SUPPORTING STATEMENT

Docket Number 2003D-0386

OMB Control Number 0910-0563

Guidance for Industry - Formal Dispute Resolution: Scientific and
Technical Issues Related to Pharmaceutical CGMP

> A. [Justification]{.underline}
>
> 1\. [Circumstances of Information Collection]{.underline}
>
> This information collection approval request is for a Food and Drug
> Administration (FDA) guidance for industry entitled \"Formal Dispute
> Resolution: Scientific and Technical Issues Related to Pharmaceutical
> CGMP.\" The guidance was drafted as part of the FDA initiative
> \"Pharmaceutical cGMPs for the 21^st^ Century: A Risk-Based
> Approach,\" which was announced in August 2002. The initiative focuses
> on FDA\'s current CGMP program and covers the manufacture of
> veterinary and human drugs, including human biological drug products.
> The agency formed the Dispute Resolution Working Group comprising
> representatives from the Office of Regulatory Affairs (ORA), the
> Center for Drug Evaluation and Research (CDER), the Center for
> Biologics Evaluation and Research (CBER), and the Center for
> Veterinary Medicine (CVM). The working group met weekly on issues
> related to the dispute resolution process and met with stakeholders in
> December 2002 to seek their input.
>
> The guidance was initiated in response to industry\'s request for a
> formal dispute resolution process to resolve differences related to
> scientific and technical issues that arise between investigators and
> pharmaceutical manufacturers during FDA inspections of foreign and
> domestic manufacturers. In addition to encouraging manufacturers to
> use currently available dispute resolution processes, the guidance
> describes a formal two-tiered dispute resolution process that provides
> a formal mechanism for requesting review and decision on issues that
> arise during inspections:
>
> ● Tier-one of the dispute resolution process provides a mechanism to
> raise scientific or technical issues to the ORA and center levels.
>
> ● Tier-two of the dispute resolution process provides a mechanism to
> raise scientific or technical issues to the agency\'s Dispute
> Resolution Panel for Scientific and Technical Issues Related to
> Pharmaceutical CGMP (DR Panel).
>
> The guidance also covers the following topics.
>
> ● The suitability of certain issues for the formal dispute resolution
> process, including examples of some issues with a discussion of their
> appropriateness for the dispute resolution process.
>
> ● Instructions on how to submit requests for formal dispute resolution
> and a list of the supporting information that should accompany these
> requests.

● Public availability of decisions reached during the dispute resolution
process to promote consistent application and interpretation of drug
quality-related regulations.

> When a scientific or technical issue arises during an FDA inspection,
> the manufacturer should initially attempt to reach agreement on the
> issue informally with the investigator. Certain scientific or
> technical issues may be too complex or time-consuming to resolve
> during the inspection. If resolution of a scientific or technical
> issue is not accomplished through informal mechanisms prior to the
> issuance of the FDA 483, the manufacturer can formally request dispute
> resolution and can use the formal two-tiered dispute resolution
> process described in the draft guidance.
>
> Tier-one of the formal dispute resolution process involves scientific
> or technical issues raised by a manufacturer to the ORA and center
> levels. If a manufacturer disagrees with the tier-one decision,
> tier-two of the formal dispute resolution process would then be
> available for appealing that decision to the DR Panel.
>
> If a manufacturer disagrees with the scientific or technical basis for
> an observation listed by an investigator on an FDA 483, the
> manufacturer can file a written request for formal dispute resolution
> with the appropriate ORA unit as described in the draft guidance. The
> request for formal dispute resolution should be made within 10 days of
> the completion of an inspection, and should include all supporting
> documentation and arguments for review, as described below. If a
> manufacturer disagrees with the tier-one decision in the formal
> dispute resolution process, the manufacturer can file a written
> request for formal dispute resolution by the DR Panel. The
> manufacturer should provide the written request for formal dispute
> resolution and all supporting documentation and arguments, as
> described below, to the DR Panel within 60 days from issuance of the
> tier-one decision.
>
> All requests for formal dispute resolution should be in writing and
> include adequate information to explain the nature of the dispute and
> to allow FDA to act quickly and efficiently. Each request should be
> sent to the appropriate address listed in the guidance and include the
> following:
>
> • Cover sheet that clearly identifies the submission as either a
> request for tier-one dispute resolution or a request for tier-two
> dispute resolution;
>
> • Name and address of manufacturer inspected (as listed on FDA 483);
>
> • Date of inspection (as listed on FDA 483);
>
> • Date FDA 483 issued (from FDA 483);
>
> • FEI Number, if available (from FDA 483);

• FDA employee names and titles that conducted inspection (from
FDA 483);

• Office responsible for the inspection, e.g., district office, as
listed on FDA 483;

> • Application number if the inspection was a preapproval inspection;
>
> • Comprehensive statement of each issue to be resolved:
>
> • Identify the observation in dispute.
>
> • Clearly present the manufacturer's scientific position or rationale
> concerning the issue under dispute with any supporting data.
>
> • State the steps that have been taken to resolve the dispute,
> including any informal dispute resolution that may have occurred
> before the issuance of the FDA 483.
>
> • Identify possible solutions.
>
> • State expected outcome.

• Name, title, telephone and fax number, and e-mail address (as
available) of manufacturer contact.

> 2\. [Purpose and Use of Information]{.underline}
>
> The guidance is intended to provide information to manufacturers of
> veterinary and human drugs, including human biological drug products,
> on how to resolve disputes of scientific and technical issues relating
> to CGMP. Disputes related to scientific and technical issues may arise
> during FDA inspections of pharmaceutical manufacturers to determine
> compliance with CGMP requirements, or during FDA\'s assessment of
> corrective actions undertaken as a result of such inspections. The
> guidance provides procedures that will encourage open and prompt
> discussion of disputes and lead to their resolution. The guidance
> describes procedures for raising such disputes to the ORA and center
> levels and for requesting review by the DR Panel.
>
> 3\. [Use of Improved Information Technology]{.underline}
>
> In the [Federal Register]{.underline} of December 11, 2003, FDA issued
> a final rule amending FDA regulations governing the format in which
> certain labeling is required to be submitted for review with NDAs,
> certain BLAs, ANDAs, supplements, and annual reports. The final rule
> requires the electronic submission of the content of labeling (i.e.,
> the content of the package insert or professional labeling, including
> all text, tables, and figures) in NDAs, certain BLAs, ANDAs,
> supplements, and annual reports electronically in a form that FDA can
> process, review, and archive.
>
> The following guidances for industry have been developed to improve
> the use of information technology in the submission of marketing
> applications for human drugs and related reports:

-   \"Providing Regulatory Submissions in Electronic

> Format\--NDAs\" (January 28, 1999). This guidance provides information
> on how to submit a complete archival copy of an NDA in electronic
> format and applies to the submission of original NDAs as well as to
> the submission of supplements and amendments to NDAs.

-   \"Providing Regulatory Submissions in Electronic

> Format\--General Considerations\" (January 28, 1999). This guidance
> includes a description of the types of electronic file formats that
> the agency is able to accept to process, review, and archive
> electronic documents. The guidance also states that documents
> submitted in electronic format should enable the user to: (1) Easily
> view a clear and legible copy of the information; (2) print each
> document page by page while maintaining fonts, special orientations,
> table formats, and page numbers; and (3) copy text and images
> electronically into common word processing documents.

-   "Providing Regulatory Submissions to the Center for

> Biologics Evaluation and Research (CBER) in Electronic Format"
> (November 12, 1999). This guidance provides information to assist
> applicants in submitting documents in electronic format for review and
> archive purposes as part of a BLA, product license application (PLA),
> or establishment license application (ELA).
>
> **•** \"Providing Regulatory Submissions in Electronic
> Format----Prescription Drug Advertising and Promotional Labeling\"
> (January 31, 2001). This draft guidance discusses issues related to
> the electronic submission of advertising and promotional labeling
> materials for prescription drug and biological products.
>
> **•** \"Providing Regulatory Submissions in Electronic
> Format----ANDAs\" (June 27, 2002). This guidance discusses issues
> related to the electronic submission of ANDAs and supplements and
> amendments to those applications.
>
> **•** \"Providing Regulatory Submissions in Electronic
> Format----Annual reports for NDAs and ANDAs\" (August 2003). This
> guidance discusses issues related to the electronic submission of
> annual reports for NDAs and ANDAs.
>
> **•** \"Providing Regulatory Submissions in Electronic
> Format----Postmarketing Periodic Adverse Drug Experience Reports\"
> (June 2003). This guidance discusses general issues related the
> electronic submission of postmarketing periodic adverse drug
> experience reports for NDAs, ANDAs, and BLAs.
>
> **•** \"Providing Regulatory Submissions in Electronic Format----Human
> Pharmaceutical Product Applications and Related Submissions\" (August,
> 2003). This draft guidance discusses issues related to the electronic
> submission of ANDAs, BLAs, INDs, NDAs, master files, advertising
> material, and promotional material.
>
> **•** \"Providing Regulatory Submissions in Electronic
> Format----General Considerations\" (October 2003). This draft guidance
> discusses general issues common to all types of electronic regulatory
> submissions.
>
> **•** \"Providing Regulatory Submissions in Electronic
> Format----Content of Labeling\" (February 2004). This draft guidance
> discusses issues related to the submission of the content of labeling
> in electronic format for marketing applications for human drug and
> biological products.
>
> These guidance documents are available at FDA\'s web
>
> site <http://www.fda.gov/cder/guidance/index.htm>[.]{.underline}
>
> 4\. [Efforts to Identify Duplication]{.underline}
>
> The information collection requested under the guidance does not
> duplicate any other information collection.
>
> 5\. [Involvement of Small Entities]{.underline}
>
> Although new drug development is typically an activity completed by
> large multinational drug firms, the information collection requested
> under the guidance applies to small as well as large companies. Under
> the Regulatory Flexibility Act, FDA regularly analyzes regulatory
> options that would minimize any significant impact on small entities.
> FDA also assists small businesses in complying with regulatory
> requirements.
>
> 6\. [Consequences If Information Collected Less
> Frequently]{.underline}
>
> The frequency of information submission recommended by the guidance is
> intended to provide assist manufacturers on how to resolve disputes of
> scientific and technical issues relating to CGMP. The guidance
> provides procedures that will encourage open and prompt discussion of
> disputes and lead to their resolution. The guidance describes
> procedures for raising such disputes to the ORA and center levels and
> for requesting review by the DR Panel. These benefits will be lessened
> without the assistance provided by the guidance.
>
> 7\. [Consistency with the Guidelines in 5 CFR
> 1320.5(d)(2)]{.underline}
>
> This guidance contains no inconsistency with the guidelines in 5 CFR
> 1320.5(d)(2).
>
> 8\. [Consultation Outside the Agency]{.underline}
>
> In the Federal Register of September 5, 2003 (68 FR 52777), FDA
> announced the availability of a draft guidance for industry entitled
> \"Formal Dispute Resolution: Scientific and Technical Issues Related
> to Pharmaceutical CGMP,\" and requested comments for 60 days on the
> information collection. No comments were received that pertained to
> the information collection estimates.
>
> 9\. [Remuneration of Respondents]{.underline}
>
> FDA has not provided and has no intention to provide any payment or
> gift to respondents under this guidance.
>
> 10\. [Assurance of Confidentiality]{.underline}
>
> Confidentiality of the information submitted under this guidance is
> protected under 21 CFR 312.130 and 314.430 and under 21 CFR part 20.
> The unauthorized use or disclosure of trade secrets required in
> applications is specifically prohibited under Section 310(j) of the
> Act.
>
> 11\. [Questions of a Sensitive Nature]{.underline}
>
> There are no questions of a sensitive nature.
>
> 12\. [Estimates of Annualized Hour Burden]{.underline}
>
> FDA has reviewed the total number of informal disputes that currently
> arise between manufacturers and investigators (and FDA district
> offices) when a manufacturer disagrees with the scientific or
> technical basis for an observation listed on an FDA 483. FDA estimates
> that approximately 12 such disputes occur annually. FDA believes that
> the number of requests for formal dispute resolution under the draft
> guidance would be higher because manufacturers have expressed
> reluctance to dispute with the agency scientific or technical issues
> raised in an investigation in the absence of a formal mechanism to
> resolve the dispute. In addition, manufacturers have requested the
> formal mechanisms in the draft guidance to facilitate the review of
> such disagreements. Therefore, FDA estimates that approximately 25
> manufacturers will submit approximately 25 requests annually for a
> tier-one dispute resolution. FDA also estimates that approximately 5
> manufacturers will appeal approximately 5 of these requests to the DR
> Panel (request for tier-two dispute resolution).
>
> Based on the time it currently takes manufacturers to prepare
> responses to FDA concerning issues raised in an FDA 483, FDA estimates
> that it will take manufacturers approximately 30 hours to prepare and
> submit each request for a tier-one dispute resolution and
> approximately 8 hours to prepare and submit each request for a
> tier-two dispute resolution.
>
> Based on the above methodology and assumptions, the chart below
> provides an estimate of the annual reporting burden for requests for a
> tier-one dispute resolution and requests for a tier-two dispute
> resolution under the guidance. FDA requests comments on this analysis
> of information collection burdens.

+---------------+------------+-----------+---------+----------+-------+
| **Estimated   |            |           |         |          |       |
| Annual        |            |           |         |          |       |
| Reporting     |            |           |         |          |       |
| Burden^1^**   |            |           |         |          |       |
+===============+============+===========+=========+==========+=======+
|               | **Number   | **Number  | **      | **Hours  | **    |
|               | of         | of        | Total** | per      | Total |
|               | Res        | Responses |         | Re       | Ho    |
|               | pondents** | per       | *       | sponse** | urs** |
|               |            | Res       | *Annual |          |       |
|               |            | pondent** | Resp    |          |       |
|               |            |           | onses** |          |       |
+---------------+------------+-----------+---------+----------+-------+
| Requests for  | 25         | 1         | 25      | 30       | 750   |
| Tier-One      |            |           |         |          |       |
| Dispute       |            |           |         |          |       |
| Resolution    |            |           |         |          |       |
+---------------+------------+-----------+---------+----------+-------+
| Requests for  | 5          | 1         | 5       | 8        | 40    |
| Tier-Two      |            |           |         |          |       |
| Dispute       |            |           |         |          |       |
| Resolution    |            |           |         |          |       |
+---------------+------------+-----------+---------+----------+-------+
| **Total**     |            |           |         |          | **    |
|               |            |           |         |          | 790** |
+---------------+------------+-----------+---------+----------+-------+

^1^There are no capital costs or operating and maintenance costs
associated with this collection.

> 13\. [Estimates of Annualized Cost Burden to Respondents]{.underline}
>
> FDA has estimated an average industry wage rate of \$50.00 per hour
> for preparing and submitting the information collection under this
> guidance. Using the averaged wage rate of \$50.00 per hour, and
> multiplied times the total hour burden estimated above, the total cost
> burden to respondents is \$39,500 (790 x \$50).
>
> 14\. [Estimates of Annualized Cost Burden to the
> Government]{.underline}
>
> FDA estimates that review by FDA staff of the submissions recommended
> by the guidance would require approximately 10 hours per request and a
> total burden of 300 hours (30 X 10). Using an hourly rate of \$50 per
> hour, the total cost to FDA would be approximately \$15,000.
>
> 15\. [Changes In Burden]{.underline}
>
> This is a new collection.
>
> 16\. [Time Schedule, Publication, and Analysis Plans]{.underline}
>
> There are no publications.
>
> 17\. [Displaying of OMB Expiration Date]{.underline}
>
> The agency is not seeking to display the expiration date for
>
> OMB approval of the information collection.
>
> 18\. [Exception to the Certification Statement - Item 19]{.underline}
>
> There are no exceptions to the certification statement
>
> identified in Item 19, \"Certification for Paperwork Reduction Act
>
> Submission,\" of OMB Form 83-I.

pracgmp.disput.ss.doc 12/18/04