Effective Responses to Form FDA 483
An FDA inspection can result in a Form FDA 483, Inspectional Observations, being issued by the FDA field investigator. How you respond can determine whether the 483 will result in a Warning Letter, the primary form of FDA enforcement actions. How to respond to a 483 is a topic of discussion for regulated industry since the 483s arose in the early 1950s, originally as an attempt by FDA to respond to industry complaints that FDA didn’t inform industry about the field investigator’s findings prior to initiating an enforcement action (at the time primarily seizures, injunctions, and prosecutions). In this Guest Commentary regular
GxP Perspectives contributors Emma Barsky and Len Grunbaum list the problems that FDA has found with responses to 483s and some proposed solutions.
Guest Commentary: One Way to Avoid a Warning Letter … Maybe
The following sentence fragments represent but a very small sample of trumpet calls heralding that a firm may have fumbled an opportunity to avoid a Warning Letter after receiving an FDA-483:
• “We have reviewed your response and have concluded that it is not adequate because…”
• “The adequacy of the response cannot be determined because the response did not include…”
• “Your response does not address…”
• “We have reviewed your firm’s response and note that it lacks sufficient corrective actions regarding…”
• “We have reviewed your firm’s responses; however we continue to have concerns related to your firm’s compliance…”
• “The adequacy of your firm’s response cannot be determined at this time…”
• “Your response is inadequate because…”
We say this because of the following: while a response to an FDA-483 is not mandatory and does not represent a final Agency determination regarding firm’s compliance, a firm’s voluntary response often does impact the Agency’s conclusion of the need for follow-up actions, one of which may be the much feared and dreaded Warning Letter. How so, you ask? Here is how….
"FDA will conduct a detailed review"
in section 5.2.7 of the Investigations Operations Manual, “If FDA receives an adequate response to the FDA-483 within 15 business days of the end of inspection [emphasis added]”, FDA will conduct a detailed review of the response before determining whether to issue a Warning Letter. Alternatively, responding late negates any chance that the FDA will consider the firm’s responses in its resolution regarding whether a Warning Letter is warranted and not responding at all, of course, has the same outcome as responding late.
This brings us to the quality of the response itself. In this context, the higher the “quality” of the response, the more likely the FDA will consider the response as “adequate” and, as a result, may not issue a Warning Letter. Since the firm’s management controls the quality and timeliness of everything that goes on, we suggest that the following guidelines be used to craft the response to the FDA-483 to increase the firm’s chances of avoiding the Warning Letter:
• Train the individuals involved in the FDA-483 response effort regarding what information should be included in the response and the format chosen to present the response.
• Assign someone to review recent FDA Warning Letters to identify those items where the FDA indicates that the response to the respective FDA-483 was not adequate and include these items in the training to ensure that known mistakes/failures are not repeated.
Focus Your Response
•
Focus on evaluating the extent of the observation in terms of whether the issue could have potentially impacted data integrity, and, if so, whether the issue is systemic (e.g., how many studies, batches, sites, etc. could be possibly affected). This is the most important point to address in terms negating the observation or softening the impact of the observation. If an observation points to actual data integrity issues, these issues need to be brought to the attention of the respective sponsors, where applicable, and responses to the FDA should be discussed with them first.
• Establish the true root cause of the observation. In doing so, look for the operational gap (e.g., inefficient project management oversight) that resulted in the regulatory deficiency (e.g., lack of timely document reviews and/or approvals) so that it can be fixed properly and permanently.
• Provide specifics regarding any corrective actions taken or proposed. It is not adequate to state that the problem was or will be corrected. Details regarding 1) what was/will be corrected (e.g., development of a remediation plan), 2) when it was/will be completed and 3) if applicable, the timeframe for training (e.g., as in case of a revised procedure) should be provided.
• Describe preventive actions that will minimize or eliminate the chance of recurrence of the problem in the future.
• Provide supporting documentation for every claim made.
• Show commitment regarding implementing all of the proposed activities by 1) specifying activities to be taken and target dates for their completion, 2) assigning accountability for the actions, 3) ensuring proper completion of each respective activity though internal audits.
The Importance of a Quality Response to FDA 483s
The quality of the response to the FDA-483 is also important for another reason: groups like FOI Services request the Establishment Investigation Reports (EIR) and FDA-483s through the FOIA, so this information eventually winds up in the public domain.
The firm can request that its FDA-483 response be published along with the FDA-483 itself, in which case the response should be such that it gives confidence not only to the FDA but also, where applicable, to existing and potential clients, that non-conformities have not and do not impact data integrity.
The bottom line is this: Do not ever get yourself in trouble with the FDA. But if you do, avoid unforced errors by 1) taking the time and making the effort to respond to the FDA-483, if you get one, in a timely fashion, 2) using the guidelines above in doing so, or 3) consulting with an expert to assist.
By Emma Barsky and Len Grunbaum, the partners of The Practical Solutions Group, LLC
Contact Emma & Len
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ExL Pharma has announced that FDA’s Dr. Leslie Ball will give the Keynote Address at the 2nd annual Developing CAPAs in the GCP Environment conference held 19-20 January in Arlington, VA. GxP Perspectives is a media sponsor.
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Read FDA Warning Letters A suggested practice is to search Warning Letters by topic or issuing office. Then sort by “Letter Issue Date – Desc” to find the most recent Warning Letters.
19 October 2011 update: FDA posted a Warning Letter to SmithKline Beecham (GSK), West Sussex, UK for serious cGMP violations stating: “Your firm has not established appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile.”
Read the Warning Letter
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On The Blogroll: Rebar Interactive (twitter: @rebarinte) has an excellent blog for clinical sites. If nothing else you MUST check out their post on:
“Patient Recruitment: Think That You Might Be Wrong,”
if for nothing else than the photo. A great blog post by Rahlyn.
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Commentary on Plan B Controversy
December 28, 2011Kathleen Sebelius Overturns FDA on Plan B
The following Guest Commentary by April Mayberry discusses this decision. In it she gives her opinion on the Plan B decision. GxP Perspectives, as always, welcomes your own viewpoints and opinions.
When Politics & Science Collide
Plan B Emergency Contraception
In her statement posted on the HHS website, Sebelius said that Teva didn’t provide sufficient evidence that Plan B could be used safely in very young adolescent girls, or that they could understand the labeling. She said if Teva could produce data to the contrary they could refile. If Sebelius’ decision was intended to protect girls, it doesn’t seem logical.
• An adolescent girl has a much higher chance of serious complications from an unintended pregnancy or an abortion than from Plan B.
• Other potentially dangerous OTCs used, and even abused, by young women have no such restrictions. This includes diet pills, cold medicines, aspirin, ibuprofen and acetaminophen, all of which are associated with serious and/or fatal AEs.
• In my experience, controversial products not indicated to treat immediately life-threatening conditions must meet a particularly high approval standard. In a public statement appearing on the FDA website, FDA Commissioner Margaret Hamburg said:
“The Center for Drug Evaluation and Research (CDER) completed its review of the Plan B One-Step application and laid out its scientific determination. CDER carefully considered whether younger females were able to understand how to use Plan B One-Step. Based on the information submitted to the agency, CDER determined that the product was safe and effective in adolescent females, that adolescent females understood the product was not for routine use, and that the product would not protect them against sexually transmitted diseases. Additionally, the data supported a finding that adolescent females could use Plan B One-Step properly without the intervention of a healthcare provider.” In the same statement Dr. Hamburg contended that:
Dr. Margaret Hamburg, FDA Commissioner
So if FDA used the standard review process why isn’t it enough? Most agree this decision was not based on science. One can only speculate why Sebelius, an Obama appointee, with a strong record regarding women’s reproductive rights, would do this. Possible reasons that come to mind are:
There has been pressure from the religious right on the government against Plan B and contraceptives in general. Plan B is of particular contention, because some mistakenly believe that it terminates pregnancy. Reportedly while governor of Kansas, Sebelius at times modified policy under pressure when it was seen as a political advantage
(also reportedly in these instances the decisions didn’t pose a risk of clinical or other harm to women. In light of reports that she is a subject of backlash by the church.) and of a lawsuit by Belmont Abbey College over the mandate requiring them to provide contraceptive coverage in their health plan, it’s feasible OTC access to Plan B for girls under 18 was sacrificed in lieu of mandates Sebelius considers more crucial, such as requiring health-care plans to provide contraceptive coverage. (Sources: RealityCheck.org, National Catholic Register, and Washington Times)
Should Teenagers Have Access to Plan B?
Women over 17 are also affected. Having to present an ID to a pharmacist can cause distress for some. Additionally many pharmacies have limited hours, and in some states some pharmacists may refuse to provide Plan B under the “conscious clause”, all causing delays in accessing it within the optimal treatment window. This is of particular concern for poor women in some rural or inner city communities with few pharmacies and for women with no ID.
Sebelius’ decision may also stifle contraceptive development. According the New York Times this is the first time that the HHS has blocked approval of a product by the FDA. This sets a precedent, allowing approval of contraceptives or other controversial medical products to be blocked without scientifically valid reasons. This is very problematic, because it allows those with political motives to take our national policies and the scientific process hostage to fulfill their own agenda, simply by applying enough political pressure.
April Mayberry, RAC, CCRA, CCRP, CFPHW *
* Certified Family Planning Health Worker
Dr. Hamburg’s Statement on Plan B
Secretary Sebelius’ Statement on Plan B
Pharmacist “Conscious Clause”
NT Times article on Sebelius curtailing availability of Plan B
National Catholic Register Article on Sebelius
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January GCP Training Opportunities:
ExL Pharma has announced that FDA’s Dr. Leslie Ball will give the Keynote Address at the 2nd annual Developing CAPAs in the GCP Environment conference held 19-20 January in Arlington, VA.
GxP Perspectives is a media sponsor.
At the same time and the same place the Trial Master File Summit is taking place with some excellent speakers. Find out more:
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