From the 1978 52nd Street album, Billy Joel sings, “Honesty is such a lonely word, everyone is so untrue; honesty is hardly ever heard, and mostly what I need from you.” While we don’t want to start out this Bulletin on such a melancholy note, the lyrics have come to mind as we have had recent client regulatory calls with the Food and Drug Administration.
Part of our day-to-day job is to help clients respond to FD-483s, Warning Letters, and other compliance and enforcement actions brought by FDA and similar regulatory bodies. At times, regulators, such as FDA, will request a meeting or — with the pandemic — a call. Depending on a number of factors, which we will discuss, this call or meeting can be a potential opportunity for the company to extricate itself from a near-fatal experience or it can, alas, accelerate the company into a likely consent decree or some other similarly devastating consequence.
In this Bulletin, we will share some of our collective experience, both gathered from 28 years of outside counseling and more than 12 years of serving at FDA. This is not an exhaustive list, and we do not intend to suggest that simply following these steps is a guarantee to success. However, we do believe it furthers the likelihood of success and, conversely, minimizes failure. Our list is in no particular order.
1. No Current Risk to the Public Health
Above all else, FDA’s responsibility and primary mission is to do what it can to ensure that the products it regulates do not harm consumers. If for no other reason than this, conducting an evaluation and determining whether, based on the concerns raised by FDA, a company should evaluate the products it currently markets to minimize any risk to the public. If there are any such concerns, the results and actions taken should be reported to FDA as soon as possible.
2. Credibility is Key
It is imperative that the company, led by senior management, show FDA that it can be trusted to fix its problems and minimize recurrences. This credibility factor becomes more acute when an FD-483 or Warning Letter refers to a “repeat observation.” The agency is expressing concern that the company is either “not getting it (the underlying problem)” or “not fixing it” — neither is good. Frustration, fueled by a developing concern that the company is distributing products that it cannot ensure is safe or effective, is starting to set in at FDA. In order to avoid further escalation, the company must definitively demonstrate that: (1) it recognizes what the regulatory and quality issues and concerns are relative to specific legal “Observations”; (2) an appropriate investigation was conducted to identify the root cause of each specific Observation; (3) action items appropriate to address and rectify each root cause of an Observation and prevent its future occurrence were developed and implemented (e.g., CAPA-like actions); and (4) implementation and effectiveness of action items were monitored and deliberate modification implemented as required.
3. State of Control
Related to the above, many in the industry might have heard of the phrase “state of control.” FDA wants to know that the company has its quality act together. The firm’s Quality Unit (“QU”) should be well organized, trained, and fully empowered by senior management to make final determinations related to Good Manufacturing Process (GMP) requirements, dispositions, and release of product into commerce. The standard operating procedures should be based on the Federal Food, Drug, and Cosmetic Act, FDA’s implementing regulations, agency written guidance, and appropriate industry standards (and, of course, all of these must be followed). The QU should review and approve all such documents.
Decisions on whether to do something (or not do something) should be thoroughly discussed internally by senior management and documented. There should be a rhyme and reason, based on science and supported by data, for why the company acted as it did. It is important that there is consistency and thoughtful deliberation to the decision-making approach. While FDA might disagree with the final decision, the company will be in a better position than if it arbitrarily acted or made an after-the-fact, reactive conclusion.
It is important to remember that, in our experience, with limited exceptions (e.g., data integrity, FDA thinks it is being lied to), FDA wants the company to voluntarily achieve compliance. The agency does not want to bring a more aggressive enforcement action (e.g., injunction, product seizure), which requires the Department of Justice to intervene and is more time-intensive.
4. Culture of Compliance
This is another phrase that many in industry have likely heard. “Compliance” cannot merely be a word on a bumper sticker or put up on the cafeteria walls. “Compliance” must be viewed as equally important as “sales.” Non-compliance is not only an unlawful act, but it will be bad for business, which a meeting or a call with FDA will often demonstrate. It is not atypical that during such a call, FDA may ask the company about whether it will recall a product or that a pending product application may be delayed approval. It has happened that a Warning Letter has been issued at the meeting or the call itself.
Senior management must show FDA that it is involved in fixing any problems and will take whatever necessary steps to achieve and maintain regulatory compliance. This does not necessarily mean only an expenditure of money or the hire of consultants but, perhaps, the non-release of products if they do not meet final product specifications or are not otherwise appropriate for distribution.
5. Be Prepared
For the call or meeting and any subsequent FDA inspection, which is inevitable after a poor inspection or regulatory call, the company should be prepared for the “why” questions — “Why did the company do x” and “Why did the company not do y?” The company should also expect that not all FDA personnel may have read the PowerPoint presentation or documents the company prepared for the meeting. Some officials will, but many will not, so the firm may need to repeat some of the material, even though the meeting is only one hour.
Be sure to have the correct personnel in the meeting to answer the questions asked by FDA. If the company personnel present for the call does not know a particular answer to a question, it is better to respond that the company will reply as soon as possible, rather than to bluff or make something up. In addition, a company should be receptive to a valid suggestion for improvement from FDA. The meeting is a dialogue, and the agency is trying to help where it can. If it’s a good idea and something can be improved, check one’s ego at the door and accept the recommendation or improvement. And, as FDA will likely be reinspecting the company in a few months, it is a good idea to consider the suggestion because the agency will be wondering whether the company was listening.
Finally, when responding to FDA, whether to an FD-483, a Warning Letter, or questions during a regulatory meeting, a company should try to see the big picture, not only the specific area of concern or observation. Clearly, the firm must address the particular issue, but it is important to recognize that the concern raised is merely an example cited. The company should demonstrate to FDA that it recognizes that it sees this as an example and has reviewed (or will review) similar areas to evaluate if there could be larger areas for improvement. This forward-thinking approach touches on many of the other high-level topics discussed previously (e.g., state of control, culture of compliance).
There is no playbook for acing a regulatory call or meeting when a compliance issue arises. However, there are some high-level themes and specific items that we remind clients of, which we believe promote success and, conversely, if not considered, maximize failure. Credibility, trust, state of control, a culture of compliance, and preparedness are some (but not all of) the major issues for companies to consider as they get ready for these nerve-wracking but potentially opportunistic meetings to demonstrate to FDA they are compliant with quality requirements.