After a fairly slow 2016, the United States Food and Drug Administration’s (FDA) Office of Prescription Drug Promotion (OPDP) issued a quick burst of letters in the span of nine days in December. This flurry of activity more than doubled the enforcement letters that had been issued up to that point in the year.
Although there was an apparent increase in enforcement activity in December (perhaps related to the new Administration and the mark the old Administration wanted to leave on the industry), the type of activity and the nature of Draft Guidances issued in 2017 prior to the Trump Administration taking office indicated a dramatic shift in OPDP’s approach from years past. After losing battle after battle in First Amendment cases, OPDP seems to be using more discretion when it comes to enforcement letters, focusing instead on omission and minimization of risk, as well as pre-approval promotion.
The FDA’s First Amendment case losses tended to focus on issues relating to information disseminated about FDA-approved or FDA-cleared prescription products, not addressing communications about investigational products for which there were no approvals or clearances.
Of the 11 letters issued in 2016, four dealt with pre-approval promotion. Given that only four of the 70 total letters issued by OPDP between 2012 and 2015 dealt with pre-approval promotion, this dramatic increase signals a potential sign of things to come in terms of OPDP’s future enforcement activities.
With regard to already marketed products, there were no letters issued in 2016 dealing solely with efficacy claims. The few letters that addressed efficacy did so briefly, with a focus, primarily, on the communication of risk information. The Draft Guidances issued in early January 2017 also reflect this approach – indicating flexibility in FDA’s traditional “substantial evidence” standard to substantiate certain product claims.
Celgene Corporation
Celgene, the manufacturer of OTEZLA, received an untitled letter for making “false or misleading representations about the risks associated with Otezla” in a TV ad.
As noted in the letter,
According to the FDA-approved product labeling (PI), Otezla is indicated the treatment of adult patients with active psoriatic arthritis. Otezla is also indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.
Otezla is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation. Otezla is associated with serious risks. The PI contains warnings and precautions regarding depression, weight decrease and drug interactions. The most common adverse reactions associated with Otezla are diarrhea, nausea, upper respiratory tract infection, and headache, including tension headache.
OPDP felt as though some of the visuals presented in the commercial (“compelling and attention-grabbing visuals and SUPERs”) compete for the consumers’ attention, therefore making it “difficult for consumers to adequately process and comprehend the risk information. The overall effect undermines the communication of the important risk information and thereby misleadingly minimizes the risks associated with the use of Otezla.
Sanofi-aventis US
Sanofi-aventis US is the manufacturer of TOUJEO, an insulin injection. OPDP issued an untitled letter to the company for a TV ad that “makes false or misleading representations about the risks associated with Toujeo.”
According to the letter, OPDP took issue with the fact that
[t]he TV ad communicates the “major statement” of serious risks through the audio and onscreen SUPERS. At the same time, the TV ad presents fast-paced visuals that feature a man continuously dancing to music from the song “Let’s Groove” throughout multiple scene changes. Specifically, the man dances while cooking, working in an office, mowing his lawn, picking tomatoes with his children, and walking his dog. The presentation of these compelling and attention-grabbing visuals, all of which are unrelated to the risk message presented in the audio and on-screen SUPERS, in addition to the frequent scene changes and the other competing modalities such as the background music, compete for the consumers’ attention. As a result, it is difficult for consumers to adequately process and comprehend the risk information. The overall effect undermines the communication of the important risk information and thereby misleadingly minimizes the risks associated with the use of Toujeo. The presentation in the video is especially problematic from a public health perspective given the serious and potentially life-threatening risks associated with the drug.
United-Guardian, Inc.
United-Guardian is the manufacturer of RENACIDIN, irrigation solution. The manufacturer submitted a professional email under cover of Form FDA 2253, however, the email makes “false or misleading claims and/or representations with regard to the risks and benefits associated with Renacidin.”
As noted in the warning letter,
According to the FDA-approved product labeling (PI), Renacidin is indicated for dissolution of bladder calculi of the struvite or apatite variety by local intermittent irrigation through a urethral catheter or cystostomy tube as an alternative or adjunct to surgical procedures. Renacidin is also indicated for use as an intermittent irrigating solution to prevent encrustations of indwelling urethral catheters and cystostomy tubes.
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The e-mail includes the following claims regarding benefits of Renacidin:
- “Simplifies long-term catheter care”
- “Easy 30 mL dosing and delivery”
No references are cited to support these general claims that Renacidin simplifies long-term care of in-dwelling catheters or is easy to use, and we are not aware of supporting evidence. In addition, the unsupported and thus misleading assertion that Renacidin has “Easy 30 ml dosing and delivery” is exacerbated by the failure of the e-mail to reveal specific information from the approved physician labeling about how the drug should be dosed and administered. Specifically, the DOSAGE AND ADMINISTRATION section of the PI states, “Instill 30 mL (one container) of Renacidin into the urethral catheter or cystostomy tube. Clamp the urethral catheter or cystostomy tube for 10 minutes. Remove the clamp and drain the bladder. Repeat the instillation procedure 3 times a day” (emphasis added). This omission of material information further exacerbates the misleading characterization of dosing and delivery in the e-mail.
Spriaso, LLC
Spriaso is the manufacturer of TUXARIN ER, indicated for the relief of cough and symptoms associated with upper respiratory allergies or a common cold in adults 18 years of age and older. Spriaso created a webpage, “Product Pipeline: Tuxarin ER” that OPDP determined made “false or misleading claims and/or representations about the risks associated with Tuxarin ER, and inadequately communicates the full indication for the drug.” As such, in December 2016, OPDP sent Spriaso a warning letter, asking the company to immediately cease misbranding Tuxarin and submit a written response, complete with a comprehensive plan of action.
According to the letter,
Tuxarin ER contains codeine phosphate, an opiate agonist antitussive. This product is associated with a number of serious risks. The PI for the drug contains a boxed warning regarding respiratory depression and death which have occurred in children who received codeine following tonsillectomy and/or adenoidectomy. Tuxarin ER is contraindicated in postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy, and in patients with known hypersensitivity to codeine, chlorpheniramine, or any of the product’s components. The PI also contains warnings and precautions regarding death related to ultra-rapid metabolism of codeine to morphine, respiratory depression, drug dependence, head injury and increased intracranial pressure, activities requiring mental alertness, obstructive bowel disease, acute abdominal conditions, and use in special risk populations. In addition, the PI indicates that common adverse reactions associated with Tuxarin ER include nausea and vomiting, constipation, abdominal distension, abdominal pain, blurred vision, diplopia, visual disturbances, confusion, dizziness, depression, drowsiness, sedation, headache, euphoria, facial dyskinesia, feeling faint, lightheadedness, general feeling of discomfort or illness, excitability, nervousness, agitation, restlessness, somnolence, insomnia, dyskinesia, irritability, and tremor.
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The webpage makes representations and/or suggestions about Tuxarin ER such as the following:
- “First Long Acting Tablet, Schedule III, Codeine Antitussive Combination with Chlorpheniramine Antihistamine”
- “No spills or taste issues”
However, the webpage fails to communicate any risk information about the product. By omitting the risks associated with Tuxarin ER, including serious and potentially fatal risks, the webpage fails to provide material information about the consequences that may result from the use of the drug and creates a misleading impression about the drug’s safety.
Furthermore, the webpage contains the following claims:
- “Minimize serious risk of over dosing”
- “Issues with Hydrocodone and Chlorpheniramine commercial products
- Current market is dominated by liquids prone to serious risk of dosing errors.”
- “Issues with Promethazine (antihistamine) plus Codeine commercial products.
- Current market is dominated by short acting liquids that are prone to dosing errors.
- FDA requires boxed warning added to all promethazine containing products
- Unlike promethazine no known serious safety issues with Chlorpheniramine”
These claims are misleading because they suggest that Tuxarin ER is safer than its competitors based on differences in dosage formulations and the safety profiles of individual ingredients. No references were cited in support of these claims and we are not aware of evidence to support the suggestion that Tuxarin ER is safer than its competitors because of its tablet formulation or because it is not associated with “dosing errors” or “serious safety issues.” On the contrary, according to the WARNINGS AND PRECAUTIONS section of the PI for Tuxarin ER, overdose of codeine has been associated with fatal respiratory depression. This section of the Tuxarin ER PI also discusses several serious safety issues such as the risk of death related to ultra-rapid metabolism of codeine to morphine, dose-related respiratory depression, and drug dependence. Furthermore, similar to the products containing promethazine referred to in the claims above, the PI for Tuxarin ER also contains a boxed warning as discussed in the Background section above. Comparing the safety profile of a single ingredient in a combination product to another single ingredient in a competitor combination product (i.e., promethazine versus chlorpheniramine) is misleading as it fails to take into consideration the overall safety profile of the entire combination product.
Such statements raise considerable public health concerns and are particularly alarming with respect to an opiate agonist product, as these controlled substances can lead to overdose, dependence, abuse, and death.
Zydus Discovery DMCC
OPDP sent an untitled letter to Zydus Discovery, the manufacturer of Saroglitazar, an investigational drug for which there is no marketing authorization in the United States. However, according to the letter, Zydus has published a video on YouTube suggesting that Saroglitazar is safe and effective for the purposes for which it is being investigated or otherwise promotes the drug.
According to the letter,
These claims and presentations promote an investigational new drug by suggesting that Saroglitazar is safe and effective for the treatment of patients with diabetic dyslipidemia and hypertriglyceridemia with Type 2 diabetes. For example, the claims and presentations, which refer to Saroglitazar by the proprietary name, “Lipaglyn”, make conclusions that the drug is “indicated for the treatment of diabetic dyslipidemia and hypertriglyceridemia with Type 2 diabetes mellitus,” is “superior” to other molecules, and is not associated with many serious risks that are generally attributed to these other molecules with similar mechanisms of action, when Saroglitazar has not been proven to be safe and effective within the meaning of the FD&C Act and has not been approved as a drug under that authority for any use. Although we acknowledge that Saroglitazar is approved for use in another country, the claims and presentations, including the broad statements regarding the drug’s approval as the “world’s first,” furthermore are misleading, suggesting that the drug is approved throughout the world, including in the United States, when that is not the case. The video does not include any specific information regarding Saroglitazar’s approval status in the world or any information to indicate that Saroglitazar is an investigational new drug that has not been approved for commercial distribution in the United States.
Chiasma, Inc.
Chiasma is the manufacturer of octreotide capsules, an investigational new drug. This is another case of a YouTube video suggesting that the investigational drug is safe and effective for the purpose for which it is being investigated, or otherwise promotes the drug. There is no marketing authorization in the United States.
According to the untitled letter, there are several claims that make
numerous positive and conclusory statements about the safety and effectiveness of octreotide capsules, such as suggesting that “the drug is safe” and “the effectiveness of the drug was proven in the clinical trials.” Thus, these claims suggest in a promotional context that octreotide capsules, an investigational new drug, is safe or effective for such uses, when FDA has not approved octreotide capsules for any use. We acknowledge that the statement “Product is an investigational new drug and not available for commercial distribution,” is included as a SUPER on the screen for eight seconds at the end of the video. However, there is no disclaimer that would sufficiently mitigate the extensive claims and presentations throughout the majority of this video that suggest in a promotional context that octreotide capsules, an investigational new drug, is safe or effective for such uses, when FDA has not approved octreotide capsules for any use.