The DOJ v Pharma Settlement Planetary System

The DOJ v Pharma Settlement Planetary System

The Department of Justice (DOJ) just released a commemorative poster highlighting the six most-recent multi-million dollar settlements that drug companies have agreed to pay for inappropriately, and in some cases illegally, promoting prescription drugs. The poster represents just the latest version of the "DOJ v Pharma Settlement Planetary System," which still has room for additional members (see unidentified objects in the poster).

Here's a description of the planets and how they were "discovered" as reported by ProPublica (here):

• The smallest "planet" in DOJ's System is AstraZeneca, which was fined $520 million to resolve allegations that it illegally promoted the anti-psychotic drug Seroquel. The drug was approved for treating schizophrenia and later for bipolar mania, but the government alleged that AstraZeneca promoted Seroquel for a variety of unapproved uses, such as aggression, sleeplessness, anxiety, and depression. AstraZeneca denied the charges but agreed to pay the fine to end the investigation. NOTE: The size of the AZ settlement "planet" is so small in comparison to the others in the System that many experts do not consider it a true "planet" at all. (The AZ planet was "discovered" in April 2010).
• Next is Merck, which agreed to pay a fine of $950 million related to the illegal promotion of the painkiller Vioxx, which was withdrawn from the market in 2004 after studies found the drug increased the risk of heart attacks. The company pled guilty to having promoted Vioxx as a treatment for rheumatoid arthritis before it had been approved for that use. The settlement also resolved allegations that Merck made false or misleading statements about the drug's heart safety to increase sales. (The Merck planet was "discovered" in November 2011).
• The fourth largest planet is the DOJ System is Eli Lilly, which was fined $1.42 billion to resolve a government investigation into the off-label promotion of the anti-psychotic Zyprexa. Zyprexa had been approved for the treatment of certain psychotic disorders, but Lilly admitted to promoting the drug in elderly populations to treat dementia. The government also alleged that Lilly targeted primary care physicians to promote Zyprexa for unapproved uses and “trained its sales force to disregard the law.” (The Lilly planet was "discovered" in January 2009).
• Next largest in size is Abbott, which was fined $1.5 billion in connection to the illegal promotion of the anti-psychotic drug Depakote. Abbott admitted to having trained a special sales force to target nursing homes, marketing the drug for the control of aggression and agitation in elderly dementia patients. Depakote had never been approved for that purpose, and Abbott lacked evidence that the drug was safe or effective for those uses. The company also admitted to marketing Depakote to treat schizophrenia, even though no study had found it effective for that purpose. (The Abbott planet was "discovered" in May 2012).
• Pfizer, which up until recently was the largest planet in the DOJ System, was fined $2.3 billion in September 2009, then the largest health care fraud settlement and the largest criminal fine ever imposed in the United States. Pfizer pled guilty to misbranding the painkiller Bextra with "the intent to defraud or mislead", promoting the drug to treat acute pain at dosages the FDA had previously deemed dangerously high. Bextra was pulled from the market in 2005 due to safety concerns. The government alleged that Pfizer also promoted three other drugs illegally: the anti-psychotic Geodon, an antibiotic Zyvox, and the anti-epileptic drug Lyrica.
• GlaxoSmithKline is currently the largest planet in the DOJ v Pharma Settlement Planetary System. GSK agreed to pay a fine of $3 billion to resolve civil and criminal liabilities regarding its promotion of drugs, as well as its failure to report safety data (see "GSK Guilty of Off-Label Marketing from 1999 to 2010: Will Pay $3 Billion Settlement"). This is the largest health care fraud settlement in the United States to date. The company pled guilty to misbranding the drug Paxil for treating depression in patients under 18, even though the drug had never been approved for that age group. GlaxoSmithKline also pled guilty to failing to disclose safety information about the diabetes drug Avandia to the FDA. (The GSK planet was "discovered" in July 2012).

FDA Guidance on Responding to Unsolicited Requests for Off-Label Information Via Social Media

FDA Guidance on Responding to Unsolicited Requests for Off-Label Information Via Social Media

Yesterday, while most of us were still on vacation, the FDA quietly issued without fanfare -- ie, no press release telling us about it or how to submit comments -- "Guidance for Industry Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices." You can find the document here.

Section VI. of this guidance addresses responding to unsolicited requests on public forums such as the Internet. While this may not be the "social media" guidance many people were expecting (see "First FDA Social Media Guidance to Address Responding to 'Unsolicited Requests' for Off-label Information"), it does include guidelines for responding to unsolicited requests for off-label information encountered through "emerging electronic media."

As with all guidances, FDA warns "Firms may choose to respond to unsolicited requests for information about off-label uses of their approved or cleared products in a manner other than that recommended in this draft guidance. Such activity would not constitute a per se violation of the law, but could potentially be introduced as evidence of a new intended use." Some drug companies (eg, Pfizer) would have preferred new legally-binding regulations rather than guidelines (see, for example, "Pfizer Asks for New FDA Regulations, Not Guidance, for Social Media"). The industry might also challenge these guidelines on legal grounds (see, for example, "Pharma Turns Up the Heat on Off-Label "Free Speech" Chilled by FDA - Implications for Social Media Marketing").

Aside from pressure by the drug industry, FDA felt the need to issue this guidance because it "recognizes that it can be in the best interest of public health for a firm to respond to unsolicited requests for information about off-label uses of the firm’s products that are addressed to a public forum, as other participants in the forum who offer responses may not provide or have access to the most accurate and up-to-date information about the firm’s products." I'm not sure I agree with that because there have been a number of surveys that indicate physicians (as well as the general public) have several other preferred sources of drug information (see, for example, "Are Pharma Reps Important to Docs or Not?"). But let's leave that issue aside for now.

Let's take a closer look at how these guidelines apply to social media such as Youtube, Blogs, and Twitter.

The guidelines break out responding to PRIVATE and PUBLIC requests for off-label information. As for handling private requests, the guidelines pretty much reiterate what the drug industry already knows. The section regarding public requests, however, is what will be of most interest to the industry. Social media is in the this category.

Youtube and Solicited Requests
The guidelines have something interesting to say about videos posted on Youtube.  Specifically, it warns about responding to public comments that may be received in response to videos that a pharma company may encourage people to post about about their own uses of the company's product. FDA gives this example:

"A firm asks or otherwise encourages users to post videos about their own uses of its product on third-party video-sharing sites (e.g., YouTube), which may result in video postings about an off-label use of its product. If the firm’s initial request for posting of videos results in any questions about off-label uses, or if any off-label video posting made in response to the firm’s 1encouragement of video postings results in questions about the product’s off-label use, these questions would be considered solicited requests."

FDA considers requests for off-label information that are prompted in any way by a manufacturer or its representatives to be solicited. If a company responds to such "solicited  requests," it must be careful because such responses  "may be used as evidence of a new intended use. Introducing a product into commerce for such a new intended use without FDA approval or clearance would, under these requirements, generally violate the law."

Is this guidance enough to encourage pharma companies to open up comments on their Youtube pages?

I doubt it. Most pharma companies are still waiting to know how they should respond to potential adverse event reports they may receive via comments before they venture into opening up comments on Youtube. It's not even likely that pharma companies will engage in branded Youtube projects in the first place, although there has been a precedent (see "Novartis Attempts Perfect Execution of Web 2.0 Trick!").

Of more interest to me are the examples FDA gives for how drug companies should respond to "unsolicited" requests via social media.

Blogger Example of "Solicited Request"
FDA cites this example: "If a firm sends out packets of information to known bloggers or online consumer reviewers and encourages them to write about an off-label use of its product on third-party sites and this then provokes a discussion about that off-label use, any requests inquiring about the product’s off-label use as a result of these blogs, whether posted as comments to the third-party site or directed to the firm, would be considered solicited requests."

Although I have never heard of a pharma company ever "encouraging" bloggers to write about off-label uses, I do know that some companies have invited bloggers to vacation sites (see "A Call for Pharma Social Media Transparency Guidelines for Patient Bloggers"). What they discuss behind closed doors is not known to me or to the FDA unless there is a blogger "mole" present.

So, how would FDA prove that the company "encouraged" off-label discussion?

One way is to examine the contents of the "packets of information" sent to the bloggers. If that packet includes off-label information, then FDA can make a case that the company encouraged the blogger to write about it.  (See "BI Masters the Art of WOM through Its 'Parrots,' er, Spokespersons" for a similar situation involving BI). The guidelines do NOT get into this level of detail, which is unfortunate and supports industry's claim that FDA guidance is often "unclear." I'm sure this will be a topic covered by comments to the FDA regarding this guidance.

Twitter Example of "Solicited Request"
FDA cites this example: "If a firm announces results of a study via a microblogging service (e.g., Twitter) and suggests that an off-label use of its product is safe and effective, any comments and requests received as a result of the original message about the off-label use would be considered solicited requests."

Many pharma company Twitter accounts have been used to announce results of studies related to unapproved uses of Rx drugs. Some such tweets may have made efficacy claims, but I am not aware of any that claimed the product was "safe." I am not sure from reading the guidelines how FDA would view such tweets.

How should pharma respond to unsolicited requests received via public Internet sites and social media?

FDA puts limits on how to respond to such requests on public sites. FDA is concerned that product information "posted on websites and other public electronic forums is likely to be available to a broad audience and for an indefinite period of time [and] that firms may post detailed public online responses to questions about off-label uses of their products in such a way that they are communicating unapproved or uncleared use information about FDA-regulated medical products to individuals who have not requested such information. In this circumstance, communications to persons who have not requested information may promote a product for a use or condition for which FDA has not approved or cleared. FDA is also concerned about the enduring nature of detailed public online responses to off-label questions because specific drug or device information may become outdated (e.g., new risk information may become available)."

In general, FDA's position is that "a firm’s public response to public unsolicited requests for off-label information about its named product should be limited to providing the firm’s contact information and should not include any off-label information."

That eliminates a "loop hole" I often worried about; namely, an anonymous agent of a pharmaceutical company can post a request for off-label information and initiate a discussion that includes information posted by the pharmaceutical company itself.

FDA suggests that a drug company handle such public requests through private channels after the requester follows up to the contact provided with a private request that will then be handled "offline."

FDA says:

• The firm’s public response should convey that the question pertains to an unapproved or uncleared use of the product and state that individuals can contact the medical/scientific representative or medical affairs department with the specific unsolicited request to obtain more information. 
• The firm’s public response should provide specific contact information for the medical or scientific personnel or department (e.g., e-mail address, telephone number, facsimile) so that individuals can follow up independently with the firm to obtain specific information about the off-label use of the product through a non-public, one-on-one communication.

Does It Serve the Public Interest?
Regarding responding to public requests; eg, via social media, FDA says "any substantive communication about off-label uses for the product, in response to the original unsolicited off label question, should occur solely between the firm and the individual who made the request," says FDA. "Regardless of the fact that the original, unsolicited off-label question may have been available to a very broad audience, the firm should not make its detailed response with off-label information publicly available within the same forum."

Unfortunately, although this may close the "loop hole" I mentioned above, this method of responding individually has a couple of negative implications:

1. First, private responses may not serve "the best interest of public health" because "public" means a bunch of people, not one person at a time. On the one hand, FDA believes responding to unsolicited requests for information about off label uses of the firm’s products serves the public interest because the firm has "robust and current information about their products." On the other hand, firms cannot distribute this information "publicly."
2. Responding privately requires more resources and expenses. Many people over the course of time may have the same questions. Instead of being able to use the power of the Internet to answer all these questions in a single message, each must be handled separately.

Sales and Marketing May be Seen, but Should NOT Be Heard From!
However the response is made, the FDA believes that "Responses to unsolicited requests for information should be generated by medical or scientific personnel independent from sales or marketing departments. FDA recommends that medical or scientific personnel have specialized backgrounds in responding to unsolicited requests for information, including important training, such as appropriately narrowing questions, tailoring responses only to the specific questions being asked, providing unbiased responses, and properly documenting responses.

"By contrast," says FDA, "because sales and marketing personnel are focused by training and experience on promoting a firm’s products, FDA recommends that sales and marketing personnel have no input on the content of responses to unsolicited questions or requests for off-label information."

There are more nuggets of information in this guidance that I haven't covered here. I look forward to the comments form the drug industry itself.

Pharma Turns Up the Heat on Off-Label "Free Speech" Chilled by FDA - Implications for Social Media Marketing

Pharma Turns Up the Heat on Off-Label "Free Speech" Chilled by FDA - Implications for Social Media Marketing

"FDA’s regulations censor manufacturers," says the Medical Information Working Group (MIWG), an "informal" group of pharmaceutical companies that includes Allergan, Amgen, Boehringer Ingelheim USA, Eli Lilly & Co., GlaxoSmithKline, Johnson & Johnson, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Purdue Pharma, and sanofi-aventis U.S.

In a "friends of the court" brief to the court hearing the appeal  of the Caronia off-label promotion case (see here), the MIWG contends that a manufacturer that "speaks about the lawful off-label uses of its products subjects itself to potential enforcement action unless FDA and DOJ determine, in their sole discretion, that they will not treat the speech as evidence of an 'intended use' for the product. This creates a chill on manufacturers’ speech, which has serious potential consequences for physicians, patients, and the public health."

Because of FDA's regulations that "lack coherence and clarity," MIWG claims physicians will have difficulty obtaining "objective, balanced, and accurate information on important unapproved uses of approved products." Furthermore, MIWG contends that pharma companies are "uniquely positioned to provide physicians with such information."

That's rich, considering that the drug industry often has difficulty providing "objective, balanced, and accurate information" on APPROVED uses of drugs as evident from all the FDA warning letters, which address this difficulty (for a list of the most recent letters, see here).

Should the heat the drug industry is bringing against FDA's off-label authority succeed, I envision off-label "woolly mammoths" (aka, sales reps) breaking free of the chilly ice and running amok among physicians offering "objective, balanced, and accurate information" - all without any oversight!

Much has been written about this legal issue, which you can find here, here, and here. Aside from the "objective, balanced, and accurate" claim, what caught my attention in the language of the brief was the overlap in the arguments presented with arguments pharma (eg, Pfizer) has made about how FDA should (or should not) regulate the promotion of Rx drugs via the Internet and social media.

On page 10 of the brief, for example, the argument is made that so-called "safe harbors" (eg, FDA guidelines for distribution of off-label reprints; see "FDA's Good Reprint Practices Guidance") are "not the product of formal rulemaking" and are "in most instances explicitly 'non-binding'." This was the argument Pfizer made against FDA issuing social media guidelines (see "Pfizer Asks for New FDA Regulations, Not Guidance, for Social Media"). As part of that argument, Pfizer said that "for FDA to regulate in this sensitive area [social media] through guidance instead of rulemaking inherently raises First Amendment concerns because of the nature of the process used to develop guidance, and the nature of the Agency pronouncements that result." (NOTE: Both documents are written by some of the same lawyers.)

Another parallel appears on page 11 of the brief, which delves into "unsolicited requests." The brief noted that FDA allows pharma company representatives (eg, paid physician speakers) to provide off-label information in response to an "unsolicited request" (eg, a question from the audience; perhaps from a physician "planted" in the audience for that specific purpose?).

Recall that the FDA's 2011 guidance "agenda" called for the agency to issue guidance regarding "unsolicited requests" from any source, including the Internet. That particular guidance, says FDA, was part of its promised social media guidance (see "FDA Drops Social Media from Its 2011 Guidance Agenda"). Before FDA can do THAT, it has to contend with the legal issues raised by MIWG in its brief.

This push for an end to FDA's off-label marketing ban is the latest industry action that puts the FDA in a very weakened position viz-a-viz issuing any marketing guidance (and certainly NOT social media guidance) for the foreseeable future. The industry hopes the court case in question -- the Caronia off-label promotion case -- will end up in the Supreme Court. In the meantime, FDA is probably thinking "let's wait and see what happens before we issue any new guidance that 'lacks coherence and clarity'."

NIH Genie Grants Pharma's Wish: Turning Old Drugs Into Cash Machines

NIH Genie Grants Pharma's Wish: Turning Old Drugs Into Cash Machines

For the first time ever, scientists are using computers and genomic information to predict new uses for existing medicines. A National Institutes of Health (NIH)-funded computational study analyzed genomic and drug data to predict new uses for medicines that are already on the market (see "NIH Program Predicts New Uses for Old Drugs").

It is predicted that this discovery will put greater emphasis "on so-called drug repositioning as a way of lowering the costs of drug development and getting therapies to patients more quickly," according to a Wall Street Journal article (here).

There's only one catch: "an advantage of finding repurposed drugs is that, since they are already approved, doctors can prescribe them off-label for patients," says WSJ. "This opens the door to very low-cost, individualized personal therapies," said Yves A. Lussier, a professor of medicine and engineering at the University of Illinois at Chicago who wasn't associated with the study.

Yeah, but if the drug is too old -- ie, off-patent -- no branded drug company will be interested in getting the drug approved for a new indication UNLESS a new USE patent can be obtained. THAT's exactly what Pfizer did to extend the patent life of VIAGRA (see "Double-Dip Viagra Patent Means No Recession for Pfizer").

QED

[This post originally appeared in Pharma Marketing Blog. 

Make sure you are reading the source to get the latest comments.]

"Reasonable" $600 MILLION Fine for Misbranding BOTOX: I Guess Allergan's Suit Against FDA Paid Off!

"Reasonable" $600 MILLION Fine for Misbranding BOTOX: I Guess Allergan's Suit Against FDA Paid Off!

Allergan -- the company that markets Botox legally for wrinkles and illegally for other things -- agreed to pay $600 million in fines, including $375 million to the government as part of a Botox “misbranding” charge. Allergan admitted that its marketing of Botox from 2000 to 2005 led to intended use in treating headache, pain, muscle stiffness and juvenile cerebral palsy. Read the media stories and press releases here.

Considering that Eli Lilly paid $1.41 billion to settle charges that it had improperly marketed  Zyprexa for elderly patients with dementia and that Pfizer paid $2.3 billion to settle charges that it had illegally marketed the painkiller Bextra, the $600 million Allergan has to pay seems "reasonable," which is exactly how  Larry Biegelsen, an analyst at Wells Fargo Securities in New York, described it: “The $600 million settlement amount appears reasonable based on industry standards.”

Why such a "reasonable" settlement for a drug company that, IMHO, is an unethical marketer and the the drug industry poster boy for off-label promotion? Allergan, for example, has refused to abide by PhRMA's DTC Guidelines as well as PhRMA's Guidelines for Interactions with Healthcare Professionals (see "Allergan Doesn't Comply with PhRMA Guidelines, Wins Kudos Anyway"). Allergan has also been cited by the FDA for other violations such as a misleading Latisse Web site (see "FDA Reads My Blog: Declares Latisse Web Site Misleading").

You must read a bit further down in the media articles about this to learn that Allergan "is required as part of the agreement to drop the lawsuit it filed against the FDA in October challenging a government rule that prohibits marketing drugs for unapproved uses."

There's a lot to ponder when reading that statement.

I ponder, for example, whether Allergan got off much easier because it agreed to drop its suit? Which was probably frivolous to begin with!

BTW, I've written about Allergan's off-label migraine shenanigans previously. See Allergan's "Eye-popping" Migraine Botox Study: Freedom of Expression or Off-Label Promo Tool?

Allergan is currently seeking FDA approval of Botox for the treatment of migraine. In the above post I reviewed a clinical study that Allergan is doing to support its case. The drug was so ineffectual that the researchers admitted they “have searched for patient characteristics that may predict a favorable treatment response.” Of course, they ultimately were successful in winnowing down the migraine population that is responsive to treatment: ie, those people who suffer from "imploding" or "eye-popping" headaches but NOT "exploding" headaches.

This would all be a joke if Botox was not such a dangerous drug, which includes a black box warning on its label. But I won't get into that -- you can read what other people have to say about the dangers of Botox here.

P.S. As part of the agreement with the Justice Department, Allergan also will be required to publish information about its payments to doctors. I am not anticipating that Allergan's physician payment information will be easy to analyze considering that much more ethical drug companies have failed to be transparent in this regard (see "Transparency Vs. Translucency in Reporting Physician Payments").

Will FDA Cite this Vyvanse Web Image as Off-Label Promotion?

Will FDA Cite this Vyvanse Web Image as Off-Label Promotion?

If an image is worth a thousand words, then this image found on the Vyvanse Web site home page is shouting off-label promotion.

Is it a coincidence that this image, showing a woman ("Fran") with a measuring tape and a dress, evokes weight loss, which is one of the common side effects of Vyvanse and similar stimulant dextroamphetamines?  (Vyvanse is a "prodrug"; it gets converted to stimulant dextroamphetamine in the body). Thanks to "Chad" who pointed this out to me via the "Contact Us" link above.

Other drugs have been promoted off-label for weight loss. Just yesterday I reported that Johnson & Johnson was fined $81.5 million for misbranding and illegally marketing Topamax for weight loss, among other things (see "Trouble in the House that McNeil Built: Why Drug Company Silos are Useful").

Compared to the Topamax off-label case, the Vyvanse off-label imagery is pretty subtle and perhaps only people like me (and "Chad") would even think it was more than a coincidence. Images in direct-to-consumer (DTC) ads, however, are carefully chosen by pharma marketers and the FDA does pay close attention to them as part of the overall message. An example is the shrinking planet Avodart ad that received an FDA letter because the image showed too much shrinkage (see "FDA Warns GSK About Enlarged Avodart Ad Imagery"). Other critics have even pointed out things like the speed of flapping bee's wings in some DTC ads (see "Ruth Day and the Bees Repeat Performance at House DTC Hearing").

These days, the FDA is paying more attention to subtleties in Rx drug promotions. For example, FDA recently sent Novartis warning letters about two unbranded Web sites that it said illegally promoted Gleevec even though the brand name was not mentioned on the sites (see "FDA Warns Novartis Over Gleevec Internet Sites").

Maybe the FDA reads this blog and will take a look at the Vyvanse Web site. If it decides to send Shire a letter, it may not happen for several months, by which time "Fran" may have been replaced by "Frank," a trucker having a late night meal at a truck stop. Pretty stimulating image, eh?