May 17 2010

DDMAC Sends Warning Letter Over Unbranded Websites

If you judge, investigate.

– Seneca

I know you just read the title, but let me say it again with some emphasis:  DDMAC Sends Warning Letter Over Unbranded Websites.  That’s right, a warning letter over websites that contained no “direct” references to a product…although, as we’ll see, the indirect references were too direct for the Division of Drug Marketing, Advertising, and Communications.

Thanks to Carrie S. Martin’s article on FDA Law Blog for bringing this to my attention.  I had flagged the letter to read because it was presented slightly differently than warning letters usually are in the “CDER New” email alerts, but her article bumped it to the top of my list.  The background she provided sets the stage well:

“FDA just released the Warning Letter it issued to Novartis Pharmaceuticals Corporation (“Novartis”) in April regarding two purportedly unbranded websites, www.gistalliance.com and www.cmlalliance.com (the “alliance websites”), which included disease-state information and clinical data about gastrointestinal stromal tumors (“GIST”) and chronic myeloid leukemia (“CML”).  DDMAC concluded that the websites promoted the use of Novartis’s product Gleevec (imatinib mesylate)—despite the fact that the websites do not specifically mention the drug’s name—in violation of the Federal Food, Drug, and Cosmetic Act (“FDC Act”).

Gleevac is approved for several indications, including the treatment of different types of CML and GIST.  Some of these indications received accelerated approval via Subpart H.”

In the warning letter, DDMAC cited numerous violations.  However, the letter first establishes its case for determining that these unbranded sites were, in practical effect, product websites.  I’ve included some pertinent quotes, but, as always, refer to the primary source for all of the details.  (Forgive the long quotes, but it’s good practice to not paraphrase warning letters whenever possible.)

Misleading Product Claim Websites

“While not using the established name of the Novartis drug product – Gleevec – the two Novartis-sponsored websites, www.gistalliance.com and www.cmlalliance.com, effectively promote this drug product for the treatment of GIST tumors and CML, respectively.


  • The websites discuss the use of tyrosine kinase inhibitors (TKIs) for the first line treatment of GIST and CML, often in conjunction with the Novartis name. Gleevec is the only tyrosine kinase inhibitor (TKI) indicated for first-line treatment of chronic phase CML; the only TKI indicated for first line treatment of GIST; and the only TKI made by Novartis that is indicated for both GIST and CML. These product details are wellknown [sic] in the oncology community.
  • The websites contain numerous references to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology, which recommend the use of Gleevec exclusively for the first-line treatment of CML and GIST.
  • The websites are perceptually similar to the Novartis Gleevec product website, incorporating similar color schemes (including a distinct orange), design layouts and other presentation elements.
  • The websites are clearly marked with the Novartis Oncology name and logo and/or the Novartis name and logo and discuss sponsorship by Novartis Pharmaceuticals Corporation.
  • The healthcare professional-directed “Targeting BCR-ABL” webpage on the CML Alliance website provides a direct link to the Novartis Gleevec product website in reference to first-line therapy for CML, while the consumer-directed version of this page provides a link to the Novartis-sponsored “My CML Circle Program” website, which discusses Gleevec as a treatment for CML.
  • The websites are registered to Novartis AG.
  • The websites present data from imatinib clinical studies, and provide the corresponding literature references, which include the drug name in the listed publication titles. At least one of the publications4 recounts the pivotal clinical trial submitted to FDA in support of the approval of Gleevec in the treatment of adjuvant GIST.

Based on this combination of factors, these websites are product specific promotions for the drug Gleevec. Consequently, these websites are subject to regulation by FDA, and are false or misleading for the reasons described below.”

Now, to be fair, if these websites had been branded, Novartis knows full well what information is required.  But these are “patient information” sites.  Those who follow advertising know that there’s been a trend towards these “unbranded” websites in recent years.  There’s a tacit understanding between drug companies (and not necessarily the FDA) that websites like these can provide supportive information to patients while complying with product promotion regulations.

That sounds perfectly OK, but it turns into a grey area if those sites could subtly guide patients to a specific product.  It’s exactly within (or, maybe, on the lighter edge of) that grey area that DDMAC has drawn a line.  With its case established that these are effectively product websites, the letter then listed how they were in violation:

1) Promotion of Unapproved Use

“We note that these statements do not explicitly include the trade name “Gleevec.” However, the footnoted references clearly indicate the established name of the drug (i.e., imatinib) used in the clinical studies and the text refers readers to the NCCN Treatment Guidelines for GIST tumors, which exclusively recommend the use of imatinib for neoadjuvant GIST therapy. The totality of this presentation misleadingly suggests that Gleevec is safe and effective for the neoadjuvant therapy of GIST tumors.”

“Gleevec is not approved for neoadjuvant use in GIST patients (nor is any other drug), and the approved PI for Gleevec does not include any information on the safety and efficacy of this drug when used before surgical resection of GIST tumors. Therefore, the webpages suggest a use for Gleevec for which safety and effectiveness has not been established, thereby creating a new intended use for the drug for which the approved PI lacks adequate directions.”

2) Omission and Minimization of Risk

“Apart from a brief list of examples of supportive care strategies that can be used to address some of the common and mild side effects, there is no mention of the serious risks of Gleevec therapy presented on these websites. The websites therefore misleadingly suggest that Gleevec is safer than has been demonstrated by substantial evidence or substantial clinical experience.”

3) Unsubstantiated Dosing Claims/Omission of Risk Information

“The totality of these presentations suggests that a lack of response in patients may be due to low plasma levels of Gleevec, and that the dose of Gleevec should be modified (i.e., increased) in the event that plasma concentrations of the drug are found to be “suboptimal.” FDA is not aware of substantial evidence or substantial clinical experience to support a correlation between patient outcome and plasma levels of imatinib. The PI for Gleevec provides very specific dosage recommendations for Gleevec in CML and GIST”

“Although clicking on the prominently displayed links on the CML Alliance and GIST Alliance websites leading to www.bloodleveltesting.com produces a pop-up window disclaimer stating that you are “moving to an external website independently operated and not managed by the Novartis Pharmaceuticals Corporation,” we note several indicators that Novartis is, in fact, responsible for the content of the website. For example, the website is registered to Novartis AG21, contains the CML Alliance and GIST Alliance logos, and makes repeated reference to Novartis.”

4) Failure to Submit

“Moreover, FDA regulations require companies to submit specimens of any labeling or advertising devised for promotion of the drug product at the time of initial dissemination of the labeling and at the time of initial publication of the advertisement for a prescription drug product. … These materials were not submitted to FDA 30 days prior to the intended time of initial dissemination or initial publication as required by 21 CFR 314.550, and were not submitted to FDA under cover of Form FDA-2253 at the time of their initial publication, as required by 21 CFR 314.81(b)(3)(i).”

Many of the points are what you would expect to see for a branded site that failed to follow promotional rules.  However, what really stands out are the items that DDMAC has used to establish that these “unbranded” sites are, in fact, promotional:

  • Referencing only a general treatment type (here TKIs) for a disease equates to promotion if your product is the only one of that type for the indication.
  • Referencing the established name (imatinib) in a footnoted reference, even when the trade name (Gleevec) is not used, in claims is violative.
  • Indirect references or links to products will be evaluated to determine if they are promotional in sum.
  • Presenting information about unapproved indications in close context to a treatment equates to off label promotion.
  • Having a similar look-and-feel between branded and unbranded sites is not acceptable.
  • DDMAC will investigate who owns/registered the websites and will use it as context for their evaluations.  (The letter also noted that Novartis was responsible for the content.)

Although directed at Novartis, this letter is a warning shot across the bow of any company that maintains patient information websites.  Providing information about diseases is acceptable, but DDMAC will be watching carefully to identify any potential violations.  The grey is not OK.

If you follow any sites like these two, pay attention and see if you notice any changes in the next few months.  Their owners are likely to sift through them very carefully.