Resolving disputes with FDA over scientific and technical issues demands familiarity with existing practices and procedures, as well as understanding recent and ongoing changes to how FDA handles disputes.
In August 2003, FDA published a new draft guidance that proposes a formal process for resolving disputes of scientific and technical issues relating to current good manufacturing practice (cGMP) requirements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:
FDA 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.
Timing 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.
Successful dispute resolution requires companies to fully understand the roles and responsibilities of each FDA functional unit and provide appropriate information to officials at each stage of the process. While some companies have expressed frustration about the multilevel review process, which can seem overly bureaucratic, their frustration often results from not understanding the agency’s processes.
Companies should provide FDA decision makers with the same data and information that was used by company experts to reach their conclusions. When company experts effectively communicate with FDA's scientific and technical experts, most issues can be resolved on their scientific merits. For issues that involve interpretations of GMPs, companies must be prepared to present their position to the appropriate decision makers at the local district office, the appropriate level in the center, OE, OGC, or DOJ.
The review of the significance of FDA-483 observations begins with a first line supervisor in the FDA district office who reviews the findings and recommends a response. If the supervisor concludes that the observations do not warrant further regulatory action, the inspection is classified as "no-action indicated" (NAI) or "voluntary action indicated" (VAI).
If the supervisor classifies the inspection as "official action indicated" (OAI), then the supervisor's recommendation is forwarded to a district compliance officer who reviews the Establishment Inspection Report (EIR) to determine whether the inspection findings warrant regulatory action. If the compliance officer concludes that regulatory action is indicated, a recommendation is forwarded to the district director for approval. Depending on the nature of the recommended action (for example, seizure, injunction, or warning letter), the regulatory case file may be forwarded to an Office of Compliance at the appropriate center. At the center level, reviewers confirm that the evidence submitted supports the proposed regulatory action according to established policies. Then, the case is forwarded through OE and OGC and eventually to DOJ.
There are three principal strategies for resolving issues pertaining to FDA-483 observations:
FDA is reluctant to initiate regulatory sanctions when it believes the company is acting in good faith to affect corrective actions in a timely manner — unless there is an immediate health hazard. Therefore, companies can usually avoid regulatory sanctions by documenting corrective actions for FDA reviewers at each level.
It is important that the company utilize personnel who are well versed in FDA practices. If the company staff have limited experience dealing with FDA, it may be prudent to seek outside assistance from persons who have either worked for the agency previously or have considerable first-hand experience. Such persons can assist in presenting relevant information to the appropriate agency personnel to convince them the company has a valid basis for their position and presenting the right information to the right person at the right time during the review process.
Deciding who will represent the company is almost as important as what is presented. Obviously, anyone presenting information or data to FDA must be knowledgeable about the issues to be discussed and must be capable of effective communications. Different qualifications and skills are needed depending upon the purpose of the meeting and the level of FDA attendees. Generally, the company sets the agenda for the FDA meeting. If FDA asked for the meeting, the company should be represented by those best suited to address any of the outstanding issues under discussion. The company should anticipate that FDA may need information for a relatively broad spectrum of topics. Consequently, company representatives should include senior management (chief executive officer, president, or vice president), technical and regulatory staff (QA/QC director and heads of production or laboratories), and possibly a company attorney.
Whether to involve company attorneys must be decided on a case-by-case basis. In some meetings (such as a review of scientific issues or GMP issues) the presence of a company attorney may discourage FDA from engaging in free and open dialogue. If the company decides that an attorney should be present, FDA may decide to have an OCC attorney represent FDA. Companies must judge when to introduce their attorneys: too soon may inhibit dialogue and too late may make it difficult to undo damage.
For situations where potential regulatory sanctions are likely, companies may need to seek outside legal counsel to assist the company's internal legal staff. Outside counsel who specialize in FDA law frequently have first-hand experience interacting with FDA officials at the various agency levels and negotiating voluntary actions in lieu of litigation.
Companies facing potential litigation also may choose to utilize outside consultants to attend FDA meetings or present written opinions about scientific or technical issues. Companies are free to choose their own consultants, but FDA may question or challenge the qualifications of consultants when their background does not match the issues being addressed. Companies should scrutinize the education, training, and experience of any consultant and verify they have helped resolve similar issues in the past.
Companies also should carefully manage the roles and responsibilities of consultants during FDA meetings. Generally, responsible management should lead the discussions, answer questions, and make commitments on behalf of the company. Consultants are most effective when there is a disputed scientific or technical issue. Consultants may prepare white papers or technical reports that help identify the issue, and the results of their independent evaluation may be provided to FDA. Consultants who are experts in a particular field may be called upon to provide opinions about a particular study or situation, but their role during FDA meetings should be narrow in scope. Management should not use a consultant as the company's spokesperson because FDA expects company management to be knowledgeable and in control of the situation.
When FDA contemplates regulatory sanctions (or has already made an adverse ruling or decision), the company must decide how much information to share. On one hand, companies should provide any information that may dissuade FDA from invoking regulatory sanctions. On the other hand, no company wants to divulge information that may be used against it in civil or criminal proceedings by the agency or in civil lawsuits. Consequently, companies face a constant dilemma between providing too much or too little information.
In most cases, the company can solicit from FDA the nature and type of information that is needed. Different types of information are appropriate for different types of disputes and at different stages of the review process.
Scientific and Technical Reviews. If an FDA reviewer is evaluating scientific or technical data, it is advisable to simply ask the reviewer what additional information or data would be helpful to them and, to the extent practical, provide all information or data that is relevant. Include all pertinent data even if some of it is less than perfect. FDA does not expect perfection, but companies are expected to document that they deal with issues in a responsible manner using sound science.
GMP Reviews. GMP reviews focus on the facts of the case and the significance of the findings. When FDA reviewers at the district office (supervisors and compliance officers) are evaluating the significance of FDA-483 observations, it is particularly important to maintain contact with the reviewers, ensuring they have all the information they need. By opening up dialogue with the local district staff, companies can learn of reviewers' concerns and provide additional information before the matter is elevated to the center level.
To support regulatory actions, FDA-483 observations must be factually correct and supported with records or first-hand observations by FDA officials. If the company has information that shows the FDA-483 observations are incorrect or misleading in any way, FDA reviewers must be given complete information to refute the observation. In this case, the company should respectfully advise FDA that the observation is incorrect and provide supporting evidence.
FDA's evaluation of the significance of FDA-483 observations follows a review process that is elevated up the chain of command from the local district to the center and eventually through the OE to the OGC. Throughout this process, the inspection findings are reviewed to verify that they warrant regulatory action. FDA utilizes it own internal "National Experts" as well as outside experts to provide independent confirmation that the conditions do not conform to cGMPs. Companies disputing FDA-483 observations or trying to convince FDA that the conditions do not warrant regulatory action also should consider obtaining an objective review by independent experts. Independent review is valuable because it affords management a set of "outside eyes," and if FDA reviewers know the outside expert to be credible, their opinions or recommendations may carry a lot of weight.
Management Review at Local Districts. Each FDA unit has its own procedures for elevating recommendations for approval. At the district level, cases are elevated to the director of the Compliance Branch or the district director. At this stage, senior management of the company should discuss their commitment to complying with the laws and regulations with the senior FDA management. They should demonstrate that global corrective actions have been initiated and, where appropriate, provide timetables for completion. Management should promise to keep FDA informed of progress, including periodic reports if corrections will span months or years. Finally, to satisfy FDA concerns, management should demonstrate that its actions are timely and sufficient. Successful discussions may convince district officials that regulatory action is not warranted.
Policy Reviews at Headquarters. Each headquarters (ORA, CDER, CBER, CVM) reviews recommendations from lower level offices. The nature of review varies with each office, but in general, the reviews ensure that the proposed regulatory sanction or administrative decision was made in accordance with established practices and policies and evidence supports the charges. Each headquarters decides whether to forward the case to the OE or OGC. The review at headquarters confirms that the recommendations follow established policies such as Compliance Policy Guides (CPGs), Regulatory Procedures Manual, and others.
Once a regulatory case or administrative matter has been elevated to the center level, there is a high probability that the regulatory action will be forwarded beyond FDA. At this stage of the process, it is vital to offer new and compelling information to headquarters officials to convince them that regulatory sanctions either are not supportable or are not warranted based on accomplished or planned corrective actions.
Generally, but not always, by the time cases are referred to headquarters, the facts and supporting evidence have been pretty well established. Therefore, discussions at this level generally do not focus on the particulars of FDA-483 observations (unless the company has been unsuccessful in resolving disputes at the district level). Such discussions are normally between senior management of the company and FDA. During such meetings, company officials must be knowledgeable about the nature and extent of corrective actions and should be able to make commitments on behalf of the company.
If the meeting goes well, a favorable outcome is possible, but if management has not prepared adequately or is unable to change the views of FDA management, the meeting will not only have had an unfavorable outcome, but might even be held against the company in the form of a prior warning.
Legal Reviews. Throughout the FDA review process at both the district and headquarters level, the particulars of the case are reviewed from a legal perspective to make sure evidence is available to support the charges. However, the formal review by FDA lawyers does not occur until a case is forwarded to the OGC. In most instances, OGC review is the last step in the review process. In the case of warning letters, OGC approves or rejects recommendations from the local districts or centers. For civil and criminal sanctions, OGC lawyers forward approved recommendations to the DOJ.
At the OGC stage of the review the company should use company lawyers or outside counsel to communicate with OGC lawyers. While other senior management may participate in the discussions with OGC, company lawyers will need to address the legal matters with the OGC lawyers. The discussions should focus on determining FDA's legal course, presenting additional information or data to negate some or all of the charges, or voluntarily committing to corrective actions that obviate the need for litigation.
Companies may invoke attorney-client privilege to protect information related to disputed issues from disclosure to the FDA (or during civil litigation, such as lawsuits by shareholders or patients). If so, the company must decide how to use any information reported under privilege during FDA's dispute resolution process. Companies must decide whether or not to waive attorney-client privilege if the agency requests protected information. They must consider the benefits to be gained from voluntary disclosures against the risk of an unfavorable ruling by FDA.
It is not uncommon for some senior management to have difficulty understanding what is important to FDA, and others may feel uncomfortable dealing with the agency (especially when they do not fully understand its processes). Regardless of the reason for an FDA meeting, careful planning is needed to ensure that the appropriate FDA staff attend and that key topics are discussed. Planning includes establishing strategy and specific objectives, as well as ground rules for meeting. Management should verify that every attendee knows ahead of time what he or she is expected to contribute to the meeting. Those who are making formal presentations should have their materials completed well in advance, and practice sessions can confirm that the materials are appropriate and the proper message is delivered. Simulated question and answer sessions may also be helpful.
Requests for FDA meetings should clearly state the reason for the meeting, outlining specific objectives and listing the names and titles of company representatives (including consultants). If the company desires certain FDA officials to be present, the request should include this information. The company should avoid the temptation to introduce issues not identified in the meeting request. For meetings requested by a company, FDA usually allows the company to set the agenda. The company should allocate enough time to address each of the meeting’s objectives. The agenda should clearly identify the issues to be addressed, as well as pertinent background information. It is important to confirm that the company's understanding of the issue is correct. Once the issue is agreed upon, the company should present its rationale and the support for its position.
During the formal presentations and the subsequent discussions, management should judge the effectiveness of the discussions and listen for signals or messages that are being delivered by FDA. Frequently FDA officials will not come right out and say they disagree with the materials presented; silence or no comment should not be interpreted as agreement. Companies may leave meetings believing they were successful because FDA did not object, while FDA officials may leave the same meeting with the impression that management "does not get it." Therefore, before the meeting is completed, management should elicit from FDA a response to the issue.
Rather than soliciting open-ended questions and comments, it is usually advisable to restate the company's conclusion and then ask FDA attendees if they agree. This should keep FDA responses directed at the specific issues of concern to the company. It also is prudent to ask FDA attendees if they have any other concerns that have not been communicated to the company.
Finally, at any FDA meeting to discuss disputed issues, it is vital that company representatives remain controlled and professional at all times. Showing frustration or open hostility will never help the company's position, and may damage its credibility. If the company still disagrees with FDA's position (after the presentation and discussions), the company should end the meeting by restating its conclusions in a deliberate manner with the supporting rationale. Meetings do not always conclude with a resolution of the disputed issue, but no meeting should finish until everyone agrees that they have a common understanding about what remains unresolved. If possible, both parties should agree upon the next steps to reach a resolution.
No dispute can be successfully resolved unless the company establishes credibility with FDA officials. Building credibility takes considerable effort and will not happen overnight. The company must communicate early, often, and effectively. FDA expects companies to respond to the issue and to understand FDA's position. Empathizing with FDA's position does not mean agreeing with FDA's position, but understanding why FDA is concerned. Credibility means being accountable for the actions of the company and not making excuses. One common mistake made by management is offending FDA reviewers by making excuses such as saying the issue was the fault of someone else or "that’s never happened before."
Credibility also means demonstrating integrity by always providing FDA with information that is truthful, accurate, and complete. FDA expects all communications to exhibit these qualities. Credibility means making commitments to achieve timely corrective actions, showing reasonable progress against a planned schedule, and notifying FDA in advance when schedules cannot be met. Credibility means learning from the experiences of the company and others in industry by not having recurring issues that could have been prevented. Credibility also means boasting loudly and proudly about correcting issues and implementing global improvements. Credibility means having the confidence to disagree with FDA when the company believes it has a valid position and is capable of presenting its rationale and support in a professional manner. Finally, credibility is established when the actions and decisions of the company clearly show a commitment to complying with cGMPs and FDA sees positive progress.
There are now new and improved opportunities for dealing with FDA-483 obserations and other disuputes that arise from FDA inspections. However, until the agency receives comments and finalizes the draft guidance published in August 2003, companies will still need to deal with disputes according to established FDA procedures and practices.
Successful dispute resolution begins by following the applicable regulations, policies, procedures, and guidance documents that define the agency's process for handling disagreements about scientific and technical issues. Companies that do not understand and follow the prescribed process for disputes can not expect to have a favorable outcome. Companies, even if they follow the process, will not have a positive outcome if they do not provide the agency with the appropriate information at the right level.
Successful dispute resolution begins with reaching a common understanding of the issue and understanding what information is needed by officials at each level of review. Companies must decide the optimum timing of FDA meetings and who will represent the company. Knowledgeable management must be aware of the issues and explain and defend the company’s position in a credible manner. Finally, successful dispute resolution depends on establishing credibility with FDA by being accountable for company actions and demonstrating a commitment to comply with the law and regulations. Credibility is established by making global corrective actions in a timely and reasonable manner and also by giving FDA confidence that the company will perform the right actions at the right time for the right reasons.
1. FDA. Formal dispute resolution: scientific and technical issues related to pharmaceutical cGMP, draft guidance for industry [draft]. 2003 August. Available from URL: