One of the basic rules when playing in the FDA’s sandbox is “when inspectional observations are awarded to an offending establishment via a Form 483, the FDA expects a response.” Can you say 15 days? Dr. D knew you could. Seriously, failing to respond to Form 483 observations is always going to end badly. Can you say FDA warning letter? Dr. D knew you could. Not only does the FDA expect a response to each Form 483 observation, they expect the response to be written in English using reasonable English composition skills. Additionally, the response should reflect enough information so the FDA has a clear understanding of the actions proposed by the offending establishment in support of remediation of objectionable practices. The doctor hopes that all chief jailable officers (CJO’s) working for device establishments that enter or wish to enter finished medical devices into commerce in the United States, understands the very basic rule that form 483 observations require a response and not a nebulous(look-it-up) response. Period!

Warning Letter – January 12, 2018

The warning letter referenced in this week’s guidance was probably issued, in part, (conjecture on the part of Dr. D) due to the fact that no response to observations was made during a September 2017 visit to the offending establishment. Simply stated, a failure to respond to form 483 observations equates to a warning letter in an offending establishment’s future. One does not need to be clairvoyant to see the regulatory can of whoop-ass about to be unleashed by the agency. Yes, there were multiple observations noted, five in all, plus a failure to establish an MDR procedure. Additionally, the agency requested a meeting with the offending company to discuss design and indication for use changes that the agency believed violated the offending establishment’s 510(k). Ouch!

Warning Letter Excerpt

“We did not receive a response from your firm to our investigator’s observations noted on the Form FDA 483, List of inspectional observations that was issued to your firm on September 11, 2017. The violations include, but are not limited to, the following…”

Compliance for Dummies

Rule number one, FDA inspects device establishments and issues Form 483 observations when violations are noted. Rule number two, device establishments are expected to respond to form 483 observations (i.e., Rule #1). My dear readers, it does not get any simpler than that. However, responding to Form 483 observations is a unique art form. For starters, the CJO should fall on the proverbial sword and be contrite if an observation is valid. CJOs should never argue with the investigator during the debrief held on the last day of the inspection. CJOs will seldom if ever win arguments during the closing meeting. Remember, the FDA is trying to perform a difficult task at best, and inspections are never fun. If a CJO disagrees with an observation, present a tactful rebuttal.
At the end of the inspection, if a Form 483 is issued, ensure it is annotated to reflect management’s commitment to correct the deficiencies noted. Device establishments do not have to provide a solution at the end of an inspection, only a commitment to correct.

When responding to the observation(s), ensure that three states are assessed, and the doctor is not talking about actual states, the states are: (a) past state, (b) present state, and (c) future state. The establishment needs to address the past state in a manner that clearly describes why the compliance lapse occurred (a.k.a. root cause). If the compliance issue impacts product already entered into commerce, the FDA is going to want to understand the potential impact (risk) to the patient and user (a.k.a. containment/present state).

Next up: The correction plan(s) should be shared with the agency. Some corrections may take some time to implement. The agency clearly understands the dilemma associated with resolving complex compliance issues versus the need for time to implement and verify that the changes are effective. Script a viable plan and stick to it. That is the FDA’s expectation.

Once the plan(s) has/have been fully executed and verification of effectiveness activities have been successfully performed (future state), provide objective (and documented) evidence of completion to the FDA. “In God We Trust; all others provide data.” If the FDA does not receive objective evidence of correction, how in the heck is the agency going to close out the Form 483 observation(s)?

Finally, Dr. D cannot place enough emphasis on documenting all of the actions taken, while providing the FDA with written responses and updates. The key to preventing a warning letter is in the timeliness of the response and the quality of the response to inspectional observations. Unlike hurling hand grenades, accuracy does count. If necessary, the CJOs of the world, once they receive a Form 483, should stand and click their heels together while chanting (three times), “15 days, 15 days, 15 days.” Why, because on Day 16, bad things will start to happen if a response is not received by FDA.

Takeaways

For this week’s guidance, the doctor will leave the readers with two takeaways. One: FDA inspectional observations require a response with 15 days. Two: The response shall be well written, intelligent and contain sufficient granularity to convince the FDA the offending establishment actual understands the problem and has proposed a reasonable plan to bring the establishment back into compliance. In closing, thank you again for joining Dr. D, and the doctor hopes you found value (and some humor) in the guidance provided. Until the next installment of DG, cheers from Dr. D., and best wishes for continued professional success.

References

1. Code of Federal Regulation. (2017, April). Title 21 Part 820: Quality system regulation. Washington, D.C.: U.S. Government Printing Office.
2. Devine, C. (2011). Devine guidance for complying with the FDA’s quality system regulation –21 CFR, Part 820. Charleston, SC: Amazon.
3. Devine, C. (2013). Devine guidance for managing key attributes of a FDA-compliant quality management system – 21 CFR, Part 820 Compliance. Charleston, SC: Amazon.
4. FDA. (January 2018). Inspections, Compliance, Enforcement and Criminal Investigations. BioModeling Solutions, Inc. Accessed January 27, 2018. Retrieved from https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm592704.htm