What everyone should know about responding to Warning Letters.

It takes less time to do something right than it takes to explain why you did it wrong.

-Lee’s Law

Interestingly enough, many people do not take advantage of the Warning Letters posted on the FDA website.  Personally, I always prefer to learn from the mistakes of others, rather than flounder through the same mistakes on my own.  Reviewing the Warning Letters and responses (and the FDA’s opinion on those responses) provides insight into both how clinical sites respond to FDA findings, and what the FDA considers an effective response.  Repeatedly, what is demonstrated is that for real estate it may be “location, location, location”, but for an effective response to Warning Letters, it’s “CAPA, CAPA, CAPA” (i.e., corrective and preventative action).  In fact, the FDA has even posted presentations on what is expected in a constructive response to FDA Form 483 observations (much of which is blatantly plagiarized here).  These guidelines for preparing an effective response apply to Warning Letters, untitled letters, and FDA Form 483 findings (if you’re confused about the differences, see the recent CATO blog by Leo DiNapoli).

So, how do you write an effective response?

Step 1: Review the regulatory requirements associated with each finding, and assess each observation individually for the following:

  • Specifics (what exactly was noted)
  • System-wide implications (what does this finding imply about the processes at the site)
  • Global implications (how could this affect the site’s conduct of studies in general and the value of the data from the current study)

It can be helpful to consider root-cause analysis.  If you understand what caused the event the FDA cited, you are more likely to be able to provide a pertinent response.  As part of your response, the FDA expects an action plan for immediate, short-term, and long-term CAPA, which leads us to the next step.

Step 2: Respond to each observation, and provide accomplished or planned corrective actions.

  • Specific (e.g. observation-by-observation)
  • Complete
  • Realistic – be able to deliver what you promise
  • Include time frames for correction
  • Include method of verifying and monitoring corrections

Completing the first two steps can convince FDA that you understand the observations, and help you regain credibility.  However, you’re not done yet.

Step 3: Convince FDA you can get it done.

  • Include a commitment/statement from senior leadership
  • Submit documentation of CAPA where possible

This step demonstrates commitment by the individuals in charge to correct the deficiencies, and provides evidence of corrective actions that have already been accomplished.  This is not a time to cast blame – there are a number of Warning Letters posted where the investigator responds to FDA that the deficiencies have been corrected by firing the staff.  Strangely, this is not considered an effective response unless it is accompanied by a CAPA plan to address training and oversight of the new staff.  For example, in a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) letter to David Loucks:

“Per the report to the Center and your response letter, dated June 4, 2008, you concur with these observations. You stated that you take complete responsibility… but that the fault lies with your “unqualified study coordinators.” You stated that you were not aware that your signature had been forged on study-related documents until November 2007. …Your written response… offered no detailed corrective action plan…On the basis of the above-listed violations, FDA asserts that you have failed to protect the rights, safety, and welfare of subjects … and the FDA proposes that you be disqualified as a clinical investigator.”

The investigator is responsible for oversight of the clinical staff – a history of poor performance by the staff is evidence that the investigator is also not performing his responsibilities adequately.  Last, but certainly not least:

Step 4: Be on time.

A response is required in 15 days or less for Form 483 findings as of 9/15/2009; Warning Letters also typically specifically request a response within 15 days.

After 15 days, FDA will take whatever steps it feels are necessary without any input from you – not a good situation.  This is not to say that FDA can’t act before the end of the 15 days, particularly if there is a significant risk to subjects in an ongoing study.  However, it’s generally better for all parties if the site can correct the problems without further FDA action.

As a case in point for effective and ineffective responses, compare these two Warning Letters, one to Ali Rezai and one to Michael Miller.  Observations were similar (protocol deviations, records and financial disclosure, versus protocol deviations, records, informed consent, and test material accountability), but the responses were diametrically opposite.  Rezai provided a response, corrective action, and preventive plan for each observation.  Miller stated that it was extremely difficult to find trained staff in his area, that his research coordinator failed to perform corrective actions, and explained that he had had a family crisis and plans to move to a more urban area where he feels he will be able to find trained staff if he ever again chooses to be involved in clinical research.  I’ll leave it to you to decide which response was considered adequate.

On the plus side for the unlucky or unprepared individuals who have received Warning Letters, FDA has instituted a Warning Letter close-out process.  Once an adequate response is received (and typically after the FDA re-inspects the facility), the FDA can issue a Warning Letter Close-Out Letter indicating the site has remedied the observed defects -just one more reason that an effective (and timely) response is critical.

This is a post by Cathy Anderson, Ph.D. Cathy is a Regulatory Scientist at Cato Research.

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