Life Science Compliance Update

May 21, 2015

FDA OPDP Issues Fifth Letter of Caution for the Year, Cites Oak Pharmaceuticals For Exhibit Banner


Almost like clockwork, the Food and Drug Administration’s Office of Prescription Drug Promotion (OPDP) has released its fifth enforcement letter of 2015—they have issued one letter in January, February, March, April, and now, as of the past week, one in May. OPDP sent the Untitled Letter to Oak Pharmaceuticals, Inc. (a subsidiary of Akorn, Inc.) regarding the company’s barbiturate anticonvulsant, Nembutal. View the promotional material here. The agency found that Oak’s table exhibit banner was misleading because it omitted “important risk information associated with the use of Nembutal,” and also omitted material facts. These violations caused the exhibit banner to be “misbranded” under the Food, Drug, and Cosmetic Act, noted OPDP.

Indeed, the banner is quite sparse, showing a picture of an approaching lightning storm, and stating: “Control the Uncontrollable. The control you need when seizures are at their worst,” followed by the product and company name. In small letters at the bottom, the banner notes: “See booth representative for full prescribing information and important safety information.” OPDP stated that this alert did not mitigate the fact that the banner leaves off risk information on the visual material itself.

In sending the Untitled Letter, OPDP reaffirms that all promotional material--including posters at exhibit booths—are subject to the requirement to be accurate and to balance all benefit information with risk information.


The OPDP is the drug advertisement watchdog; the agency keeps a look out for false and misleading advertising and promotion through comprehensive surveillance. They inspect Form FDA-2253,  receive complaints from competitors, monitor promotional material at medical conferences, and have instituted the “Bad Ad” Program, which encourages doctors to alert the OPDP of potentially false or misleading advertisements. The Agency may then issue “Warning Letters” or less serious “Untitled Letters” to the manufacturers behind any problematic ads. Whereas Untitled Letters require companies to cease using the violative materials and recall them, Warning Letters may also require the company to make a plan for “corrective advertising,” which includes prompt dissemination of accurate and complete information.

Oak Untitled Letter

Oak Pharmaceuticals is a subsidiary of Akorn, Inc., and markets the Nembutal Sodium Solutions, a short-acting injectable barbiturate used to control seizures and for sedation. According to the OPDP, the company displayed an exhibit banner for Nembutal at the American Society of Health-System Pharmacists (ASHP) Meeting held in Anaheim, CA in December last year, which was viewed by two OPDP representatives. Oak received an Untitled Letter a few months later based on the banner’s omission of risks and omission of material facts. 

  • Omission of Risk Information

The Nembutal exhibit banner includes claims such as, “Control the Uncontrollable” and “the control you need when seizures are their worst;” however, it omits all of the contraindications, warnings and precautions, and common adverse reactions associated with the use of Nembutal, states OPDP. "By failing to present any risk information associated with Nembutal, the exhibit banner misleadingly suggests that Nembutal is safer than has been demonstrated."

FDA acknowledges that the statement: “SEE BOOTH REPRESENTATIVE FOR FULL PRESCRIBING INFORMATION AND IMPORTANT SAFETY INFORMATION,” is included at the bottom of the exhibit banner, but that it does not mitigate the misleading omission of risk information. Risks associated with barbiturates include, perhaps most notably, that they are habit forming. The product labeling for Nembutal also contains warnings and precautions regarding IV administration, acute or chronic pain, use in pregnancy, synergistic effects, and central nervous system (CNS) depressant effects. 

  • Omission of Material Facts

In addition to risks, OPDP found that the banner did not accurately portray the approved indication for the drug.  Specifically, the agency found the  materials omitted the fact that Nembutal should only be used "in anesthetic doses, in the emergency control of certain acute, convulsive episodes, e.g., those associated with status epilepticus, cholera, eclampsia, meningitis, tetanus, and toxic reactions to strychnine or local anesthetics."

OPDP's letter indicates that they request Oak to "immediately cease branding Nembutal," and to submit a written response to the agency's letter stating whether the company intends to comply with the request, listing all promotional materials (with the 2253 submission date) for Nembutal that contain presentations such as those described above, and explaining their plan for discontinuing use of such materials.


Before sending this letter to Oak, OPDP most recently sent an Untitled Letter to Otsuka Pharmaceuticals in April, citing a pharmacology aid for their antidepressant and bipolar treatment, Abilify. This is a notable letter if solely because it implicates a large pharmaceutical company, and a bestselling drug that only recently received generic competition. OPDP criticized the ad, which showed three light switches at low, middle, and high to represent how Abilify can modulate dopamine and serotonin activity. However, “the totality of these claims and presentations misleadingly implies a greater degree of certainty about the mechanism of action of Abilify in humans than is currently known,” notes the letter. Furthermore, according to OPDP, the promo is “misleading because it implies that Abilify offers advantages over other currently approved treatments for bipolar disorder or [major depressive disorder] when this has not been demonstrated.”

See OPDP’s list of enforcement letters here


May 11, 2015

Amarin v. FDA and Public Meeting On Off-Label Promotion Signal An Important Year For Clarity Around Scientific Exchange and the First Amendment


2015 could prove to be a significant year for how the Food and Drug Administration approaches drug companies’ off-label speech. FDA has stressed that they are in the process of attempting to “harmonize” their promotional guidances with the First Amendment, and recently announced that they will hold a public meeting during the summer to address this issue.  Fast-tracking a potential resolution, Amarin Pharmaceuticals just filed suit against the FDA arguing that the agency’s restrictive interpretations would effectively prevent Amarin from sharing “truthful and non-misleading information with healthcare professionals” that FDA would consider off-label.

View Amarin’s complaint against the FDA: Amarin v. FDA


To be approved by the FDA, a prescription drug must pass a series of rigorous clinical trials that test a drug’s safety and effectiveness for a specific condition and a defined group of patients. But once approved by FDA, doctors may prescribe that drug in a different dosage to treat different conditions and different patient groups. This is known as “off-label” prescribing, and accounts for 10-20 percent of the prescriptions in the United States.

While doctors can and do prescribe off-label, FDA prohibits drug manufacturers from promoting off-label indications to these doctors. Despite being in the best position to understand their own products, manufacturer can only be the source of off-label information in a number of narrow exceptions, including responding to unsolicited requests by healthcare providers.

Drug companies have argued with increasing success, however, that preventing truthful, non-misleading speech both violates a company’s First Amendment right to free speech and is harmful to doctors who could use the most up-to-date medical information to best treat their patients. Under the Food, Drug, and Cosmetic Act, a manufacturer may not introduce or deliver for introduction into interstate commerce any “new drug” that FDA has not approved or any drug that is “misbranded,” even if FDA has approved the drug. In 2012, the Second Circuit in U.S. v. Caronia held that the FDCA cannot be interpreted to “criminaliz[e] the simple promotion of a drug’s off-label use” due to First Amendment concerns.

At the recent CBI Pharmaceutical Compliance Conference in Washington, DC, Thomas Abrams, Director of FDA’s Office of Prescription Drug Promotion, acknowledged Caronia. Abrams stated that “in light of emerging case law involving the First Amendment, FDA is currently engaged in comprehensive review of regulations and guidance documents in an effort to harmonize the fundamental public health interest underlying the FDA’s mission and statutory framework along with the interests in disseminating truthful and non-misleading information.”

Reuters reported last week that FDA will hold a public meeting in the next few months to address the agency’s approach to off-label. “The meeting, announced last month by FDA chief counsel Elizabeth Dickinson, comes as a bill known as 21st Century Cures, designed to speed new drugs to market, is moving through Congress,” the article states. “Language in the bill is adding pressure on the agency to relax its guidelines.” Indeed the 21st Century Cures bill seeks to add more flexibility to companies speaking about evidence that doesn’t quite meet the standard “two-adequate well-controlled studies,” as well as open the line of communication regarding health economic data.  Other types of evidence a company may have to support an off-label use, include observational studies, post-hoc studies, meta-analysis, or comparative effectiveness data.

Despite Caronia and potential new guidances, the threat of costly enforcement remains a real deterrent to this communication exchange between companies and doctors due to the fact that FDA and the Department of Justice have used evidence of off-label promotion to build a case that pharmaceutical companies have submitted false claims to the government. These “False Claims Act” cases have settled for hundreds of millions and even billions of dollars in the last 5-6 years. 

Amarin v. FDA

Despite the Constitutional concerns, few manufacturers have challenged FDA’s interpretation in a lawsuit. A notable exception was in 2009, when Allergan sued the FDA, claiming it had a right to make off-label claims about Botox. However, in 2010, Allergan agreed to pay $600 million in civil and criminal penalties related to off-label promotion of Botox, and dismiss its First Amendment challenge. (See Arnold and Porter’s article, “Requiem for the Off-Label Regime?). Ironically, soon after the settlement, the FDA approved an amendment to Botox’s label, “making the same advertising practices for which Allergan just paid $600 million in fines completely legitimate.” (SeeThe Changing Landscape of the Commercial Speech Doctrine and FDA Advertising Regulation: Off-Label Marketing in the Wake of Sorrell v. IMS”).

Now, just last week, Amarin Pharmaceuticals, along with four physicians, have filed a lawsuit to permit the company to share truthful and non-misleading off-label information without penalty. The company has tapped one of the nation’s top free speech attorneys, Floyd Abrams, to represent them in their First Amendment case.

Amarin’s only FDA-approved product is Vascepa, a prescription omega-3 fatty acid approved for marketing to reduce triglyceride levels in adult patients with very high triglycerides—a lipid in the blood linked to heart disease. A difference exists between patients with very high triglycerides (defined as above 500 mg/dL of blood) and persistently high triglycerides, found in patients with 200-499 mg/dL of blood, despite the use of statins. Doctors routinely prescribe Vascepa for patients with very high triglycerides, and also “off-label” to treat patients with persistently high triglycerides.

According to Amarin’s lawsuit, they have conducted a double-blind, placebo-controlled clinical trial demonstrating that Vascepa reduces triglyceride levels and has other favorable effects in adult patients with persistently high triglycerides. However, the lawsuit noted that while “FDA does not dispute the success of this trial,” the agency “refuses to approve the promotion of Vascepa for use in treating this patient population.” At issue is the fact that while the clinical trial demonstrated that Vascepa lowers triglyceride levels, the drug has not been proven to reduce the risk of heart disease. There’s research linking the two, but not yet definitive “clinical evidence affirmatively demonstrating that lowering triglyceride…in such patients ultimately reduces cardiovascular risk.”

FDA’s decision leaves Amarin in a “bind,” as they put it—unable to discuss with physicians any information about a significant clinical trial for fear of off-label enforcement. Indeed, the company notes that “for years and until recently, FDA has permitted manufacturers of other triglyceride-lowering drugs, such as fenofibrates, niacin, and another omega-3 fatty acid-based drug, to market their drugs for treatment of persistently high triglycerides.” Amarin argues that in proscribing new information exchange about “potentially better treatment alternatives,” the agency is doing a disservice to doctors who only know about older treatments and are unable “to make fully-informed decisions about what is best for their patients.”

Adding insult to injury is the fact that manufacturers of fish oil diet supplements, also containing a type of omega-3, are not restricted to nearly the same lengths as FDA-approved drug products. Amarin notes that diet supplement labels are free to make the following assertion not only to highly-educated physicians but to consumers themselves:


In the lawsuit, Amarin is seeking a court declaration that they may communicate to healthcare professionals (not the general public) the following information with respect to Vascepa:

  • Efficacy data from Amarin’s clinical trial of Vascepa in patients with high triglyceride levels despite statin therapy, which met all primary and secondary endpoints and was conducted under a special protocol assessment agreement with FDA (safety data is already reflected in approved Vascepa labeling);
  • The qualified health claim that the FDA has permitted for over a decade for omega-3 dietary supplement products: “Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease;” (as seen in the image above) and
  • Peer-reviewed scientific publications relevant to the potential effect of EPA on the reduction of the risk of coronary heart disease.

Amarin makes clear that they are not seeking to compel FDA to expand Vacepa's indication, nor are they seeking to strike down off-label promotion laws and regulations as facially unconstitutional. 


Amarin v. FDA will certainly be an important case for the life sciences industry to follow closely. The plaintiffs have many significant facts on their side:

  • A product with virtually no known harmful side effects;
  • Clinical trial information showing significant attributes about a drug that a company cannot share to doctors based on FDA’s regulations;
  • The fact that diet supplements are currently using the very statements that Vascepa is prohibited from communicating, despite not going through a rigorous clinical trial process.

The case and other off-label developments reportedly brewing around the FDA promise to make 2015 a significant year for achieving some much-needed updates to the way that companies can communicate truthful speech about the attributes of their products.  


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