Terry Winchell

	My background with government inspection has been on both sides, being an Inspector & Investigator with the FDA (U.S. Food & Drug Administration) for about 10 years, then working in industry primarily in the area of GCP (Good Clinical Practice). I’ve seen the results of many inspections, investigations and audits, done 100’s myself in various industries regulated by FDA, including the GCP and GMP (Good Manufacturing Practice) areas, and am going to focus this brief article on some of the very basic things I’ve learned, some of them obvious, and some not so obvious. While the general focus of this article will be on GCP & CQA (Clinical Quality Assurance), these principles can be applied to any audit or government inspection.

	There are 3 basic factors affecting the outcome of any FDA GCP inspection, generally in this order of priority:

	This one is obvious and overall is the most significant, however just because the inspected site is essentially in compliance doesn’t necessarily mean it will, at least initially, pass the inspection. Even if the site is in general compliance there is often information that is not communicated well or is simply misunderstood by the Inspector. While there are checks and balances to prevent this from happening, the complex nature of many inspections offer increased opportunity for misunderstanding. Additional contributing factors include but are not limited to: 

		Communication problems either by personalities involved or language barriers

		Inexperience on the part of management staff reviewing the Inspector’s report

		The Inspector not providing complete written explanations in their report

		The inspected site being afraid, not having the time, experience, or ability to defend themselves against questionable observations 

	The good news here is that if an inspected site is in compliance, misunderstandings can often be explained later, but the effort to do so could be a significant drain on time, money, and reputations in the meantime. 

	There can be a vast difference in this area. This isn’t meant to diminish the value of inspections & audits or the general competency of the staff performing them, everyone goes through a learning curve on any job. In particular though with GCP, there are numerous judgement calls that must be made regarding the relevance of each observation. 

	In the clinical trial industry, mistakes are nearly always made at every research site with every protocol. We’re dealing with live subjects, numerous physician controlled sites conducting studies all over the country or the world, constantly changing protocols, investigational new drugs, safety issues, etc. An absolutely perfect study is nearly impossible to attain, and if one is submitted that in itself would be suspect, calling into question the legitimacy of the data. Unlike GMP, GCP has a different system of operation at each site, often without the benefit of onsite QA (Quality Assurance) or QC (Quality Control) (1) as is routinely the case with GMP or GLP (Good Laboratory Practice) operations.

	In the area of FDA GCP, Inspector judgment is critical, but equally critical and possibly even more so are the judgments made by those directing the Inspector(s) and reviewing their report. Even the best Inspectors & Investigators never get 100% of the relevant information. Going into a place of business for a 1st very limited period of time and understanding everything completely is very difficult, and can never be to the level of the people that work at the inspected site on a daily basis. There typically are some misunderstandings, if these happen to be in a critical area it could affect the overall assessment of the inspection, I have seen this happen. Those misunderstandings can be compounded by the multiple levels of review as the Inspector’s report is processed through the agency or audit organization. 

	Competency of the Inspector does not necessarily favor an eventual positive or negative outcome for the inspected site. An inexperienced Inspector may overlook critical items that would trigger an out-of-compliance assessment. On the other hand, and this is particularly true with GCP, deficiencies that don’t fall into the critical areas of subject safety, valid data or investigational product control (2), are at times considered more significant than they actually are, potentially resulting in an essentially in compliance site being assessed as out-of-compliance.

	In the area of clinical trials this is the only inspection outcome area that can be controlled by the inspected site after the study has been completed. There are articles written on how to manage this type of FDA (GCP) inspection (3) but that is not the focus here. The point is that how the inspection is managed can have a significant impact on the outcome, and that impact can either be positive or negative, particularly so in the case of borderline situations that could be assessed on either side of the coin. 

	An essential ingredient of inspection management is good communication, an Inspector may be unaware of mitigating circumstances that could explain a questionable observation. Other significant ingredients of inspection management include but are not limited to:

		Selection of the right individual (“point person”) to accompany the Inspector and initially field questions

		Having a detailed SOP regarding how to handle government inspections & industry audits

		Having a designated room for record review and being aware of Inspector’s location at all times

		Making duplicate copies of all documents copied by Inspectors in case questions arise later

		Answering questions honestly and completely but not going further unless necessary to explain

		Promising and following through with corrective actions at the conclusion of the inspection

		Being available throughout the inspection and checking with Inspector(s) daily to see if questions arise

		Providing a written response to any List of Observations left by Inspector such as Form FDA 483

		Knowing what is subject to inspection and what is not (such as internal QA audits)

		Not routinely signing any written statements or Affidavits

	And the list goes on. The goal is to make the inspection process as expedient & efficient as possible, provide honest accurate information, and to be well organized, but also realizing that you are dealing with a law enforcement organization in the case of government inspections and it is prudent to know your rights, what is subject to inspection, and most of all to communicate information succinctly and accurately. If there are misunderstandings that are discovered later those should also be clearly explained in the same professional manner. Most Inspectors & Auditors will appreciate this organized approach since it often makes their job more expedient as well. 

	The value of this process is significant. It’s quite true that you cannot change what has already occurred in a clinical trial, but you can effectively control the accuracy, efficiency, and positive communication of what did occur and why. 

	The best defense against any audit or government inspection is to know what is required and to do it right from the very start, always beginning this proactive approach as far up stream in the process as possible (4). 

	After a clinical trial has been completed you are then faced with the possibility of inspection. When that occurs the inspected site is somewhat at the mercy of the Inspector(s) involved. An inexperienced Inspector can err on either side, one being exploiting deficiencies that have no significant bearing on the trial, the other being overlooking critical problems, both of which are tentatively in control of the Inspector. What can be controlled by the inspected site at the time of inspection is how the inspection is managed. This can without a doubt have a significant impact on the eventual assessment, and if done right it will be a positive one even if significant deficiencies are found. 

	The outcome of any inspection or audit is a blend of the compliance level of the inspected site, Inspector/Auditor & reviewing agency competence, and how well the audit or inspection is managed. The interplay of these 3 factors, which can be comingled in a variety of interesting ways, determines the eventual outcome. 

	1), T. Winchell, J. Avellanent, “PART 1 - Cost-Effective GCP Auditing”, Smarter Compliance Vol 4 Issue 8, p. 1, 6/7, August 2010

	2) T. Winchell, “The Heart of GCP”, SOCRA Source p. 41, February 2006 

	3) T. Winchell, “Preparing for an Imminent FDA Clinical Investigator Inspection”, Quality Assurance Journal, p. 126/131, March 2011 (hardcopy) via December 2009 issue

	4) T. Winchell, “Is It Too Late for Quality?”, Quality Assurance Journal, p. 294/296, December 2005

	Terry Winchell is an author for GCP Innovative Dynamics, LLC and can be reached at 

Articles

This article focuses on the 3 essential factors that have a significant impact on the outcome of any inspection or audit. The author applies this primarily to GCP (Good Clinical Practice) inspections, but the principles are universal, being applicable to any government inspection such as the FDA (U.S. Food & Drug Administration) or industry QA (Quality Assurance) audit.

Terry Winchell

Articles

The 3 Essential Factors Affecting FDA Inspection Outcome