In August 2003, FDA published a new draft guidance that proposes a formal process for resolving disputes of scientific and
technical issues relating to current good manufacturing practice (cGMP) requirements (1). FDA is opening new opportunities
for companies to interact with agency officials to resolve disputes more formally than in the past. FDA is now proposing to
raise such disputes to the Office of Regulatory Affairs (ORA) and center levels — Center for Drug Evaluation and Research
(CDER), Center for Biologics Evaluation and Research (CBER), and Center for Veterinary Medicine — with options for reviews
by a Dispute Resolution Panel for scientific and technical issues pertaining to pharmaceutical cGMP issues.
(Click here for a review of FDA dispute resolution practices and procedures: www.biopharm-mag.com/biopharm/article/articleDetail.jsp?id=77430.)
Although the agency proposes to adopt some new and novel ways to handle disputes, resolution can not be expected unless companies
understand and follow certain practices and procedures that have been in place for many years. This article describes effective
techniques to prevent disputes from arising and offers companies some practical ways to reach closure when they find there
are legitimate differences of opinion between their experts and those of FDA.
In every case, successful dispute resolution depends on both the company and FDA reaching a common understanding of the issue
at hand. Once the issue is clearly identified, the company may explain why the ruling or decision is inappropriate and may
even challenge the underlying premise or approach that is being taken by the agency.
Companies have always had the opportunity to obtain clarification of scientific or technical issues from the inspection team
at any time during an inspection, but the practices and procedures followed by FDA were not always optimal for promoting dialogue
between FDA and manufacturers. Furthermore, while FDA has always allowed companies to present the rationale behind disputed
issues, many company officials did not know what specific data and information to provide.
During an FDA inspection — either a preapproval inspection, technical review of an application, or routine surveillance or
compliance inspections — a company may find itself in disagreement with FDA about scientific or technical issues (or it may
disagree with the basis for a ruling or decision). There are a number of key actions that can improve the chances of a successful
outcome, including, but not limited to the following:
Agree on The IssueFDA officials make decisions and rulings based on information and data that have been provided by the company in their applications
or the findings of FDA investigators during inspections of manufacturing facilities. When FDA is contemplating regulatory
sanctions or withholding approval of applications, it usually provides companies with advance notification describing their
rationale for planned actions or decisions. Companies normally have ample prior notification, and they have the opportunity
to present their position. However, many companies are not always adept at recognizing the signals and clues the FDA provides,
and others unknowingly provide information that is not satisfactory.
Some companies have difficulties because they do not fully understand FDA's processes, or they fail to focus on the issues
that are of the greatest concern to the agency. For example, if an FDA inspection discovered significant GMP deviations related
to aseptic processing controls, and FDA reviewers expressed concerns about the sterility assurance levels for marketed products,
the issue at hand is not the actions taken to correct the deviations. If FDA has deemed the product to be adulterated because
it was produced under conditions that did not assure the sterility of the product, then the issue is the rationale for releasing
the product to market or continuing to allow sales of the product. Moreover, FDA will likely want to know whether the firm
intends to recall the product — and if not, what information and data are available to justify the decision. If the company
focuses on corrective actions without justifying their basis for leaving the product in the market, FDA will consider the
firm to have been non-responsive even if they considered the company's detailed corrective action program adequate.
Decide the Timing of FDA MeetingsTiming is crucial when requesting meetings with FDA to discuss disputed issues. Timing depends on the stage of the review
process and the level to which the matter has been elevated. For example, if the observation is relatively minor with little
or no likely regulatory consequences, then the matter may be best dealt with in a written response. Conversely, if the company
intends to dispute an FDA-483 observation they believe to be incorrect and potentially damaging, they may want to request
an immediate meeting with the district office in hopes of deleting the observation.
When FDA inspections have detected significant GMP issues, companies should anticipate that the district office might recommend
regulatory sanctions. Companies should carefully assess their regulatory risks and decide whether meetings are warranted at
the district level and at the center level. While meetings may be held with the local district office to inform the agency
about planned corrective actions, the company must identify any issues where the company disputes the accuracy or completeness
of FDA-483 observations. Under such circumstances, the company should respond to the FDA-483 by respectfully disagreeing with
the observation as written, providing the justification and documentation for their position and offering to meet with FDA
officials to resolve the issue.
Once the local district has forwarded to the center a recommendation for regulatory action, there is a high probability of
adverse consequences unless the company can convince the agency to forego further actions. At this level of review FDA wants
to make certain their case is supportable if the company contests the regulatory action. Consequently, FDA reviewers want
to be aware of any disputed issues before cases are forwarded to Office of Enforcement (OE), Office of General Counsel (OGC),
or Department of Justice (DOJ).
To resolve disputes at the lowest level possible, companies must know the review process and should have frequent communications
with FDA officials so they are aware of the timing of review stages. When meetings are indicated, it is best to meet with
decision makers before they have forwarded their recommendations to the next level. If disputes can be resolved at lower levels,
FDA may decide that regulatory action is not warranted. If the matter is elevated, information presented by the company will
be included for review by officials at the higher level.
By maintaining effective communications, the company should be able to track the FDA review process and decide how to appeal
unresolved disputes. Again timing is key. Prematurely contacting a senior manager will only result in the official stating
that the case is still under review at lower levels. If the disputed issue has a significant bearing on FDA's decision, then
it is usually prudent to elevate the dispute to senior FDA management.
When elevating the dispute, companies should be careful not to retrace the same steps already covered with lower level officials,
because they will be part of the administrative record.
Senior FDA officials will be less concerned with details of scientific and technical issues than with its ability to defend
its position in court. The company must present credible information and data (and expert opinions if necessary) to convince
reviewers that there are substantial questions about the basis for the recommended action. Information about current industry
practices and current FDA compliance policies on the disputed issue is especially persuasive at this level of review. FDA
management may decide against approving a recommended action if the company can successfully demonstrate that the disputed
practice is consistent with current industry practices or established FDA policies.