bmartin: January 2011 Archives
Today's Duke Chronicle reports the retraction of yet another article by geneticist Anil Potti. (For important story background, go here, here, and here.) On Friday, editors of The Lancet Oncology and the article's European coauthors justified their retraction of "Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy," expressing "concern over the validity of the results."
They continued:
The chemotherapy sensitivity predictions reported in the Article were based on an approach described by Anil Potti and colleagues in Nature Medicine. Re-examination of the validation datasets used for the Nature Medicine study has uncovered errors in the labeling of the clinical response in some of the datasets. Reanalysis of the predictive accuracy with correctly labeled data has shown that in two instances the reported signatures do not predict the response of the validation samples to chemotherapy.
In other words, the article was retracted because the results were founded on the flawed (ie, mislabeled) data from another retracted article by Potti et al (in Nature Medicine). An investigation into the validity of the Lancet Oncology article was begun last October, when editor David Collingridge relayed an "expression of concern" from 15 European investigators who were coauthors with Potti and 3 other Duke researchers. After a damning report in July from biostatisticians at M. D. Anderson about data-labeling errors in another article by Potti et al, the Lancet Oncology coauthors repeatedly attempted to contact their Duke colleagues, but they were ignored, wrote Collingridge.
This is the third article by Potti to be retracted since his work was called into serious question last year. A 2007 article in the Journal of Oncology was retracted in December, and the Nature Medicine article was pulled this month. In October, Collingridge also revealed that "a large group of scientists" wrote to NCI director Harold Varmus on July 19th, expressing their concerns about the validity of a) Potti's cancer-treatment prediction models and b) 3 clinical trials that were based on these prediction models.
On a related note, Friday's The Cancer Letter (subscription required), by way of The Great Beyond Blog, reveals that FDA auditors have visited Duke to determine if the university obtained proper approval for 3 cancer trials, which were based on the demonstrably flawed work of geneticist Anil Potti. At issue, from the agency's standpoint, is whether Duke obtained an Investigational Device Exemption (IDE), which was necessary because genomic chips were used to identify genetic biomarkers on which treatments was based.* There was evidently some confusion at Duke about whether an IDE was needed.
* The trials used Potti's (mislabeled) data to determine what anticancer drugs or combination of drugs cancer patients would receive on the basis of genetic biomarkers.
(2010): Ilisa Barbash and Lucien Castaing-Taylor record the last American to herd his sheep into the federally protected Absaroka-Beartooth wilderness of Montana, circa 2001. Unlike what we've come to expect from contemporary documentaries (or fabulist tales passing as documentaries—we're looking at you Michael Moore), it's an adventure filmed as objectively and as minimalistically (and consequently, as beautifully) as possible.
The filmmakers actually seem to make a point of not insinuating themselves into the story. There are no off-camera exchanges with human subjects or even explanatory voiceovers. Just the incessant bleating of sheep and howling of wind interrupted by snoring, cussing, whining, crying, and..the occasional crack of gunfire.
While MedPage Today reported yesterday that Gabrielle Giffords remains in a Houston ICU because of a ventricular drain (due to, presumably, obstructive hydrocephalus), the hospital implies today that she will be moved to a rehab center imminently. Clarifying details should be provided this afternoon by the Congresswoman's doctors at Memorial Hermann, who will discuss her condition and progress at a press conference.
When Giffords's ventricular drain was placed is unclear from news sources, but logic and experience suggest that it was inserted either 1) at the time of Giffords's initial brain surgery, immediately after her injury as a prophylactic measure or 2) while she was in the Tucson ICU, because of developing hydrocephalus detected by a routine pressure monitor and/or follow-up brain images. [01/27/11 update: ABC News indicates that the drain was placed sometime last week.]
At Houston, surgeon John Holcomb emphasized to MedPage Today that the drain would either need to be removed or replaced with a permanent shunt before Giffords moved to a rehab facility. The anticipated move suggests that the issue of the shunt has been resolved or is about to be.
On seeming cue, neurosurgeons at the University of Alabama at Birmingham published a retrospective study this month in Neurosurgery of risk factors for conversion to a permanent ventricular shunt after traumatic brain injury (TBI). A minority of 71 TBI patients, about 22%, required a permanent device during hospitalization. The risk of a permanent device was elevated more than 5-fold if a patient had to undergo craniotomy within 48 hours of admission (as Giffords did) or showed bacterial contamination of spinal fluid (which is unknown in Giffords's case). However, the requirement for a permanent shunt did not appear to affect the disposition at discharge. [01/27/11 update: In an interview with one of Giffords's Houston doctors, ABC News reveals that there have been "no signs of infection."]
As far as Giffords's neurologic deficits are concerned, news reports (taken collectively) indicate some type of preserved vision (eg, aversion to shined light per her doctors, possibly watching television per her husband) and flaccid paralysis of her right arm. She is reportedly able to follow commands with her left body (indicating comprehension or a receptive speech capacity), but she has demonstrated no or minimal attempts at speech (suggesting a significant productive speech deficit).
These signs have traditionally been categorized as Broca's or expressive aphasia (in contradistinction to Wernicke's or receptive aphasia); although such a diagnosis is probably far too simplistic—especially without other details about her speech capabilities or disabilities. Moreover, it is really too early to guess at her speech deficits until she has spent considerable time in rehab and has reached a medical plateau.
01/27/11 update: News sources covering yesterday's press conference (like ABC News) report that Giffords ventriculostomy was removed 3 days ago (Monday) and that she was transferred to rehab. Futhermore there have been "no signs of infection," presumably referring to the ventriculostomy. Although not stated explicitly, it is also presumed that Giffords did not require a permanent VP shunt.
Two musts in a Valentina Cortese film festival are noir favorites: Jules Dassin's Thieves' Highway (1949) and Robert Wise's The House on Telegraph Hill (1951)—both of which are probably Cortese's highest-profile Hollywood movies.
The Milano actress with a mercurial face shows a decent range in a span of about 2 years, first playing a sympathetic prostitute (in a supporting role to Richard Conte's Nick Gargos) and as a concentration-camp survivor (in a Hitchcock-like starring role*). The common thread for both movies is the on-site filming in San Francisco, and native Eddie Muller, as ever, provides engaging color commentary for, and justified criticism of, the latter movie. Notably Muller's recommendations would have changed House from a merely entertaining movie, thanks to Cortese's vulnerability and Wise's editing, to a possible masterpiece.
* Think a less compelling Rebecca here.
I'm scratching my head over an FDA advisory panel's unanimous recommendation to endorse Lilly's amyloid tracer, florbetapir. While the panel did not recommend approval of the tracer at this time, it did unanimously (16-0) endorse conditional approval on the basis of a big stipulation: Namely that Lilly must run a trial confirming the reliability of scan interpretations. But this stipulation entirely misses the point of having a reliable (meaning, useful and not confusing) test for Alzheimer disease.
Regardless of the accuracy of PET interpretation, an amyloid scan for AD is worthless without clinical context. And in the context of normal cognition in the elderly, scan results are arguably irrelevant—because such a large majority of cognitively normal, older individuals will demonstrate brain amyloid. In the context of clinical dementia (which is the context in which a scan would be ordered, I would think), a positive scan may be supportive of the diagnosis of AD. But again, if amyloid is found in such a large majority of elderly brains anyway, what's the point of the scan—which costs thousands of dollars—when AD is already suspected clinically?
Perhaps a negative scan in the context of clinical dementia might steer a clinician away from the diagnosis of AD and onto another (and potentially reversible) cause of dementia. But again, what's the point of such an expensive imaging test, if the clinician is already looking for reversible causes of dementia (as she will), and the scan results are unlikely to substantively change recommendations for care—like if the patient has another irreversible dementing illness, say Pick's disease?
In short, I don't know what diagnostic niche Lilly (or the FDA advisory panel) is hoping for here: The proposed indication for a florbetapir-enhanced PET scan is to rule out "the presence of pathologically significant levels" of amyloid in the brain. The operative words here seem to be "pathologically significant," and that's where variabilities in scan interpretation become important (and worrisome). What we don't really know from the submitted trial results (which were published this week in JAMA) is the frequency of clinical dementia in the 29 end-of-life patients (or at least these data aren't provided in the abstract). About half of these patients' brains showed pathologic evidence of AD at autopsy. The presence of scan-detected amyloid correlated well with autopsy findings. But that's it. There's no clinical (ie, cognitive) correlate as far as I can tell. [01/24/11: See an important update below.]
ABC News and MedPage Today interviewed at least 2 AD experts—neurologist Richard Caselli and scientist William Thies—who are equally at sea about what to do with such an amyloid scan in practice. In my previous discussions on the subject, here, here, and here, I viewed florbetapir only as an adjunct to the clinical investigation of anti-amyloid treatments for AD,* which is how Lilly's been using the agent. But the company's evidently pushing for primetime use and a chance to recoup something on its, in my opinion, misguided investment.
* Which, on a related note, have not panned out terribly well to date.
01/24/11 update: A review of the published article indicates that what the authors are really arguing is that B correlates with C, in which B is AD findings at autopsy, and C is the detection of amyloid by florbetpair-enhanced PET scans. The correlations are respectably robust—0.71 and 0.78 (depending on the autopsy staining techniques).
What's importantly missing is the A-to-B-to-C correlation (or A-to-C correlation), in which A is dementia during late life. While Table 1 of the published article, which list the features of the patient enrollees, gives the cascading impression that normal cognition (or dementia) in late life directly relates to amyloid-related autopsy findings (and therefore PET amyloid findings), any calculations of such an A-to-C correlation are notably absent.
There is also precious little acknowledgement of the high prevalence of brain amyloid in the general population of cognitively normal elderly. Importantly the authors do recognize the lack of an absolute relationship between clinical cognition in late life and brain findings at autopsy, citing that 10%-20% of patients clinically diagnosed with AD don't show AD findings at autopsy. But, in head-spinning fashion, they talk out of the other side of their collective mouth, emphasizing the importance of amyloid detection during life,
There is a growing body of evidence that the presence of [beta]-amyloid aggregates in individuals prior to developing AD is a significant and independent risk factor for cognitive impairment and eventual development of AD.
The authors' hedging follow-up conclusion, however, is one that I agree with—namely that florbetapir-enhanced PET imaging is merely, at present, an investigative adjunct to clinical trials of anti-amyloid drugs (which don't seem to be panning out particularly well).
[B]rain florbetapir-PET imaging of [beta]-amyloid aggregates has the potential to improve selection and monitoring of patients considered candidates for studies of disease-modifying AD treatments.
Last November, Eli Lilly promised $300 million upfront* to snap up Avid Pharmaceuticals and its PET (and pet?) tracer florbetapir (or Amyvid) for detecting amyloid in the brain. The offer may have been for relative naught, as predicted here. And now, a newly released FDA review of the tracer's clinical data, made in anticipation of an advisory committee meeting on January 20, indicates that the agency is, likewise, sorely underwhelmed.
The first concern of the regulatory body, as previously forecasted here, is whether the amyloid tracer (or any amyloid tracer, for that matter) has any real clinical utility for diagnosing Alzheimer disease. Avid's own proposed marketing for florbetapir tepidly stipulates, "A negative florbetapir-PET scan is clinically useful in ruling out the presence of pathologically significant levels of [beta]-amyloid in the brain." But the clinical utility of a positive scan is unreliable (if not terribly confusing), because most brains (up to 80%) of cognitively normal older people will carry some amyloid burden. Consequently a positive scan (which is not just possible, but probable, in the elderly) is irrelevant in the population in which it is intended for use.
Although the FDA doesn't have problems with the scan being able to reliably detect brain amyloid (on the basis of postmortem correlations), it also has concerns about inter-rater reliability with respect to scan interpretation. The agency concludes,
Overall, FDA's major concerns with the Amyvid application relate to an apparent insufficient development of the reader training methods proposed for clinical use, including verification that these methods ensure acceptable reader-to-reader consistency in image interpretation across a patient population representative of that proposed for clinical use as well as reliability of the image interpretations with respect to the truth standards used in the phase 3 clinical trial.
PET = positron emission tomography.
* The company would offer another $500 million on the basis of florbetapir's FDA approval and other "commercial milestones," which seem unlikely at this point.
Photograph of atrophied brain from person with AD: National Institute on Alcohol Abuse and Alcoholism.
Yesterday's press release and press conference from the University of Arizona Medical Center provide more clues to the nature of Rep. Giffords's injury. In addition to performing a tracheotomy* and inserting a percutaneous feeding tube on Saturday, neurosurgeon Lemole and other physicians also performed a "minor" 2-hour repair of a right "orbital roof fracture" on Giffords. (Giffords sustained bilateral orbital roof fractures, but the left-sided injury, according to Lemole, did not require surgical repair.)
Lemole said that bone fragments from the right-sided fracture were "pushing down enough on the eye and the contents of the eye socket," so that an oculoplastic surgeon (Lynn Polonski) needed to perform a "quick releasing-and-incision operation" on the day of Giffords's injury. On Saturday, the full extraction procedure was performed, which necessitated a craniotomy (ie, an opening "just above the [right] eyebrow"). Once the bone fragments were removed, a metal mesh was placed in the roof of Giffords's right orbit. Lemole emphasized that, postoperatively, Giffords returned to her preoperative level of consciousness and functioning.
Given the description of orbital roof fractures, it appears that Giffords probably sustained significant injury (via the bullet exit entry wound) to her left (and possibly right) inferior frontal lobes. If previous descriptions of Giffords's brain injury are correct—namely that the bullet did not cross the hemispheric midline—the right-sided orbital injury may merely be collateral damage from the bullet exiting entering her left forehead.
The roof of the orbital socket, largely composed of the orbital plate of the frontal bone (of the skull), is relatively thin and therefore vulnerable in cases of traumatic injury—like a gunshot wound to the head.
Ophthalmologists are encouraged—nay, urged—to weigh in.
* At the press conference, Dr. Randall Friese, who performed the tracheotomy, indicated that Giffords cannot produce audible speech because the tracheostomy that she has in place "does not allow air to get past her vocal cords." But, he added, "she could certainly mouthe words...when she's ready to do that." Friese did indicate, later in the Q&A portion of the conference, that Giffords hasn't attempted speech.
Images of branded orbital meshes or plates in the inferior aspect of the orbit from Synthes.
Whirlpool (1949): Patient privacy is merely a thing of the future in this Fox noir movie, ruddered (yet again) by Otto Preminger and starring (yet again) Gene Tierney. General plausibility is also laughably out the window, which makes viewing with a small, vocal crowd almost mandatory.
As the wife of an ever-understanding, if boneheaded, psychiatrist (Richard Conte, in an unusal casting move), Tierney* hides her lifelong neurosis and insomnia with incredible ease. But when forced, she seeks mental help from a charismatic charlatan (Jose Ferrer), who uses hypnosis to his highly creative advantage.
* Who had real-life mental troubles of her own.
Yesterday Merck announced major changes to 2 mammoth, placebo-controlled phase 3 trials of its novel antiplatelet agent,* which the company acquired by way of its famous merger with Schering-Plough. The use of vorapaxar,** specifically a thrombin-receptor antagonist, will be discontinued completely in the TRACER study, a hospital-based study of patients with acute coronary syndrome, and discontinued partly in the TRA-2P (or TIMI-50) study, a trial enrolling patients with prior MI, stroke, or peripheral artery disease. In the TRA-2P study, the drug will be stopped in stroke patients only, which make up about 25% of the study population, says the company's press release.
Reasons for the trial changes, which were made on the basis of a review by the Data and Safety Monitoring Board, are speculative; but the logical conclusion is that bleeding events were substantially greater in patients receiving the investigational drug. An article describing the TRA-2P study, published last year in the American Heart Journal by the TIMI Study Group, suggested that bleeding risks might be (relatively) reduced with varapaxar, because it "does not interfere with other pathways for hemostasis." (The standard, comparator antiplatelet would be aspirin, which acts fairly high up in the clotting cascade.)
Analysts' responses to Merck's news were cautious (which can be interpreted as extremely bearish). The company's share value was (probably overly) slammed on the news, by losing about 6% of its value.
Others are questioning whether the Merck-Schering merger was worth it, given the latest performance of this frontrunner compound—on which Merck (and others) placed high blockbuster-like hopes.
* Not to be confused with an anticoagulant and the developing market for this class of compounds.
** Aka SCH 530348.
01/20/11 update: In yesterday's press release, Merck reveals that, yes indeed, the reason that stroke patients are being removed from the TRA-2P study is because of an increased risk of hemorrhage—specifically an increased risk of intracranial hemorrhage. Patients with MI or peripheral vascular disease will continue on in the secondary-prevention* study of the company's novel antiplatelet agent.
According to the venerable Eugene Braunwald, Harvard cardiologist and chairman of the study, the Data and Safety Monitoring Board "observed an increase in intracranial hemorrhage in patients with a history of stroke that is not outweighed by their considerations of potential benefit."
Although TRA-2P is placebo controlled, all enrollees are receiving standard of preventive care in the form of aspirin or clopidogrel. The design of the trial is such that patients are undergoing (or underwent) randomization to treatment on the basis of their vascular disease and whether they were to receive clopidogrel. (So as far as I can tell, the study is one of really dual-antiplatelet therapy—in patients assigned to the investigational drug.)
* Or tertiary prevention, depending on how you define the term.
Eli Lilly's investigational anti-amyloid drug for Alzheimer disease may (with emphasis on "may") be associated with vasogenic brain edema, just like Pfizer/JNJ's anti-amyloid compound in development. According to a Reuters report, Lilly's CEO said yesterday at the ongoing JP Morgan Healthcare Conference that 1 patient in a trial of solanezumab developed temorary brain swelling—although it's not clear if the patient is/was actually taking the investigational drug or placebo, because the trial remains blinded.
Last year, Lilly scrapped its clinical development of semagacestat, an anti-amyloid compound with a different mechanism of action, because semagacestat-treated patients actually faired worse than placebo-treated patients. Nevertheless Lilly's CEO is talking up the company's remaining investigational compound for AD...because that's what CEOs do.
Vasogenic brain edema has plagued the clinical development of bapineuzumab, another anti-amyloid mAb, which is in development by Pfizer/JNJ. It is speculated that the compound (at the highest dosage, anyway) promotes vascular leakage in the brain by attacking blood-vessel-associated amyloid. If that's the case, then it makes sense that any anti-amyloid compound would do the same.
mAb = monoclonal antibody.
Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.
If reports are true—namely that the bullet that hit Arizona Congresswoman Gabrielle Giffords entered her left forehead, missed her ventricles and language areas, and exited her left occiptal or parietal area*—then the bullet path (confined to the left hemisphere) seems subcortical (ie, below the surface of the brain) and fairly superior (ie, high or close to the top of the head).
Guessing her consequent deficits is probably a fool's task, even for a neurologist, but damage to the visual cortex may have been averted if the bullet exit wound was superior enough. Otherwise, transection of subcortical motor and sensory tracts and injury to the some portion of the frontal cortex by the bullet seem likely. Nevertheless, early reports indicate that Giffords (before a chemical coma was induced) had preserved motor function, along with basic comprehension of simple commands.
Injury-associated brain edema (swelling), which can lead to midline shift and deadly brain herniation, is being addressed (as expected) surgically with removal of a large portion of Giffords's skull and by ventilatory settings and drugs, say news reports.
According to a 2009 review by Maiden on gunshot wounds, the extent of brain damage is dependent on the bullet type, shape, construction, velocity, and mass and the nature of the injured tissue. He also writes, "[B]ullets which display greater yaw [side-to-side movement] will be associated with increased temporary cavitation [of tissue]." Cavitation of the brain could place strain and traction on adjacent tissue; although early brain swelling may make this issue an academic point, I would argue. A ballistics tutorial, including a discussion of yaw and what it means to tissue injury, is provided through the website of the University of Utah Health Sciences Library.
Reports indicate that Giffords was shot in the head with a 9-mm handgun at a range of about 4 feet. The 22-year-old alleged (and apparently seriously troubled) perp shot 19 other people, 6 of whom have died so far.
* It's not entirely clear from news reports whether the bullet entered Giffords's forehead or the back of her head.
From http://www.nlm.nih.gov/visibleproofs/education/medical/index.html: Postmortem image of coronal brain section showing path of a fatal bullet that entered the right temporal area and lodged in left frontal lobe.
Update: According to the LA Times, the bullet entered the back of Giffords's head.
01/12/11 update
: Although Dr. G. Michael Lemole, Jr, Giffords's treating neurosurgeon, reports that the congresswoman is scratching her nose—a excellent clinical sign—he does not say (importantly) which hand she used.However, according to an MSNBC report, Giffords is moving both of her arms and that she "previously raised two fingers with her left hand and gave a thumbs-up when responding to doctors' verbal commands [emphasis added]." (With a left hemispheric injury, paralysis or paresis of the right arm and/or leg would be expected.) In addition, Dr. Peter Rhee, trauma chief at the University of Arizona, indicated (in a sort of groan-inducing fashion) that Giffords has a "101 percent chance of surviving."
In short, Giffords is extremely lucky in her extreme unluckiness.
Described by several sources as the first film noir, Stanger on the Third Floor (1940) can only viewed on one of the many burned-to-order, no-frills DVDs from Warner Brothers' archive collection.
In this meandering RKO production, 2 murders are ultimately suspected to be serial crimes by a city reporter and his girlfriend—who eyeballs a suspect character (Peter Lorre) in the reporter's apartment building. The movie's direction is notable for a lengthy, stylized dream sequence, in which the reporter imagines himself responsible for the death of a neighbor, and a surprisingly effective death scene that clearly uses rear projection.
We made the decision because the drug has a marginal effect on tumor growth in breast cancer and in light of Avastin's severe side effects, the risks outweigh the limited benefit.
Pazdur cited "issues" and "problems" with a pivotal study, E2100, which showed that Avastin (with paclitaxel) delays the growth of advanced breast cancer for 5 months. Not surprisingly, drugmaker Genentech, a subsidiary of Roche, rejects the FDA's view of the controversial study and its results. But follow-up studies failed to confirm the favorable results of E2100, reports the WSJ. Some insurance companies, acting independently of the FDA, have already denied coverage for the use of Avastin in metastatic breast cancer.
Namely the staff at Nature and the journal's The Great Beyond blog continue to investigate Anil Potti, the former Duke University researcher whose genetics work on personalized chemotherapy has been called into serious question. Potti's dubious work informed the design of several clinical trials that were haltingly reviewed and then ultimately closed by university administrators. (For important background on this story, go here and here.)
The latest development: Nature has obtained, under the US FOIA, a year-old university report on Potti's work. This report, in a more heavily redacted form, had been previously obtained by an investigative reporter from The Cancer Letter, who originally outed Potti's false claim to have been a Rhodes Scholar (or finalist) and who described the claims of M. D. Anderson biostatisticians. The biostatisticians discovered "a series of errors," including mislabeling errors, in a seminal article by Potti and others.
The upshot of the Duke panel's December 2009 report: The members could validate Potti's work, but they seriously erred in not correcting Potti's mislabeling errors. Moreover one of the M. D. Anderson biostatisticians, Keith Baggerly, had contacted Duke's VP for Research and VP for Medical Affairs a month before the report was completed, alerting them to the mislabeling errors; however, Baggerly's alert was not forwarded to the panel members. In a tepid apology, the Duke VPs offered their excuses for failing to ensure that these crucial corrections be provided to the panel.
[I]t was determined that it would be best to let the data, publications, etc., speak for themselves and not bias the independent investigation for or against any party. In retrospect, we did not realize that the data provided by our investigators were flawed (as the public record now shows), rendering an outside review addressing the methodology flawed as well. In hindsight, we would have ensured that the IRB provided all communication with Dr. Baggerly, recognizing the risk of bias. We've learned considerably from this process and are introducing key changes in the way we deal with research that will be translated to the clinical arena as a result.
According to The Great Beyond blog, a second university investigation is ongoing, and a report will be submitted to the Office of Research Integrity at the DHHS.*
DHHS = Department of Health and Human Services; FOIA = Freedom of Information Act.
* Some of Potti’s work was funded through NIH grants.
Photo of Anil Potti, formerly from the ISGP web site.
And now there are 3 FDA-approved clinical trials for human embryonic stem cells (hESCs).
Yesterday Advanced Cell Technology announced that it received the agency's nod to begin an hESC trial in 12 patients with dry age-related macular degeneration (AMD), the most common form of the eye disease. The company's hESC-derived retinal pigment epithelial cells (RPE), which will be injected into the retinal space of affected patients, will be assessed for safety first and efficacy second in the initial phase 1/2 study.
In November, a similar trial was approved by the FDA for Advanced Cell Technology's RPEs in an inherited form of macular degeneration, Stardgardt's disease, which affects about 30,000 Americans. (Dry AMD, however, is much more prevalent—affecting 10-15 million Americans.) Since the announcement of the company's hESC trial in November, its penny-stock value has more than quadrupled.
Last July, the FDA lifted its regulatory hold on Geron's clinical trial program for hESC-derived oligodendrocytes in subacute spinal-cord injury.
Image of undifferentiated hESCs from http://www.nih.gov/catalyst/2007/07.01.01/page1.html.
The lawyers, Wendy Mariner, George Annas, and Leonard Glantz, describe (unlike Yale's Jack Balkin), the "continuing uncertainty over the constitutionality" of PPACA on the basis of "conflicting trial court rulings and scholarly commentaries." They cite 4 reasons for why the "constitutional question," as they call it, is so damned thorny.
1. Congress has never required anyone to buy a product from private industry. What isn't in doubt, Mariner et al acknowledge, is Congress's power over the health-insurance industry under the Commerce Clause. What is unclear, however, is whether Congress can demand that uninsured Americans buy health insurance (so that the insurance risk is spread and that costs remain manageable, as a result).
2. The answer to reason no. 1 depends on how the Supreme Court (or other federal courts, for that matter) will interpret the scope of the Commerce Clause. To confuse predictions, the high court has lately provided both conservative and liberal readings of the Clause, which "makes it almost impossible to predict how it will view the requirements of [PPACA]."
3. The thorniest issue, the lawyers propose, is whether inactivity (ie, not buying health insurance) actually "qualifies as an activity that affects interstate commerce." If the Commerce Clause allows Congress to penalize (or tax?!) Americans for inactivity (really activity), the Obama administration will have to demonstrate why this reasoning doesn't allow Congress wider authority (via the Commerce Clause). For instance, the Justice Department will have to show why Congress couldn't penalize Americans for not buying a car to sustain a failing automotive industry. Now the argumentative distinction may lie in the necessity of the purchase, the authors counter. The DoJ might rebut to the Supremes: People require health coverage but not necessarily a car.
4. But this pro-mandate rebuttal might be difficult. There are other necessary or simply good-for-you commodities—like water, food, broccoli—but Congress doesn't legislate their purchase or the purchase of insurance to pay for them (when Americans can't afford them).
Mariner et al provide no pat answers (unlike Jack Balkin), but their closing thought is an intriguing one: The Constitutionality of the insurance mandate is an issue that is distinctive to PPACA. It would not be raised (and is not raised) in the cases of Medicare, Medicaid, and Veterans Affairs medical services, because these are government healthcare programs supported by Congressionally imposed taxes. If PPACA had provided a national healthcare program (eg, had expanded Medicare to everyone) instead of accommodating a private healthcare insurance industry, there would be no Constitutional argument.
