer) and placebo was approximately 3 points at 30 weeks in patients with mild-moderate AD. The basic patent on Aricept, the most widely used AD drug, will expire in 2 years.

According to Medivation, Dimebon has been shown to inhibit brain-cell death in preclinical models of AD. A PubMed search reveals at least 4 rodent studies and 1 pilot study of the agent at the Moscow Center of Gerontology. The company further proposes that Dimebon confers benefits in AD by "improving mitochondria function."

Also according to Medivation, the Russian study can be used as 1 of 2 pivotal trials to support the FDA approval of Dimebon, as long as a "significant portion" of the current phase 3 trial occurs within the United States. A 6-month, placebo-controlled phase 3 trial of Dimebon (5 or 20 mg tid) in 525 patients with mild-moderate AD was initiated in the second quarter of this year; results are expected in 2010, reports The Street. Dimebon is also being assessed in combination with donepezil in a phase 1 study.

ADAS-cog: Alzheimer's Disease Assessment Scale-cognitive subscale; MMSE = Mini-Mental State Examination.

* 10 mg tid for 7 days, followed by 20 mg tid. 

Images of defunct Russian and defunct Russian antihistamine from Wikipedia.

Before Eric Bogosian needed real money, he was this performance artist/stand-up comic/monologuist/writer guy known mostly to New Yorkers. Sex, Drugs, Rock & Roll (1991) is probably the best example of Bogosian's ability to fuse all of his scary talents into a spare one-man performance, but I've had a devil of a time finding the recording on DVD (Luddites can watch the show on VHS). The next best thing is the bluer Wake Up and Smell the Coffee (2001); however, I can only vouch for the live performance, seen at Chicago's Park West venue in the waning months of the 20th century.

A bonus funny: Bogosian gets uppity with a fan and reviews his own work at Netflix.

The overwhelming majority of American toddlers (age, 19-35 months) received at least 1 recommended vaccine last year, according to data from the National Immunization Survey (NIS), and coverage for at least 1 dose of varicella reached 90% for the first time. Detailed data from the survey were reported in this week's MMWR.

The coverage rate in 2007 for the recommended 4:3:1:3:3:1 series* of vaccinations was 77.4%, which was comparable to rates of previous years. However, the NIS report noted "substantial variability" of coverage among states (Maryland, 91.3%; Nevada, 63.1%) and urban areas (Philadelphia, 82.2%; San Bernardino, 69.6%). Nevertheless, very few children in the examined age group (0.6%) received no vaccinations whatsoever.

Coverage rates for the 4:3:1:3:3:1 series were not significantly different among racial or ethnic groups after adjusting for poverty status, but certain vaccines (ie, 4th dose of DTaP and 4th dose of PCV7) were less likely to be received by children living at or below the poverty level, according to the report. The ethnic group composed of American Indians and Alaska Natives had the highest coverage rates for the vaccination series and specifically for MMR (96.2%), HepB (96.7%), and varicella (94.9%). 

Despite the record number of measles cases reported this year in the United States, the percentage of toddlers who received at least 1 dose of MMR vaccine has remained stable since 2004 (Table). Still nearly 8% of American toddlers did not receive vaccination for the disease in 2007, and small geographic clusters of unimmunized children appear to account for this year's record number of cases of the highly contagious disease. (For those parents who remain wary of MMR vaccination owing to unsubstantiated fears of autism, yet another study published in this week's PLoS One dispels the connection. Orac provides the necessary background and details, sparing others the trouble of posting on the subject. Hosanna.)

Year	≥1 MMR Dose, %
2003	93.0
2004	93.0
2005	91.5
2006	92.3
2007	92.3

Data for the NIS were collected by means of telephone survey for more than 17,000 children (household response rate, 64.9%). The report acknowledges a possible underestimate of vaccine coverage owing to the exclusive use of provider-verified histories. In addition, clusters of unimmunized children were not likely to be detected, given the survey methods.

* Vaccine doses: 4 DTP/DTaP/DT, 3 polio, 1 MMR, 3 Hib, 3 Hep B, and 1 varicella.

Photo of toddler receiving pneumococcal vaccine from the CDC.

Anyone who has followed the Vytorin soap opera, from the troubled ENHANCE study to reports of cancer in the SEAS study, can recognize a pattern. Cardiologist Steven Nissen is certainly available to more than one media outlet for more than one derisive, highly quotable quote about the drug, the drug's studies, or the drug's comarketers (Merck and Schering-Plough).

That's not to say that Dr. Nissen isn't entitled to a scathing opinion...or two, or three, or more. However, the subtext of vitriol in these running opinions, as quoted by the media, suggests that Dr. Nissen's thoughts on anything related to Vytorin are informed by something more than dispassionate assessment—at least in my opinion.

For instance:

On the negative results of the simvastatin-controlled ENHANCE study in patients with heterozygous familial hypercholesterolemia (in which a substantial percentage of the carotid-ultrasound data were allegedly missing or of low quality).

To Alex Berenson of the NYT: "Shocking...This is as bad a result for the drug as anybody could have feared."

To CBS News: "My advice to physicians is not to use this drug Vytorin, nor to use Zetia [ezetimibe], as first-line agents any more. These should be really relegated to drugs of last resort, until we have some evidence that they produce a health-outcomes benefit...Right now, 5 years into this, with nearly 1 million prescriptions per week being written, there is no evidence that the drugs actually produce any benefit for patients."

To the Washington Post/HealthDay: "This wraps it up. That's all there is. There just isn't any evidence that adding ezetimibe to simvastain produces any advantage."

To Forbes: "This drug [Vytorin] doesn't work. Period. It just doesn't work."

On the FDA's approval of Vytorin, which was based on a statistically significant 20% lowering of LDL cholesterol, when compared with simvastatin alone. 

To Alex Berenson (again) of the NYT: "The FDA set the bar too low on the initial approval [of Vytorin]. It would have been a lot better if the agency had said, 'Show us that you do more than lower LDL a little bit; show us evidence of effectiveness.'"

On evidence of an increased cancer risk in the SEAS trial and lack thereof in the ongoing studies of SHARP and IMPROVE-IT (background post here).

To Dow Jones Newswires: "Even though they [SHARP and IMPROVE-IT] are shorter," they nearly reached a statistically significant link to cancer. "They definitely do not rule it out."

To Bloomberg: "There is clearly a signal for excess cancer and cancer mortality in SEAS. I do not believe that unblinding 2 incomplete trials to try to refute that signal is scientifically appropriate. The bottom line is we just don't know if ezetimibe is associated with an increased incidence of cancer or cancer mortality."

To Forbes: "What you're seeing here is the behavior of a company that is under siege by the failure to do the right studies. And they're trying to spin the results using media-relations strategies rather than the proper scientific approach...I think those studies [SHARP and IMPROVE-IT] should never have been unblinded. That's very regrettable."

But Dr. Nissen did provide at least one quotable caveat for patients who may act on medical information (or physicians' quotes) in the lay press.

To CBS News: "People should talk to their doctor. No one should stop taking medication because they hear a news report."

2006 photo of Steven Nissen testifying at the Hearing on Building a 21st Century FDA.

The Vytorin-cancer scare resurfaces with the simultaneous presentation of data from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial at the annual congress of the European Society of Cardiology (ESC) and the online publication of study results in the NEJM. Accompanying the NEJM article are an analysis of cancer data from 3 Vytorin studies (including the SEAS trial) led by biostatistician (Sir) Richard Peto and a cautionary editorial headed by the journal's Jeffrey Drazen.

Peer-reviewed results from the prospective, randomized, double-blind, placebo-controlled SEAS trial (N = 1873) are consistent with those in a Merck/Schering-Plough press release from July (previous post here). Namely Vytorin did not reduce the relative risk of the primary endpoint, major cardiovascular events associated with aortic valve or atherosclerotic disease, at a median follow-up of 52.2 months. Moreover, cancer (but not cancer deaths) occurred significantly more often in Vytorin-treated patients (105 vs 70; P = .01). The latter finding was driven by a significantly higher incidence of (unspecified) skin cancer with Vytorin treatment (18 vs 8; P = .08).

In their analysis of the cancer data, Peto et al compared the rate of cancer in the SEAS trial (mean follow-up, 4.1 years) with unblinded cancer data from 2 larger, ongoing Vytorin studies, SHARP (N = 9264) and IMPROVE-IT (N = 11,353). Data from the SEAS trial revealed an increase in new cancer from several sites with Vytorin treatment in this analysis (105 vs 65), but there was no increase in the risk of cancer overall or at a particular site in SHARP and IMPROVE-IT (313 vs 326). When combining data from these 2 studies, cancer deaths were nonsignificantly increased with Vytorin treatment (97 vs 72; P = .08). But Peto et al argue that any increase in the risk of cancer death should be accompanied by an increased risk of cancer, which was not observed.

In their editorial, Drazen et al advise caution when interpreting the cancer analysis of Peto et al given the relatively short follow-up times of SHARP and IMPROVE-IT (2.7 and 1.0 years, respectively), despite that fact that these studies are much larger than the SEAS trial. The editorial also notes that Peto et al have received research funding from Merck and Schering-Plough (intimating some kind of conflict of interest), although the cancer analysis was performed independently of the companies.

Forbes's Matthew Herper, an avid follower of the Vytorin story, covers the clinical divide created by these recently presented data (a divide that has arguably been fomented by media outlets like Forbes). At the center of the cancer controversy is how Vytorin, and specifically the ezetimibe component, might increase the risk of cancer. Some argue that the drug may block the absorption of anticancer plant sterols, reports Herper, a touchy-feely explanation that MD Anderson's biostatistician Donald Berry* finds "pretty weak."

Another debate is whether it's statistically sound to pool cancer data from all 3 studies, SEAS, SHARP, and IMPROVE-IT, in which case there are significantly more cancer deaths with ezetimibe treatment than placebo or simvastatin (Zocor) treatment. According to Forbes, cardiologist Steven Nissen, who's made a national name for himself by performing inherently problematic meta-analyses, advocates the act; statisticians Peto and Berry advise against it—possibly because of substantial differences in the designs of these studies.

Debate will undoubtedly continue, given the results of the SEAS trial and a fervent interest in anything remotely anti-Vytorin. In the meantime, Merck and Schering-Plough are left with the very difficult task of proving a negative—namely that ezetimibe is not associated with an increased risk of cancer or cancer deaths. Even if clinical doubt could be removed by positive, final data from SHARP or IMPROVE-IT, these data won't be available for at least 2 years.

IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; SHARP = Study of Heart and Renal Protection.

* Berry was cited in a previous post on drug-testing stats.

With tony simulation devices for graduate and postgraduate training, well-endowed university medical centers can afford to snub commercial support of traditionally produced CME.

This is the cat-bird seat specifically for Stanford University, which (as of yesterday) prohibits industry funding of any specific CME course or program that uses the Stanford name or is directed or initiated by its medical school faculty. Instead pharma companies hoping to support Stanford-sponsored CME must give their funds to Stanford's Office of CME, which will coordinate and distribute the funds for educational activities within 4 broad categories: medical, pediatric, and surgical specialties; diagnostic and imaging technologies and disciplines; health policy and disease prevention; and "other areas approved by the Office of CME."

The new policy does not outrightly prohibit Stanford medical faculty from delivering industry-funded CME that is certified by another ACCME-accredited organization (such as a MECC); although the policy implicity discourages the act. Also it is unclear how the Stanford name, in the form of a faculty member's affiliation, may be used in such a CME activity.

The new Stanford policy follows other university actions, beginning in 2006, when Stanford adopted a center-wide policy that prohibits the acceptance of any industry-supplied gifts* (including food) by medical faculty, healthcare staff, or medical students in any clinical setting. Last year, Stanford revised its annual conflict-of-interest and commitment disclosure for faculty to address personal and family ties to industry that may influence clinical practice.

While supporting CME, Stanford acknowledges that the effect of traditional programs—typically in the form of lectures or discussion groups—on healthcare improvement has not been demonstrated. The university implies that interactive education may be more effective by advising, "Future CME programs should take advantage of emerging technologies and should be more focused on the professional and technical development and education of the learner."

A press release from Phillip Pizzo, MD, the Dean of Stanford's School of Medicine, refers to novel programs available through high-tech university-based learning centers—such as the Goodman Simulation Center and the future Li Ka Shing Center for Learning and Knowledge. Funding for Stanford's educational simulation programs is unclear, although the $90-million Li Ka Shing Center has been made possible by a very generous donation from a Hong Kong entrepreneur. 

ACCME = Accreditation Council for Continuing Medical Education; CME = continuing medical education; MECC = medical-education communications company.

* It is not clear from the online policy if gifts include drug samples.

Photo: Screen of virtual procedural simulation from the Goodman Simulation Center.