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.
I Soliti Ignoti (1958), aka Persons Unknown or Big Deal on Madonna Street: If this farcical heist movie doesn't make you shrug, wave your hands, and argue in gibberish Italian with the nearest person, I don't know what will.
Marcello Mastroianni plays just one of several incompetent, demonstrative, thieving wannabes.
The usual nod and thanks to KTG.
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.
The Conversation (1974): Come on. It's been how many years since you've seen this movie? Rediscover what a national treasure Gene Hackman is. It's also one of Coppola's best, and I'm including The Godfather and The Godfather: Part II.
For my part, I've watched this film, about a wiretapper with a Catholic conscience, more times than I care to admit outside a group of drooling cinephiles: There's the pulling of focus to complement audio lapses; the showing of character (Hackman picking up sidewalk trash to emphasize his character's fastidiousness); the best dream sequence on film; the confession (play close attention to the developing mismatch between the audio and Hackman's lips*); tech geeks cutting loose; the wry nod to Psycho in the hotel bathroom; John Cazale (fer Christ's sake!); a fetal Harrison Ford; the surveillance camera-like closing. Yes. YES. YES!
* This guy's so wound up he can't even tell his deepest secret to a priest in a confessional.
In an apparent effort to atone for every Microsoft error message, the Gateses are committing $10 billion USD over the next 10 years for the research, development, and delivery of mortality-reducing vaccines to "the world's poorest countries." Some details of the financial pledge are available in today's press release from the couple's philanthropic foundation. The donated money is in addition to the foundation's already committed $4.5 billion for vaccine R&D.
The foundation's new support is motivated by recent data from the Johns Hopkins Bloomberg School of Public Health, which showed that a 90% vaccination-coverage level* in developing countries would prevent the deaths of about 7.6 million young children during the next decade. The number of lives saved could be ramped up to 8.7 million, if a malaria vaccine is introduced in the year 2014.
Another inspiration for the Gateses' pledge is the success of the rotavirus vaccine. In this week's NEJM, pooled results of a randomized, multicenter trial in South Africa (n = 3166 infants) and Malawi (n = 1733 infants) showed that a live, oral rotavirus vaccine (Rotarix; GSK) reduced cases of severe gastroenteritis due to the organism by 61% (4.9% vs 1.9%).**
Also reported in this week's issue, the recent introduction of rotavirus vaccines in Mexico reduced diarrhea-related deaths by 35% among children younger than 5 years of age (18.1 vs 11.8 deaths per 100,000 children). The life-saving benefit of vaccination was even more apparent among infants younger than 11 months (41% mortality reduction).
Vaccine researchers looking for a chunk of the Gateses' big money can start here. But the foundation only accepts letters of inquiry (LOIs) from 501(c)(3) organizations and other nonprofits. Individuals need not apply.
* Which would include new vaccines for diarrheal illnesses and pneumonia.
** Although there was no significant difference in mortality, 2.5% vs 2.6%.
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).
While plowing through Novartis's newly released financial report for 2009, I found this quiet gem: the "dossier" for Gilenia, the proposed trade name for fingolimod or FTY720, was submitted to the FDA and the European Medicines Agency in December. Now by "dossier," I assume that the company means its new drug application for the investigational compound; certainly the media are reasonably interpreting dossier as NDA.
This under-the-radar news of the NDA submission comes as a surprise—not because the fingolimod NDA was submitted (that was actually expected back in December), but because the news was provided so sotto voce.* I merely stumbled across the information while I was looking for more dirt on the company's recent Trileptal plea agreement.
And just in case I missed news of the NDA submission back in December (despite blogging semi-feverishly about the race between Novartis and Merck Serono to market the first-ever disease-modifying pill for multiple sclerosis), I rechecked the Google news archives. Nope, nothing.**
So the question is: Why no big announcement of the Gilenia NDA submission, Novartis? In typical fashion, Merck Serono trumpeted the submission of its NDA for the fast-track approval of oral cladribine in September.
Perhaps the answer has something to do with the FDA's December announcement that it refused to file Merck Serono's cladribine NDA. But I have to admit: I'm kind of flummoxed.
* Not to mention, a month after it happened.
** Although, last week, both Dow Jones and Reuters reported Novartis's NDA submission of fingolimod. I am mentally flaggellating myself for missing these reports.
