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Pharmaceutical cGMPs for the 21st
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
I. Introduction
- In August 2002, FDA announced a new initiative,
"Pharmaceutical cGMPs for the 21st 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.
II. Background
- 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.
III. Objectives of Proposed Dispute Resolution 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).
IV. Proposal for a Dispute Resolution Process
- 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.
A. Informal Dispute Resolution Process
- 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.
B. Formal Dispute Resolution Process
District and Center Levels
- 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.
Dispute Resolution Panel
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).
V. Proposal for a Pilot Dispute Resolution Process
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.
VI. Communication and Applicability of Agency Decisions
- 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).
VII. Summary
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.
VIII. Issues to be Resolved
- 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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