Review of FDA Dispute Resolution Practices and Procedures

To be effective in dispute resolution, companies must be well versed in the rules that the district or center employees are expected to follow. Only then can the company present the appropriate information in a manner that FDA officials can effectively and efficiently process. Companies that do not understand or fail to follow FDA processes are unlikely to have a successful outcome to their negotiations. The following summarizes a few of the key regulations and guidance documents that apply to ORA, CDER, CBER, and CVM.

21 CFR Part 10, Part 10.70. Documenting significant decisions in administrative files requires FDA decision makers to include a written record of factual, scientific, or legal issues involving significant differences of opinion and their resolution (1).

21 CFR Part 10, Part 10.75. Internal agency review of decisions outlines the process to be used by FDA when a company requests agency review of disputed issues (2). This regulation provides for elevating disputes to supervisory staff, and ultimately center directors. If companies introduce new information not in the administrative file, the matter is returned to the appropriate agency level for re-evaluation. This requirement is intended to preserve the integrity of the review process, ensuring FDA reviewers have been provided complete, accurate, and truthful information.

Section 404 of the 1997 Food and Drug Modernization Act requires FDA to establish procedures for dispute resolution wherever the Federal Food, Drug & Cosmetic Act (FD&C) or applicable regulations do not already contain provisions for such (3). Due to the significant differences in statutory requirements and existing dispute resolution procedures for the various products regulated by FDA's centers, FDA did not include specific procedures for requesting reviews of scientific controversies in § 10.75. Rather, FDA allows each center to develop and administer its own procedures for reviewing scientific controversies.

On November 18, 1998, FDA amended 21 CFR Part 10.75(b)(2) to include the following statement:

"A sponsor, applicant, or manufacturer of a drug or device regulated under the act or the Public Health Service Act (42 U.S.C. 262), may request review of a scientific controversy by an appropriate scientific advisory panel as described in section 505(n) of the act, or an advisory committee as described in section 515(g)(2)(B) of the act. The reason(s) for any denial of a request for such review shall be briefly set forth in writing to the requester. Persons who receive a Center denial of their request under this section may submit a request for review of the denial. The request should be sent to the Chief Mediator and Ombudsman"(4).

21 CFR Part 312.48, Dispute Resolution, Investigational New Drug Application (IND) — This regulation defines procedures for resolving disputes during the review of INDs (5). First, the sponsor is expected to try to resolve the issue with the appropriate CDER or CBER division. If division level review is unsuccessful, they may request a meeting with management representatives and reviewing officials. FDA may refer technical and scientific issues to outside experts if the applicant requests it. Applicants can elevate disputes to a higher level by contacting the designated ombudsman for each center, who resolves difficulties in scheduling meetings and facilitates timely replies to inquiries.

21 CFR Part 314.103 — This regulation is quite similar to 312.48 and contains additional details for moving scientific or medical disputes through the chain of command: from reviewers through division director, office director, and center director. Also companies may request that FDA seek advice from outside experts, and FDA may refer issues to a scientific advisory committee.6

CBER's Manual of Standard Operating Procedures and Policies (SOPPs) — CBER's manual describes the processes for reviewing applications, including resolving disputes. Before considering a dispute with FDA, companies are advised to fully understand each of the SOPPs that apply during the review. If reviewers fail to follow FDA procedures, this may be grounds for disputing decisions, but companies should not raise disputes until they are fully versed in FDA's procedures. Two SOPPs specifically address disputes: SOPP 8005, Major Dispute Resolution Process (7)nd SOPP 8006, Resolution of Differences in Scientific Judgment in the Review Process (8).

CDER's Manual of Policies and Procedures (MaPP) — Like CBER, CDER also has a manual that describes the review process for new drugs.

MaPP4151.1 describes CDER's process for documenting the scientific review process and dealing with internal disagreements among FDA reviewers of new drug applications (9). In particular, the FDA's internal review must be based on information in the administrative file. The basis for FDA decisions must be documented, and if there are "significant controversies or differences of opinion," then the administrative file must reflect this information. Unresolved disagreements at any level of the review process must be documented to show the nature of the difference of opinion, reasons for different opinions, and recommended changes. The basis for disagreements must be documented at each organizational level, including reviewer, supervisors, division director, office director, and deputy center director.

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