bmartin: January 2009 Archives

A fine, early example of a character-driven set piece is John Ford's The Lost Patrol (1934). In the Middle Eastern theater of WWI, 11 British soldiers are stranded at a Mesopotamian oasis after their commanding officer is shot and their horses are stolen by unseen Arabs. Desert snipers then serially pick off the men during their various displays of bravery, recklessness, and insanity.

Overacting even by his contemporary standards, Boris Karloff nevertheless cuts a striking figure as a religious fanatic before the movie's climax. The film also features the solidly built Victor McLaglen, who became a staple in Ford's films.

Unable to top yesterday's gross-out post from the WSJ Health Blog—which described mold and roach problems at a Georgia peanut plant implicated in the latest food-borne Salmonella outbreak—this blog can only remind readers that seemingly competitive food brands are often made in the same place. The moral of the story: Buy on the cheap.

Today's MMWR provides an early-release report of the latest Salmonella outbreak, which has sickened nearly 530 Americans in 43 states (and 1 poor Canadian); led to the hospitalization of 116; and possibly killed 8. Investigators traced the source of the outbreak to a peanut plant in the self-described "Peanut Capital of the World," Blakely, Georgia, which manufactured PB and peanut paste.* Brands specifically implicated are King Nut** creamy PB—sold in massive 5-pound containers to schools and nursing homes—and Austin and Keebler PB crackers.

All King Nut PB was produced by the family-owned Peanut Corporation of America (PCA) at its Blakely, Georgia, plant, and the Austin and Keebler PB crackers were made at 1 unnamed plant, which received its peanut paste from PCA.

* The difference between peanut butter and peanut paste is lost on me.

** I'm king of the nut!

N.B.: As it turns out, Austin and Keebler are both Kellogg brands.

Photo of unnaturally orange PB crackers (which, up until now, I have loved unconditionally) from austinqualityfoods.com.

Bum-bum-bum, bum-ba-dum, bum-ba-dum.
Bum-bum-bum, bum-ba-dum, bum-ba-dum.

Sorry.

Nine FDA scientists who complained to the House Energy and Commerce Committee and Obama's transition team about lax medical-device reviews at the FDA's Center for Devices and Radiological Health (CDRH) are now targets of an internal criminal investigation, writes Gardiner Harris in today's NYT. The scientists reported this new development in their ongoing struggle with CDRH's management in a letter sent to President Obama on Monday and also provided to the paper.

Harris quotes the letter: "It has been brought to our attention that FDA management may have just recently ordered the FDA Office of Criminal Investigations to investigate us rather than the managers who have engaged in wrongdoing! It is an outrage that our own agency would step up the retaliation to such a level because we have reported their wrongdoing to the United States Congress."

Harris implies that the alleged criminal investigation may relate to the scientists' sharing of confidential CDRH documents, including e-mail messages, with the NYT. On January 12, Harris wrote that a CDRH supervisor overruled agency scientists and approved iCAD's SecondLook Digital Computer-Aided Detection System for Mammography, after receiving a phone call from former Connecticut congressman Christopher Shays. The device is used in conjunction with screening equipment made by Fujifilm Medical Systems, which is based in Stamford, CT, the center of Shay's former district. Harris's article was evidently prompted by FDA documents, which were given to the NYT by the dissident scientists.

Harris also wrote that a recent report from the Government Accountability Office largely validated the FDA scientists' claims of a broken approval process at CDRH.

Something to blog about other than the Pfizer-Wyeth merger/acquisition:

Merck KGaA and its Merck Serono division will submit phase 3 data to the FDA in mid-2009 for the fast-track approval of oral cladribine in patients with relapsing-remitting multiple sclerosis (RRMS). The companies issued a press release on Friday, describing favorable 2-year data from an extension phase of a pivotal phase 3 trial, CLARITY.

In the 2-year, randomized, double-blind international study (N = 1326), the annualized relapse rate (the primary endpoint) with various cladribine regimens was approximately 60% lower than that with placebo (P < .001). Secondary endpoints of the study, including a reduction of MRI lesion activity, relapse-free rates, and disability progression were also significantly lower with cladribine.

Cladribine-specific adverse events included the expected lymphopenia. In addition, 4 cases of cancer—early-stage cervical, melanoma, ovarian, and pancreatic—occurred in RRMS patients who received cladribine, reports today's Bloomberg. Nevertheless, completion rates in the study were very high: 90% of cladribine-treated patients and 87% of placebo-treated patients.

Currently available, FDA-approved disease-modifying medications for RRMS must be administered by injection. These include a subcutaneous formulation of interferon beta for multiple sclerosis, Rebif, which is marketed by Merck Serono. Cladribine, a purine analog, has been marketed as the injectable Leustatin by Ortho-Biotech since 1993 for the treatment of hairy cell leukemia. Nonproprietary formulations are available from Bedford and Abraxis, according to the FDA web site.

Novel oral compounds in phase 3 development for MS include fumerate (Fumaderm or BG-12; Biogen Idec), fingolimod (Novartis), laquinimod (Teva), and teriflunomide (sanofi-aventis).

CLARITY = CLAdribine Tablets Treating MS OrallY.

Congratulations to Chicago stage actor Michael Shannon, who received an Academy Award nomination this week for his supporting role in Revolutionary Road.

I first saw Shannon onstage several years ago at a tiny Chicago venue, A Red Orchid Theatre,* where he reprised his role as the very disturbed Peter in Tracy Letts's very disturbing Bug. Shannon's performance was possibly the most riveting I've seen in any theater (his leading lady, Kate Buddeke, was also outstanding).

Since that rare experience, I've seen Shannon in several other stage productions, including Martin McDonagh's The Pillowman, Craig Wright's Lady, and Denis Johnson's Shoppers Carried by Escalators Into the Flames. In all cases, Shannon either supported the beauty of the work (as in the case of The Pillowman) or transcended it (as in the case of Johnson's theatrical misfire).

The same can be said of Shannon's consistently engaging work in a wide and growing list of films—as well as an obligatory "Law & Order" episode. However, I've found Shannon most compelling when he's embodied the very odd guy in a thin shell of normalcy, as he did in Revolutionary Road. (I'm prone to imagine that this is how the actor himself routinely goes through life.) A currently available example on DVD is Shannon's interpretation of US Marine Dave Karnes in World Trade Center (2006), a surprisingly intimate treatment of the 9/11 tragedy, given that the production was steered by blowhard Oliver Stone.

* At 1531 N. Wells. I'm terrible at square-footage estimates, but the seating area was probably the size of a large living room. It's important to state that I'll never see the movie version of Bug, lest the film spoil my memory of the stage production.

Photo of Michael Shannon from A Red Orchid Theatre.

Yesterday, Chinese courts handed down sentences in proceedings against 21 defendants who were charged with involvement in the country's recent scandal regarding melamine-tainted milk. Sentences ranged from execution to prison time, with the heaviest penalities for 3 men.

• Zhang Yujun, a Hebei province dairy farmer (described by the court as the single largest source of melamine in the country), received the death penalty for "producing and selling poisonous food" or "endangering public security." Zhang reportedly produced 776 metric tons of melamine, 600 of which were added to milk. The court charged that he made $1.26 million in the process.
• Geng Jinping, a small dairy operator in Zhengding County, Hebei province, received the death penalty for "producing and selling poisonous food" or "endangering public security." The court claimed that Jinping added melamine to raw milk and sold "hundreds of tons" of the product to Sanlu, the Chinese dairy-products company.
• Gao Junje, a small business operator, received the death penalty for "producing and selling poisonous food" or "endangering public security." Junje's death sentence was suspended for 2 years.
• Tian Wenhua, 66, former chairwoman of the now-bankrupt Sanlu, received life in prison for "producing and selling shoddy goods." Wenhua pleaded guilty to the charge and was also fined $4.5 million. Some affected parents are reportedly upset that Wenhua was not sentenced to death for her role in the scandal.
• Three former (unnamed) Sanlu executives received 5-15-year prison terms for "producing and selling shoddy goods."

The group of 22 implicated dairies is also offering 200,000 yuan (~$30,000 USD) to parents of a dead child, 30,000 yuan (~$4400) to children with severe kidney stones, and 2000 yuan (~$290) to less severe cases. Total compensation would run to 1.1 billion yuan (~$160 million). State-run television indicates that 90% of families have taken the time-limited and government-backed financial compensation. However, the Toronto Star reports that hundreds of affected parents have rejected the offers.

Melamine, a fake protein additive, in baby formula caused the deaths of at least 6 Chinese infants and sickened nearly 300,000 last year, according to various news sources. But lawyers for the affected families suggest that as many as 10 children died after consuming melamine-laced milk. The Chinese Health Ministry admits that more than 300 affected infants remain hospitalized.

Sources: Toronto Star; China Daily; AP

Depiction of melamine chemical structure from Wikipedia.

In yet another news story about autism and its therapy, Jane Brody of the NYT reports on the anecdotal use of a slew of unproven and potentially risky alternative therapies for the severely autistic son of a lawyer couple. Their train of interventions over the years included several dietary changes, a truckload of supplements, glutathione cream, chelation, and hyperbaric oxygen treatments.* With reference to the last invention, Brody writes about the couple's perception of its efficacy for their son.

Only well into the article does Brody allude to the unproven nature of these interventions, by introducing Dr. Michael Fitzpatrick, a general practitioner in London who also has an autistic son. Fitzpatrick is the author of MMR and Autism and the recently published Defeating Autism: A Damaging Delusion. Brody quotes Fitzpatrick, when he likens the use of alternative therapies for autism as a return to "medicine's dark ages."

And in the last 4 paragraphs of her article, Brody finally (finally) describes the use behavioral therapy for autism, a scientifically validated (but labor-intensive) approach to improve an autistic child's communication skills. Brody would have performed a greater journalistic service by describing this intervention and highlighting its benefits from the get-go.

* At least Brody didn't imply any relation between autism and the boy's vaccination status.

This frigid week, the reader is referred to an update of a previous Kick-Back post.

(And just for the record, the answer to "Who is Number 1?" isn't "Pittsburgh.")

Not only have US rates of pneumococcal meningitis dropped. The reduction in pediatric hospitalizations for pneumonia has been sustained since the introduction of the pneumococcal conjugate vaccine PCV7 (Prevnar; Wyeth) in 2000, reports the CDC. An update of the center's surveillance data for the years 2005 and 2006 is available in today's issue of the MMWR.

By drawing on data from a nationwide inpatient database,* the CDC found pediatric hospitalization rates (per 1000 children) for all-cause pneumonia and nonpneumonia acute respiratory illness (ARI) as follows:

Patient Group	1997-1999	2005	2006	Rate Ratio (2006 vs 1997-1999)
All-cause pneumonia
<2 years	12.5	9.1	8.1	0.7
2-4 years	4.1	4.8	3.9	1.0
Nonpneumonia ARI
<2 years	28.1	24.6	21.9	0.8
2-4 years	5.8	6.5	5.6	1.0

According to the report, the rate reduction for all-cause pneumonia in 2006 represented an estimated 36,300 fewer hospitalizations for children younger than 2 years of age (when compared with the 1997-1999 period). Likewise, the rate reduction for nonpneumonia ARI in 2006 represented an estimated 51,500 fewer hospitalizations in the same age group.

Rate reductions for all-cause pneumonia in children aged 2-4 years were not observed, despite the fact that rates of invasive pneumococcal disease have definitely decreased in this age group since the introduction of PCV7. The authors speculate that organisms other than Streptococcus pneumonia may be more common causes of pneumonia in this age group.

Nevertheless, these data suggest that the benefits of PCV7 extend beyond those of reducing the incidence of invasive disease that is known to be due to S. pneumonia (although the CDC stresses that a causal relationship between vaccination and hospitalizations has not been established).

The concomitant decline in the rates of nonpneumonia ARI among children younger than 2 years of age indicates that the reduction in hospitalizations for all-cause pneumonia is not due to a shift in coding behavior. One explanation for this reduction is that S. pneumoniae may contribute to a wider range of childhood respiratory illnesses than previously thought. Data from trials assessing a 9-valent PCV in Israel and South Africa support this conjecture.

* The Nationwide Inpatient Sample, which contains data on inpatient stays from states that participate in the Healthcare Cost and Utilization Project. Information for roughly 8 million hospitalizations in 2006 was recorded.

Scanning electron micrograph of S. pneumoniae from the CDC/Dr. Richard Facklam.

Uptake of the pneumococcal vaccine PCV7 (Prevnar; Wyeth) is associated with the reduced incidence of pneumococcal meningitis,* the most common cause of bacterial meningitis in the United States. This conclusion was reached by the Active Bacterial Core surveillance group of the CDC, which analyzed of the rates of pneumococcal meningitis between 1998 to 2005 at 8 US sites.** Their results are available in this week's NEJM.

The surveillance group identified 1379 cases of pneumococcal meningitis during the study period, in patients aged 2 days to 93 years. The case fatality rate in children was 8.4%, and that in adults was 22.3%. Fatality rates were similar in HIV-positive and HIV-negative adults.

From 1998-1999 to 2004-2005, the incidence of pneumococcal meningitis (cases per 100,000 persons) caused by PCV7 serotypes or PCV7-related (ie, cross-reactive) serotypes declined significantly overall, and rates of PCV7-serotype meningitis declined significantly in the youngest and oldest subpopulations. However, the relative incidence of meningitis caused by non-PCV7 serotypes during this time increased significantly—especially in children younger than 2 years of age. Particularly concerning is the rise of non-PCV7 strains that are not susceptible to antibiotics, report the authors.

Table. Cases of Pneumococcal Meningitis per 100,000 Persons

Group	1998-1999	2004-2005	Relative Decline, %
All serotypes
All ages	1.13	0.79	30 (P < .001)
<2 y	10.6	3.66	64 (P < .001)
≥65 y	1.9	0.87	54 (P < .001)
PCV7 serotypes
All ages	0.66	0.18	73 (P < .001)
<2 y	8.2	0.59	93 (P < .001)
≥65 y	0.82	0.27	66 (P < .001)
PCV7-related serotypes
All ages	0.14	0.10	32 (P = .08)
<2 y	1.2	0.2	84 (P = .01)
≥65 y	0.29	0.10	66 (P = .07)
Non-PCV7 serotypes
All ages	0.32	0.51	–60 (P < .001)
<2 y	0.77	2.87	–275 (P = .001)
≥65 y	0.79	0.50	37 (P = .12)
Non-HIV-infected    adults (18-39 y)	0.14	0.24	–67 (P = .15)
Non-HIV-infected    adults (40-64 y)	0.41	0.54	–31 (P = .22)

Vaccination with PCV7, which covers 7 pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F), is currently recommended by the Advisory Committee on Immunization Practices for all US children aged 2-23 months and for children aged 24-59 months who are at increased risk of pneumococcal disease (eg, those with sickle cell disease or HIV). The vaccine was licensed in 2000 and is intended for children younger than 2 years of age, because the (old-as-dirt) 23-valent pneumococcal vaccine (eg, Pneumovax; Merck) does not protect this age group (who demonstrate the highest rate of pneumococcal disease). Also Pneumovax does not reduce nasopharyngeal colonization with pneumococci, a primary mode of bacterial transmission.

The authors report the following coverage with PCV7 in US children aged 19-35 months during 2006: ≥4 doses, 68%; ≥3 doses, 87%. Previous data have shown a reduction in the incidence of invasive pneumococcal disease generally (but not pneumococcal meningitis specifically) since the licensing of PCV7.

In development are 2 pneumococcal conjugate vaccines with additional serotypes: PCV10 and PCV13. PCV10 includes the PCV7 serotypes plus 1, 5, and 7F, which would have covered 27% of meningitis cases in 2004-2005, claim the authors. PCV13, with the PCV10 serotypes plus 3, 6A, and 19A, would have covered 50% of cases.

HIV = human immunodeficiency virus; PCV = pneumococcal conjugate vaccine.

* Caused by Streptococcus pneumoniae.

** San Francisco County, CA; CT; 20-county Atlanta, GA, area; 6-county Baltimore, MD, area; 7-county area in MN; 7-county Rochester, NY, area; 3-county Portland, OR, area; and 5 urban counties in TN (N > 18 million).

Scanning electron micrograph of S. pneumoniae from the CDC/Dr. Richard Facklam.

Measles is unlikely to be eradicated in Europe anytime soon, according to the Euvac.net group, a surveillance network for vaccine-preventable diseases. The group's conclusion is based on the relatively high incidence of measles and the prevalence of unvaccinated or incompletely vaccinated children throughout the continent. The group's study of the persistence of measles in Europe, despite the fact that the measles vaccine became a part of routine vaccination more than 20 years ago, was published in the latest issue of The Lancet.

Recent 2-year surveillance data (2006-2007) from 32 European countries revealed a total of 12,132 measles cases; 85% occurred in 5 countries: Romania, Germany, the United Kingdom, Switzerland, and Italy. Most of those affected were either unvaccinated or incompletely vaccinated children; however, nearly 20% were adults. Measles caused the deaths of 7 children.

Age of Deceased	Country	Cause of Death	Vaccination Status
9 months	Romania	Pneumonia	Unvaccinated (below recommended age)
20 months	Romania	Pneumonia	1 vaccine dose
23 months	Romania	Pneumonia	Unvaccinated
13 years	UK	Pneumonia	Unvaccinated (immunosuppressed)
2 years	Germany	Acute encephalitis	Not reported
"Infant"	Germany	Acute encephalitis	Not reported
10 years	Italy	Pneumonia	Not reported (immunosuppressed)

In 2006, 10 cases of acute measles encephalitis* (including the 2 deaths) were reported. Six of those affected had not been vaccinated; one had received a single vaccine dose; and the vaccination status was not known for the remainder. In 2007, 7 individuals, none of whom had been vaccinated, acquired acute measles encephalitis.

On the basis of these data, the group expresses "serious doubts" that measles will be eliminated from Europe by 2010, the current goal of the World Health Organisation. According to WHO, the elimination of measles requires the achievement and maintenance of a minimum 95% vaccination coverage with 2 doses of the measles vaccine. In European countries where there were no measles cases during 2006 and 2007 (Finland, Iceland, Slovenia, Slovakia, and Hungary), vaccination coverage (2 measles vaccine doses) has been historically and consistently high.

* As opposed to subacute sclerosing panencephalitis (SSPE), a rare, fatal complication of measles, which can develop years after the incident infection.

Photo of child with measles rash from the CDC.

For patients with idiopathic Parkinson disease (PD), deep-brain stimulation (DBS) may be the best thing since levodopa, but the procedure is relatively risky.

In the latest issue of JAMA, a large, multicenter, randomized, rater-blinded VA study reveals that DBS, when compared with best medical therapy, significantly improved several motor and functional outcome measures* at 6 months, in 255 patients with advanced PD. These efficacy data essentially mirror those of a smaller, randomized study of DBS vs medical therapy in a younger set of PD patients.

However, in the latest study, DBS was more frequently associated with falls, gait disturbance, imbalance, depression, and dystonia than medical therapy, and surgical-site infection and pain were respectively experienced by 10% and 9% of patients who received DBS. These patients were also more likely to experience serious adverse events, most of which related to surgery, the stimulation device, or stimulation therapy. One patient who received DBS died as a result of cerebral hemorrhage. Nevertheless, an important finding of the study is that younger and older (≥70 years of age) patients tolerated DBS equally well.

The procedure, which has become increasingly popular for PD during the last decade, involves the stereotactic placement of stimulation electrodes in the bilateral subthalamic nucleus or globus pallidus internus under local anesthesia. The exact site of electrode implantation is ultimately determined by its intraoperative clinical effect on PD symptoms at the lowest possible level of stimulation. Each electrode is connected to a pulse generator (eg, Medtronic's Kinetra), which is implanted just below the clavicle under general anesthesia. According to Deuschl et al, the standard pulse setting for DBS stimulation in PD is 60 μsec at 130 Hz (C below "middle C"?); voltage settings are individualized per patient.

DBS is intended to modulate activity of the basal-ganglia loop, a complex neuronal circuit that is involved in the genesis of higher cortical behavior—including motor and cognitive tasks. The substantia nigra, which degenerates in PD, activates this circuit. In the case of PD, loss of substantia-nigra input into the basal-ganglia loop results in the overactivity of some cell groups, like those in the subthalamic nucleus or globus pallidus internus. DBS is intended to attenuate this overactivity. (The second phase of the JAMA study will specifically compare the separate effects of DBS on these 2 different subcortical areas.) 

What isn't known is the optimal timing of DBS and its long-term effects, including neuropsychiatric effects. According to Deuschl (in an accompanying JAMA editorial), most patients undergo the procedure more than 10 years after disease onset, when PD is advanced. He anticipates that the use of DBS for PD will increase, as the population ages. Data from 55 medical centers are currently available for more than 5300 PD patients who have undergone DBS.

For more info about DBS and PD, see the web sites for the NINDS and the National Parkinson Foundation.

VA = Veterans Affairs.

* Mean "on" time without troubling dyskinesias (the primary endpoint), motor function, and quality-of-life measures.

Depiction of DBS from the FDA.

With director William Wyler, DP Gregg Toland, screenwriter Lillian Hellman, and Humphrey Bogart, Dead End (1937) is perhaps, astonishingly, a film that is less than the sum of its parts. Nevertheless, Wyler—with a fine ensemble cast (including the stage play's original "Dead End" kids)—effectively recreates a highly theatric, claustrophic corner of Manhattan, a place where slum met urban renewal in the early 20th century.

P.S. It took me forever to place a young Ward Bond as the doorman, maybe because Dead End is not a western.

At least according to the FDA.

The agency announced yesterday that patients should not stop taking Vytorin (ezetimibe/simvastatin) or any other cholesterol-lowering medication on the sole basis of the ENHANCE trial results. The conclusion follows the FDA's review of the final trial report, in which the combo drug was no better than simvastatin alone for reducing carotid intima-media thickness (CIMT) at 2 years. However, the LDL cholesterol level dropped 56% with Vytorin and 39% with simvastatin alone—a statistically significant difference.

The FDA maintains that an elevated LDL cholesterol level is an important risk factor for cardiovascular disease and that lowering the LDL level reduces that risk. The FDA also speculated as to why a larger reduction of the LDL level with Vytorin was not associated with a significantly reduced CIMT in the ENHANCE trial*:

• Because the ENHANCE population had received prior lipid-altering or statin therapy, subjects demonstrated relatively normal CIMT values at baseline, which made it harder to demonstrate a CIMT difference with Vytorin therapy.
• The duration of the ENHANCE trial, 2 years, was too brief to demonstrate a difference in CIMT with therapy.
• Unknown effects of ezetimibe may negate the beneficial effects of LDL lowering on CIMT.

The FDA advises that the much larger, ongoing IMPROVE-IT study, which pits Vytorin against simvastatin alone and has a primary composite endpoint of cardiovascular events and stroke, should provide more definitive information about the clinical benefits of the drug. The trial, however, won't be completed until 2012.

* The FDA doesn't mention previously reported problems with the CIMT data in the ENHANCE trial, such as missing or biologically implausible data.

ENHANCE = Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia; IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL = low-density lipoprotein.

Yesterday, 9 FDA scientists sent a letter to Obama's transition team, pleading with the President-Elect to restructure the "fundamentally broken" agency, reports today's WSJ. The scientists allege that FDA managers "ordered, intimidated and coerced" the scientists to manipulate data during product reviews, particularly within the Center for Devices and Radiological Health (CDRH). The letter's authors were not reported.

A similar letter was sent in October to the House Energy and Commerce Committee, but yesterday's correspondence is more detailed, writes the WSJ, describing allegations like the "threat of disciplinary action against scientists who dissent from management." The letter also specifies that past CDRH approvals of certain computer-aided detection devices for mammography were not supported by scientific evidence, writes the WSJ.

The following excerpts from the scientists' October letter likely indicate the nature of their complaints in yesterday's correspondence:

Managers at CDRH have failed to follow the laws, rules, regulations and Agency Guidance to ensure the safety and effectiveness of medical devices and consequently, they have corrupted the scientific review of medical devices. This misconduct reaches the highest levels of CDRH management including the Center Director and Director of the Office of Device Evaluation (ODE).

Managers at CDRH with no scientific or medical expertise [redacted] devices, or any clinical experience in the practice of medicine [redacted] have ignored serious safety and effectiveness concerns of FDA experts and have ignored scientific regulatory requirements. To avoid accountability, these managers at CDRH have ordered, intimidated and coerced FDA experts to modify their scientific reviews, conclusions and recommendations in violation of the law. Furthermore, these managers have also ordered, intimidated and coerced FDA experts to make safety and effectiveness determinations that are not in accordance with scientific regulatory requirements, to use unsound evaluation methods, and accept clinical and technical data that is not scientifically valid nor obtained in accordance with legal requirements, such as obtaining proper informed consent from human subjects. These same managers have knowingly avoided and failed to properly document the basis of their decisions in official Agency records.

Under the banner of regulatory "precedent," managers at CDRH have demanded that physicians and scientists review regulatory submissions employing methods, and accepting evidence and conclusions, that are not scientifically proven and clinically validated. 

The letter goes on to describe the scientists' complaint to FDA Commissioner Andrew von Eschenbach in May 2008, which led to an investigation with William McConagha, Assistant Commissioner for Integrity and Accountability. The investigation culminated in a September meeting among FDA scientists, representatives from the Commissioner's office, and the CDRH Director, Daniel Schultz.

The meeting prompted Schultz to conduct his own investigation of CDRH. But Schultz concluded, according to the letter, that the "FDA physicians and scientists need to 'move forward,' thus allowing managers to avoid and evade any accountability and without taking any curative or disciplinary actions whatsoever." Schultz is also alleged to have allowed the continuation of management reprisals against FDA reviewers, including threats of job loss and "illegal and improper employee performance evaluations." 

Schultz, a medical doctor, is a career FDA officer who was appointed CDRH Director in 2004. Donna-Bea Tillman, PhD, is Director of the ODE.

01/13/09 update: In yesterday's NYT, Gardiner Harris reveals that an FDA supervisor overruled FDA scientists and approved iCAD's SecondLook Digital Computer-Aided Detection System for Mammography, after receiving a phone call from former Connecticut congressman Christopher Shays. (FDA approval info here.) The device is used in conjunction with screening equipment made by Fujifilm Medical Systems, which is based in Stamford, CT, the center of Shay's former district.

Harris's article was evidently prompted by FDA documents, which were recently provided to the NYT. In e-mails, FDA scientists claimed that a supervisor forced them to change their reviews of iCAD's breast-imaging device, despite the fact that "iCAD never tested the device by the intended users (ie, radiologists) under the intended conditions of use." An FDA review indicated that the iCAD device was associated with unacceptable false-negative and false-positive rates, which resulted in missed cancers or unnecessary surgery and even radiation therapy. In response, iCAD's CEO told the paper, "We have done all the appropriate testing to get the product approved." 

For his part, Shay claimed that he called an FDA supervisor 1 year ago "only to demand that the agency make a final decision, not that it approve the product." A spokesperson for Fujifilm admitted to the NYT that the company requested local congressional support to "get clarification on the FDA process."

In his article, Harris also cites the arguably inappropriate, abbreviated FDA review of complex, novel devices at the behest of FDA managers. One such example is the FDA review of AngioCT from Shina Systems. 

In a country checked by stratospheric inflation and political corruption, a persistent cholera epidemic in landlocked Zimbabwe has now taken more than 1700 lives and sickened 35,330, according to the latest report from the World Health Organisation.

Since August 2008, the epidemic has affected all provinces in the country, reveals WHO; however, a large percentage of cases have been documented in Budiriro, a congested suburb of Harare, and in Beitbridge, a border town with South Africa. The overall fatality rate of disease is reported at 4%, but death rates have escalated to 20%-30% in remote areas.

The organization Medecins Sans Frontieres (Doctors Without Borders) reports a "clear shift" in cholera cases from Zimbabwe's urban areas to suburban and rural towns, which logistically confounds disease management. Nevertheless, unlike WHO, MSF reports an overall decrease in the number of cholera cases in Zimbabwe. MSF suggests that tally differences between the 2 organizations may be a function of the spread of disease and disease-reporting capabilities. Sources cited at Wikipedia indicate that the cholera epidemic has spread to neighboring countries Botswana, Mozambique, South Africa, and Zambia.

Cholera, caused by the bacterium Vibrio cholerae, is primarily transmitted through contaminated food or water. The characteristic symptom of copious, watery diarrhea, caused by the bacterial enterotoxin, can lead to death through dehydration. The collapse of clean water supplies, sanitation measures, and garbage collection in Zimbabwe are aggravating factors of the epidemic. Professional medical care in Zimbabwe has also been stymied by the country's economic crisis. To top it off, the rainy season began in November.

WHO currently urges proper food safety and personal hygiene, as well as the use of oral rehydration salts to reduce the mortality risk associated with cholera. Prophylactic antibiotics are discouraged, and once an outbreak has begun, the "internationally available WHO prequalified oral cholera vaccine" is not recommended. (The parenteral cholera vaccine was never recommended by WHO because of its low efficacy and risk of adverse events.)

Map showing spread of cholera in Zimbabwe as of December 6, 2008, from Wikipedia.

On the morning of November 30, 1982, Nancy Haigwood walked out of her Gaithersburg, MD, townhome to find "KKG" carefully spray painted on her fence, sidewalk, and the rear window of her fiancé's car. Haigwood, a member of the sorority Kappa Kappa Gamma, had moved in only a few months earlier. Her address, she claimed, had not been published.

At the time, Bruce Ivins, a USAMRIID scientist, lived just a block away. Haigwood had known Ivins, an acquaintance, through their recent postgraduate studies at the University of North Carolina. He was an unusual, officious kind of guy who, according to Haigwood, had shown a specific interest in her ΚΚΓ membership. She was sure that Ivins was the vandal and confronted him during a chance encounter soon afterward. He denied it.

Months later, a "Nancy L. Haigwood" wrote the following letter to the editor of The Frederick News-Post. The letter, published May 9, 1983, was in response to a buried AP story in the paper about a University of Montana frat member* who had floated a dead kitten in a block of ice in a punch bowl. Despite the fact that the article did not mention fraternity hazing, the letter defended the practice.

It seems that every time I read an article in the News-Post about college fraternities or sororities, the tone of the article is decidedly negative. "Frat member floats kitten in punch" (April 15, 1983) continues that unfortunate tradition.

As a member of Kappa Kappa Gamma, one of our nation's oldest and most prestigious college sororities, I am continually dismayed by attempts of the media and other outsiders to disparage the Greek System. I am especially incensed at vitriolic attacks on our practices of "hazing," which non-Greeks fail to realize serve numerous valuable functions that I would like to briefly enumerate.

First of all, hazing strengthens the mettle of pledges by preparing them for the many trials they will surely face in later life. Secondly, hazing builds loyalty to the pledge class and to the overall organization. Last but not least, hazing is the final stage of the all-important weeding-out process.

Charges that actives are to blame for accidental injuries which sometimes occur during pledge hazing are totally without foundation. No active ever forces any pledge or initiate to do anything in a sorority or fraternity—an individual is free to depledge at any time.

Charges that hazing and other related activities are detrimental to the academic performance of pledges obviously come from individuals who don't realize that the primary education in a college or university environment doesn't come from reading a book or sitting in a classroom, but rather from dynamically interacting with one's peers.

No one ever hears non-Greeks laud the accomplishments of those within the ranks, yet the proud Halls of American History are lined with men and women who were members of college fraternities and sororities. No matter what the press may say about us, I'm still proud to be in a sorority, proud to be counted among our country's very best.

NANCY L. HAIGWOOD
10265 Ridgeline Drive, Gaithersburg

Haigwood maintains that she never wrote the letter and believes that Ivins did. If true, the letter's author would have been a 37-year-old, male, USAMRIID scientist who had just published data about plasmid-mediated toxin production in Bacillus anthracis and the enhanced culture of the bacterium. 

During the last few years, as jimmyflathead at Wikipedia, Ivins showed an interest in ΚΚΓ hazing by attempting to contribute information about the subject (see previous post here).

* God only knows where that creep is now.

Primary source: Microbiologist says she was stalked by Ivins. See also the FBI's Amerithrax search warrants for more information about Ivins's alleged online activity.

Public domain photograph of Daschle "anthrax" letter from Wikipedia.

Whether you believe that Bruce Ivins perpetrated the 2001 "anthrax letter attacks," one assertion is difficult to refute: The guy was more than just an affable oddball; he was chronically and seriously disturbed.

In yesterday's NYT, Scott Shane profiles the USAMRIID microbiologist, who is alleged to have mailed spores of Bacillus anthracis, the cause of anthrax, in block-letter-addressed envelopes to news organizations and congressmen shortly after 9/11. Shane's profile is not so much an examination of the scientific evidence against Ivins but a character portrait derived from, in part, interviews with family and friends and Ivins's own e-mails.

One notable feature of the NYT piece is the observation that Ivins led a highly compartmentalized life, in which he kept his long-time obsession with sororities in general and Kappa Kappa Gamma in particular from his family. His consuming thoughts about the sorority are germane to a behavioral study of the anthrax-letter perpetrator, because the Princeton, NJ, mailbox, from which all of the letters were posted, is 60 feet from a ΚΚΓ office.

Ivins's obsession materialized most disturbingly and concretely in his fixation on microbiologist and ΚΚΓ member Nancy Haigwood, a fixation that manifested in criminal activity according to Haigwood—namely, the vandalism of personal property and the usurpation of Haigwood's identity in the early 1980s. This information has been previously reported by other news sources (for instance, here). Also, like reporters before him, Shane reveals that Ivins spent an inordinate amount of time posting online about sororities by using the names kingbadger, jimmyflathead, and goldenphoenix.

Notably jimmyflathead's contributions to Wikipedia* include mention of Haigwood as an eminent ΚΚΓ member. Below are excerpts (not mentioned in the NYT article) that contribute to Bruce Ivins's very sad, strange, and enduring legacy:

Eelmonkey, I'm not a member of KKG, but at one time I had a copy of the Book Of Ritual. I'm familiar with their secrets and rituals, but I don't think that the organization would want them revealed. I would respectfully suggest you ask the opinions of some of the Kappas who have posted here. jimmyflathead 19:40, 7 July 2007 (UTC)

Eelmonkey, I also want to add that unless you have a copy of the KKG Cipher (decoder), or you have a decoded copy of the Book of Ritual, simply having the Book of Ritual won't do you any good...unless you got the information from the Fraternitysecrets.com message board which has now been down for quite some time. For example, do you know about the ***** room and *** room services? Do you know the secret names of the chapter officers? Do you know the terms for voting "yes" and "no?" Do you know what the Three Ideals of KKG are and what the Spirit is? Do you know what the ΚΚΓ Greek letters stand for? (It's NOT Key to the Kingdom of God, by the way.) The ritual book without the cipher is useless to you.jimmyflathead 19:19, 8 July 2007 (UTC)

Also, I'd like to see some Kappas put down for their scientific achievments[sic]. It's not my job to do it, but I can think of Dr. Nancy Haigwood and Dr. Gail Williams Wertz immediately as alumae who have distinguished themselves. It would look good, but I'm not about to go create a Wikipedia page for them just so they can be on the Kappa page. I just get tired of seeing lots of TV and moviestars, but scientists get short shrift. jimmyflathead 03:14, 15 August 2007 (UTC)

Last, I created a stub for Nancy Logan Haigwood, but she does not currently meet the criteria of having a wiki page. If we are going to keep her on the list, I think it at least makes sense for a page to be created. I don't know enough to make one - but jimmyflathead

I'm not in favor of removing Dr. Haigwood's name from the list of notable Kappas. I believe that her accomplishments warrant her inclusion and I know for certain that she is not only a KKG member, she was the chapter adviser (University of North Carolina at Chapel Hill) while in graduate school. I don't believe that fame or renown must derive from an individual's GLO membership and, as such, we may barely see a reference to it when describing the chief of neurosurgery at Johns Hopkins, or a Nobel lauriate[sic] in one of the scientific fields. There is certainly sufficient knowledge that the public can obtain (such as college yearbooks and the student newspaper, "The Daily Tarheel," to verify membership. jimmyflathead 00:25, 17 September 2007 (UTC)

* After Haigwood reluctantly struck up an e-mail correspondence with Ivins in 2006 at the behest of the FBI.

N.B. The NYT reveals that Ivins had stolen the KKG ritual book and cipher device during one of his 3 uninvited, post-college visits to a university chapter house. It is not known by me how or if Ivins ever knew Gail Wertz, PhD. Update: According to Wikipedia, there was no known relationship between Wertz and Ivins.

Public domain photograph of Daschle "anthrax" letter from Wikipedia.

Addendum: More about Ivins's activity as jimmyflathead at Wikipedia can be found here. His edits at the online encyclopedia almost exclusively concerned ΚΚΓ and escalated into an editing war, in which Ivins threatened to post derogatory or confidential information about the sorority if his additions were deleted or edited by another contributor. In at least one instance, Ivins attempted to add (and possibly re-add) information about hazing incidents. 

The subject is important vis-a-vis Ivins, because a 1983 letter to the Frederick News-Post, signed by "Nancy L. Haigwood" defended the practice of hazing; however, Haigwood recently claimed to news sources that she never wrote the letter and suspects that Ivins did—several months after he allegedly spray painted "KKG" on property at her Gaithersburg, MD, home.  

Before Cate Blanchett or Helen Mirren drew on the role of Elizabeth I (like it was a freaking annuity), the Virgin Queen was reliably portrayed by Glenda Jackson. Following the 6-part mini-series "Elizabeth R" in 1971, Jackson almost immediately repeated her performance in Mary, Queen of Scots. However, most of the screen time in this film belongs to a dewy Vanessa Redgrave, as the very Catholic Mary Stuart and rival for England's throne.

There are some artistic liberties taken with the story of the royal conflict between the cousins, so don't let teenagers use the movie as a historic reference. But do point out actors, including Redgrave,* that they'll recognize from more recent films—like Timothy Dalton (aka Simon Skinner in Hot Fuzz) as Lord Darnley or Ian Holm (aka Bilbo Baggins) as David Riccio.

* For instance, kids, Redgrave was the old Briony in Atonement. Aha.

01/15/09 update

: Kids won't know him, but the rest of us raised by 60s television will recognize Patrick McGoohan, aka Number 6, as Mary's half-brother, James Stuart. According to CBS news, McGoohan died Tuesday at the age of 80, after a "short illness." In memorium and as a remedy for the current deep freeze, cocoon with McGoohan's you're-so-messin'-with-my-mind-man "The Prisoner" on DVD.

So much for looking forward. The new year begins here with leftover business—namely, leftover Vytorin business.

In this year's brand-spanking-new issue of the NEJM, cardiologist and consistent Vytorin critic Steven Nissen officially charges that September's ezetimibe-cancer analysis of Sir Richard Peto et al, in which the authors concluded that the cancer risk with ezetimibe is not increased, "raises disturbing scientific and ethical questions." The Peto analysis was performed in response to a finding in the SEAS trial that ezetimibe, one half of the combo Vytorin pill, may increase the risk of cancer. However, Peto et al found that unblinded adverse-event data from the much larger, ongoing SHARP and IMPROVE-IT studies did not confirm the finding.

Among his criticisms of the Peto analysis, Nissen cites the following in his correspondence:

• The premature unblinding of the ongoing trials, which is "not a reliable approach to the evaluation of drug safety."
• The insufficient exposure to ezetimibe in IMPROVE-IT for assessing drug hazards.
• The failure of Peto et al to report the relative risk of cancer mortality in the 2 studies.
• The limited statistical power of the 2 studies to assess the risk of cancer death with ezetimibe.

Elsewhere Nissen has argued that data from all 3 studies should have been combined to assess cancer risk with the drug.

In their reply, Peto and coauthor Rory Collins stress the importance of separating data in a hypothesis-generating trial—in this case, the SEAS trial—from data in hypothesis-testing studies. They implicitly rationalize the unblinding of cancer data from SHARP and IMPROVE-IT by noting that these are the only large, randomized data sets from which relevant cancer data may be obtained to confirm any increased risk with ezetimibe. They also cite the magnitude of these studies in relation to the SEAS trial; together SHARP and IMPROVE-IT generated 4 times as many cancers as the SEAS trial, but their data did "not suggest any increase in cancer incidence."

Peto and Collins also correct Nissen in his mistaken charge that the authors did not report the relative risk of cancer mortality (and the associated 95% confidence interval) in SHARP and IMPROVE-IT. (The data were right there in the Fig. 4 legend.) Although there were more deaths due to cancer with ezetimibe in the analysis, the difference was not statistically significant (P = .07).

Last, although Nissen did not allege an industry-related conflict of interest by Peto et al (and Nissen's hardly in a position to do so), Peto and Collins, both from the UK, cite their not-so-dispassionate response to the US Congressional Committee on Oversight and Investigations, which raised the issue.

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

Public-domain image of Hamilton-Burr duel, which admittedly took place in New Jersey (not New England), from Wikipedia.

 ...before looking forward.

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

10. Gunvalson v. PTC Therapeutics

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

8. Hand, Foot, and Mouth Disease in China

7. Continuing Backlash Against Pharma

6. Media Obsession With Delayed Results of ENHANCE Trial

5. Investigational Drugs for Alzheimer's Disease Disappoint

4. Milder Rotavirus Season Coincides With Vaccine Uptake

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

2. Resurgence of Measles

1. Intentional Drug and Food Tampering in China

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

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