Guest Column | February 22, 2016

6 Rules For Responding To FDA 483s And Warning Letters

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By Angela Brown, Halloran Consulting Group

It happens again and again in the industry, from brand-new technologies to established product lines, from startups to the most recognized and respected medical device companies: an FDA compliance action. Quality units are routinely slapped with significant 483 observations or, even worse, a warning letter, whenever FDA has concerns about product quality, organizational control, complaint handling, or management oversight.

The unfortunate reality is that FDA’s view of a company’s performance may differ from a firm’s self-assessment. Sometimes, the cause is a drift over time in quality oversight. Other times, it's a lack of resources. Whatever the cause, FDA has a way of finding vulnerabilities, and the company is left with a new reality where remediation is a mandate, along with running the actual business.

In this article, we’ll discuss how to respond when your organization receives one of these formal declarations of FDA concern. These practices are based on our years of experience, including guiding clients through the journey from citation to successful remediation.

Let’s begin by setting the context. The cost of quality and compliance grows exponentially the further you are in the development of your product, and a 483 observation is like an IRS notice:  It doesn’t go away. So, if one comes along, commit to a thorough response with actionable follow-ups that the FDA can measure. That can avoid escalation to a warning letter.

Remember: the sky is not falling, but it may be a bit cloudy for a while. A quality remediation project can last from a few months to over a year, pulling resources from development or ongoing business operations. Like any business obstacle, a response requires dedicated, focused efforts to resolve the problem and, ultimately, leave your company with a competitive advantage.

To that end, here are the six essential best practices to navigate a 483 or warning letter response:

1. Immediately secure executive leadership support and the right expertise.   

While your head of RA/QA is tasked with leading the response, he or she cannot do it alone. Executive management should be brought on right away to enable and support the response, marshal resources, prioritize company attention, and run external interference. Their support will be key to closing your 483s and warning letters.

Remember, this is an extremely labor-intensive effort and timelines are short, so make sure you have the right in-house resources and expertise and, if not, consider outside help. Regulatory legal advisors and expert regulatory consultants are great at shaping the overall message — both the content and the delivery — in a way that protects your business. For example, they will know how to set the right tone, when to include company executives on correspondence, and how often to correspond with FDA.

Identify leaders within each function area that pertains to the 483; typically, these would be regulatory, quality, compliance, and clinical. This team will be responsible for overseeing the response and the daily (or every-other-day) briefings that will keep executives apprised of progress and prevent meddling.

2. Set the emotional tone: calm and supportive

Remain calm. Once people understand management is committed and in control, they’re likely to stick around and contribute to remediation.

It is also important to acknowledge the severity and significance of the situation. Some portion of the staff will have an “I told you so” attitude, while others will be dazed by the sudden change they are facing.  Listen, engage, and respond to concerns and comments, as your staff may offer useful information for your response to FDA.

Your staff and other stakeholders will realize that the response to FDA is like a new full-time job on top of their regular job. Acknowledge this new reality and show that the company is committed to easing the burden either by providing more resources or temporarily removing some responsibilities.  One of our most successful response teams for a client was composed of 12 dedicated resources, assigned just for the response. The CEO stood in front of his entire team and said, “We do not have to do this alone.  The cavalry is here to help us.  And if we need more help, we will get it!”

3. Organize: Open the communication channels and keep them open.

Writing a response to FDA can be a little like coming across an automobile crash on a busy highway. It's human nature to want to rush in and get involved. It is important to harness this enthusiasm and create parallel work streams. Assign teams to work on responses to each observation. This can also free up time for RA and QA to guide or lead efforts to collect and analyze data. 

Inform the members of the teams about needs to be done, who is going to do what, how everyone will be kept on the same page, and what the timeline is. This is an ideal time to have your executive support on display, committed to getting resources and acknowledging what lies ahead.

It is critical to hold a regular team meeting — typically weekly, in the beginning — to provide status updates on how observation responses are coming together. Inquire if executive management wants to participate. This structure allows staff to stay connected, holds workstream leads accountable, and provides a non-threatening environment for executive involvement in the response. Use one of the first status meetings to craft a communication plan that helps maintain broad stakeholder alignment.

An often-overlooked element of compiling a response is basic logistics. A response to FDA can be a hefty document — many are in paper form — with hundreds of attachments.  It may seem mundane, but make sure you have the right tools to carry out this labor intensive, paper-laden, organizationally demanding project. For example, printing 8 to 10 copies of a two- to three-volume response can take an entire day on a standard speed printer.  

4.  Write a thorough, proactive response.

Issuing the initial response to a 483 is one of the most critical regulatory responses you will ever have to provide to FDA. A well-done, thorough response can change the tenor of the interaction with FDA and establish your company’s commitment to quality. Conversely, a misguided or antagonistic response can be a key reason for escalation to an enforcement action.

A well-constructed cover letter that emphasizes your company’s (and its executive team's) commitment to quality and compliance sets a positive stage for responding to any FDA findings. Like all good scientific writing, a good cover letter should state up-front what you are going to tell the agency. A message of “we hear you” and “commitment to patient safety is paramount” should be reiterated throughout the response. In cases where the 483 is complex or resources are limited, it may be wise to state up front that expert consultant(s) have been engaged to assist in remediation, showing the company's commitment to thorough remediation.

The more comprehensive the response, the more FDA will be assured that your company takes its concerns seriously. We were recently engaged by a client who received a warning letter following three inspections over three years, each with 483 observations  Every response to FDA contained rationales as to why the inspectors missed key data or were just plain wrong. While in some cases the assertions may have been accurate, three years of observations, by different teams and with no evidence of real evaluation and change by the company, had the predictable outcome of a warning letter. The takeaway lesson is the importance of a proactive response.

Although it can be difficult to distinguish between them, 483 observations can be divided into “one-off” or systemic observations. However, a good root cause analysis will help determine if, for example, a complaint that was not closed on time was due to sub-par operator performance or poor processing flow of that complaint. 

Every observation should have a thorough root cause analysis performed and, if necessary, one or more corrective and preventive actions (CAPAs) identified, along with a CAPA reference. (Next month’s article will discuss why you should embrace your CAPAs.) In the case of “one-off” observations, adequate responses are often based on surveillance and training. A systemic observation usually requires fundamental or broad process changes, which must be described in the response. 

The final element of a successful response is the description of a set of actions or programs to correct and prevent recurrence of FDA observations. Instill confidence in the remediation plan with realistic due dates, competent people to lead them, and specific outcomes that can be measured and documented. This is where the proverbial rubber hits the road:  Failure to demonstrate proof of corrections could lead to more compliance risk, escalating a 483 to a warning letter or a warning letter to a consent decree.

A note about timelines: FDA would rather see viable due dates that correct the root cause with a sustainable solution than quick, superficial corrections that could result in further FDA inquiry. As with most projects, it’s better to set up a realistic timeline and come in early than to explain a delay.

5. Engage a range of internal and external stakeholders to thoroughly review the response.

As this massively important document comes together and the reply deadline is fast approaching, who should review and comment?  Internal reviewers typically include executive management, key functional heads, regulatory/quality, legal, and compliance. Many times, marketing and R&D also weigh in, depending on the observation. These are important voices and represent the teams that will have to implement any follow-up actions committed to by the company.

External reviewers can provide a second or third opinion to identify gaps in the response or tweak key messages. Regulatory advisors or consultants experienced with FDA communication should review the response. We often recommend more than one review — for example, a review on day one or two to hone the theme, and another once the draft is compiled, to fine-tune specific messages.

6. Timing is everything.

Remediation should start the day after receiving a notice of 483 or a warning letter. FDA requires a response to most compliance notices within 15 business days. Although FDA doesn’t have to confirm your response, it is a good idea to contact the agency and confirm receipt.   

In your written response to FDA and in any phone/email correspondence, voluntarily establish a follow-up plan. Set a schedule for providing regular updates following the response. Monthly updates often make sense, but for warning letters or field actions, bi-monthly is recommended. Whatever schedule you choose, it is important to demonstrate your company’s commitment by sticking to the schedule.

Take and maintain control to achieve a successful response

Although responding to a 483 can be a complicated process, it can be reduced to several key components: Acknowledge the observation at the executive level, quickly ascertain the root cause, react with commitment and urgency, acknowledge when you need outside expertise, and show progress. Follow these steps and you’re well on your way to a successful response.

About The Author

Angela Brown joined Halloran Consulting Group in 2015 with 20 years of regulatory affairs and quality assurance experience in the medical device industry. Angela has experience in successful global regulatory strategy for new and existing product lines, developing quality systems processes, and working across multiple commercial and R&D functions. At Halloran, she focuses on regulatory strategies and submissions as well as the development and implementation of quality processes.

Prior to joining Halloran, Angela served as VP of regulatory affairs and quality assurance at Plasma Surgical, where she addressed strategic initiatives, obtained worldwide regulatory approvals, implemented and maintained quality systems to meet global compliance requirements, and lead and developed staff. Prior to Plasma Surgical, Angela held contributing roles for more than 15 years C. R. Bard as the director of regulatory affairs and at Teleflex as a senior manager of regulatory affairs in various regulatory and quality roles, including sterilization, environmental monitoring, audits, compliance, training, design controls, U.S. and OUS regulatory submissions, and recall assessment and management.

Angela earned a bachelor of science in biology from Campbell University in Buies Creek, N.C. She is an active member the Regulatory Affairs Professional Society (RAPS), where she has published papers and has been a guest speaker at multiple events. Angela is Regulatory Affairs Certified (RAC).