Summary of FDA Advertising and Promotion Enforcement Activities

E-ALERT | Food & Drug
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December 20, 2011
SUMMARY OF FDA ADVERTISING AND PROMOTION ENFORCEMENT ACTIVITIES
NOVEMBER 2011
This e-alert is part of a monthly series of e-alerts summarizing publicly-available FDA enforcement
letters (i.e., warning letters and untitled letters) relating to the advertising and promotion of drugs,
biologics, and medical devices. In November 2011, FDA’s Office of Prescription Drug Promotion
(OPDP) posted the following enforcement letters on its website: 1
� Untitled letter to Otsuka Pharmaceutical Development and Commercialization, Inc. re: Busulfex®
(busulfan) Injection (October 17, 2011) (“Otsuka Untitled Letter”) 2
� Untitled letter to Lantheus Medical Imaging, Inc. re: TECHNELITE® (Technetium Tc 99m
Generator) (October 25, 2011) (“Lantheus Untitled Letter”)
The letters raise a variety of allegations and conclude that the cited advertising/promotional issues
render the subject products misbranded.
This alert merely summarizes the allegations contained in FDA’s letters. It does not contain any
analysis, opinions, characterizations, or conclusions by or of Covington & Burling LLP. As a result,
the information presented herein does not necessarily reflect the views of Covington & Burling LLP
or any of its clients.
Overstatement of Efficacy
FDA’s letters contain the following allegations under an “Overstatement of Efficacy” subheading:
Otsuka Untitled Letter: The website for Busulfex contained a graph titled “Overall Survival and
Disease-free Survival.” The graph was misleading because the endpoints were incorrectly
calculated. According to OPDP, “[t]he accurate method of calculating probability estimates for these
endpoints takes into consideration the number of patients who are still alive or free from disease
after each pre-specified event has occurred (defined as the population at risk) as well as the number
of patients censored from analysis at each time point during the period of observation.” The graph,
however, divided the number of patients alive at day 100 by the total number of patients who
received Busulfex during the entire clinical trial. Because this calculation did not accurately reflect
the number of patients still at risk for the defined events, the graph overstated the efficacy of
Busulfex. Moreover, the PI and the single-arm open-label pivotal trial cited on the webpage do not
1 Only enforcement letters posted to FDA’s website in November 2011 are included herein. Letters issued in
November but not posted to the website by November 30, 2011 will be summarized in our alerts for the
months in which those letters are posted. The Office of Compliance and Biologics Quality (OCBQ) in FDA’s
Center for Biologics Evaluation and Research (CBER) and the Office of Compliance in FDA’s Center for Devices
and Radiological Health (CDRH) did not post any applicable letters in November.
2 The date referenced for the letters are the issue dates.

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support the graph because “single-arm trials do not adequately characterize time-to-event
endpoints.”
Unsubstantiated Superiority Claim
FDA’s letters contain the following allegations under an “Unsubstantiated Superiority Claim”
subheading:
Lantheus Untitled Letter: An exhibit panel claimed that TechneLite was the “preferred choice,” which
misleadingly implied that TechneLite is favored over other generators. According to OPDP, “[t]he
term ‘preferred’ encompasses a variety of factors such as convenience, dosing, dosage form,
efficacy, and adverse events. Generally, claims about preference must be supported by adequate
and well-controlled, head-to-head clinical studies using well-developed instruments that can evaluate
all determinants of preference.”
Unsubstantiated Claims
FDA’s letters contain the following allegations under an “Unsubstantiated Claims” subheading:
Lantheus Untitled Letter: The exhibit panel misleadingly claimed that use of TechneLite is “simple”
and “hassle-free.” According to OPDP, the product’s PI describes a “complex” process required for
proper preparation, administration, and disposal. For example, the required route of administration
varies based on the specific diagnostic procedure being performed.
Otsuka Untitled Letter: The Busulfex website made claims relating to the consistency of area under
the curve (AUC) values and the predictability of the pharmacokinetic (PK) profile. For support, the
pages cited the pivotal study for the drug, which involved blood sampling only every four hours after
the end of infusion. Given the three-hour half-life, “[a]n acceptable sampling schedule to determine
first dose AUC would need to extend up to 15 hours post infusion. Therefore, the first dose AUC was
extrapolated by a range of 2% to 68% in order to calculate” AUC, which “renders a comparison
between first dose AUC values to AUC values of subsequent doses invalid.” In addition, the
presentation misleadingly implied that there is a correlation between a predictable PK profile and the
ability to induce myeloablation in a controlled way. OPDP, however, “is not aware of substantial
evidence or substantial clinical experience that supports any kind of causal or correlative
relationship between pharmacokinetic profile and such clinical benefits.”
Misleading Claim
FDA’s letters contain the following allegations under a “Misleading Claim” subheading:
Otsuka Untitled Letter: The website for Busulfex presented the claim “Straightforward IV
administration.” The PI for the product, however, contains “several instructions” relating to proper
administration, such as using an administration set with minimal residual hold-up volume. The
detailed administration information was presented elsewhere on the website, but it was not
sufficient to mitigate the misleading impression.
Minimization of Risk
FDA’s letters contain the following allegations under a “Minimization of Risk” subheading:
Otsuka Untitled Letter: The website for Busulfex included several claims that the product was
associated with a “low incidence of severe toxicities.” The PI, however, includes a Boxed Warning
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relating to cytotoxicity, profound myelosuppression, and other significant side effects. This claim was
therefore misleading and significantly minimized the risks associated with the drug. In addition, one
webpage included several statements suggesting that concomitant administration of lorazepam
eliminates the risk of seizures with Busulfex therapy. The cited study was a retrospective review of
29 pediatric patients and did not constitute substantial evidence. Moreover, the PI for Busulfex
states that patients should be premedicated with phenytoin to reduce the risk of seizures and warns
that other anticonvulsants may result in a higher risk of certain side effects, including seizures.
Omission of Risk Information
FDA’s letters contain the following allegations under an “Omission of Risk Information” subheading:
Lantheus Untitled Letter: The exhibit panel made several efficacy claims regarding use of
TechneLite, but failed to include material risk information. This suggested that the product is safer
than has been demonstrated by substantial evidence or substantial clinical experience. The panel
did state “Please see a representative in this booth for full Prescribing Information,” but this did not
mitigate the misleading impression.
Omission of Material Facts
FDA’s letters contain the following allegations under an “Omission of Material Facts” subheading:
Otsuka Untitled Letter: One webpage for Busulfex contained pediatric dosage and administration
information, but failed to present risks related to the use of the drug in the pediatric population. The
page also presented more general administration information, but omitted material facts relating to
the need to pre-medicate patients with antiemetics. In addition, the Important Safety Information at
the bottom of each webpage omitted material facts relating to certain side effects, such as specific
ways to detect hepatotoxicity. These omissions suggested that the drug is safer than has been
demonstrated by substantial evidence or substantial clinical experience.
Inadequate Presentation of Established Name
FDA’s letters contain the following allegations under an “Inadequate Presentation of Established
Name” subheading:
Lantheus Untitled Letter: The exhibit panel for TechneLite failed to present the established name in
“direct conjunction” with the proprietary name where the latter was featured in the headline, as
required by 21 C.F.R. 201.10(g)(1).
* * *
If you have any questions concerning the material discussed in this client alert, please contact the
following members of our food & drug practice group:
Michael Labson 202.662.5220 mlabson@cov.com
Erika Lietzan 202.662.5165 elietzan@cov.com
Scott Cunningham 202.662.5275 scunningham@cov.com
Scott Danzis 202.662.5209 sdanzis@cov.com
Emily Alexander 202.662.5665 ealexander@cov.com
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The information presented in this alert does not necessarily reflect the views of the firm or any of its clients.
This information is not intended as legal advice. Readers should seek specific legal advice before acting with regard to the subjects
mentioned herein.
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