FDA Warning Letter

The pharmaceutical industry is highly regulated, especially with communications that are made from a company or an individual. The FDA, a main regulator of the industry, utilizes an enforcement action called a Warning Letter. A Warning Letter is a formal notification sent to a company or individual stating that the recipient is in violation of laws enforced by the agency, such as the Food, Drug, and Cosmetic Act, or FDCA.¹ These letters serve as an official notice that the agency has observed serious violations and expects corrective actions to be promptly taken by the recipient.

The entities that letters are issued to include pharmaceutical and medical device companies, food and dietary supplement manufacturers, cosmetic companies, and tobacco product firms. This article focuses on the pharmaceutical industry. Potential violations include inaccurate or misleading product claims, product advertising violations, product marketing violations, failure to report adverse events, clinical trial violations, and CMGP violations.² With the ever-evolving digital age of product communication, a company’s website or social media posts can result in a violation if the content is deemed misleading or non-compliant. 

These violations can pose significant risks to patient safety as well as public health decisions and behavior. As a result, the FDA treats violations with a serious manner. A recent study found that, from assessing violations that resulted in a letter from 2010 to 2020, the most frequently cited violations were omission and misleading risk information, as well as overstatement of efficacy.³ This finding coincides with what I expected due to the very large volume of product communications put forth daily. Within the communications, companies aim to be creative while staying true to the data. Being creative with messaging comes with a risk of tilting towards violative messaging. When this happens, a letter will follow. 

The purpose of a Warning Letter is to notify the recipient of a violation while allowing the opportunity to voluntarily comply with violated regulations through corrective actions. The letter outlines the specific violations, references the relevant legal provisions, and often includes documentation to support the agency’s findings. Corrective actions are requested by the FDA and outlined near the end of the letter. The FDA also provides the number of days the recipient has to rectify the violation. The FDA expects a comprehensive and well-documented response from the recipient. Companies typically have 15 business days to respond, and the response should not only address each of the violations cited but also include a root cause analysis, corrective and preventive action plans, and timelines for implementation. If corrective actions are not taken within the designated timeline, the FDA reserves the right to enforce more severe enforcement actions. These could include product seizures, injunctions, civil money penalties, or even criminal prosecution. In addition, a vague or inadequate response may result in escalated enforcement actions. Therefore, many companies seek legal and regulatory consulting expertise when drafting their responses.

Warning Letters are made public on the FDA's database to promote accountability and encourage compliance throughout the pharmaceutical industry. Public access to the letters allows other entities to learn from the experiences of their peers and proactively assess their compliance practices. It also means that receiving a warning letter can negatively impact a company’s reputation and stakeholder trust. Receiving a Warning Letter can lead to significant operational and financial consequences. Within the pharmaceutical industry, a letter may delay product approvals, trigger recalls, or halt manufacturing in an affected facility. In addition, companies receiving multiple or egregious letters may face increased scrutiny from investors, healthcare providers, and regulatory bodies globally.

The FDA’s Bad Ad Program aims to educate healthcare providers on how to identify and report potentially false or misleading prescription drug promotion. The program also serves as a precedent for other companies and aims to ensure that prescription drug promotion is truthful and not misleading. In its effort to provide continued learning, it provides case studies and webinars of previous violative prescription drug promotion. 

In August of 2023, the FDA issued a Warning Letter after the agency found fault with a sales aid for Breztri, a combination inhaler indicated for the maintenance treatment of chronic obstructive pulmonary disease (COPD) in adults. The agency was critical of “misleading” claims about the effect of the inhaler on all-cause mortality, or ACM. The aid originally claimed a “49% observed relative difference with BREZTRI vs LAMA/LABA.” In other words, the aid claimed that Breztri had a 49% relative difference in time to ACM compared to other inhalers indicated for COPD. The FDA deemed the messaging misleading due to the suggestion of a positive impact on ACM and reduction in risk of death in COPD patients not being supported by the clinical trials cited in the aid. Overall, the trials do not allow for conclusions to be drawn from the ACM data, as they did not show statistically significant results on specific endpoints. One cited trial was designed to remove patients from inhaled corticosteroids (ICS) before entering the treatment arm. As a result, the withdrawal of ICS may be a confounding factor when assessing any positive effect associated with ACM. With the FDA deeming the aid to make misleading claims and misbranding Breztri, the distribution of the aid became violative.^4,5 The letter also stated that the sponsor company had 15 business days to submit a document addressing the FDA’s concerns and explain plans for discontinuing use of the sales aid.

In some cases, the FDA may follow up with a re-inspection to verify that corrective actions have been effectively implemented. If the agency is satisfied with the corrective efforts, the matter may be closed without further action. If violations persist or worsen, the FDA has the authority to escalate the matter quickly, including banning imports, halting clinical trials, or withdrawing product approvals.

Overall, Warning Letters are compliance tools aimed at protecting public health by ensuring that products are safe, effective, accurately labeled, and accurately represented in product promotion. They reinforce the importance of sponsors adhering to regulations and guidances, and they provide companies with steps to return to compliance. Proper handling of a Warning Letter can help a company restore credibility and continue its operations without further regulatory action.

Resources:

1. Fuerst D and Ittleman J. FDA Enforcement Actions: Warning Letters and Untitled Letters. FIDJ Services. Food & Drug Law.
2. U.S. Food and Drug Administration. About Warning and Close-Out Letters. Compliance Actions and Activities.
3. Mohite N, Funtanilla V, Muzumdar J, Park T. Content Analysis of 2012-2019 FDA Warning Letters and Notices of Violations using the Economic, Clinical, and Humanistic Outcomes (ECHO) Model. Innov Pharm. 2021;12(1):10.24926/iip.v12i1.3420.
4. U.S. Food and Drug Administration. Warning Letter MARCS-CMS 664789. Compliance Actions and Activities. 2023.
5. Fierce Pharma. AstraZeneca Hit With FDA Warning Letter Over ‘Misleading’ Breztri Efficacy Claims. Marketing. 2023.

*Information presented on RxTeach does not represent the opinion of any specific company, organization, or team other than the authors themselves. No patient-provider relationship is created.