Pharmaceutical cGMPs for the 21^st Century: A Risk-Based Approach

Progress Report Proposed Process for Dispute Resolution

Comments on this report or on the activities of this working group should be submitted to the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with Docket Number 03N-0059.

Electronic Management Comment Form:  Docket 03N-0059 - Pharmaceutical Current Good Manufacturing Practices for the 21st Century: A Risk-Based Approach

• In August 2002, FDA announced a new initiative, "Pharmaceutical cGMPs for the 21^st Century: A Risk-Based Approach." The initiative focuses, in part, on FDA's current Good Manufacturing Practice (cGMP) program and covers the manufacture and product quality of veterinary and human drugs, including human biological products.

• The Dispute Resolution Working Group was formed as part of the initiative. The working group comprises representatives from the Office of Regulatory Affairs (ORA), Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), and Center for Veterinary Medicine (CVM).

• The working group is developing policies and procedures that will allow rapid, objective resolution of scientific and technical questions and issues that may arise either during an inspection or as the result of an inspection. The goal of the working group is to promote integrity, neutrality, consistency, transparency, fairness and scientific soundness in the dispute resolution process.

• As part of its overall mission to protect the public health, the FDA conducts inspections of manufacturers of drugs to ensure product and manufacturing quality.

• Scientific and technical questions and issues that arise during an inspection may produce a difference of opinion between manufacturer and investigator. These questions and issues may relate to important aspects of the manufacturing process may involve complex scientific and technical issues.

• Although there are existing processes to encourage dialogue between FDA and firms on manufacturing issues, FDA is seeking to enhance them through the cGMP initiative. The following dispute resolution processes are currently in place.

• 21 CFR 10.75, Internal Agency Review of Decisions, allows firms to ask for a review of agency decisions at each successive supervisory level through the chain of command, ending with the FDA Commissioner's office.

• Guidances for resolving scientific disputes have been written by CDER/CBER and CVM. The scientific disputes described in these documents relate to product-specific drug development, new drug review and post-marketing oversight processes. The dispute resolution process described in this concept paper is specifically targeted to scientific disputes that arise as a result of the inspection process.

• The working group has developed a proposed dispute resolution process described in section IV below, that is intended to address areas where perceived problems may exist. Some examples reported to the Agency are:

• To avoid a delay in the approval of a product, an applicant may make changes in the manufacture of or the control of the manufacturing process for the product to correct deficiencies identified during an inspection, even when the firm believes that corrective action is not consistent with available scientific/technical evidence or is based on an inaccurate observation.
• Incorrect or scientifically invalid observations may become a part of the public record and become a de facto standard in the absence of more specific agency guidance.

• Occasionally, inspectional observations are recorded, or warning letters sent, that might have been avoided if the Agency were able to consult with internal experts concerning certain scientific and technical issues relating to advanced technology and innovative manufacturing processes.

• The proposed dispute resolution process is intended to promote open, prompt discussion of questions and issues raised during an inspection and as the result of an inspection and bring them to early resolution.

• It is intended that the proposed process will not cause significant delays in product approval time, will not unduly burden agency resources, will only be used in situations that meet criteria set by FDA, and will not inhibit appropriate enforcement actions.

• The working group considered technical and scientific issues and answers that might arise following drug quality related inspections, such as Good Manufacturing Practice (GMP) inspections, Pre-Approval Inspections (PAI), and CBER Pre-License Inspections (PLI).

• Three levels of dispute resolution are proposed: an informal process, and two levels in a formal process. The process will be modified as necessary to accommodate different types of inspections and the different processes used by CBER, CVM, and CDER.

• The working group proposes an informal dispute resolution process prior to the issuance of a Form FDA 483 (483). The purpose of the informal dispute resolution process is to address issues early and to avoid, to the extent possible, incorrect or inconsistent observations on 483’s.

• This informal process builds upon existing inspectional procedures. During inspections, investigators are encouraged to discuss observations relating to manufacturing quality as they are observed, or on a daily basis to minimize surprise, errors, and misunderstandings when the 483 is issued. At the conclusion of an inspection, investigators conduct a discussion with the firm's management to again discuss observations and solicit the firm's views and any additional relevant information.

• Firms will be encouraged to discuss with investigators, as soon as practicable, any observation noted by an investigator that a firm believes is not justified from a scientific standpoint. In such instances, investigators will be encouraged to contact the district office and, as needed, the districts will contact the relevant program center. Investigators will use their judgment in determining if such consultation is needed. Certain scientific/technical issues may be too complex or time-consuming to resolve at this stage, but may be raised again after issuance of the 483.

• To allow time for clarification of issues and an opportunity to informally resolve disputes that occur late in the inspection process, the working group is considering the possibility of allowing a short post-inspection delay (e.g., 48 hours) prior to issuing the 483.

• If a dispute is not resolved during the informal dispute resolution process, a firm may request formal dispute resolution with the district office regarding the scientific basis for an observation issued in written form on a 483.

• If the district office agrees with the firm, the district will respond in writing to note its resolution of the dispute.

• If the district disagrees with the firm, the district will forward the dispute to the relevant program center for review. The center will review and evaluate the information provided and, in consultation with the district, will render its final decision on the scientific issue in question.

• Decisions will be communicated to the affected firms and to the relevant program Center. Decisions will also be publicly documented, perhaps via a web site, after redacting any confidential, commercial, or trade secret information.

If a firm disagrees with the decision made by the district and center, the firm may seek to appeal that decision to a proposed FDA dispute resolution panel.

• Criteria will be developed for how and when a firm may ask for consideration by the panel. The Center, in consultation with the District, will determine whether the dispute meets the applicable criteria and is appropriate for review by the panel. Criteria will also include when FDA centers may request panel consideration.

• The concept of an FDA dispute resolution panel is intended to allow a firm the opportunity to appeal a district/center decision concerning the science underlying an inspectional observation.

• Firms would provide all supporting documentation and arguments. Any new information, however, will not be considered by the panel. All new information will be returned to the applicable center for review and decision.

• Panel deliberations would, in appropriate circumstances, include an opportunity for the firm to present its case before the panel.

• The working group proposes that a dispute resolution panel would reside in the Office of the Commissioner and be chaired by a representative from that office. The panel would also contain a representative from each of the drug program centers (CDER, CVM, and CBER), the Office of Chief Counsel, and the Office of Regulatory Affairs. Selected ad hoc experts may serve on the panel depending on the issue to be reviewed. These experts could be Special Government Employees (SGE’s).

• The working group proposes a 12-month pilot for the dispute resolution process. This pilot would allow FDA to evaluate the process and to answer questions about the effects of the process on industry as well as on FDA. Criteria to evaluate the pilot will need to be developed with internal and stakeholder input.

• Decisions made in the dispute resolution process would be communicated to affected firms in writing and be made publicly available to foster knowledge within FDA as well as within the industry.

• Methods for communicating decisions and for capturing relevant information need further consideration (e.g. how to correct public records, how to share outcomes of dispute resolutions across FDA centers, and how to incorporate principles into FDA training and guidance documents).

The Dispute Resolution Working Group proposes a three-stage dispute resolution process to resolve scientific and technical disagreements between FDA and firms that arise as a result of the inspection process. Highlights of the process are:

• Informal dispute resolution process that:

• Reaffirms the need for investigators to discuss findings with firms during the inspection, not just at the closeout discussion with management.
• Establishes better communication between the field and centers and makes program experts available to advise investigators on scientific disputes.
• Encourages firms to identify disputes early to allow rapid resolution.

• Formal dispute resolution process that incorporates Center review in the resolution of a disagreement.

• FDA dispute resolution panel that reviews certain disputes not resolved at the district or center level.

• 12-month pilot to assess whether the process meets the group’s stated objectives and to evaluate the impact on agency programs.

• Consideration of a short post-inspection delay (e.g., 48 hours) in issuing the Form FDA 483.

• Process to resolve internal disagreements between Agency components.

• Ways to disseminate information on resolved disputes.

• Criteria to determine whether an issue is appropriate for dispute resolution processes (e.g., what is a scientific or technical issue?)

• Criteria to determine how and when a dispute will be considered by the dispute resolution panel.

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Date created:  February 27, 2003

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