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 Â§ 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.
MaPP 4150.1. Role and Procedures of the CDER Ombudsman, describes the roles of CDER's ombudsman who receives complaints from industry, trade associations, and other interested persons (10). The CDER ombudsman serves as an independent, neutral advocate for fair processes within CDER and as a confidential source of advice on CDER policies and procedures. The CDER Ombudsman can facilitate dispute resolution and can help with questions about intercenter product jurisdiction. Additional information about the CDER Ombudsman can be found at www.fda.gov/cder/ombud/default.htm.
"Formal Dispute Resolution: Scientific and Technical Issues Related to Pharmaceutical CGMP, (Draft Guidance)" August 2003 — While this is a draft that will be revised based on comments, it reveals the current thinking of key FDA units that enforce cGMPs in the pharmaceutical industry (11). The agency is proposing a formal process for resolving disputes of scientific and technical issues relating to current good manufacturing practice (cGMP) requirements. FDA is now proposing to raise such disputes to the Office of Regulatory Affairs (ORA) and center levels (e.g., CDER, CBER, and CVM) with options for reviews by a Dispute Resolution Panel for scientific and technical issues pertaining to pharmaceutical CGMP issues.
"Dispute Resolution Procedures for Science Based Decisions on Products Regulated by the Center for Veterinary Medicine (CVM)," 16 May 2003 — This guidance provides for handling of scientific controversies where there are unresolved disagreements between applicants and Division Directors (12). The guidance is not intended for situations involving "incomplete letters." When the division director and the company have legitimate differences of opinion, CVM can request: specific studies from an applicant to meet minimum preapproval data requirements, changes to agreed upon protocols based on newly discovered information, and additional information or data. This guidance describes the process for escalating disputes through the deputy center director and ultimately to the Veterinary Medicine Advisory Procedure as provided for under 21 CFR 10.75(b)(2).
The document also describes the role of the CVM ombudsman in the dispute resolution process. The ombudsman is intended to have a neutral role in facilitating dispute resolution at the center level. Companies that do not fully understand the dispute resolution process may find the ombudsman to be an excellent resource. As a neutral party, the ombudsman may suggest alternatives that are agreeable to both the applicant and center officials. Additional background is described in the Federal Register dated 18 November 1998 (2) and Administrative Dispute Resolution Act (ADRA) of 1996 (13).
"Progress Report Proposed Process for Dispute Resolution" 27 February 2003 — It is notable that FDA established a dispute resolution working group under its program "Pharmaceutical cGMPs for the 21st Century: A Risk Based Approach" (14). The working group is developing policies and procedures for dealing with scientific and technical issues during or following an FDA inspection. FDA is well aware of the adverse impact on drug manufacturers resulting from incorrect or invalid FDA-483 observations including: FDA-483s become part of the public record, even if the disputed issue is eventually resolved to FDA's satisfaction; while disputes are being resolved there may be delays in the approval of applications which can be costly.
The working group recommended a twelve-month pilot project using a three-tiered approach including an informal process at the district level, a formal dispute process at the district and center levels, and a formal Dispute Resolution Panel in the Office of the Commissioner that allow companies to escalate issues when they disagree with both the district and center. The recommendations of the working group were published on the FDA website, but the procedures have yet to be implemented. The agency is proceeding with its implementation plans as evidenced by the August 2003 Guidance document.
"Formal Dispute Resolution: Appeals above the Division Level," February 2000 — This guidance document describes the procedures followed by CDER and CBER when disputes can't be resolved at the division level (15). FDA's rationale for issuing this guidance can be found in the preamble to the final rule that revised 21 CFR 10.75(b)(2).
1. FDA. 21 CFR Part 10.70, Documentation of significant decisions in administrative file. Washington DC: U.S. Government Printing Office.
2. FDA. 21 CFR Part 10.75, Internal review of agency decisions. Federal Register 1979; 44:22323 (as amended at Federal Register 1985; 50:8994 and Federal Register 1988; 63:63982).
3. Food and Drug Administration Modernization Act (FDAMA). Available from URL: www.fda.gov/cder/guidance/105-115.htm.
4. FDA. Administrative practices and procedures; internal review of decisions. Federal Register 1998; 63:63978-63982 [docket No. 98N-0361].
5. FDA. 21 CFR Part 314.103, Applications for FDA approval to market a new drug, dispute resolution. Washington DC: US Government Printing Office.
6. FDA. 21 CFR Part 312.48, Investigational new drug application, dispute resolution. Washington DC: US Government Printing Office.
7. FDA. CBER manual of regulatory standard operating procedures and policies, SOPP 8005. Available from URL: www.fda.gov/cber/regsopp/8005.htm.
8. FDA. CBER manual of regulatory standard operating procedures and policies, SOPP 8006, Available from URL: www.fda.gov/cber/regsopp/8006.htm.
9. FDA. CDER manual on policy and procedures, MaPP 4151.1. Available from URL: www.fda.gov/cder/mapp/4151-1.pdf.
10. FDA. CDER manual on policy and procedures, MaPP 4150.1. Available from URL: www.fda.gov/cder/mapp/4150.1.pdf.
11. FDA. Formal dispute resolution: scientific and technical issues related to pharmaceutical cGMP, draft guidance for industry [draft]. 2003 August. Available from URL: www.fda.gov/cder/guidance/5804dft.htm.
12. FDA. Dispute resolution procedures for science based decisions on products regulated by the Center for Veterinary Medicine (CVM). Available from URL: www.fda.gov/cvm/guidance/dguide79.pdf.
13. Administrative Dispute Resolution Act (ADRA) of 1996. 5 U.S.C. 571, 573. Available from: www.usdoj.gov/adr/pdf/adra.pdf.
14. FDA. Progress report proposed process for dispute resolution. Available from URL: www.fda.gov/cder/gmp/gmpdispute.htm.
15. FDA. Guidance for industry, formal dispute resolution: appeals above the division level. Available from URL: www.fda.gov/cder/guidance/2740fnl.htm.