Recently in Ethics Category
Recently I wrote that "plaintiff-sponsored research is disturbing and represents a potentially significant conflict of interest for the investigator who accepts plaintiff funds to perform related studies—particularly studies that may be used to the advantage of the plaintiff in ongoing litigation." This statement was in response to a recent court opinion that dismissed the plaintiff-funded study of Bremner et al, who attempted to associate altered brain metabolism with Accutane exposure. The study was published in a 2005 issue of the peer-reviewed American Journal of Psychiatry, which acknowledged the study's funding source.
The reflexive "ick" to plaintiff-sponsored research or, more broadly, litigation-driven research is undoubtedly related to the fact that the outcome is intended to support one side of an argument. This inherent bias in litigation-driven research is, therefore, completely contrary to the fundamental tenet of scientific endeavor, which is to investigate the universe with as much objectivity as possible.
By comparison, there is generally less disgust when considering industry-funded, and in particular, pharma-funded, research—although agendas certainly exist among the financial supporters of these clinical studies. The reasons for the relatively ease with which we accept pharma-funded research, despite the fact that these studies are designed and performed to sell prescription drugs, are threefold: 1) there is a longtime precedent of reviewing and accepting pharma-funded research; 2) the intended outcome of pharma-funded research is less overt than that of litigation-driven research; and 3) the drug industry is government regulated. Specifically much of the clinical research supported by pharma, including raw data, is subject to the scrutiny of FDA officials (which is why reasons 1 and 2 exist, for the most part).
But law professor William Childs, in a 2006 paper, argues that litigation-driven research should not be dismissed out of hand by the scientific community. Moreover, litigation-driven research may add importantly to the foundation of science by funding studies that would not have been performed otherwise. And the validity of litigation-driven research, especially if it has been published in a peer-reviewed journal, will likely be subjected to a lengthy Daubert hearing—which is used by many courts to determine the admissibility of expert testimony.
This legal scrutiny of scientific research, Childs argues, goes beyond peer review*—the parameters of which are limited and vary widely from journal to journal—to examine researchers' methodologies and, importantly, their raw data. For instance, in the case of Bremner's Accutane-PET study, a lengthy pretrial court hearing revealed that the authors did not follow their methodology as described, and that there were outcome-altering errors in data entry. Without the hearing and the resulting court opinion, these shortcomings of the peer-reviewed study would not have been known.
It therefore goes to reason that researchers who perform litigation-funded research, knowing that their research will likely be subjected to cross-examining attorneys and the scrutiny of opposing expert witnesses, should be sufficiently motivated to perform their research with irreproachable standards. These standards should certainly include avoiding dishonesty or the appearance of it.
Childs writes that, while "it is highly unusual for a party's retained expert to testify contrary to the party's litigation position,"** checks exist to ensure the integrity of litigation-driven research through the possibility of subpoenas and depositions and any consequent risk to a researcher's reputation—"the coin of the realm in academia."
* In fact, Daubert hearings reveal the shortcomings of peer review to reliably ferret out scientific fraud.
** And the plaintiffs' retention of an expert "is dependent on whether the results support the plaintiffs' argument." Recently Bremner emphasized that he was retained as an expert witness by the Accutane litigation plaintiffs after the PET study was completed--which means that his retention as an expert witness by the plaintiffs was dependent on the results of his study.
Image of vintage Pepto-Bismol ad from Flickr.
It's one thing for a physician to serve as a medical expert for plaintiffs in court cases. It's very much another when plaintiffs actually commission a physician to conduct a study—the results of which are intended to support their litigation. (Think Andrew Wakefield and the associated antivaccination mess.)
Now, according to a newly released court opinion (courtesy of Jim Beck at the Drug and Device Law blog), it is revealed that plaintiffs in the Accutane litigation* specifically commissioned Emory psychiatrist J. Douglas Bremner to conduct a PET study, which led to the conclusion that Accutane reduces metabolism in "a brain area known to mediate symptoms of depression." The results of the uncontrolled study were published in a 2005 issue of the peer-reviewed American Journal of Psychiatry,** and for the purposes of the court case, "Bremner issued an expert report opining that Accutane can cause depression and suicide."
If this conflict of interest isn't sufficiently disturbing, the court opinion reveals further that Bremner's commissioned data were highly suspect.
During a lengthy pretrial hearing, in which Bremner was questioned about the PET study by defendant's counsel,
Bremner was repeatedly confronted with problems in the PET study, including missing data, inaccurate data, and deviations from the methodology he claimed to have followed. As a result...the court permitted Bremner to re-work his study data and issue a supplemental expert report and allowed defendant to re-depose him. When the hearing resumed, Bremner admitted that certain underlying data, known as "Bmax numbers" which had been used to make critical calculations in the study, [were] not retrievable from its computerized format, and some of the data concerning individual study subjects [were] still inaccurate.
(I could be wrong here, but Bmax, in this context, appears to be a maximum basal metabolic rate of the brain area in question—a necessary reference standard from which to calculate any metabolic changes.)
The opinion goes on to state,
[T]hat Bremner did not actually use the methodology he claimed to have used. Although his PET scan article was peer-reviewed, he admitted that he did not in fact follow the steps described in the article.
Significantly, contrary to representation made in the article, [Bremner] did not get before-and-after Skindex questionnaires from many of the subjects. Those questionnaires were designed to elicit the extent to which the subjects might be worried about their acne. This was relevant because some scientists were of the view that worrying, as well as depression, could affect activity in the orbital frontal cortex.
Note: The orbitofrontal cortex is the brain area in question. Reduced volume of the orbitofrontal cortex has been implicated in major depressive disorder. According to Bremner's published article, the Skindex questionnaire was "administered before and after treatment." The implication is that it was administered to all participating subjects.
The opinion continues,
Bremner also could not document much of the data on which his published results were based. Further, he admitted that some of the statistical analysis was inaccurate. For example, in the October 2, 2006 hearing session, Bremner admitted that, for each study participant, comparing the activity in the orbital frontal cortex with the activity in the whole brain revealed no difference between the subject who took Accutane and those who took antibiotics.
Retreating from the results claimed in his 2005 article, he testified at the hearing that the "absolute metabolic rates" for the two groups was significantly different, and contended that was the key finding of the PET study. However, Bremner claimed that he could not produce the source data for that analysis because the "Bmax" numbers used to calculate those metabolic rates was on an optical computer drive that could not be opened.
Further, while he admitted that some of the Bmax numbers he used in his calculations were inaccurate, he could not check the accuracy of the remaining numbers because the original data could not be retrieved.
An expert's scientific peers cannot fairly judge the expert's written work, including whether it is worthy of publication, if his article does not accurately represent either the underlying data or what the author did to produce his results. We agree with the trial judge that, in essence, Bremner's study was not "soundly and reliably generated."
While this information indicates that Bremner and his coauthors should have retracted the PET study from publication in the AJP, the shaken peer-review process is sustained by a mere notice of correction. At the end of the Letters to the Editor section in a 2008 issue of the AJP is this short paragraph in reduced type:
Corrections
In the article "Functional Brain Imaging Alterations in Acne Patients Treated With Isotretinoin," by J. Douglas Bremner et al. (Am J Psychiatry 2005; 162:983-991), only seven subjects in each treatment group completed the Skindex posttreatment. The secondary analysis that included whole brain metabolism before and after treatment did not reach significance on re-analysis.
In the meantime, the authors of at least 42 articles, according to a Google search, have cited Bremner's PET study. These authors include Bremner himself, who wrote in 2008, "Administration of [Accutane] (but not antibiotic) was associated with a 16% decrease in brain metabolism in the orbitofrontal cortex after four months of treatment."
Also a blogger, Bremner, in an ironic turn, charged conflicts of interest among Roche's key opinion leaders who believe that Accutane does not cause depression.
PET = positron emission tomography.
* Specifically Palazzolo v Hoffman-LaRoche, in which a mother argued that Accutane caused the suicide of her teenage son. Since July 2009, Roche's trade name for the drug is Roaccutane.
** Published disclosures do reveal that the PET study was "[s]upported by funding from Liam Grant, director of the Roaccutane Action Group (80%), and by lawyers involved in Accutane litigation (20%)." The amount of money that Grant provided is not clear; however, information provided by Bremner here indicates that Grant, whose son committed suicide while taking Accutane, contacted Bremner directly and gave an "unrestricted grant" to Emory for the PET study. A 2005 article in USA Today indicates that Grant spent about $1 million to fund the Emory PET study and a rodent study at the University of Massachusetts.
Unrelated, generic PET image from Wikipedia.
02/06/10 addendum: At his blog, Bremner responded today to Jim Beck's post and this post. Bremner harshly and wrongly, in my opinion, describes our discussions of the court opinion as "an outpouring of hate." (I think "criticism" is a better descriptor.) He also casts aspersions at Beck's and my respective alliances with the pharmaceutical industry. (Beck makes it no secret that he represents drug companies in related litigation. I make it no secret that I have worked in pharmaceutical marketing.* While this information is important to know, it doesn't make our criticisms or concerns about plaintiff-sponsored research necessarily baseless.)
Bremner continues by denying that his PET study was "commissioned for the litigation," despite the fact that the court opinion states, on page 3, "There is no dispute that the study was commissioned specifically for use in this litigation." This statement clearly indicates that opposing parties in the litigation did not contest this point, despite the fact that Bremner disagrees with it.
Bremner then fails to support his disagreement. He merely affirms that 80% of the PET study was funded by an Accutane plaintiff (Liam Grant) and writes that Roche wouldn't perform a study (presumably a PET study) or supply medication for a study. Bremner's allegation that Roche wouldn't participate in an Accutane-PET study hardly refutes the statement that Bremner's PET study was commissioned by the plaintiffs. And the fact that the drug industry supports a lot of clinical research, much of it under FDA scrutiny as Jim Beck stresses, doesn't mean that a) a physician is justified in accepting plaintiff money to perform research (whether intended for use in their litigation); b) a physician who accepts plaintiff money for research is immune to plaintiff bias; or c) accepting plaintiff money somehow makes up for any potential bias in pharma-funded research.
Bremner then addresses the study's missing data (which he says were erroneously labeled "Bmax" by the court). According to Bremner, these data were eventually retrieved, albeit after "a court deadline had passed"; however, Bremner does not address the court's disturbing statement, "some of the data concerning individual study subjects [were] still inaccurate."
Bremner minimizes the court's allegation that he did not follow the study's described methodology with respect to the use of the Skindex questionnaire, by stating that "[i]t was by no means the primary outcome of the study" and that "there was no correlation between this item and brain function." He alleges that the questionnaire was added "late" to the study protocol at the request of a "dermatologist who was later found to be a paid consultant to Roche." The implication is that Roche, through this dermatologist, somehow tried to manipulate Bremner's PET study. (It should be noted that the authors of the study do not include a dermatologist, as far as I can tell; so if a dermatologist had significant input into the study protocol, this should have been revealed in the study article.)
The Skindex questionnaire (if a PubMed search is any indication) appears to be a widely used, quality-of-life measure in dermatologic studies. The court wrote that the consistent use of the Skindex questionnaire "was relevant because some scientists were of the view that worrying, as well as depression, could affect activity in the orbital frontal cortex." The article by Bremner et al indicates that the Skindex questionnaire was 1 of 3 components of the study's behavioral assessment (the other 2 being the Hamilton Depression Rating Scale and a clinician-administered acne questionnaire).
In any event, Bremner et al wrote that the Skindex questionnaire was "administered before and after treatment" in his 28-person PET study. This information, it turns out, was misleading, if not outrightly false. The questionnaire was administered to only half of the enrollees before and after treatment, according to the 2008 correction.
Bremner does acknowledge that "some data entry errors were found" in his study but that a "re-analysis of the study resulted in no change in the conclusion." This latter statement doesn't appear to be entirely true, at least according to the court opinion and to the 2008 correction.
In their 2005 AJP article, Bremner et al wrote,
Administration of [Accutane] but not antibiotic was associated with decreased brain metabolism in the orbitofrontal cortex after 4 months of treatment...This effect was seen for both absolute metabolism...and for the ratio of orbitofrontal to whole brain metabolism (F=4.64, df=1, 110, p<0.05). A secondary analysis included pretreatment whole brain metabolism in the model and also showed greater reductions in orbitofrontal metabolism after treatment in the isotretinoin group than in the antibiotic group (F=9.66, df=1, 104, p=0.002).
But the court wrote,
[I]n the October 2, 2006 hearing session, Bremner admitted that, for each study participant, comparing the activity in the orbital frontal cortex with the activity in the whole brain revealed no difference between the subject who took Accutane and those who took antibiotics.
And the 2008 correction states,
The secondary analysis that included whole brain metabolism before and after treatment did not reach significance on re-analysis.
Bremner concludes his rebuttal by stating that "it doesn't matter" and provides a link to a 2008 review article he cowrote. In this article, Bremner proposes how retinoids (like Accutane) may be involved in the neurobiology of affective disorders and cites 2 suggestive mice studies. Among the clinical studies described by Bremner, none of which is well-controlled, the results are mixed. Some suggest a link between Accutane use and depression, and others do not.
I have no vested interest in whether Accutane causes depression or suicide; however, the data, as they currently exist and as Bremner presents them, are not abundantly compelling.** Furthermore, I maintain that plaintiff-sponsored research is disturbing and represents a potentially significant conflict of interest for the investigator who accepts plaintiff funds to perform related studies—particularly studies that may be used to the advantage of the plaintiff in ongoing litigation.
Whether the results of Bremner's PET study, which the court found problematic, are valid can only be determined by their reproducibility—ideally in a randomized, double-blind trial.
* However, during the last 6 years, I've worked in continuing medical education (CME); during the last 2 years, this has been in a freelance capacity. I'm most certainly not paid by anyone to blog.
** Which is why plaintiffs are interested in funding research.
Raising a host of questions, from practical to philosophical, English and Belgian investigators showed that some patients with profound disorders of consciousness may be able to communicate—albeit in rudimentary fashion and with the aid of a million-dollar machine. Their functional MRI study of patients in persistent vegetative or "minimally conscious" state is available online today at the NEJM web site.
Among 54 severely disabled patients, investigators found that 5 could "willfully modulate their brain activity," as seen on fMRI pictures, in response to suggested motor imagery. Specifically when these patients were asked to imagine playing tennis, parts of the supplementary motor area reliably lit up. Four of the 5 patients could also respond to suggested spatial imagery, like navigating through a familiar city, by activating the parahippocampal gyrus. Follow-up bedside testing showed "some sign of awareness" in 3 of the 5 patients—suggesting that voluntary behavioral cues were missed before the fMRI assessment or that fMRI training primed these patients to respond behaviorally at the bedside (the former seems more likely).
The investigators then selected 1 patient with reliable fMRI responses to undergo training that correlated the motor imagery with "yes" and the spatial imagery with "no." The patient was then able to use the technique during fMRI to accurately answer yes-no questions, like Is your father's name Alexander? However, back at the bedside, no form of communication could be established with this patient.
All 5 responsive patients had traumatic brain injury without anoxic damage (among 32 in the study population). It is important to note that none of the 16 patients with anoxic brain injury responded (a fact that editorialist Allan Ropper also stresses).* Before fMRI testing, 4 of the responsive patients were diagnosed with vegetative state, including the patient who underwent communication training.
The American Academy of Neurology, the flagship organization for practicing US neurologists, provides the following criteria for the diagnosis of vegetative state:
- No evidence of awareness of self or environment and an inability to interact with others
- No evidence of sustained, reproducible, purposeful, or voluntary behavioral responses to visual, auditory, tactile, or noxious stimuli
- No evidence of language comprehension or expression
- Intermittent wakefulness manifested by the presence of sleep-wake cycles
- Sufficiently preserved hypothalamic and brainstem autonomic functions to permit survival with medical and nursing care
- Bowel and bladder incontinence
- Variably preserved cranial nerve and spinal reflexes
Minimally conscious state, which acknowledges the intermediate stage between no and some awareness in the severely brain damaged, is defined as follows:
A condition of severely altered consciousness in which minimal but definite behavioral evidence of self or environmental awareness is demonstrated.
Diagnosis: limited but clearly discernible self or environmental awareness on a reproducible or sustained basis by demonstrating one or more behaviors, including, following simple commands, gesturing yes/no answers to questions, intelligible verbalizations, purposeful behavior, appropriate smiling or crying, reaching for and touching objects, and pursuit eye movements.
Course: may be a transient stage in the recovery after severe head injury or other brain insult or a permanent condition.
Results of this fMRI study suggest that the imaging technique might be useful for distinguishing the 2 conditions (and that, perhaps, the definition of minimally conscious state should include fMRI-dependent findings) and for establishing communication in patients with reproducible fMRI responses.
* Ropper also concludes his NEJM editorial with a groan-inducing pun that should not be reproduced.
Image of Berkeley's fMRI machine from Wikipedia.
That rang 12 years ago.
Yesterday, editors of The Lancet officially retracted publication of a 12-year-old debunked study that linked the MMR vaccine to autism, according to the journal's web site, numerous news sources, and countless blogs. The study is believed to be responsible for declining vaccination rates among children in the United Kingdom and the resurgence of measles.
The journal's decision comes on the heels of an announcement last week from the UK's General Medical Council, which found that 3 of the article's authors—Andrew Wakefield, John Walker-Smith, and Simon Murch—did not act in the best interests of the study's 12 pediatric enrollees. Wakefield, in particular, was cited for "callous disregard" toward his subjects, by plying them with a few pounds in exchange for blood samples at a birthday party. The GMC's report is provided courtesy of Kathleen Siedel at her neurodiversity blog.
The Council's investigation of Wakefield and others was prompted by the investigative reporting of Brian Deer from The Sunday Times. Beginning in 2004, Deer alleged that Wakefield not only held significant financial conflicts of interest, but that he actually manufactured data. Responding to Deer's initial investigation, 10 of the study's 13 authors (including Walker-Smith and Murch) retracted their "interpretation" in a letter to The Lancet.
So where does a discredited UK doctor go? Austin, Texas, evidently. Wakefield is Executive Director of The Thoughtful House Center for Children, a questionable research and treatment center for children with autism. However, Wakefield does not have a license to practice medicine in the state, according to the online database of the Texas Medical Board.
A London pediatrician's diary shows that Haiti desperately needs, more than surgeons, supplies and coordination.
Writing for the Evening Standard, Dr. Nathaniel Segaren of the Caris Foundation, logs his week of guilt, frustration, appall, effort, and anguish among the mayhem. He concludes, "I realise we can be of most help with our knowledge of the city's geography and our ability to speak a combination of French, English and Creole." The ultimate intent becomes to select, with exceptional agony, those patients for transfer to a floating US Navy hospital—which is already beyond capacity.
"There are lots of egos here and mini power struggles," Segaren observes, "People are desperate to claim credit and get maximum media coverage."
From the UN via Flickr: Photo of 18-year-old Haitian girl with head trauma being transported to USS Comfort, a floating hospital.
In Orange County, California, opening statements began yesterday in a multi-plaintiff civil case against Allergan, maker of Botox. The plaintiffs, including the mother of a deceased 7-year-old Texas girl with cerebral palsy, argue that off-label use of the company's drug caused severe adverse reactions including death. Trial coverage is provided in frustratingly nonlinear stories from ABC News and the LA Times.
Piecing together the information, the case against Allergan appears to rest on these issues:
- Can injected botulinum toxin migrate sufficiently, especially when used for spasticity, to cause paralysis of respiratory muscles?
- Can injected botulinum toxin cause seizures?
- Did Allergan promote the off-label use of Botox for pediatric spasticity?
Related to the third issue is whether Allergan promoted the off-label use of Botox a) at particularly high doses and b) despite being aware of the related dangers.
For its part, Allergan is claiming that Botox did not cause the death of the 7-year-old girl, Kristen Spears, who received a series of 7 Botox treatments, beginning at the age of 6 years, for muscle spasticity in her legs, groin, and chest. Spears's mother alleges that these treatments led to the girl's clinical deterioration. Already underweight and with a baseline seizure disorder, Kristen allegedly experienced more severe seizures and swallowing difficulties after her treatments began. The latter problem, along with breathing problems, led to 10 hospitalizations. Kristen died of respiratory failure and pneumonia in November 2007, reports the LA Times.
Apparently on the basis of Kristen's case and others, the FDA announced last year that it had received postmarketing reports of toxin spread, when the drug was used to treat spasticity in children or adults. The reported symptoms were essentially those of botulism: dysphagia and respiratory compromise. Consequently the agency required makers of botulinum toxin products to add a black-box warning to their drug labels, advising of the risk of toxin spread.
But in its very recent review of published trials, the American Academy of Neurology (AAN) did not find evidence of drug-associated hospitalization or death when botulinum toxin was used to treat limb spasticity in children. All trial-based adverse events—the most common being localized pain, excessive weakness, unsteadiness, increased falls, and fatigue—were transient. Dysphagia was observed in 2 patients among more than 500 children. Seizures or the increased severity of seizures were not reported.*
The plaintiffs also argue that Allergan, in violation of federal law, promoted the off-label use of Botox for pediatric spasticity and specifically in the case of Kristen Spears. The company allegedly paid for the girl's pediatrician, Rolf Habersang, and his nurse practitioner wife to attend sponsored training seminars in 2000 and 2001 and arranged for Dr. Habersang to receive instruction from an Arkansas pediatric neurologist. In depositions, Habersang testified that he learned to use Botox at a dosage of 15 units/kg—a high, but not-unheard-of, dose in the case of CP-related spasticity in kids. The suit also alleges that Allergan sales reps discussed the off-label use of Botox repeatedly with the Habersangs and provided the dosage range of 10-15 units/kg for juvenile spasticity.
While the off-label promotion reportedly took place, the company knew of mounting Botox-related adverse events, the plaintiffs claim. Beginning in 2005, Allergan became aware of European reports of toxin spread that led to aspiration and death, and the company accumulated its own safety database, at least some of which it shared with the FDA. Also according to the plaintiffs, Allergan knew of reports of Botox-related seizures.*
The plaintiffs' allegations of off-label promotion, if true, are at complete odds with Allergan's current stance against the FDA, which requested last year that the company disseminate safety information about the off-label use of Botox. The agency's request led to Allergan's pending federal suit against the government, which seeks "declaratory relief" from the FDA's long-time restrictions against the discussion of off-label uses of prescription drugs.
To confuse matters even further, Allergan's supplemental biologics license application (sBLA) for the use of Botox in upper-limb spasticity after stroke is currently being considered by the FDA. The goal date for the agency's decision is April 1st.
Currently Botox is approved to treat spasticity associated with pediatric CP in more than 60 countries, according to news reports. In the United States, the drug's off-label use for CP-related spasticity is, by and large, considered standard practice.
* Because the effects of botulinum toxin are strictly confined to the neuromuscular junction, it seems highly unlikely that a direct mechanism exists for the drug to cause or exacerbate seizures. However, it is conceivable that the drug, through respiratory compromise, could indirectly precipitate or exacerbate seizures through hypoxic brain damage. The case of Kristen Spears, as reported, is unusual in that she received injections of botulinum toxin in her chest, which could have paralyzed her intercostal muscles.
02/01/10 addendum: The total doses used in the pediatric Botox studies that were assessed by the AAN ranged from 2 to no more than 13 U/kg for upper-extremity spasticity (n = 193; age range, 2.5-10 years) and from 4 to 30 U/kg for lower-extremity spasticity (n = 286; age range, 2-16 years). Ranges of respective per-muscle doses, when provided, were 0.3-4 U/kg and 4-6 U/kg (only 1 lower-extremity study provided these data).
Yesterday, James Beck over at the Drug and Device Law blog provided an update on Allergan v the United States of America et al—last year's No. 5 story at this-here Pathophilia blog. I completely missed it, but 4 days ago the government responded to Allergan's "free-speech" complaint of last year with its own "45-page whopper" (Beck's words) of a motion to dismiss or for summary judgment.
Plowing through the document, my non-legal mind distills the government's 2 basic counterarguments to Allergan "free-speech" complaint to the following.
1. The argument for dismissal: The case isn't "ripe"—meaning, Allergan hasn't said anything yet to potentially violate the law. Of course, this argument highlights the double bind in which the FDA has put the company. Allergan has been asked by the agency to publish safety information about the off-label use of Botox for spasticity; but Allergan logically fears that if it does so, it will run afoul of federal law that prohibits drug promotion for off-label purposes. Allergan's fear is justified by text in the government's own motion, which reads, "advertisements for prescription drugs may not 'recommend or suggest' the drug for unapproved uses."
But the government allows itself a little wiggle room, by also stating, "It is critical to understand, however, that not all speech or actions by a manufacturer regarding an unapproved use is taken by the FDA to be evidence of intended use." However, I find the government's extended argument confusing: "Absent promotion, the dissemination of safety information relating to an unapproved use would not establish that the use is an intended use, and therefore would not trigger either the new drug approval process or the misbranding provisions of the FDCA [Food, Drug, and Cosmetics Act]."
The crux of the issue seems to be whether safety information regarding the off-label use of a drug, on its face, promotes a drug for that off-label use. The government says not necessarily. (In other words, "Hey, trust us. We won't prosecute you for something we ask you to do...unless we decide you've gone too far."). But again, how can a company know when off-label safety information constitutes illegal promotion before it potentially breaks the law?
2. The argument for summary judgment: Allergan's suit is a "frontal assault" (not a full-frontal assault?) on the 1962 Harris-Kefauver Amendment to the FDCA, which requires that a company prove the efficacy of a prescription drug for a particular indication before it can be promoted and sold in interstate commerce. The government lays out a series of contradictory (at least to me) arguments, while invoking a couple of metaphors from Greek mythology (to Beck's amusement).
Essentially the government claims a) current regulatory laws restricting commercial speech are Constitutional, and 2) if it prevailed, Allergan's complaint would allow the promotion of drugs for unapproved uses, thus placing the public health in jeopardy. Beck parses out the government's arguments in reader-friendly bulleted fashion and provides pointed commentary (like a parsimonious "Wow").
But what gets me (again) are the government's incongruous or ambiguous statements, which (as Beck points out) emphasize the vagueness of regulations that restrict the speech of a drug company—and specifically, 21 § CFR 201.128 regarding intended uses. The government writes stuff like...
The Act and regulations leave ample room for Allergan to disseminate truthful, non-promotional information about dangers associated with unapproved uses of Botox, above and beyond the information that FDA has already directed Allergan to provide. [emphasis added]
Okay, the issue again: How do we distinguish between promotional and nonpromotional information?
Well, try this head-spinner on intended uses:
When a manufacturer engages in speech such as advertising or promotional labeling that expressly or implicitly promotes a particular use, FDA treats such speech as evidence that the use is intended. [emphasis added]
Oy.
Beck's even more impressed with the vagueness of this statement.
In practice, FDA usually does not treat an unapproved use as an intended use solely because the manufacturer knows that the unapproved use is taking place.
Usually. [shudder]
But all of this legal maneuvering between Allergan and the FDA may be moot (or "moo," as Joey on "Friends" would say*), according to the government's motion. In August 2008, Allergan submitted a supplemental biologics license application (sBLA) for the use of Botox in upper-limb spasticity after stroke—one of the off-label indications at issue. However, in May 2009, the FDA declined to approve the drug for the new indication, citing application deficiencies. Then 4 months later, Allergan resubmitted its sBLA. The "goal date" for the FDA's decision, per the motion, is April Fool's Day.
So is the government saying, "Wait. Give us time to approve Botox for spasticity, and this whole free-speech mess we've created will go away"?
N.B. A motion hearing in Allergan v the United States of America et al (09-cv-1879) is still scheduled for March 2nd, in the US District Court for the District of Columbia.
* Which is just about the only funny thing that was said on "Friends."
No. 3: The Transparency Movement Takes a Vice-Like Hold
The push to uncover every potentially relevant tie between physicians and commercial interests, every medical writer behind a figurehead author continued with a vengeance in 2009.
In December, Northwestern University became the latest medical school to voluntarily disclose the financial relationships of its faculty with drug or device companies at its web site. The Chicago-based university joined Stanford, which provided similar online information in August, and the Cleveland Clinic, which boarded the disclosure train last year.
A handful of pharma companies, perhaps in an effort to avoid legislated disclosure,* also committed to posting some of their payments to physicians. This year, Eli Lilly, Merck, and GlaxoSmithKline began revealing various forms of compensation to healthcare professionals for a variety of services, like consulting or speaking. And Pfizer promised to disclose comprehensive data (for instance, meals exceeding $25) beginning in the new year.
Caught up in the spirit of transparency—the Accreditation Council for Continuing Medical Education (ACCME), the US organization that accredits other organizations to provide certified CME—released detailed data on 729 accredited providers in August. In an impressive data dump, the ACCME revealed each provider's accreditation status and whether they received commercial support or income from advertising or exhibits (without, however, disclosing dollar amounts). The vast majority (81%) received some type of commercial support.
Peer-reviewed medical journals published at least 2 press-worthy studies that outlined the prevalence of industry ties among academic physicians (53%) and the incomplete disclosure practices of orthopedic surgeons specifically (nearly 30% of payments, some of which exceeded $1 million). An example of the exhaustive transparency to be expected in medical journals today: the author disclosures in a highly publicized, company-sponsored study in Alzheimer disease consumed roughly 3 columns of small type in the journal Neurology.
In addition to flushing out the financial ties of physician authors, journal editors launched the age of "ghostbusting." The practice and that of honorary authorship (eg, adding the name of a laboratory head to lend cachet or credibility to an article) were found to be relatively common in the most prestigious medical journals, including The New England Journal of Medicine and the Journal of the American Medical Association, according to survey results presented publicly in September.** For offenders whose work is published in PLoS Medicine, the editors recommended immediate article retraction, lifetime banning of the named author, and a report to the author's institution for investigation. Ouch.
Recently Cochrane reviewers became concerned about the actual involvement of listed authors, the possibility of ghostwriting, and the quality of the data from a 2006 analysis of 10 Roche-sponsored trials of oseltamivir (Tamiflu). The drug company received a very public comeuppance from BMJ editor Fiona Godlee this month, for resisting unconditional access to the trial data (see BMJ Editor Bitch Slaps Roche). Godlee concluded that the joint investigation by the Cochrane reviewers, BMJ editors, and a British TV news station "cast doubt not only on the effectiveness and safety of [Tamiflu] but on the system by which drugs are evaluated, regulated, and promoted."
* Either through the proposed Physician Payments Sunshine Act or healthcare reform bills.
** Nosing in on the ghostbusting movement was Senator Chuck Grassley (IA-R), ranking minority member of the Senate Finance Committee. In November, Grassley sent a letter (personally written by the Senator?) to the deans of 10 medical schools, asking them to respond to 6 essay-type questions regarding their schools' policies on ghostwriting and plagiarism.
No. 5: Allergan Challenges FDA's Speech Restrictions
In what may turn out to be a pivotal case on the rights of commercial speech, Allergan, the maker of Botox (onabotulinumtoxinA), filed a suit against the US government in October. The company seeks declaratory relief from the FDA's long-time restrictions* against the discussion off-label uses of prescription drugs.
Turns out the FDA really brought this trouble on itself by creating a double bind for Allergan and other makers of botulinum toxin. In April, the agency required such companies to add a boxed warning to the drugs' labels and provide other public information regarding the risks of toxin spread when botulinum is used in certain forms of spasticity, like those related to cerebral palsy or after stroke. Problem is: botulinum toxin hasn't been approved for these conditions, and companies are prohibited by law from proactively discussing off-label conditions.
Allergan logically claims that it cannot reasonably abide by the FDA's safety mandate regarding the off-label use of Botox without fear of prosecution. In its complaint, the company argued that much of its proposed speech about the safety of Botox would "fall within the FDA's expansive definition of 'labeling'" and could lead to federal misbranding charges. Discussions about the safety of Botox treatment for spasticity might also be interpreted as promoting Botox for spasticity, and such an interpretation could lead to charges of distributing an unapproved "new drug" in the eyes of the FDA (meaning, an existing drug for a new indication).
Following the logic a step further, Allergan wrote: "Even by filing this complaint and thereby exercising its First Amendment right to petition the Government, Allergan fears that it will run afoul of the FDA's regulatory regime by demonstrating its knowledge that Botox is sold to physicians who use it to treat spasticity and other off-label conditions. On the Government's view, Allergan's possession of this knowledge—and its choice to defend its constitutional rights—violates 21 CFR §201.128 [which relates to the drug maker's knowledge of intended uses] on its face."
Allergan justified its fear of prosecution for the off-label promotion of Botox by acknowledging that the company is the subject of a DoJ investigation in the Northern District of Georgia.
According to the schedule of the US District Court for the District of Columbia, a motion hearing in Allergan v the United States of America (09-cv-1879) will occur March 2, 2010.
* Mandated by the Federal Food, Drug, and Cosmetic Act of 1938. The FDCA dictates that an approved drug is "misbranded," if it is marketed (in interstate commerce) for an unapproved use. The act stipulates that the product's approved label, in this case, does not provide "adequate directions for use."
Fifty-four of 57 Nigerian children died between October 2008 and January 2009 after receiving a liquid acetaminophen preparation that was tainted with diethylene glycol (DEG). Exposure to the branded teething product, My Pikin,* was determined in 96% of the identified cases of unexplained acute renal failure (ARF) in the 57 children, according to a retrospective surveillance study performed by Nigerian officials, the CDC, and the US FDA. Their report is available in the latest issue of the MMWR.
The surveillance study was prompted by clusters of unexplained ARF cases in very young children (≤3 years of age) among hospitals in Lagos, Kadun, and Osun in the fall of last year. Initial reports led to the identification of the DEG-tainted product, a full product recall, and the shutting down of the responsible manufacturer in Lagos, Barewa Pharmaceuticals. Despite a nationwide recall and a press release in November of last year, which resulted in the confiscation of 7616 of 15,000 bottles of the contaminated drug, more than a quarter of the affected children received the product after the recall was announced.
Among children for whom data were available, the median time from drug exposure to ARF was 5.6 days (range, 0-24 days), and the mean time between the onset of ARF and death was 6.8 days (range, 1-19 days). Treatments with dialysis, received by 24 children, and the ethylene-glycol antidote fomepizole, received by 2 children, did not appear to prolong survival.
The MMWR editors report at least 12 episodes of DEG contamination in oral or topical medications during the last 70 years, which have caused at least 450 deaths. (Most of these episodes are described here and here.) The contamination was almost always due to the intentional economic-driven substitution of DEG for the more expensive solvents of glycerin or propylene glycol. (An account of the US deaths that occurred in 1937 due to a DEG-tainted antibiotic solution has been provided in numerous serial posts at this blog [search for "sulfanilamide" or "Massengill," for example], and the deceased are listed on this page.)
Prevention of DEG-contaminated drugs is easy and cheap, according to the editors. "Simple, rapid, and low-cost assays" that use thin-layer chromatography are available to detect and measure DEG at levels of 2% in liquid acetaminophen products and 6% in glycerin, they report.
* DEG accounted for 17%-21% of the My Pikin liquid medication by weight in sampled bottles. According to the MMWR, another contaminated acetaminophen-based syrup, made by a different manufacturer, was discovered to contain 0.5% DEG.
Photo of My Pikin Baby Teething Formula from Vanguard.
