December 2009 Archives
No. 1: Pandemic H1N1
You were expecting something else?
Coming out of left field (ie, Mexico)* in April, the novel 2009 H1N1 ("swine flu") virus caused an official global pandemic in June, according to the World Health Organization. Cases mounted rapidly, but fear of disease was mitigated by its relatively low mortality rate.** Drawing on their experience from the swine-flu epidemic of 1976, leading US neurologists first believed that a government-led vaccination campaign would be unlikely because of 1) low mortality and 2) the possibility of vaccine-associated Guillain-Barre syndrome (GBS). Boy, were they wrong.
In August, the CDC released its recommendations for the administration of developing H1N1 vaccines to 5 groups. The surprise: Instead of the historically targeted elderly, the CDC prioritized vaccination for children, young adults, and pregnant women because of their emerging risks of disease-related complications and death. Consequently vaccination was recommended for an estimated 159 million Americans as soon as vaccines became available, sometime in mid-October.
In May, the DHHS had contracted with 5 companies—CSL Biotherapies, GSK, MedImmune, Novartis, and sanofi-pasteur—to produce either injectable or nasally administered vaccines for pandemic H1N1 to the tune of $932 million. Government orders for another $883,977,920 and $438,143,025 were placed in July and September, respectively. The total amounted to about 9 bucks per vaccine, which was being produced by the traditional method of viral incubation in fertilized chicken eggs.
This tried-and-true method ultimately led to a delay in vaccine production for 2 primary reasons: the fastidious nature of the 2009 H1N1 virus (when compared with seasonal influenza viruses) and limited chicken eggs. Turns out the pandemic virus required 2 eggs to create a single vaccine dose, instead of the usual one. By October, the federally contracted companies had only cranked out about 10% of the promised 120 million vaccine doses for US residents. Time was a-wastin'.
In October, the CDC investigators estimated that about 3 million citizens had already experienced symptomatic pandemic flu between April and July, on the basis of a probabilistic model. Confirming previous assessments, the incidence of disease and disease-related hospitalizations were considerably higher in children and young adults. Pandemic flu, overall, had necessitated about 14,000 hospitalizations and had caused about 800 deaths in the United States.
The following month, the CDC estimated that up to 34 million Americans had been infected between April and mid-October. Respective hospitalizations and deaths now ranged from 63,000 to 153,000 and from 2500 to 6000. Another age breakdown revealed that disproportionate numbers of younger adults (and to a lesser extent, children) remained susceptible to pandemic flu generally and severe disease specifically. About 45% of Americans who had died from pandemic flu had been healthy.
And then disease began to wane. Earlier this month, only 25 states reported widespread activity. At the same time, data showed that the pandemic flu vaccines (the supplies of which were up) remained effective and were comparably safe. Specifically the risk of GBS appeared no higher than the typical background rate.
The latest recommendations: More than 30 "major health care provider organizations," including the American Medical Association, the American Academy of Pediatrics, and the American Red Cross, are encouraging all US residents to receive a pandemic flu vaccine in anticipation of another wave of infection. An "open letter" to the American people states,
The H1N1 flu vaccine is safe, effective, and the best way to protect yourself and your family from the H1N1 flu. Over 110 million doses...are now available, with more coming every day. Now is the time to protect yourself and those around you by getting vaccinated against the H1N1 flu.
Links to selected Pathophilia posts on pandemic flu (and a few on seasonal flu) are provided here in chronological order.
* Instead of the historically expected East Asia.
** Estimated in the United States at 0.007%-0.032%.
Depiction of H1N1 virus from Wikipedia.
No. 2: US House and Senate Pass Their Respective Healthcare Reform Bills
They said it couldn't be done, and they might still be right; but with a strong administrative push to reform America's sickly healthcare system, both the House and the Senate passed their respective bills this year. To the tune of more than $1 trillion in anticipated costs, the House measure narrowly passed on November 7. The price tag for the Senate bill, which ultimately prevailed on Christmas Eve, is a relative bargain at $871 million. The major difference between the two bills: the creation of a new government (ie, public) insurance plan, which the House bill stipulates.
Not much posting here at the Pathophilia blog about healthcare reform, largely because the topic seemed like such a complicated mess. The New York Times is the recommended go-to source, however. Among the paper's many useful features on the subject is a comparison of the proposed bills, an abbreviated version of which is tabulated here.
|
Bill Feature |
House |
Senate |
|
Mandates minimum-level health insurance, with penalties for uninsured |
Yes |
Yes |
|
Requires most employers to contribute to coverage for employees, with penalties for not complying |
Yes |
Sort of |
|
Creates insurance "exchange," or competitive insurance marketplace, for individuals and employers |
Yes [a] |
Yes [b] |
|
Creates new government (ie, public) insurance plan |
Yes |
No |
|
Subsidizes (ie, provides tax credits to) low- or middle-income persons to buy insurance |
Yes |
Yes |
|
Subsidizes small business to provide employee insurance |
Yes |
Yes |
|
Expands Medicaid |
Yes |
Yes |
|
Defines minimum allowable insurance package |
Yes |
Yes |
|
Prohibits denial of coverage owing to preexisting conditions |
Yes |
Yes |
|
Requires plans to offer coverage for dependents up to at least 25 years of age |
Yes |
Yes |
|
Creates voluntary federal disability-insurance program |
Yes |
Yes |
|
Requires coverage for abortion |
No |
No |
|
Allows illegal immigrants to buy exchange plans |
Yes [c] |
No |
|
Eliminates Children's Health Insurance Program (CHIP) |
Yes [d] |
No [e] |
a. At national level.
b. At state or regional level.
c. But not eligible for federal subsidies.
d. Coverage now through Medicaid or national insurance exchange.
e. Would extend CHIP.
The House's reform would be supported by new taxes on medical devices and individuals with very high incomes (eg, >$500,000). The Senate would levy a hefty tax on high-premium group-health plans and charge annual fees to drug, device, and insurance companies. Both bills would attempt to "squeeze" hundreds of billions of dollars out of Medicare by restricting its growth.
To my knowledge, neither bill proposes cost savings through the use of information technology (IT)—which is probably wise. Harvard researchers recently concluded that IT doesn't reduce hospital costs.
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. 4: Medical Science Crawls Toward an HIV Vaccine
In October, peer-reviewed results of a mammoth Thai trial (>16,000) showed modest (and possibly statistically significant) protection against HIV infection after a series of shots in moderate-risk adults. The trial results, although only marginally positive, are generating optimism after 2 decades of failure and, specifically, 3 negative trials (published in 2005, 2006, and 2008) of assorted vaccine regimens in high-risk adults.
In the latest placebo-controlled Thai study, vaccine efficacy—defined as the percentage reduction of HIV infection—climbed to a significant 31.2% in the modified intent-to-treat analysis.* Compare this value with the highest estimated vaccine efficacy in the previous large-scale studies, only 6%, and you get an idea of why some investigators believe that we're actually getting somewhere.
The trial's vaccine regimen consisted of 4 "priming" injections of a recombinant canarypox-vector vaccine (Alvac-HIV; sanofi-pasteur) and 2 booster shots of a recombinant glycoprotein-120 subunit vaccine (AIDSVAX B/E; VaxGen). The prime-boost vaccination series was chosen on the basis of previous trials (Belshe et al, 1994; Russell et al, 2007; and AIDS Vaccine Evaluation Group 022 Protocol Team, 2001), wrote the study investigators. Previously unsuccessful vaccine regimens in high-risk adults consisted of 7 injections of VaxGen's AIDSVAX B/B vaccine; 7 injections of VaxGen's AIDSVAX B/E vaccine; and 3 injections of Merck's trivalent adenovirus-vector vaccine.
The next steps are to determine the immune mechanisms that conferred protection in the Thai trial and to create a vaccine that will maximize those responses.
HIV = human immunodeficiency virus.
* Which excluded 7 individuals who were discovered to have HIV infection at baseline.
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."
No. 6: Big Trouble in the AD Pipeline
First suggested by last year's news, targeting amyloid buildup in the brains of people with Alzheimer disease doesn't seem to be the way to go.
In April, Elan and codeveloper Wyeth (now a part of Pfizer) announced that the highest dosage of bapineuzumab, an anti-amyloid mAb that Elan sold to JNJ in September,* would be discontinued in ongoing phase 3 trials. The reason: vasogenic brain edema in phase 2 assessment.
The peer-reviewed, phase 2 dose-ranging trial,* which was finally published in Neurology in September, revealed vasogenic edema in nearly 10% of bapineuzumab-treated enrollees with mild-to-moderate AD (n = 12/124). Vasogenic edema, possibly due to the effect of bapineuzumab on perivascular amyoid, was dose-dependent and more common in subjects who were ApoE4 carriers. Moreover, data supporting the efficacy of the drug were underwhelming, despite manipulation of the primary outcome and the use of a modified population for analysis. The authors concluded that the "trial provides insufficient evidence to support or refute a benefit" of bapineuzumab. Nevertheless, phase 3 study of the drug continues.
Then, 2 short weeks ago, Elan announced the deaths of 9 subjects in a company-sponsored phase 2 trial of another AD drug candidate, scyllo-inositol. The cause or causes of the deaths were not provided, but Elan (along with codeveloper Transition Therapeutics) discontinued the highest-dosage arms (1000 and 2000 mg bid) in development. All that's left now is the hope of blocking the accumulation of soluble amyloid plaques with a measly 250 mg of scyllo-inositol twice daily.
mAb = monoclonal antibody.
* JNJ bought Elan's AD immunotherapy program for $1.4 billion.
** The phase 2 results were originally made public in Elan's less-than-candid July 2008 press release, which the SEC is investigating.
Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.
No. 7: Pinning Down the Risk of PML With Tysabri
So do the benefits of Tysabri (natalizumab; Biogen Idec/Elan) in MS still outweigh the potentially deadly risk of progressive multifocal leukoencephalopathy (PML)?
Uh, probably. But as they say: Axe your doctor.
Head-to-head data with the standard treatment of interferon beta don't exist; but if we're using the common benchmark of placebo treatment,* the monoclonal antibody reduces the risk of clinical relapses by about 70% at 1 year. The interferon betas are about half as good.
At last count (October), there were 24 cases of PML linked to Tysabri since the drug's reintroduction into the marketplace in 2006, said the European Medicines Agency. But the risk of PML appears to depend on the length of therapy—an issue addressed in September by Shirley Wang of the WSJ.
According to Biogen Idec, the absolute risk of PML with Tysabri is 0.01%. However, the risk appears to increase with prolonged therapy (eg, >12 months)—which necessitates the use of an actuarial calculation, argued Wang and Cleveland Clinic neurologist Robert Fox in the WSJ. Wang calculated the actuarial risk of Tysabri-related PML at about 0.08%, and Fox reported a PML risk of more than 0.1%, when therapy extends beyond 30 months. The increased risk of PML with prolonged therapy has led some neurologists to advocate the use of so-called drug holidays; although data to support their use are lacking.
The risk of subclinical PML with Tysabri therapy appears to be substantially higher. In September, the NEJM published a study by Chen et al, who detected a significant rise in titers of JC virus, the cause of PML, among 19 MS patients after 1 year or longer of therapy. (The same NEJM issue also offered 2 case reports of attempted, and reasonably successful, therapy for PML.)
A quantitative risk-benefit analysis, published last year in Neurology, indicated that the "actual" risk of PML with Tysabri would have to increase more than 7 times to reduce the relative benefit of therapy below that of interferon beta. (The authors used an annual PML risk that was based on the published risk estimate of 1 per 1000 patients treated for an average of 17.9 months.)
The flagship organization for US neurologists, the American Academy of Neurology, provided its most recent recommendations for the use of Tysabri in MS last year. Because of the associated risk of PML, the AAN recommended that the drug be reserved for selected patients who are intolerant of other therapies (eg, interferon beta or glatiramer acetate [Copaxone; Teva]) or whose disease is unresponsive to other therapies.
This month, the journal Multiple Sclerosis printed a company-sponsored supplement, defining "best practice recommendations" for the use of Tysabri. The 6-member panel, which was selected by Biogen Idec and led by neurologist Patricia Coyle, encouraged the "earlier and more rapid transition from first-line treatment to Tysabri." Editorial support for the supplement was provided by The Falk Group, LLC, a pharmaceutical marketing and advertising agency—a fact that doesn't necessarily negate the supplement's recommendations but makes their objectivity suspect.
In the meantime, the SEC is investigating Elan for its filing dated July 31, 2008, in which the company described 2 European patients with MS who developed PML after prolonged Tysabri monotherapy. The reason for the SEC's investigation of this particular filing remains unclear.
* Which is, admittedly, problematic.
No. 8: The Approval Race for an MS Pill
In 2009, Novartis and Merck Serono became the main contenders to market the first-ever pill for relapsing-remitting multiple sclerosis (RRMS).
Aaaaand they're off. Quickly way out, in the middle of the track, Merck Serono takes the early lead.
In January, Merck Serono described favorable 2-year data from an extension phase of its placebo-controlled phase 3 study (CLARITY) of an oral form of cladribine.*
He's challenged on the outside by Novartis, as they race into the turn.
Several months later, Novartis announced positive data from its phase 3 study, in which the novel oral agent, fingolimod, outperformed the standard treatment (not placebo) of IM interferon beta (Avonex; Biogen Idec).
Novartis moving up on Merck Serono as they round the turn.
In August, the FDA announced the approval of Novartis's copycat version of Betaseron (interferon beta-1b; Bayer Schering) for RRMS. Approval came by way of an intricate manufacturing deal with Bayer Schering that began 2 years ago and was apparently intended to prime Novartis's sales team in the MS market.
In the stretch. It's Merck Serono still in front. Merck Serono by a length and a half.
In October, Merck Serono announced its NDA submission for the fast-track approval of oral cladribine for RRMS.
But here comes Novartis on the outside. Novartis comin' after him.
The same day, Novartis announced positive data from its 2-year placebo-controlled phase 3 study of fingolimod in more than 4000 individuals with RRMS (FREEDOMS).
Also getting involved is Teva and Biogen Idec, and looking for a hole on the inside is sanofi-aventis.
Other novel oral compounds in late-stage development for MS include Teva's laquinimod, Biogen Idec's dimethyl fumarate, and teriflunomide from sanofi-aventis.
Oh, going down now, going down, Merck Serono. Merck Serono takes a spill.
In December, the FDA announced that it refused to file Merck Serono's NDA for oral cladribine, probably on the basis of an incomplete application. The company said that it would request a meeting with the FDA to understand any deficiencies in its application.
Novartis had previously announced that it would file its NDA for fingolimod by the end of the year, but it doesn't look like that's going to happen.
The race isn't over.
CLARITY = Cladribine Tablets Treatment MS Orally; FREEDOMS = FTY740 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis; NDA = new drug application.
* Cladribine, a purine analog, has been marketed as the injectable Leustatin [Ortho-Biotech] since 1993 for hairy cell leukemia.
No. 9: Belimumab Buzz
There were few notable FDA approvals for "new molecular entities" (NMEs) in 2009:
- Urolic (febuxostat; Takeda) is the first new treatment for gout in more than 40 years. (But come on: it's gout.)
- Simponi (galimumab; Centacor/Ortho Biotech) is yet another TNF inhibitor for rheumatoid arthritis.
- Effient (prasugrel; Lilly) is an antiplatelet therapy poised to take market share away from chemically related Plavix (clodigrel; BMS/sanofi-aventis)—but only in the setting of angioplasty and stent placement.
- Sabril (vigabratin; Lundbeck) is the first anticonvulsant approved for the treatment of infantile spasms, a rare and devastating form of pediatric epilepsy.
And there were drugs approved for even rarer disorders: Ilaris (canakinumab; Novartis), for the cryptic cryopyrin-associated periodic syndromes; and Kalbitor (ecallantide; Dyax) for hereditary angioedema. Add to those: approvals for yet another statin, another fluoroquinolone, another antidiabetic agent...and you get the idea of the ho-hum-ness of 2009.
In pharma, expectations currently run low for groundbreaking treatments, whether for rare or common disorders. One exception, however, may be Benlysta (belimumab). The human monoclonal antibody, codeveloped by Human Genome Sciences and GSK, inhibits the activity of B-lymphocyte stimulator (BLys), which otherwise promotes the survival of antibody-producing B cells. The drug's mechanism of action supports its use in autoimmune disorders, like systemic lupus erythematosus (SLE).
To that end, favorable data from 2 phase 3 trials of Benlysta (BLISS-52 and BLISS-76) in patients with SLE were reported in July and November. The positive clinical data are notable, because there hasn't been a new treatment for the 1.5 million Americans with lupus in about 30 years, says the Lupus Foundation of America. Even the almighty Rituxan (rituximab; Genentech/Roche) bit the dust this year in phase 3 studies of patients with SLE. And another great hope for SLE, CellCept (mycophenolate mofetil; Roche), died a death of noninferiority after it performed no better than cyclophosphamide for the induction treatment of lupus nephritis.
Excitement over Benlysta should be tempered, however, by the fact that neither phase 3 study has been published in a peer-reviewed journal—yet. Human Genome Sciences indicates that applications for the approval of Benlysta in the United States and Europe will be submitted during the first half of 2010.
TNF = tumor necrosis factor.
Another Winter Solstice, another anniversary for the Pathophilia blog. Today marks 2 years of up-and-running blog time, which is 3½ years in Hollywood-marriage time.
And because anniversaries and a closing year prompt reflection, here are Pathophilia's top 10 stories for the year in medicine, pharma, and film noir on DVD. (Ho-ho-ho! So rare that I get to use the blog's strikeout feature as lame joke.)
No. 10: More Dumping on Merck's Vytorin, Zetia
The year began with continued debate (to put it nicely) about how to assess emerging cancer data from clinical trials of the anti-cholesterol combo drug Vytorin (ezetimibe/simvastatin; Merck). (For lots of necessary background, start at last year's No. 6 story.)
In a Smackdown: New England-Style, prominent cardiologist Steven Nissen essentially charged Sir Richard Peto and his colleagues with unethical behavior, when they separately analyzed cancer data from the SEAS trial (which suggested an increased drug-related cancer risk) and data from the ongoing SHARP and IMPROVE-IT studies (which did not). Nissen believed that data from all 3 studies should have been combined for the analysis (which would have affirmed a cancer risk); but Peto, a statistician and epidemiologist, stressed the importance of separating data in a hypothesis-generating study (eg, the SEAS trial) from data in hypothesis-testing studies (eg, SHARP and IMPROVE-IT). His analysis did not indicate an increased cancer risk with the drug.
At the same time, the FDA attempted to quell some of the anti-Vytorin sentiment and downright company-directed schadenfreude caused by the delayed results of 2008's troubled ENHANCE study. (And if you still don't know what the ENHANCE study is, go back to last year's No. 6 story.) The agency emphasized the importance of lowering the LDL cholesterol level (which Vytorin does) to reduce cardiac risks, like MI. The FDA also weighed in on why the ENHANCE study did not show a reduction of another surrogate marker for vascular disease, CIMT, with the addition of ezetimibe to simvastatin. Speculation included the selectiveness of the study population.
Months later, an Abbott-sponsored phase 4 trial (ARBITER 6-HALTS), which pitted the company's Niaspan (extended-release niacin) against Zetia (the ezetimibe half of Vytorin) was terminated early—and not because of safety concerns. The Street speculated that Abbott's drug had outperformed Zetia in the open-label study of high-risk adults. The Street was right.
At the Scientific Sessions of the American Heart Association in November, results of ARBITER 6-HALTS showed that Niaspan outperformed Zetia in 5 of 7 outcomes, including a composite clinical outcome. Many media reports played up Niaspan's effects on CIMT at the expense of Zetia, while downplaying tolerability issues (eg, flushing) and the fact that the study population was small (N = 208) and selective: enrollees were statin-treated adults who had already attained target LDL levels (<100 mg/dL) and had moderately low HDL levels. Niaspan in such patients would be expected to elevate HDL, and Zetia would be expected to further lower total cholesterol and LDL levels—which is what the investigators found.
Relatively minimal attention was given to another small placebo-controlled study of extended-release niacin, also presented at the AHA sessions, in which changes in carotid-wall plaque (via MRI) were comparable in the 2 treatment groups.
Merck's Zetia/Vytorin-related troubles, vis-a-vis 2-plus years of media coverage, were epitomized in an end-of-year article by Forbes reporter Matthew Herper—who showed his continued disdain for the drugs and their marketing in a less-than-objective synopsis of results from relevant clinical trials.
Herper and others like him have 2 more years to capitalize on the controversies surrounding Zetia and Vytorin. At that time, results of the long-running IMPROVE-IT study, in which Vytorin is compared with simvastatin monotherapy in at-risk adults, will be available. The primary and major secondary endpoints in this study aren't surrogate markers, like LDL and CIMT, but actual clinical events.
ARBITER 6-HALTS = ARterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 - HDL and LDL Treatment Strategies in Atherosclerosis; CIMT = carotid intima-media thickness; ENHANCE = Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia; HDL = high-density lipoprotein; IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL = low-density lipoprotein; SEAS = Simvastatin and Ezetimibe in Aortic Stenosis; SHARP = Study of Heart and Renal Protection.
Public-domain image of Hamilton-Burr duel, which admittedly took place in New Jersey (not New England), from Wikipedia.
12/22/09 update: The FDA says it's "unlikely" that Vytorin and Zetia increase the risk of cancer; although the agency can't rule out the possibility, according to today's WSJ. The agency's announcement comes after its own review of cancer data from the SEAS trial.
From 2002 to 2006, the prevalence of autism spectrum disorders (ASDs) increased significantly among 8-year-old American boys and girls.* This conclusion is based on a newly published, retrospective review from the CDC's Autism and Developmental Disabilities Monitoring (ADDM) Network. The CDC investigators ascribe the increased prevalence of ASDs to improved recognition and documentation, but they cannot dismiss a concomitant "true" increase in ASDs.
On the basis of an examination of health and education records at 11 US sites participating in the ADDM Network, the average prevalence of ASDs among 8-year-olds in 2006 was 9.0 per 1000 children (range, 4.2-12.1), or nearly 1%. Among the 10 US sites that provided data for both 2002 and 2006, the overall prevalence of ASDs increased significantly, by 57%. This finding contrasts with a comparison of data from 2000 and 2002, which revealed no significant increase in the overall prevalence of ASDs.
Below are the tabulated prevalence values for ASD at the 10 common sites, stratified by sex, ethnicity, and IQ. These data show consistent across-the-board increases in ASD among the assessed pediatric subgroups.
|
Group |
ASD Prevalence, |
Statistically Significant Increase, % | |
|
2002 |
2006 | ||
|
Overall |
6.0 |
9.4 |
57 |
|
Boys |
9.5 |
15.2 |
60 |
|
Girls |
2.3 |
3.4 |
48 |
|
Non-Hispanic white children |
6.6 |
10.2 |
55 |
|
Non-Hispanic black children |
5.4 |
7.6 |
41 |
|
Hispanic children |
3.2 |
6.1 |
91** |
|
IQ ≤70 |
2.6 |
3.5 |
35 |
|
IQ 71-85 |
1.0 |
1.4 |
90 |
|
IQ >85 |
1.8 |
3.1 |
72 |
The CDC investigators note that the average prevalence of ASDs was higher at sites that had access to health and education records (10.0) than at sites with only health records (7.5). This observation suggests that more opportunities for ASD documentation increase the prevalence of the condition (artificially). Investigators also found that, generally, ASDs were recognized at younger ages in 2006 than in 2002. (And if I'm correctly reading the CDC data, they indicate that significantly more children with below-normal IQs are being classified as having ASDs—a phenomenon that may also explain an increased prevalence of ASDs.)
Most of the children identified as having ASDs in 2006 (70%-90%) displayed developmental problems (eg, language delay) before the age of 3 years; however, the average age at diagnosis was considerably later, at about 4½ years (suggesting lost time for crucial behavioral interventions). In 2006 assessment, most 8-year-olds with ASDs (76%-96%) were receiving special education through public-school programs, under a wide variety of rationales (eg, autism, emotional disturbance, learning disability, language impairment, etc).
The CDC advises that the ADDM Network surveillance sites were selected "on the basis of their ability to conduct active ASD records-based surveillance," and were not intended to be a nationally representative sample. However, the Network accessed the records of more than 300,000 children, representing nearly 8% of all 8-year-olds in the United States.
Data supporting the approximate 1% prevalence of ASDs include a 2007 parent survey and several contemporary international studies, says the CDC.
* ASDs are defined on the basis of documented behaviors consistent with the DSM-IV-TR criteria for autistic disorder; pervasive development disorder, not otherwise specified; and Asperger disorder. The age of 8 years is identified as a "reasonable index age at which to monitor peak prevalence for ASDs." ASD symptoms are usually observed before the age of 3 years.
** The whopping increased prevalence of ASDs in Hispanic children is attributed to the increase in the Hispanic population overall and a prevalence increase of 144% in Arizona. The other Network sites did not reveal an increased prevalence of ASD among Hispanic children.
Unexplained bone-marrow failure (ie, agranulocytosis) in residents of New Mexico, Washington, and Canada led to the discovery of levamisole, an antiparasitic antibiotic, as a prevalent cutting agent in cocaine. A report of the investigation by public health officials, which began last year and identified 21 affected Americans, is available in the latest issue of MMWR.
According to the report, levamisole, as a treatment for rheumatoid arthritis or breast cancer, causes agranulocytosis in 2.5%-13% of patients; however, use of the drug is currently and primarily restricted to veterinary practice (eg, to deworm livestock and aquarium fish).
As of July of this year, about 70% of seized cocaine entering the United States contained levamisole, according to the DEA. The concentration of the additive is approximately 10%, says the agency. Given these statistics, MMWR editors suspect that levamisole-associated agranulocytosis due to cocaine use is vastly underrecognized and underreported.
The reason why levamisole, in particular (versus, say, Italian baby laxative a la Atlantic City) is added to cocaine "remains unclear." Online sources indicate that the antibiotic is a white- to pale cream-colored, odorless or nearly odorless, crystalline powder.
According to the SF Chronicle, by way of Wikipedia, levamisole and cocaine were detected in the body of DJ AM.
A novel, online tool that estimates the 90-day risk of recurrent stroke has been created by investigators at the Massachusetts General Hospital. The tool is based on the retrospective review of clinical and MR data from more than 1400 consecutive patients presenting with a stroke to the center. The methods used to develop the tool are available in an advanced online publication of Neurology.
The tool provides weighted scores for features on a patient's brain MR images (if obtained within 72 hours of stroke onset) and those for the apparent cause or causes of the index stroke.
|
Independent Variable |
Score |
|
MR imaging data |
|
|
Multiple infarcts of different ages |
1 |
|
Simultaneous infarcts in different circulations |
1 |
|
Multiple acute infarcts |
1 |
|
Isolated cortical infarcts |
1 |
|
History of TIA or stroke within previous month |
1 |
|
Causative classification of stroke on admission |
|
|
Large-artery atherosclerosis |
2 |
|
Cardio-aortic embolism |
2 |
|
Small-artery occlusion |
0 |
|
Other cause(s) |
3 |
|
Undetermined cause(s) |
1 |
The cumulative score is then correlated with an estimated 90-day risk of recurrent stroke on the basis of whether MR imaging data are available. (The validity of the risk estimate appears to be more robust if early MR data exist.)
|
Total Score |
Estimated Risk of Recurrent Stroke Within 90 Days, % | |
|
No 72-Hour MR Data |
72-Hour MR Data Available | |
|
0 |
1.1 |
0.7 |
|
1 |
3.4 |
3.9 |
|
2 |
5.9 |
4.2 |
|
3 |
19.1 |
27.3 |
|
4-6 |
45.3 |
38.8 |
The authors note that models currently available to estimate the risk of recurrent stroke, like the Stroke Prognosis Instrument II and the Essen Stroke Risk Score, are "designed to assess long-term risk [2 and 1 years, respectively] and have not been validated for short-term risk prediction." These longer-term models also use clinical factors, like hypertension and diabetes, that don't appear to influence the risk of recurrent stroke during the immediate 90-day post-event period.
Because most stroke patients will not sustain a recurrent ischemic event, the authors argue, a tool that identifies higher-risk patients will enable the directed use of timely, preventive therapies.
Caveats for using the model are provided in the article and an accompanying editorial ("Here comes the sun?"). Notably the number of identified recurrent strokes in the retrospective study was small (60), which limits the predictive power of the tool. The online accessibility of the tool, however, should facilitate its use and real-world validation. If, in fact, the tool is predictive, it should aid the assessment of short-term stroke therapies, like various forms of anticoagulation.
MR = magnetic resonance; TIA = transient ischemic attack.
Image of MR machine from NIH's Stroke: Challenges, Progress, and Promise.
After 13 years as the number-one prescription treatment for Alzheimer disease, Aricept—a branded cholinesterase inhibitor that generated nearly $1.9 billion in US sales this year for its Japan-based developer Eisai and US comarketer Pfizer—is now (officially) available generically in the United States.
Yesterday the FDA announced the approval of a generic formulation of Aricept (or more correctly, donepezil) in orally disintegrating tablets. The generic manufacturer is the privately owned Mutual Pharmaceutical (URL Pharma), which will produce the drug in 5- and 10-mg strengths.
Other branded, FDA-approved treatments for AD include the NMDA-receptor antagonist memantine (Namenda; Forest) in tablets or solution and the cholinesterase inhibitors galantamine (Razadyne; Ortho-McNeil) in extended-release capsules, tablets, or solution and rivastigmine (Exelon Patch; Novartis). The patent for galantamine, originally marketed as Reminyl in the United States, expired in December 2008, and the drug is available generically in its various formulations.
According to the FDA's Orange Book, the following patent and exclusivity expirations apply to Namenda and Exelon*:
|
Drug |
FDA Approval |
Patent Expiration |
Exclusivity Expiration |
|
Namenda tablets |
Oct 16, 2003 |
Apr 11, 2015 |
Oct 16, 2008 |
|
Namenda solution |
Apr 18, 2005 |
Apr 11, 2015 |
Oct 16, 2008 |
|
Exelon patch |
Jul 6, 2007 |
Aug 14, 2012 |
Jul 6, 2010 |
(Differences between a drug's patent and exclusivity are explained by the FDA here.)
On November 24, Eisai announced that the FDA accepted for review its NDA supporting the use of a 23-mg extended-release tablet version of Aricept in AD. The NDA is based on a head-to-head study (N > 1400) between the new formulation and the old Aricept 10-mg tablet. This study, apparently, has not been published yet in a peer-reviewed journal. In its 2009 report, Eisai also reveals that it is developing transdermal patch and jelly formulations of Aricept.
Very recent controlled studies of immediate-release Aricept in patients with amnestic mild cognitive impairment (aMCI) suggest that the drug delays the progression to AD among depressed individuals, but Aricept had only a modest effect on cognition in a more inclusive population with MCI.
NDA = new drug application; NMDA = N-methyl-D-aspartate.
* Rivastigmine is generically available in capsules; however, this formulation is no longer marketed by Novartis. It is also reported that Forest applied for a "patent term restoration" for Namenda, which would extend protection until September 2013.
Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.
Nine deaths in an Elan-sponsored phase 2 trial of oral scyllo-inositol (aka ELND005 or AZD-103) in Alzheimer disease have led to the discontinuation of the highest-dose arms in clinical development. The cause (or causes) of the deaths was not provided in today's company press release or by news sources, like Reuters. The investigational drug is intended to prevent the buildup of amyloid in the brains of AD-affected patients.
According to the NIH registry, the trial (which is conducted in collaboration with Transition Therapeutics) is a randomized, double-blind, multicenter US and Canadian study that was comparing 3 doses of the experimental agent with placebo in more than 300 individuals with mild-moderate AD.* Elan states that the study completed enrollment in October; the study duration is 18 months (with results anticipated in May of next year, according to the NIH database). The discontinued dosages are 1000 and 2000 mg bid in both the blinded, phase 2 study and an open-label trial. All patients assigned to scyllo-inositol treatment will now receive the lowest dosage, 250 mg bid.
In August, Elan and Wyeth announced that the highest dosage of its anti-amyloid mAb, bapineuzumab, would be discontinued in 2 ongoing phase 3 studies of ApoE4 noncarriers (40%-70% of AD patients), because of the risk of vasogenic edema.
In September, JNJ closed its highly publicized buyout deal with Elan, in which JNJ acquires the rights to Elan's AD immunotherapy program (which Elan shared with Wyeth). The program includes the development of bapineuzumab but not scyllo-inositol.
A couple of previous Pathophilia posts about Elan's troubles:
mAb = monoclonal antibody.
* Approximately 353, per Elan.
Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.
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.
The estimated mortality rate of pandemic influenza in England is 0.026% (case fatality rate, 26 per 100,000), according to a report in this week's BMJ. This rate is similar to the mid-level US mortality rate that has been estimated by CDC officials.
Approximately 540,000 people (range, 240,000-1,100,000) have sustained symptomatic infection with pandemic influenza in England between June 1 and November 8 of this year, with 138 deaths meeting the described H1N1 case definition. Death rates appear to be highest for individuals aged 65 years or older and lowest for school-aged children and young adults. (By using midlevel estimates from the CDC, the case fatality rate for US individuals aged 65 years or older is substantially lower, at 32 per 100,000.)
|
Age Group, y |
Case Fatality Rate* |
Mortality Rate, |
|
<1 |
30 (2-260) |
0.030 |
|
1-4 |
27 (3-120) |
0.027 |
|
5-14 |
11 (3-36) |
0.011 |
|
15-24 |
12 (3-40) |
0.012 |
|
25-44 |
30 (10-88) |
0.030 |
|
45-64 |
64 (21-200) |
0.064 |
|
≥65 |
980 (300-3200) |
0.980 |
|
All |
26 (11-66) |
0.026 |
|
Age Group, y |
US Case Fatality Rate* |
US Mortality Rate, |
|
0-17 |
7 |
0.007 |
|
18-64 |
28 |
0.028 |
|
≥65 |
32 |
0.032 |
|
All |
21 |
0.021 |
As in the United States, there was no or only mild preexisting illness in about one third of England's fatal cases of pandemic flu. Most (78%) of these patients were prescribed antiviral drugs, but three quarters did not receive them within 48 hours of illness onset.
Despite England's relatively low mortality rate, the authors conclude that it "is not a justification for public health inaction." On the contrary, they argue, their data support expansion of the vaccination program to lower-risk groups [blogger's note: which evidently should include England's elderly] and the timely use of antiviral treatment.
* Deaths per 100,000 cases of pandemic influenza.
Depiction of H1N1 virus from Wikipedia.
The Racket (1951): Howard Hughes remakes his 1928 film of the same name, which was based on Capone-inspired play. (Unfortunately the earlier film, which is reportedly better, is not on DVD.) Certain aspects of the reworked plot don't make much sense, as commentator Eddie Muller (whose encyclopedic knowledge of film noir is just scary) admits; and Robert Mitchum pretty much phones it in as an incorruptible police captain. But Robert Ryan, as a snarly thug and the captain's longtime nemesis, is in usual top form. With an extremely laconic William Conrad as a corrupt cop and the husky-voiced Lizabeth Scott as a "tommy" "canary." Directed by, well, a number of people.
P.S. All physicians will have fun randomly quoting this line from Ryan's bully of a character: "Blow, shyster!"
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.
Nilotinib (Tasigna; Novartis) may be poised to become first-line treatment for Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia (CML), like its sister drug imatinib (Gleevec; Novartis). In a company-funded, open-label, randomized head-to-head phase 3 study, nilotinib treatment produced significantly higher major molecular response* (MMR) rates at 1 year than imatinib in patients with newly diagnosed Ph+ CML. Results of the study were presented Tuesday at the annual meeting of the American Hematology Society (ASH) in New Orleans.
In addition, nilotinib treatment was associated with significantly higher rates of a complete cytogenetic response (CCyR)—the absence of Ph+ cells in bone marrow. All-important survival outcomes were apparently not included in the study, which is ongoing. (Long-term [ie, 60-month] data for first-line imatinib in Ph+ CML indicate an overall survival rate of 89%.)
|
Outcome |
Nilotinib |
Nilotinib |
Imatinib |
|
MMR | |||
|
3 mo, % |
9 |
5 |
1 |
|
6 mo, % |
33 |
30 |
12 |
|
12 mo, % |
44 |
43 |
22 |
|
Overall, % |
57 |
54 |
30 |
|
12 mo in high-risk pts, % |
41 |
32 |
17 |
|
Complete cytogenic response (CCyR) | |||
|
By 6 mo, % |
67 |
63 |
45 |
|
By 12 mo, % |
80 |
78 |
65 |
|
Est. rate of progression to accelerated phase/blast crisis at 12 mo, % |
<1 |
<1 |
4 |
|
Discontinuation due to adverse events or lab abnormalities, % |
7 |
11 |
9 |
Both nilotinib and imatinib are designed to inhibit the tyrosine-kinase portion (ie, the working end) of the abnormal fusion protein, bcl-abl, which is characteristic of Ph+ CML; but nilotinib is a more selective inhibitor than imatinib.
According to the WSJ, Gleevec, which is currently approved for the first-line treatment of Ph+ CML, generated $3.7 billion in sales last year for Novartis. But the drug's patent will expire in 2015. Nilotinib, 400 mg bid, is currently approved for the treatment of chronic- or accelerated-phase Ph+ CML that is resistant to imatinib. The FDA's Orange Book indicates that the patent on nilotinib will expire in 2023. Treatment with either drug costs more than $40,000 per year.
Last month, Kareem Abdul-Jabbar announced that he was diagnosed with Ph+ CML in December of 2008. It has been inferred here that he is or has been treated with imatinib.
N.B.—Trial name is Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients, abbreviated ENESTnd.
* Defined by the elimination of bone-marrow cells that carry the disease-defining bcr-abl fusion protein.
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.
Lack of funds may stall the Measles Initiative, a multi-organization program designed to reduce the worldwide mortality of measles. Despite the fact that all regions, except for Southeast Asia, have achieved the United Nations goal of reducing measles mortality by 90% from 2000 to 2010 (and have, thereby, prevented 12.7 million measles deaths), the reduction in measles mortality has leveled off since 2007, and the Initiative is facing a funding gap of $59 million, reports the World Health Organization. (WHO's complementary report on the progress toward reducing measles-related deaths can be found in the latest issue of the MMWR.)
Lack of financial resources could suspend the Initiative's pivotal vaccination efforts next year in densely populated regions like China, Indonesia, Pakistan, Bangladesh, Vietnam, Nigeria, and Ethiopia. And because measles is highly contagious, the disease can flourish rapidly if immunity is lacking, report WHO officials.
Although measles-related deaths fell 78% globally, from 733,000 in 2000 to 164,000 in 2008, 77% of last year's deaths (126,000) occurred in Southeast Asia. Experts fear that there could be a significant uptick in measles-related deaths, to an estimated 1.7 million between 2010 and 2013, if vaccination efforts do not continue.
Estimated No. Measles Deaths, 2000-2008, and Projected Deaths, 2009-2013
§ 95% uncertainty intervals.
Vaccines for pandemic influenza appear to be as safe as current seasonal influenza vaccines, reports the CDC. The Center's preliminary assessment of safety reports from the US Vaccine Adverse Events Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) are available in the latest issue of the MMWR.
Data from VAERS*—which includes publicly volunteered information—reveal overall adverse-event (AE) rates of 82 per 1 million doses of pandemic flu vaccine (0.0082%) and 47 per 1 million doses of seasonal flu vaccine (0.0047%). Respective rates of serious AEs (eg, death, life-threatening illness, hospitalization, prolonged hospitalization, persistent or significant disability, congenital anomaly) are 4.4 and 2.9 per 1 million vaccine doses each. However, the percentage of serious AEs among all reports is slightly higher with seasonal flu vaccines (6.1% vs 5.4%). No substantial differences are noted between pandemic and seasonal flu vaccines in the types of serious AEs reported, and no AE differences between injectable and intranasal vaccines are apparent.
Among the 13 reported deaths of those who received the pandemic flu vaccine, 9 were associated with a "significant" underlying illness; 1 was the result of a motor vehicle accident; and 3 cases are under review by the CDC. There are 12 reports of Guillain-Barre syndrome (GBS), 4 of which currently meet diagnostic criteria, and 19 reports of possible anaphylaxis. (The background incidence of GBS is 1-2 per 100,000.)
In the VSD**—which includes data from more than 400,000 vaccinated individuals among 8 managed-care organizations—there are no reports of GBS and only 1 case of anaphylaxis. Increased rates of other neurologic or allergic conditions have not been detected.
Historically higher rates of GBS associated with the swine-flu vaccination in the mid-1970s may be related to contemporary methods of vaccine production, the CDC speculates. The Center reports that it continues to monitor vaccine-associated AE data and advises that the number of vaccines administered in the VSD population, in particular, may be too small as yet to detect an increased risk of vaccine-associated GBS.
As of December 3rd, more than 72 million doses of pandemic flu vaccine have been allocated in the United States.
N.B. The CDC states that it used a number of methods (eg, advertising in medical journals) to enhance the reporting of vaccine-associated AEs to VAERS this season.
* As of November 24, 2009.
** From October 1 to November 21, 2009.
Only 25 US states are reporting widespread activity of pandemic influenza, according to the latest update from the CDC. During the previous 3 consecutive weeks, widespread activity was reported in 46, 43, and 32 states. The CDC advises, nevertheless, that most indicators for flu activity remain higher than normal for this time of year.
As of December 3rd, more than 72 million doses of pandemic flu vaccine have been allocated (ie, ready for distribution) in the United States; more than 63 million have been shipped to ordering states or US territories. Approximately one half of the supplies have been allocated for 10 states.
|
State |
Doses Allocated as of 12/03/09 |
|
California |
8,296,500 |
|
Texas |
5,565,000 |
|
New York* |
4,536,300 |
|
Florida |
4,306,800 |
|
Pennsylvania |
2,544,500 |
|
Ohio |
2,672,100 |
|
Illinois |
2,422,300 |
|
North Carolina |
2,172,500 |
|
Michigan |
2,329,000 |
|
Georgia |
2,280,900 |
* Including New York City.
The Asphalt Jungle (1950): Longing to buy back his family's Kentucky horse farm, a "hooligan" (Sterling Hayden) joins a team-driven jewel heist in San Francisco. What could possibly go wrong?
With James Whitmore, a vulnerable Jean Hagen (Singin' in the Rain), and a young Marilyn Monroe. Directed by John Huston.
Perennial HT: KTG
Addendum: Well I thought it was San Francisco (maybe I recognized some exterior shots). But the movie apparently takes place in some nameless Midwestern city.
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.
In an effort to market the first FDA-approved oral treatment for multiple sclerosis, Merck Serono may have submitted an incomplete NDA for cladribine. The suggestion is provided by the consistently informative and entertaining* In Vivo Blog.
Although the FDA has not publicly addressed its refusal to file Merck Serono's cladribine NDA, the agency's John Jenkins, director of the Office of New Drugs, provides a hint, according to the blog. Yesterday, during the FDA/CMS Summit, Jenkins addressed the agency's refuse-to-file notifications and a primary reason for drawing them up.
Jenkins implicitly chastised pharma for submitting incomplete NDAs and then providing additional information during the drug-review process—which may require an extension owing to the lack of necessary data.** Jenkins reportedly said that pharma execs who delay the submission of an NDA to ensure its completeness will ultimately save themselves time.
NDA = new drug application; PDUFA = Prescription Drug User Free Act.
* Hey, In Vivo Blog, you can quote the flattery.
** And thereby violates the 6-month "PDUFA clock."
Fred Hassan, former CEO of the former Schering-Plough, believes that genomics will breathe new life into the pharmaceutical industry. His cheerleading prediction for how the study of the human genome will invigorate the flagging drug business, personalize healthcare, and extend lives is available at the HuffPo.
It's not an original thought, but Hassan (like the rest of us) recognizes that we're probably on the cusp of finally realizing tailored or boutique-style medicine. One case in point is the apparent, relative benefit and safety of the anti-amyloid bapineuzumab (JNJ; Wyeth) in individuals with Alzheimer disease who don't carry the ApoE4 allele.
In a more tangible way, genomics is informing the development of vaccines and the control of infectious diseases. In a recent PLoS review article ("The Key Role of Genomics in Modern Vaccine and Drug Design for Emerging Infectious Diseases"), Novartis employees describe how knowledge of pathogen and host genomes can be used to identify and select vaccine targets in a process known as reverse vaccinology.
As proof of this concept, the authors describe how whole-genome sequencing led to the identification of vaccine-candidate antigens against Neisseria meningitidis serogroup B. An 18-month analysis of the bacterial genome ultimately led to the identification of 570 genes that likely encoded surface-exposed or secreted proteins—more vaccine-candidate antigens than those discovered during 40 years of conventional analysis. Further antigen screening resulted in the development of a "multi-component" recombinant vaccine (Novartis's MenB vaccine), which is in phase 2/3 development.
The subject of hot partisan debate, the current version of the Senate healthcare reform bill, HR 3590 (the "Patient Protection and Affordable Care Act"), provides a much-needed and long-overdue financial incentive for primary care physicians to continue to offer primary care. In its present version, the proposed bill states,
In the case of primary care services furnished on or after January 1,
20012011, and before January 1, 2016, by a primary care practitioner, in addition to the amount of payment that would otherwise be made for such services under this part, there also shall be paid (on a monthly or quarterly basis) an amount equal to 10 percent of the payment amount for the service under this part.
The bill defines a primary care practitioner as 1) a physician who has a primary specialty designation of family medicine, internal medicine, geriatric medicine, or pediatric medicine,* and 2) a healthcare professional whose billed primary care services make up at least 60% of practice. (Primary care services, defined by CPT codes, are essentially all non-procedure-related services—ie, evaluation and management services.)
The problem with the current wording of the bill—as far as neurologists and their flagship organization, the American Academy of Neurology (AAN), are concerned—is that the primary care incentive omits neurologists: physicians whose practices, like those of traditionally defined primary care physicians, consist of substantial face-to-face time and care.
According to AAN officers in today's member teleconference, the bill's oversight is partly due to congressional ignorance: MedPAC, the government agency that makes recommendations to Congress about Medicare policy, mistakenly assumed neurology to be an internal medicine specialty, like rheumatology or endocrinology. (In the eyes of the government, a physician's specialty is determined by a designated specialty code. Unlike neurologists, rheumatologists or endocrinologists can designate themselves as internal medicine practitioners on the basis of their postgraduate clinical training and/or board certification.) The other gross misjudgment is that neurology is synonymous with the wildly different practice of neurosurgery.
The continued omission of neurology from the bill's definition of primary care, the AAN reasonably argues, would further erode a valuable medical specialty—which currently matches only 52% of available residency slots.** And yet, despite the shortage of neurologists, their services have been shown (for example, in the case of stroke patients) to reduce hospital stays and costs and to improve clinical outcomes.
The AAN reports that Senator Amy Kobuchar (D-MN) has agreed to introduce an amendment that would add "neurology" to the pertinent section of HR 3590. The proposal is currently in need of a Senate cosponsor. Several patient groups, representing individuals with Parkinson disease, epilepsy, traumatic brain injury, ALS, or headache, advocate the inclusion of neurology in the bill's incentive section for primary care physicians.
To support the inclusion of neurology as a primary care practice in healthcare reform legislation, the AAN recommends that members visit BrainPAC and write their federal legislators.
* Nurse practitioners, clinical nurse specialists, and physician assistants are also included. In the House bill, obstetricians/gynecologists are included.
** Neurology's match percentage is comparable to that of family medicine and internal medicine, according to AAN President-Elect Bruce Sigsbee, MD.
The US FDA has refused to file Merck Serono's application for oral cladribine as a treatment for relapsing-remitting multiple sclerosis (RRMS). News of the agency's surprising decision was provided yesterday in a company press release.
Merck Serono submitted its NDA for the fast-track approval of oral cladribine at the end of September. According to yesterday's press release, the FDA acted within its allotted 60-day time frame to determine whether the company's NDA permits a "substantive review"; the agency evidently determined that the application was not "sufficiently complete."
Merck Serono states that it will request a meeting with FDA officials to understand and remedy any deficiencies of its NDA for oral cladribine. (The FDA's possible reasons for refusing to file an NDA can be found here.)
Data to support the review and approval of oral cladribine as a treatment for RRMS include the CLARITY and ORACLE MS studies, both of which are 2-year, placebo-controlled, phase 3 trials of monotherapy. A phase 2 study of oral cladribine as add-on therapy to interferon beta, the ONWARD study, was also used to support the NDA. Although publicly presented, none of these studies (to the best of my knowledge) has been printed in a peer-reviewed journal.
Another oral MS therapy, Novartis's fingolimod, is also in late-stage clinical development for RRMS. The company has indicated that it will submit an NDA for approval in the United States and Europe at the end of this calendar year...which is nigh approaching.
CLARITY = Cladribine Tablets Treatment MS Orally; ORACLE MS = Oral Cladribine in Early MS; ONWARD = Oral Cladribine Added on to Interferon Beta-1a in Patients With Active Relapsing Disease.
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.
