FDA gives Astrazeneca a Little Slap for Off-Label Promotion

Shame on Astrazeneca for getting ahead of itself and promoting an off-label use of Seroquel. Naughty, naughty. Yes, I know that Seroquel is probably the atypical antipsychotic most used in depression, probably even more than Abilify (which has an indication in adjunctive use AND the DTC campaign to back it up). Perhaps this sales rep is among the list of upcoming layoffs...

Here's the FDA letter for those who care to get the whole dirt.

TRANSMITTED BY FACSIMILE James L. Gaskill, Pharm.D. Director, Promotional Regulatory Affairs AstraZeneca LP 1800 Concord Pike, P.O. Box 8355 Wilmington, DE 19803-8355
RE: NDA # 20-639, 22-047
Seroquel (quetiapine fumarate) Tablets Seroquel XRTM (quetiapine fumarate) Extended Release Tablets MACMIS ID #16370

Dear Dr. Gaskill:
The Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S. Food and Drug Administration (FDA) has become aware of oral statements made by an AstraZeneca LP (AZ) sales representative on January 3, 2008, to a healthcare professional, and a mailing from AZ dated January 4, 2008, to the same healthcare provider, regarding its drugs, Seroquel (quetiapine fumarate) tablets (Seroquel) and Seroquel XRTM (quetiapine fumarate) Extended Release Tablets (Seroquel XR). The representative and the mailing recommended or suggested a use for Seroquel and Seroquel XR that has not been approved by FDA, and thus created a new "intended use" for Seroquel and Seroquel XR for which the products lack adequate directions. Thus, these promotional activities and materials misbrand the drugs in violation of the Federal Food, Drug, and Cosmetic Act (Act), 21 U.S.C. 352(f)(1), and FDA implementing regulations. 21 CFR 201.1 00(c)(1) & 201.128.

Background According to the Indications and Usage section of its FDA-approved product labeling (PI),1 Seroquel is indicated, among other things, for the following:

Bipolar Disorder
SEROQUEL is indicated for the treatment of both: • depressive episodes associated with bipolar disorder • acute manic episodes associated with bipolar I disorder as either monotherapy or adjunct therapy to lithium or divalproex. The efficacy of SEROQUEL was established in two identical8-week randomized, placebo-controlled double-blind clinical studies that included either bipolar i or II patients. Effectiveness has not been systematically evaluated in clinical trials for more than 8 weeks. The efficacy of SEROQUEL in acute bipolar mania was established in two 12-week monotherapy trials and one 3-week adjunct therapy trial of bipolar I patients initially hospitalized for up to 7 days for acute mania. Effectiveness has not been systematically evaluated in clinical trials for more than 12 weeks in monotherapy. The efficacy of SEROQUEL as adjunct maintenance therapy to lithium or divalproex was established in 2 identical randomized placebo-controlled double-blind studies in patients with Bipolar i Disorder. The physician who elects to use SEROQUEL for extended periods in Bipolar Disorder should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

Schizophrenia
SEROQUEL is indicated for the treatment of schizophrenia.
The efficacy of SEROQUEL in schizophrenia was established in short-term (6-week) controlled trials of schizophrenic inpatients. The effectiveness of SEROQUEL in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use SEROQUEL for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
According to the Indications and Usage section of the FDA-approved Pi2 for Seroquel XR:
SEROQUEL XR is indicated for the treatment of schizophrenia.
The efficacy of SEROQUEL XR in schizophrenia was established in part, on the basis of extrapolation from the established effectiveness of SEROQUEL. In addition, the efficacy of SEROQUEL XR was demonstrated in 1 short-term (6-week) controlled trial of schizophrenic inpatients and outpatients.
The effectiveness of SEROQUEL XR in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use SEROQUEL XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Promotion of Unapproved Use

On Thursday, January 3,2008, at approximately 3:00 p.m., a sales representative from AZ in the - bt4)-made an unsolicited sales call to a physician at his office. The representative stated that Seroquel was approved for treatment of major depressive disorder (MDD). This representation was not made in response to a request for such information by the physician. As a result of this representation, the physician requested that AZ provide written information to support the claim that Seroquel has been approved for the treatment of MDD. In response to this request, AZ sent the physician a mailing dated January 4, 2008. The mailing contained information about Seroquel and Seroquel XR's use for MDD, and included summaries of eight clinical trials with referenced citations. This mailng was not the result of an unsolicited request by the physician, but rather was prompted by the sales representative's statements.
According to their Pis, Seroquel and Seroquel XR are not FDA-approved for the treatment of MDD.3 Therefore, the oral statements made by the sales representative and the information provided in the January 4, 2008, mailng, misleadingly suggest a new "intended use" for Seroquel and Seroquel XR. Because the Pis for Seroquel and Seroquel XR lack adequate directions for this use, the drugs are therefore misbranded. Although the letter to the physician states that "(AZ) does not recommend the use of SEROQUEL or SEROQUEL XR in any other manner than as described in the enclosed prescribing information," this disclaimer is insufficient to mitigate the promotion of a new "intended use" for which the products lack adequate directions.
Conclusion and Requested Action
The oral statements made and information provided by AZ and its representative recommend or suggest a use for Seroquel and Seroquel XR that has not been approved by FDA, and thus misbrand Seroquel and Seroquel XR in violation of the Act, 21 U.S.C. 352(f)(1), and FDA implementing regulations. 21 CFR 201.1 00(c)(1) & 201.128.
DDMAC requests that AZ immediately cease the dissemination of violative promotional materials for Seroquel and Seroquel XR such as those described above. Please submit a written response to this letter on or before December 15, 2008, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) in use for Seroquel and Seroquel XR as of the date of this letter, identifying which of these materials contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials. Please direct your response to me at the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville, MD 20705-1266, facsimile at 301-847-8444. In all future correspondence regarding this matter, please refer to MACMIS #16370 in addition to the NDA number. We remind you that only written communications are considered officiaL.
The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibilty to ensure that your promotional materials for Seroquel and Seroquel XR comply with each applicable requirement of the Act and FDA implementing regulations.
Sincerely, {See appended electronic signature page} Amy Toscano, Pharm.D., CPA Regulatory Review Officer Division of Drug Marketing, Advertising, and Communications
1 At the time of this violative action, the approved Pi (and the version referred to within this letter) for Seroquel was the version dated July 30,2007. Although not relevant to the issues cited in this letter, the most recent version of the Seroquel PI was approved on May 13, 2008. 2 At the time of this violative action, the approved Pi (and the version referred to within this letter) for Seroquel XR was the version dated May 17, 2007. Although not relevant to the issues cited in this letter, the most recent version of the Seroquel XR Pi was approved on October 8, 2008. 3 Seroquel is approved for the treatment of depressive episodes associated with bipolar disorder, which is a disease state that is distinct from MDD. On October 8, 2008, Seroquel XR was also approved for the treatment of depressive episodes associated with bipolar disorder.
This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature. /s/ Amy Toscano 12/1/2008 03: 13: 05 PM

Life is Good at JNJ (if you're not an atypical antipsychotic): A reaction to Johnson & Johnson Earnings Call

JNJ had a nice quarter, in spite of losing Risperdal to genericsville and Invega sitting firmly on its flat launch curve. In truth, the big generic hit will start this quarter as the generics start shipping. Last quarter for Risperdal was a decline simply because the wholesellers quit building inventory. Invega is another story. Well, it just sucks. According to Dominic Caruso, Vice-President, Finance and Chief Financial Officer, "Invega is continuing to improve quarter after quarter but I would say consistent with our prior comments it’s not where we had expected it to be. It’s not the launch we had hoped for as we had commented before but we do see steady improvement with Invega. We believe it’s a viable alternative for patients and when used physicians comment very favorably about the effect with patients." It's not hard to improve quarter after quarter when a) the market is expanding and b) you're starting with such a small base.

Oh the Horror! PhRMA Bans Physician Gifts

Oh what a sorrowful day it is as I mourn the loss of the ubiquitous pharmaceutical sales rep tchotchke. Today, PhRMA announced a voluntary ban on the pens, pads, clocks, clipboards, shirts and anything else you can brand that reps have been dangling to docs for years as added incentive to prescribe their product. And, let me tell you, they did it because it worked. So, if you're a rep, your bag just got a little lighter, but your job just got a lot harder. If you don't have new clinical information for a physician then why in the world would he/she meet with you now - just drop those samples off at the front and move on to the next office. Today marks another nail in the death of the sales rep model.

Astrazeneca Saves Seroquel

Astrazeneca got incredibly great news today from a NJ court that Novartis and Teva will not be able to pursue their desired genericization of Seroquel. This stands in stark contrast to yesterday's post on Risperdal which just went generic. This is good news for all the branded atypicals as now there is just risperidone as the sole generic. Had Seroquel gone generic it would've turned the atypical market upside down. Seroquel and Seroquel XR as branded products make up over a 30% share of all atypical antipsychotics as it is and with juggernaut new indications coming in Major Depressive Disorder and Generalized Anxiety Disorder, it's not going to get any smaller anytime soon. Had it gone generic, it's likely that Abilify and Geodon would have been particularly hard hit so I'm sure their respective marketing teams are exhaling a sigh of relief.

First Generic Atypical Antipsychotic (Risperdal becomes risperidone)

Yesterday Teva announced they received FDA approval to produce a generic version of Risperdal. We all knew this was coming. Teva was ready with product to ship and JNJ was ready with their own in-house generic version in hopes of cannibalizing some Teva sales at the expense of their former cash cow.

What does this mean for the common man?

Well if you're schizophrenic, bipolar, autistic, or an off-label user, it means that the price you pay just got a whole lot cheaper AND after Teva's 180 days of exclusivity as the sole competitor allowed to sell risperidone, the price will drop even lower as more competition enters the market.

If you're a sale rep. for Invega (the bastard child of Risperdal), your sales goals just got a wee bit more difficult now didn't they because who wants to buy Risperdal-lite when you can get the original for pennies on the dollar. Wonder what that already stellar *saracasm* Invega uptake curve is gonna look like now.

And what if you're Abilify, Geodon, Seroquel or Zyprexa? Well, you hope and pray that your marketing and sales folks have done a good job differentiating their product from the competition because the price differential between you and the generic just went exponential.

And what of the insurers you may ask. Can you say fail first? I'm sure it's already begun.

Ooh, exciting times in the Atypical Antipsychotic Market!

Abilify for the Kids

Bristol-Myers Squibb released their earnings last week. No real news on the Abilify front. It continues to grow year over year and now has the pediatric bipolar and adolescent schizophrenia indications in its pocket to be the kid-friendly atypical anti-psychotic. Analysts didn't really press on Abilify since the Mead Johnson IPO idea started all their wheels turning.

Guess we can look for the Abilify reps in our pediatrician's office the next time the kids' need a sports physical.

Just How Bad is it for Invega / Teva's Generic Risperidone

For the past couple of earnings calls, JNJ has been hiding the Invega debacle within their Risperdal numbers by reporting the total sales of Risperdal and Invega together. Yesterday they switched strategy and instead hid Invega in the Other category. That's rich. Here's the relevant details from the conference call. Watch as they duck and weave the analyst's request to get to the Invega numbers...

Glenn Reicin - Morgan Stanley
That’s very helpful. Okay, and then also just two other quick questions -- INVEGA, is that included in the RISPERDAL number or is that separate now?
Dominic J. Caruso
That’s separate now in Other.
Glenn Reicin - Morgan Stanley
Okay, and you are not going to tell us what that number is?
Louise Mehrotra
No, not right now.
Glenn Reicin - Morgan Stanley
Okay, so all the other numbers you’ve given us in the past are going to be restated for that change?
Louise Mehrotra
The numbers that you have in the schedule have your comparables for prior year.
Glenn Reicin - Morgan Stanley
In prior quarters did INVEGA, was that included under the anti-psychotic number?
Louise Mehrotra
Yes, it was. And the numbers --
Glenn Reicin - Morgan Stanley
Okay, so we’re going to get restated schedules for all of the quarters going back or no?
Louise Mehrotra
What we have given you here is 2007 restated to take INVEGA out. We certainly could give you -- break out the RISPERDAL Oral and we could put that up.

Hahahahaha Ridiculous. Full transcript available here.

The good news for JNJ is that it looks like Teva will get the 6 month exclusivity on generic risperidone. Good news because JNJ can keep the generic price higher with only one other player in the market. The price for the generic will thus likely bottom out at the beginning of 2009 given current expectations for multiple entrants.

Astrazeneca's Major Depressive Disorder (MDD) filing for Seroquel on 2/29

Well, this answers the burning question of how many licks it takes to get to the Tootsie Roll center of a Tootsie Pop. The answer varies widely. Oops that's a different question. I meant how many filings does it take for Seroquel to get an MDD indication? 7? Well, maybe. Let's see we've got 4 for monotherapy, 2 for adjuctive therapy to ongoing anti-depressant therapy (like Abilify), and 1 more for maintenance. That's quite a shotgun effect. How exactly to you plan positioning for a product in MDD with this many possible outcomes?

The answer is it doesn't matter. Because regardless of the indication you still have to deal with the sedative, weight, and metabolic issues attached to your product and the class.

I wonder how many they'll bring for Generalized Anxiety Disorder (GAD) in the next couple of months. Should be interesting...

Atypical Anti-psychotic Monopoly

Perhaps it's more of a quintopoly. Since Abilify's launch in late 2002, Astrazeneca, Jansen, Eli Lilly, BMS/Otsuka, and Pfizer have had free reign over the atypical anti-psychotic market. Starting with schizophrenia but gradually expanding to bipolar disorder, autism, major depression, and generalized anxiety disorder coming soon, these products are infiltrating every corner of the mental health market in all age groups. I don't have a lot to say here, just that's interesting how the increasingly more restrictive FDA is crushing potential competition through its tenor. bifeprunox is dead. asenapine is alive and may actually get the bipolar mania label. And, Fiapta (iloperidone) is crippled by its patent life, lack of sales force, and second-line at best status in schizophrenia.

Damn it must feel good to be one of the big five.

Eli Lilly's long-acting Zyprexa short-lived

The FDA issued a non-approvable letter for the long-acting injectable version of Zyprexa due to concerns over excessive sedation. That won't do much to stem Zyprexa's hemorrhaging market share. Guess that's just a little less milk for this cash cow.

Wyeth says good-bye to Solvay and bifeprunox

From potential blockbuster to zilch in about 6 mths. Without Wyeth's marketing power and a nonapprovable letter requiring a second positive maintenance study in schizophrenia, bifeprunox is as good as dead.

Vanda's Atypical Antipsychotic iloperidone has a new name.... Fiapta

"I am extremely pleased with the successful submission and acceptance of the Fiapta(TM) NDA filing in 2007. This important achievement would not have been possible without the commitment and dedication of the Vanda team," stated Mihael Polymeropoulos, M.D., President and CEO of Vanda. "I am looking forward to an exciting 2008 during which we expect the results from our VEC-162 Phase III chronic insomnia clinical trial and the PDUFA action for Fiapta(TM)."

OK it's got a name (weird name - perhaps they were foreshadowing its potential market performance compared to its remaining patent life i.e. a Fiasco). Also it looks like it's going to have the same kind of activating problems that come with Geodon and Abilify given the insomnia trial. Doesn't really bode well for use in severe schizophrenics who most medical staff would prefer to keep sedated...

The PDUFA date is July 27 so I wonder when we're going to hear about the sales force issue. Do they really plan to go it alone? (perhaps it was discussed on yesterday's call -- anyone know?)

No News, Vanda, Wyeth, Seroquel, Abilify depression, risperidone generic

It's been a month, and there's basically no news on the atypical antipsychotic front. Vanda still has no sales force for iloperidone, Wyeth still has no chance with bifeprunox, and Seroquel still dominates the marketplace. The only thing new is that Abilify is making a foray into the PCP arena now that they have the adjunctive depression label. Risperdal and Zyprexa continue to lose share. Clearly the big event or perhaps non-event of 2008 will be generic risperidone, and I don't think anyone knows how that will play out.

Pfizer Inks Deal with Taisho for Schizophrenia Drug

Anytime the behemoth gets behind a drug, it's news. Geodon will be long gone by the time this hits the sample closets. Perhaps their reps will have something to talk about then...