Takeda's Clinical Symposia: It's all about Rozerem

Today's New York Times has a nice piece by Stephanie Saul on sleeping pills, entitled "Sleep Drugs Found only Mildly Effective, but Wildly Popular." She covers a recent NIH-funded report which concludes that sleeping pills "reduced the average time to go to sleep 12.8 minutes compared with fake pills, and increased total sleep time 11.4 minutes." Saul focuses particularly on Rozerem, which has been heavily promoted in direct-to-consumer ads, and yet was found by NIH to be one of the less effective pills. To quote Saul: "Consider that it costs about $3.50 a pill; gets you to sleep 7 to 16 minutes faster than a placebo, or fake pill; and increases total sleep time 11 to 19 minutes."

I am not anti-sleeping pill by any means. I prescribe plenty of them, and sometimes take them myself. They certainly work. But I am not convinced that the brand-name pills are worth their higher prices. I prescribe plenty of trazodone, temazepam, and diazepam for sleep, as well as generic Ambien (zolpidem). Occasionally I'll go to pricey Ambien CR for patients who like Ambien but who wake too early in the morning.

I have had a grand total of one patient respond to Takeda's Rozerem. Nonetheless. The journal Clinical Symposia, in a recent edition sent free to all physicians, likes Rozerem so much that it highlights the melotonin receptors on the picture of the brain on the cover (see above). That seemed odd to me, since this was an issue on insomnia for primary care physicians, and Rozerem is hardly the drug that PCPs would or should turn to first when treating insomnia. Once I flipped it over, the mystery was solved, as this entire issue was sponsored by Takeda. In addition, the first author, Gary Richardson, M.D., is a prominent Takeda speaker. See, for example, this website, "SleepJournalClub.org," chaired by Richardson, funded by Takeda, and providing CME credit for reading journal articles on insomnia. I suggest you click on "archived events" and scan through the 11 articles posted thus far. I went through this exercise in an effort to determine whether the articles chosen were biased either in favor of Rozerem or against its competitors. Here's what I found:

1. Effects of NG2-73 On Sleep Onset, Quality and Next Day Function In a Transient Insomnia Study. A clinical study of a new compound, NG2-73, manufactured by Neurogen, which acts as a partial GABA agonist. Does not promote Rozerem.

2. A Review of the Evidence for the Efficacy and Safety of Trazodone in Insomnia. A review of trazodone concluding that it has little supporting evidence as a hypnotic and that is has significant side effects. Promotes Rozerem by trashing its main generic competitor.

3. Highlights from APSS (a sleep conference) 2007. Reviews a study showing that Ambien causes the elderly to be shaky on their feet, and refers to Takeda-funded studies (read abstracts here) showing that Rozerem does not have this liability. Promotes Rozerem.

4. The Brain’s Master Circadian Clock: Implications and Opportunities for Therapy of Sleep Disorders. Emphasizes the importance of the melatonin system in insomnia. Promotes Rozerem.

5. Safety of Ramelteon in Individuals With Mild to Moderate Obstructive Sleep Apnea. Need I say more? Promotes Rozerem.

6. Combined Therapeutics for Insomnia: Should our First Approach be Behavioral or Pharmacological? Unsponsored paper on therapy vs. meds for insomnia. Does not promote Rozerem.

7. Tiagabine Enhances Slow Wave Sleep and Sleep Maintenance in Primary Insomnia. Promotes Tiagabine.

8. Influence of Pharmacokinetic Profiles on Safety and Efficacy of Hypnotic Medications. Funded by Sanofi, maker of Ambien CR, this article is strongly and cleverly promotional of Ambien CR.

9. The Management of Insomnia: From Herbals to Hypnotics. While this is a review of all sleeping pills, it ends with several extraordinarily positive statements about Rozerem (eg., "The selective melatonin receptor agonist ramelteon represents the first major advance in the treatment of insomniain more than 40 years.") Promotes Rozerem.

10. Insomnia and Hypnotic Use, Recorded in the Minimum Data Set, as Predictors of Falls and Hip Fractures in Michigan Nursing Homes. Study showing that hypnotics do not increase the risk of nursing home fractures; rather, insomnia does. While this is not specifically promotional of Rozerem, this fits in well with Takeda's promotion of Rozerem as being safer than Ambien for the elderly. Promotes Rozerem.

11. Relative Abuse Liability of Hypnotic Drugs: A Conceptual Framework and Algorithm for Differentiating Among Compounds. This article, sponsored by Takeda, is essentially a prolonged advertisement for Rozerem, highlighting its main advantage: lack of abuse liability. Promotes Rozerem.

Conclusion? In my analysis (certainly biased by my heightened sensitivity to underlying promotional agendas), 7 out of 11 articles in this Takeda-sponsored CME program are promotional of Rozerem.

Mais bien sur, you say. Why else would Takeda pay Richardson and colleagues to chair this journal club? If they didn't choose articles that made Takeda happy, these physicians would be "missing their dreams" of fat honoraria checks!

Of Buzzing Bees and Direct-to-Consumer Drug Ads

Congress is scrutinizing direct-to-consumer drug marketing, and Allison Bass (author of a new book on the deceptive marketing of Paxil) posted this interesting entry on her new blog. Researchers at Duke University have listed cognitive techniques drug-makers use to distract them from comprehending all the pesky negative information that the FDA requires be disclosed. For example, in an ad for the allergy drug Nasonex, a distracting animated bee appears during the rapid fire recitation of side effects. But when the benefits of Nasonex are described, the bee hovers quietly.

In the past, I have supported DTC ads (see here) because I have felt the public health benefits may outweigh the problems with biased drug information. After reading about this new study, I may have to revise my position!

Historic IOM Report: A Knock-Out Blow to Greed in Medicine

The long awaited report on conflict of interest from the Institute of Medicine has been released, and it is a landmark document in the history of medicine.

Before reviewing the report, what is the Institute of Medicine, and why is everybody making such a fuss about what it has to say? The IOM was created in 1970 by the federal government as part of the National Academy of Sciences. According to its website, “The nation turns to the Institute of Medicine (IOM) of the National Academies for science-based advice on matters of biomedical science, medicine, and health.”

You can think of the IOM as the most important advisor to Congress and the White House on medical issues. It is not formally a part of the government, and therefore none of its recommendations have the force of law. However, when the IOM speaks, everybody who is anybody listens very closely.

This 300 page report, formally titled “Conflict of Interest in Medical Research, Education and Practice,” can be accessed here.

Pared down to the essentials, its recommendations are:

1. Drug companies must disclose any payments they make to doctors, hospitals, and many other institutions. This is similar to the proposed Physician Payments Sunshine Act, but goes further because it recommends that these financial disclosures extend to consumer groups (such as the National Alliance for the Mentally Ill), medical societies (i.e., the American College of Cardiology, which is the new poster child for industry money-lust), and medical education companies. Basically, IOM is saying, “no more hiding any money that you may be using to surreptitiously influence medical care.” This is an extremely powerful and sweeping recommendation, and will complete the process of bringing integrity back to medicine.

2. Doctors should no longer accept any free meals, gifts or other items from companies. Various academic medical centers have already announced such rules but they vary in the details. For instance, Johns Hopkins says "no gifts" except expensive medical textbooks and educational charts, and "no free meals" except for a long list of examples where free meals are okay. IOM endorses a very simple policy—no meals or gifts of any kind.

3. Doctors must not participate in speaker’s bureaus for drug companies.

4. Doctors must not do clinical research if they have a financial interest in the outcome of the research. As Dr. Carroll points out in Health Care Renewal, this rule would have prevented the unfortunate series of events involving Dr. Alan Schatzberg, Stanford University and the NIH.

5. Revamp the system of continuing medical education (CME) so that there is no more industry influence in the content.

The actual verbatim recommendation regarding CME is:

"RECOMMENDATION 5.3: A new system of funding accredited continuing medical education should be developed that is free of industry influence, enhances public trust in the integrity of the system, and provides high-quality education. A consensus development process that includes representatives of the member organizations that created the accrediting body for continuing medical education, members of the public, and representatives of organizations such as certification boards that rely on continuing medical education should be convened to propose within 24 months of the publication of this report a funding system that will meet these goals."

Industry funding of CME was the most controversial issue faced by the IOM, and you’ll notice that the above recommendation is rather artfully crafted to avoid explicitly calling for a ban on industry funding. In the subsequent discussion, the IOM explains that some committee members were worried about “unintended consequences” of an immediate funding ban, such as fewer courses. But guess what? There are far too many redundant industry-funded courses anyway, on the same topics over and over again—treatment of carefully hand-picked conditions with drugs made by the sponsor.

Nonetheless, later in their report, the IOM makes quite a strong statement anyway. Some industry funding might be acceptable, they say, but only if funneled into pooled sources of money over which the companies have no control. Crucially, direct funding—which constitutes essentially all of industry-funded CME as currently practiced--would be forbidden under the new system:

“Both direct company funding to institutions for specific continuing medical education programs and direct company provision of unrestricted grants to institutions offer clear opportunities for undue influence, particularly for continuing medical education providers that also receive the great majority of their funding from companies. A plan for a system free from industry influence would exclude such funding as well as funding from company-controlled foundations.” (section 5, page 32).

The bottom line is that this report will serve as the authoritative guide for medical centers and policy makers for the next several years as they clean up conflicts of interest in medicine. Change is coming, big time.

What's Wrong with DTC Ads?

According to the Wall St. Journal's Health Blog, John Edwards is calling for a two year post-approval ban on direct-to-consumer drug ads. Having stayed up for the past several nights watching my team win the World Series, I have certainly received an excessive dose of DTC ads for the likes of Cialis, Flomax, and Lipitor (is anybody else creeped out by Jarvik as he cocks his head and bats his baby blue eyes?) And, yes, I get that DTC's encourage consumers to ask their doctors to prescribe the newest and most expensive meds.

But banning them doesn't make sense. Why? For one, it's one of the only arenas where drug companies advertise their products with full disclosure. Everybody knows it's an expensive ad paid for by the company. There's no pseudo-legitimate journal or medical education company pretending to be a scientific article, when in reality it's a paid advertisement.

Second, they do serve an educational function for consumers, if biased. There are a lot of guys out there urinating very frequently who would not consider this a potentially treatable issue if they hadn't seen those irksome Flomax commercials, the ones featuring the sports-crazed baby boomers who get to hang out in their kayaks longer without having to run into the woods--all because they're taking their Flomax. Sure, viewers are going to run to their doctors and ask for Flomax my name, but it's up to the docs to decide which drug is best. And meanwhile, some men will find out they have early prostate cancer (rather than benign prostatic hyperplasia) and might get their lives saved in the bargain.

I say let the companies have their DTC ads, and use the extra money they gain from increased sales to fund a government-administered pool of money to pay for unsponsored continuing medical education. This will save the health care system much more money in the long run.

Seroquel XR and Marcia Angell's Blueprint for the FDA

There's a nice editorial by Marcia Angell (former editor of New England Journal of Medicine and author of the classic book The Truth About Drug Companies) in today's Boston Globe.

Dr. Angell lays out seven specific recommendations for changes in FDA policy, all of which are sensible and will encourage better drug pipelines and safer medications.

Before presenting them, I want to highlight her recommendation number 5, which is that the FDA should be able to require drug companies to compare new drugs with existing drugs of the same type. This is especially relevant in the context of an upcoming meeting of the FDA's Psychopharmacological Advisory Committee. Tomorrow it will begin a two day meeting to discuss, among other things, AstraZeneca's application to approve Seroquel XR for generalized anxiety disorder (GAD) and major depression (you can learn the particulars here).

Seroquel XR is, indeed, more effective than placebo for both depression and GAD. Nonetheless, the application should be soundly rejected, unless AZ can show that Seroquel XR works better than the dozens of other drugs that are already available for these conditions. Why approve an antidepressant that causes weight gain, diabetes, and cardiac death, when there are equally effective alternatives that cause none of these side effects?

I doubt that AZ has done such comparative studies, because they were not forced to do so. From their stockholders' perspective, they would be foolish to conduct such studies, because there's a good chance that Seroquel would do no better than drugs like Zoloft or Celexa. Its disadvantageous side effect profile would be highlighted in a head-to-head trial. And as we know from recent court documents, AZ has done everything it can to bury the truth about Seroquel's side effects.

Marcia Angell's Seven Recommendations for a Better FDA:

1. Congress should repeal the Prescription Drug User Fee Act.

2. Consultants for drug companies should no longer be permitted to serve on FDA advisory panels.

3. The agency should see that the post-marketing studies it mandates are actually carried out.

4. The FDA should review generic drugs as fast as brand-name drugs.

5. Congress should give the FDA the authority to require drug companies to compare new drugs with existing drugs of the same type.

6. The FDA should stop approving me-too drugs on the basis of surrogate endpoints.

7. The FDA should prohibit direct-to-consumer advertising for three years after drugs are approved.

First, Data Mining; Now, "Patient Priming"

Thought you'd seen it all? Well, the infiltration of drug company marketing into every corner of our lives scoffs at boundaries. Now that nearly half of all states are considering laws banning prescription data mining, the industry is developing a new technique: "patient priming."

What is it, exactly? It's so breathlessly new that I'm not entirely certain what it is. But it can't be good. You can certainly learn more if you register for this webcast to take place February 5, produced by Medical Marketing & Media magazine and sponsored by HealthGrades. Here's how they describe the event:

"Understanding and Priming the Pre-Visit Patient

The point at which a patient plans and schedules a visit to their doctor represents a significant window of opportunity for promoting treatment options and maximizing the growth of specific brands. Experts in patient engagement and marketing from the pharmaceutical, agency and media fields discuss pharma's role in priming the pre-visit patient for a more beneficial dialogue with their physician.

Featured speakers:
Jan R. Rutherford, Jr., Senior Vice President, Sponsorship and Advertising, HealthGrades
Robert Palmer, Managing Partner, S&H Digital, Sudler & Hennessey Company"

I'm guessing this is a scheme cooked up by HealthGrades to convince more drug companies to advertise on their site. I just went to the HealthGrades page evaluating me as a doctor, and noticed a banner ad for Concerta. I assume Mr. Rutherford will entice companies to use HealthGrades to prime "pre-visit patients" and encourage them to demand specific brands from their physician. Yes, this is just another version of direct-to-consumer advertising, but the Orwellian language makes it all sound particularly insidious.

Signed,

Your Pre-Visit, Pre-Primed Physician

Seroquel gets the Abilify FDA Treatment

The FDA's Psychopharmacological Advisory Committee voted last week to recommend that Seroquel be approved as an adjunctive treatment for depression, but it rejected AstraZeneca's request that the drug be approved as monotherapy treatment for depression or generalized anxiety disorder.

According to this article in The Philadelphia Inquirer, "Panel members, including scientists from outside the FDA and consumer advocates, said Seroquel's risks in depression and anxiety outweighed its benefits."

One of the panel members, Richard Malone, explained that "the risks are fairly well-documented, and I don't think they are acceptable for this use."

While I agree with the committee's rejection of two indications, I'm concerned that they were inappropriately impressed by the Seroquel augmentation data. As far as I know, the augmentation studies have not been published, but a summary can be found on page 27 of AZ's briefing document. It looks like they used the same research design as BMS did in their Abilify augmentation studies, and that the Seroquel results were equally unimpressive (see this article at Clin Psych for a slam of the Abilify data). Seroquel reduced the MADRS depression score by about 15 points, while placebo decreased it by about 12 points. This 3 point advantage is tiny, considering that the MADRS is a 60 point scale. Personally, I don't think that this 5% advantage (3 divided by 60 possible points) is worth Seroquel's side effects.

Particularly since this recently published randomized trial showed that when Seroquel was added to Prozac, it yielded no advantages over placebo, aside from helping patients sleep better over the first few weeks. This was not a study of treatment-resistant patients (unlike the FDA data) but it nonetheless shakes my confidence in the potency of the medication.

If the full FDA decides to go along with the committee's recommendation, AZ will mount the kind of mega direct-to-consumer marketing campaign that we have seen with Abilify (for background, see two excellent LA Times pieces here and here), and consequently there will be a little epidemic of obesity among depressed patients. Now that's what I call depressing!