Saturday, October 9, 2010
"We have reviewed your firm's FDA483 response, however..."
I remember a class exercise in "Quality School" in which you counted the number of F’s in a paragraph. Remember? The one where you got a different number with each try? The point was to illustrate: one hundred percent inspection does not detect defects one hundred percent of the time.
That exercise came to mind again when I tried counting how many times some form of the word "inadequate" appeared in the recent Gilead Warning Letter1. I think it was eighteen times. But—I’m not absolutely sure.
Most likely eighteen is not the record, but the point is not lost on the reader: the Gilead response to their FDA483 was—shall we say—inadequate. This prompted the Warning Letter.
FDA told the company dominating the HIV treatment market that their response was inadequate because:
· Your rationale was incomplete
· You do not have justification
· You provide no timeframe
· You provide no details
· You did not specify how you intend to document
· You did not provide the scientific rationale
· You did not describe how you will evaluate
We should have a pretty good idea of how to respond to FDA483's by now, since the FDA has been publicly pointing out inadequate responses to FDA483s in Warning Letters on their website since 1996.
More specifically, Anita Richardson, Associate Director for Policy, Office of Compliance and Biologics Quality, has given suggestions for writing an effective response.2
It's like being given the answers in the back of the book, except it's not just for the odd-numbered problems.
So take notes, class. Ms. Richardson says:
1. Include a commitment/ statement from your senior leadership
2. Address each observation separately
3. Note whether you agree or disagree with the observation
4. Provide corrective action accomplished and/or planned. Tell the FDA the plan.
a. Be specific (e.g., observation-by-observation)
b. Be complete
c. Be realistic
d. Be able to deliver what you promise
e. Address affected products
5. Provide timeframes for correction
6. Provide method of verification and/or monitoring for corrections
7. Consider submitting documentation of corrections where reasonable and feasible
8. BE TIMELY (Ms. Richardson’s emphasis.)
Unfortunately, by the time an FDA483 response filters through layers of management and the legal department, some industry responses read as though the following principles had been applied:
1. Have the communications department write a sincere cover letter for the president to sign.
2. Never agree with the observation, as this will be interpreted as admitting guilt.
3. Respond as generally as possible to allow maximum flexibility.
4. Don’t look anywhere else other than the specific problem cited in order to limit our liability.
5. Don't give lot numbers of potentially affected product, since this will provide the seizure list to FDA.
6. Don’t put anything in writing because documents are legally discoverable.
7. Don't provide additional documents, as this gives the FDA more material to find objections.
Ms. Richardson’s advice is excellent, and my parody—although used at some firms—just calls fire on your position.
In summary, count the F’s:
For faring fine in the future with our federal friends, firms must faithfully follow forthright fundamentals. Felonious firms finesse and finagle forgetting that forthwith our federal friends will find and fine them.
1 Gilead Warning Letter, San Dimas, CA, September 21, 2010
2 Richardson, Anita, Writing an Effective 483 Response
The QA Pharmhttp://theqapharm.blogspot.com