Recently in Marketing Category
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).
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."
In the midst of the 2009 pandemic influenza epidemic, BMJ editor Fiona Godlee takes Roche to task for not supplying the necessary data to confirm or refute the benefits of oseltamivir (Tamiflu) in otherwise healthy people with influenza. In one of 2 BMJ editorials, Godlee chides Roche for not supplying unconditional access to raw data from a pooled analysis of 10 company-sponsored trials (Kaiser et al; PubMed link here) to Cochrane reviewers Jefferson et al. Consequently the reviewers were "obliged to disregard" the bulk of these data (8 of the 10 trials) and were unable to verify that oseltamivir prevents lower-respiratory-tract complications (eg, pneumonia) due to influenza.
In their previous 2006 Cochrane review, Jefferson et al had concluded that oseltamivir 150 mg daily prevents such complications on the basis of the Kaiser article. However, the authors were criticized through a public feedback mechanism for using the 10-trial analysis without having access to the raw data. Prompted by this criticism, Jefferson et al then conducted another review, published this week in the BMJ, in which they affirmed their critic's perspective:
Data on the effectiveness of oseltamivir against complications of influenza principally came from one study...This was a meta-analysis of 10 trials containing a mixture of published and unpublished data, two of which are reported in this update and the remainder inaccessible to proper scrutiny, so that we are now obliged to disregard them. The remaining data showed no benefit for oseltamivir against complications.
In her editorial, Godlee asks, "Where does this leave oseltamivir, on which governments around the world have spent billions of pounds?" She, moreover, emphasizes that the Cochrane review data apply only to healthy adults with influenza, but they "say nothing about [oseltamivir's] use in patients judged to be at high risk of complications—pregnant women, children under 5, and those with underlying medical conditions." Even the drug's ability to reduce influenza-related symptoms (which Jefferson et al reconfirmed) are doubted, because there are no head-to-head studies with oseltamivir and NSAIDs, for instance.
In another BMJ editorial (with Cochrane director Mike Clarke), Godlee concludes that the latest Cochrane review and a "linked investigation undertaken jointly by the BMJ and Channel 4 News cast doubt not only on the effectiveness and safety of oseltamivir (Tamiflu) but on the system by which drugs are evaluated, regulated, and promoted." In their investigation, Cochrane reviewers became concerned about the actual involvement of listed authors on the Kaiser analysis, the possibility of ghostwriting, the high rates of influenza in the trials, and the low rates of serious adverse events.
Initial responses from Roche employees, who first declined to provide the data and then offered selected files, were less than satisfactory to the reviewers. The latest response from the company: it is "committed to making the 'full study reports' available on a password protected site soon."
On the basis of this experience, Godlee and Clarke conclude that the current system for reporting drug research "isn't working" and offer a number of potential remedies—including government-mandated access to raw data that are used to license and market a drug (eg, something in the spirit of the FDA Amendments Act of 2007).
News sources are all over this story (eg, Bloomberg), and the BMJ offers full-text access to the following relevant articles, including a response from a Roche employee—who chastises Jefferson et al for enlisting the investigative help of a TV news station.**
- Godlee F. We want raw data, now.
- Godlee F, Clarke M. Why don't we have all the evidence on oseltamivir?
- Smith J, on behalf of Roche. Roche replies to the authors of the Cochrane Review on oseltamivir.
- Cohen D. Complications: tracking down the data on oseltamivir.
- Doshi P. Neuraminidase inhibitors--the story behind the Cochrane review.
- Freemantle N, Calvert M. What can we learn from observational studies of oseltamivir to treat influenza in healthy adults?
- Jefferson T, Jones M, Doshi P, Del Mar C. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis.
- Web extra (including the criticism that got the ball rolling).
* And I mean that in the nicest possible way.
** Roche's Smith writes, "It is unclear to us why Dr Jefferson would adopt this approach, particularly given that he was a paid ad hoc consultant to Roche working on flu and oseltamivir between 1997 and 1999. During that period he worked closely with Roche experts, many of whom are still in the company, and he would therefore not have had difficulty in contacting them directly to discuss his requirements."
Photo from Vermin Inc at Flickr.
For what it's worth (perhaps a teeny-tiny indicator of an economic rebound?), pharma's spending on direct-to-consumer (DTC) advertising increased substantially during the third quarter of this year, to about $1.26 billion according to data from TNS Media Intelligence.* Numbers provided directly by the "intelligence" firm indicate that pharma's investment in DTC advertising increased by nearly 16% during July-September of 2009, when compared with DTC expenditures during the same time last year.
The following figures from TNS show that the latest quarterly increase in pharma's DTC ad spend has stabilized the declining trend in DTC investment for the year. (According to the latest data from the Congressional Budget Office, DTC expenditures by pharma totaled $4.7 billion in 2008—which has declined from a peak of $5.4 billion in 2006.)
|
Time Period |
DTC Spend, 2008 |
DTC Spend, 2009 |
Change |
|
Q1-Q2 |
$2,373,589,000 |
$2,221,822,000 |
–6.4% |
|
Q1-Q3 |
$3,462,700,000 |
$3,483,600,000 |
+0.6% |
|
Q3 |
$1,089,111,000 |
$1,261,778,000 |
+15.9% |
Television advertising still gets the biggest share of the DTC pie, about 65% of the outlay, according to the data; although investment in TV prescription drug ads dropped slightly (by 3.9%) during the first 2 quarters of 2009. Spending on Internet-based drug advertising (ie, banner ads) increased dramatically during the first half of the year, from about $36 million in 2008 to roughly $116 million (an increase of >200%).
|
Media |
DTC Spend, Q1-Q2 2008 (Thousands) |
% |
DTC Spend, Q1-Q2 2009 (Thousands) |
% |
Year-to-Year Change |
|
TV |
$1,524,602 |
64.2 |
$1,465,068 |
65.9 |
–3.9% |
|
Magazine |
$738,326 |
31.1 |
$583,217 |
26.2 |
–21.0% |
|
Newspaper |
$66,833 |
2.8 |
$44,980 |
2.0 |
–32.7% |
|
Internet |
$35,945 |
1.5 |
$116,178 |
5.2 |
+223.2% |
|
Radio |
$6002 |
0.3 |
$11,208 |
0.5 |
+86.7% |
|
Outdoor |
$1881 |
0.1 |
$1173 |
0.1 |
–37.6% |
|
Total |
$2,373,589 |
100.0 |
$2,221,824 |
100.0 |
–6.4% |
DTC Perspectives,* also referencing data from TNS Media Intelligence, indicates that spending on Internet-based ads more than tripled during the first 9 months of 2009, to $221 million.
Money spent advertising the top 10 promoted drugs to consumers accounted for nearly 40% of DTC expenditures during the first half of 2009. Again, these data are provided directly by TNS Media Intelligence.
|
Brand Name Drug (Company) |
DTC Spend, Q1-Q2 2008 (Thousands) |
DTC Spend, Q1-Q2 2009 (Thousands) |
|
Lipitor (Pfizer) |
$28,066 |
$117,014 |
|
Abilify (BMS/Otsuka) |
$53,557 |
$114,506 |
|
Cymbalta (Lilly) |
$84,527 |
$93,004 |
|
Advair (GSK) |
$93,643 |
$87,390 |
|
Plavix (BMS/sanofi) |
$94,952 |
$81,585 |
|
Ambien (sanofi-aventis) |
$79,808 |
$79,458 |
|
Lyrica (Pfizer) |
$87,436 |
$75,734 |
|
Cialis (Lilly) |
$65,750 |
$70,660 |
|
Singulair (Merck) |
$51,284 |
$70,628 |
|
Crestor (AstraZeneca) |
$62,135 |
$68,739 |
|
Total |
$701,158 |
$858,718 |
|
Percentage of DTC $ |
29.5% |
38.6% |
* DTC Perspectives, citing TNS Media Intelligence, indicated that pharma's DTC spending for Q3 of 2009 was about $1.16 billion, which is $100 million off from my calculation. DTC Perspectives Q3 calculation was requoted by Pharmalot.
While news outlets focus on pharma's investment in direct-to-consumer (DTC) advertising, the Congressional Budget Office reminds us that the drug industry spends heavily and increasingly on sales-rep detailing (despite the notable rep layoffs).
Promotional Spending by Type of Marketing Activity, 1989-2008
Released Tuesday, the CBO report (found here) provides the following expenditure data for the US pharmaceutical industry in 2008.
|
Expenditure Type |
$, Billions |
Percentage* |
|
Promotional efforts (total) |
20.5 |
100 |
|
Professional journal ads |
0.4 |
2 |
|
Professional meetings |
3.5 |
17 |
|
DTC ads (mostly TV) |
4.7 |
23 |
|
Detailing |
12.0 |
59 |
|
Domestic R&D |
38.0 |
— |
Last year, promotional expenditures equaled about 11% of domestic sales ($189 billion)—a percentage that is consistent with those recorded since the early 1990s (10%-12%), the CBO reports.
The CBO also notes that the growth of pharma's overall promotional spending has flattened considerably since 2003 and 2004, when marketing expenditures grew annually at a "double-digit" pace. The decline is probably related to fewer drug approvals and generic competition, the Office speculates.
The favored medium for DTC spending remains television, while Internet advertising (eg, banner ads) takes up a sliver (~4%) of the DTC pie.
The question of whether DTC efforts translate into increased sales remains unanswered. The CBO cites Bradford et al and Law et al, who report conflicting data. A more recent, longitudinal study by Law et al indicates that DTC advertising had no effect on the increasing rate of clopidogrel (Plavix) prescriptions for Medicaid recipients.
* Sum exceeds 100% because of rounding.
Never missing an opportunity to engage in a Zetia (aka ezetimibe) pile-on, Forbes reporter Matthew Herper shows his continued disdain for the drug and its marketing in his most lopsided article yet. Herper's less-than-objective synopsis of Merck's Zetia-related troubles follows results of a recent, small head-to-head study, in which Abbott's Niaspan (extended-release niacin) outperformed Zetia in a highly selected population.
The essential problem with Herper's (and others') coverage of Zetia: He fails to stress that the drug significantly lowers LDL cholesterol—a well-recognized risk factor for vascular disease and a primary target of prevention guidelines. Herper is correct in writing, "No trials show that [Zetia] prevents heart attacks"; but he neglects to remind his readers that, at one time, the same could have been said of Pfizer's blockbuster statin Lipitor (atorvastatin).
Lipitor came to market in 1996 because it significantly lowered LDL-C; but Lipitor had not yet been shown to prevent clinical vascular events like other statins. Nevertheless, Lipitor quickly became the number-one statin because 1) it reduced LDL-C by a relatively greater percentage than other statins and 2) clinicians believe that the LDL-C level is directly related to the risk of vascular events. Lipitor wasn't approved to reduce the risk of vascular events until 2004.
Herper claims, "Merck's clever marketers have spun straw into gold"—a metaphor that wrongly equates the lowering of the LDL-C level with worthless "straw." To support his claim, he cites results of the Niaspan study and the infamous ENHANCE study, both of which enrolled highly selective at-risk populations and used another surrogate marker for vascular disease—the ultrasound measurement of carotid intima media thickness (CIMT). Merck (and Schering-Plough) reportedly struggled with the quality of the CIMT measurements in the ENHANCE study, and some investigators have questioned the usefulness of CIMT generally to assess cholesterol-lowering drugs. For instance, in the placebo-controlled CASHMERE trial, Lipitor failed to significantly alter CIMT in postmenopausal women, despite that fact that the statin undeniably reduces the risk of cardiac events and stroke.
Herper adds Zetia-disparaging quotes from prominent cardiologists, like Sanjay Kaul (who described Zetia as "the miracle of marketing, not the miracle of medicine") and renowned Zetia/Vytorin basher Steve Nissen ("We've spent billions on a drug that may turn out to be a placebo.") Herper also implicitly chastises Merck for waiting 3 years after Zetia approval (in 2002) to begin the IMPROVE-IT study, in which Vytorin (the combination of ezetimibe and simvastatin) is being compared with simvastatin alone to reduce the risk of a composite vascular outcome. Vytorin was FDA approved in 2004.
Herper also unfairly casts aspersions at prominent cardiologists Michael H. Davidson and Antonio M. Gotto, Jr, for providing "lecture and consulting" services to Merck after the results of the ENHANCE study became public. Herper implies that these physicians were paid off to promote the drug, despite the fact that the small and troubled ENHANCE study failed to show the benefit of adding Zetia to statin therapy in a highly select group of patients (ie, individuals with familial hypercholesterolemia). Herper's information was evidently supplied by the office of Senator Grassley, ranking minority member of the Senate Finance Committee.
A quick examination of the medical literature reveals that both physicians (like so many others) endorse the vascular benefits of lowering the LDL-C level. For instance, in a recent editorial, Gotto writes, "Lowering elevated [LDL-C] is a surefire way to reduce cardiovascular risk." But he also acknowledges the potential drawbacks of using surrogate markers to assess the protective benefits of drugs by adding, "As monotherapy, [Zetia] at 10 mg reduces LDL-C by approximately 17%, but when added to any dose of statin, it reduces LDL-C by an additional 25%. Given the well-established log-linear relationship between LDL-C and relative risk for [coronary heart disease], these greater degrees of LDL-C reduction can be expected to result in improved clinical outcomes, although this has not yet been proven in the case of ezetimibe."
In another editorial ("Is LDL-C passed its prime?"), Davidson more clearly lays out the shortcomings of applying general guidelines to what is probably a very heterogenous at-risk population. He notes that the rising number of patients with metabolic syndrome and those currently taking statins present more complex portraits of dyslipidemia and its associated vascular risks. He argues that, in these subgroups, other lipid markers—like apoB, LDL-particle number, and non-HDL levels—become relatively more predictive of coronary heart disease. Consequently drugs that specifically affect these levels (for example, niacin) may be more protective in these specific populations.
CASHMERE = Carotid Atorvastatin Study in Hyperlipidemic Postmenopausal Women; ENHANCE = Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression; IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL = low-density lipoprotein.
It's been implied that direct-to-consumer (DTC) advertising of prescription pharmaceuticals is a major cause of rising healthcare costs generally and of rising expenditures for drugs specifically. For example, in mid-October, NPR's "Morning Edition" ran a piece in which DTC ads were correlated with rising prescription drug use among Americans and associated costs. But the NPR show failed to note that spending on DTC ads has actually decreased since 2006, while drug costs have grown annually at an average rate of about 7% [1].
To more thoroughly examine the possible effect that DTC advertising has on prescription drug use and costs, US and Canadian researchers examined reimbursement for clopidogrel (Plavix; BMS/Sanofi) [2], a blockbuster antiplatelet launched in 1997, in the US Medicaid program before and after the advent of DTC advertising in December 2001. The results of their study are available in the latest issue of the Archives of Internal Medicine.
The crux of their findings:
Clopidogrel use: From 1999 to 2005, the trend [3] of ever-increasing clopidogrel use (units dispensed per 1000 Medicaid enrollees) did not change significantly after the fourth quarter of 2001, when DTC advertising began.
Medicaid reimbursement per clopidogrel unit dispensed: DTC advertising for clopidogrel was associated with a significant one-time bump in Medicaid reimbursement for the drug ($0.40 per unit). However, the slope of the line depicting increasing reimbursement for the drug remained unchanged after this bump.
Total Medicaid reimbursement: Owing almost exclusively to the price bump, the quarterly rate of Medicaid reimbursement increased significantly after the advent of DTC advertising for clopidogrel. Quarterly rate increases in Medicaid reimbursement for clopidogrel use: before DTC advertising, $95.68 per 1000 enrollees; after DTC advertising, $136.26 per 1000 enrollees. The increased total reimbursement rate resulted in an additional $207 million Medicaid dollars spent for clopidogrel use in 27 states after DTC advertising, the authors calculated.
The authors assume that the one-time bump in Medicaid reimbursement for clopidogrel use was due to an increase in the manufacturer's price (which just happened to coincide with the advent of DTC advertising); however, this assumption cannot be confirmed, because pricing data are confidential, they report. BMS/Sanofi's motives for increasing the unit cost of clopidogrel at the time of DTC advertising include an attempt to offset expenses for DTC marketing [4], the anticipation of increased sales, and general conditions of the market.
N.B.--Data after 2005 were not used in this study, because many Medicaid-eligible individuals were transferred to Medicare Part D plans in 2006.
1. According to the McKinsey Global Institute, the rise in prescription drug costs is due "almost equally" to an increased in consumed drug volume and a rise in drug costs. These increases have been offset, however, by "a [small] trend toward a less expensive drug mix."
2. Converted to 2005 USD.
3. In other words, the slope of the line depicting increasing clopidogrel use.
4. According to the authors, total DTC ad costs for clopidogrel in the United States (2001-2005) totaled more than $350 million.
Image of Plavix box from Wikimedia Commons.
Here's something any perpetrator should catch hell for: changing the primary outcome of a trial.*
In studies of gabapentin (funded by Parke-Davis and later by Pfizer) for neuropathic pain, bipolar disorder, or migraine prevention (all off-label uses), the protocol-defined primary outcome was often changed in the published report. This is just one observation of Johns Hopkins investigators after their analysis of internal documents from 20 industry-sponsored gabapentin studies. Their full report is available in the latest issue of the NEJM.
Among the 20 trials assessed, only 12 (60%) were published (see Table); the results of 9 trials were reported as full-length articles. In 8 (67%) of the 12 trials, the protocol-defined primary outcome differed from the primary outcome in the final report. In 6 (50%) studies, a completely new primary outcome was introduced; and in 5 studies, the new primary outcome favored gabapentin treatment.
|
Article |
Statistical Significance Favoring Gabapentin? |
|
Primary outcomes agreed with protocol | |
|
Yes | |
|
Backonja M, Mutisya EM. Review of gabapentin dosing in five placebo-controlled clinical trials for neuropathic pain. Eur J Neurol. 2002;9(suppl 2):191. |
No |
|
Yes | |
|
Gomez-Perez FJ et al. Gabapentin for the treatment of painful diabetic neuropathy: dosing to achieve optimal clinical response. Br J Diabetes Vasc Dis. 2004;4:173-178. |
Yes |
|
Primary outcomes did not agree with protocol | |
|
Mathew NT et al. Efficacy of gabapentin in migraine prophylaxis. Headache. 2001;41:119-128. |
Yes |
|
Wang PW et al. Gabapentin augmentation therapy in bipolar depression. Bipolar Disord. 2002;4:296-301. |
Yes |
|
Yes | |
|
Yes | |
|
Gorson KC et al. Gabapentin in the treatment of painful diabetic neuropathy: a placebo-controlled, double-blind, cross-over trial. Neurology. 1998;50(suppl 4):A103. |
Yes |
|
Wessely P et al. Preliminary results of a double-blind study with the new migraine prophylactic drug gabapentin. Cephalalgia. 1987;7(suppl 6):477-478. |
No |
|
No | |
|
No | |
Other scientifically unsound behavior included the failure to differentiate between primary and secondary outcomes (2 trials), the relegation of primary outcomes to secondary outcomes (2 trials), and the failure to report 1 or more protocol-defined primary outcomes (5 trials). The Hopkins investigators found that trials with statistically insignificant primary outcomes were more likely to be partially reported or reported with a changed primary outcome.
The internal documents were made available to the Hopkins researchers as a result of ongoing litigation regarding the improper marketing of gabapentin. The anchor author of the analysis (Kay Dickersin, PhD) has served as a paid expert witness in litigation related to gabapentin clinical trials, and the lead author (S. Swaroop Vedula, MD) has received fees from plaintiffs' lawyers.
A study published earlier this week, in the Annals of Family Medicine, revealed that the primary outcomes of randomized studies published in 5 highly regarded journals (including the NEJM), were often changed from those defined in the trials' registry listings. The original primary outcomes of the gabapentin trials were only known through access to internal documents. Dickersin argued to MedPage Today that public registration of industry-sponsored trials should be mandatory to aid the transparency of these clinical studies.
N.B.--In 2004, Pfizer paid a $430-million fine to the government for the off-label marketing of gabapentin (ie, Neurontin).
* Without a darned-good reason.
A brief history of the direct-to-consumer (DTC) ad biz for prescription drugs, provided today by NPR's "Morning Edition," requires the following contextual notes—largely because the piece falsely implies that DTC advertising is responsible for escalating healthcare costs.
- While the estimated, annual spend on DTC advertising for prescription drugs is approximately $4 billion (according to most sources), the DTC spend has actually been decreasing since 2006 (from a peak of $5.4 billion). One pundit predicts that the total dollars dished out for DTC ads this year will shrink by 11%. The prevailing speculation for the trend: general economic constraints. Clearly decreases in DTC spending do not parallel steadily increasing healthcare costs, including costs for prescription drugs (see item 2).
- While prescription drugs (along with "nondurables") are, in fact, the third most costly aspect of the US healthcare system, they account for only about 12% of the overall healthcare spend (and are arguably one of the most cost-effective aspects of healthcare). In 2006, the spend on outpatient care was $850 billion (~41% of overall costs), and that on inpatient care was $458 billion (~22%), according to the McKinsey Global Institute. From 2003 to 2006, the costs for outpatient care, inpatient care, and drugs grew annually at rates of 7.5%, 6%, and 6.9%, respectively. The rise in prescription drug costs is due "almost equally" to an increase in consumed drug volume and a rise in drug costs. These increases have been offset, however, by "a [small] trend toward a less expensive drug mix."
- While it is generally quoted that Americans received an average of 12 prescriptions in 2008,* they use approximately 10% fewer drugs (on a per capita basis) than Europeans and Australians—again according to the McKinsey Global Institute. Prescription drug prices in the United States are about 50% higher than those for Europeans. (Notably branded drugs for Americans are about 77% more expensive, but US generic drugs are about 11% cheaper.) The higher cost of prescription drugs for Americans is due to the use of a more expensive "drug mix"** and higher drug prices. It is generally believed that higher US drug prices subsidize pharmaceutical R&D for the world; however, the R&D subsidy does not sufficiently explain the higher costs of branded drugs for Americans.
* Note that this statement does not indicate that Americans consume 12 prescription drugs simultaneously on a regular, daily basis.
** Although there is a small trend among Americans toward a less expensive drug mix (see item 2).
Image of Novartis's now-defunct Digger the Dermatophyte for Lamisil: Not just responsible for toenail fungus, according to NPR.
