APPENDIX B TO SUBPART A OF PART 26— LIST OF AUTHORITIES

1. For the United States: In the United States, the regulatory authority is the Food and Drug Administration.

2. For the European Community: In the European Community, the regulatory authorities are the following:

Belgium: Inspection générale de la Pharmacie, Algemene Farmaceutische Inspectie.

Denmark: Laegemiddelstyrelsen.

Germany: Bundesministerium für Gesundheit for immunologicals: Paul-EhrlichInstitut, Federal Agency for Sera and Vaccines.

Greece: Εθνικός Οργανισμος Φαρμακου, Ministry of Health and Welfare, National Drug Organization (E.O.F).

Spain: For medicinal products for human use: Ministerio de Sanidad y Consumo, Subdirección General de Control Farmacéutico. For medicinal products for veterinary use: Ministerio de Agricultura, Pesca y Alimentación (MAPA), Dirección General de la Producción Agraria.

France: For medicinal products for human use: Agence du Médicament. For veterinary medicinal products: Agence Nationale du Médicament Vétérinaire.

Ireland: Irish Medicines Board.

Italy: For medicinal products for human use: Ministero della Sanità, Dipartimento Farmaci e Farmacovigilanza. For medicinal products for veterinary use: Ministero della Sanità, Dipartimento alimenti e nutrizione e sanità pubblica veterinaria-Div. IX.

Luxembourg: Division de la Pharmacie et

ative list of products covered by this arrangement is given below:

-human medicinal products including prescription and nonprescription drugs; -human biologicals including vaccines, and immunologicals;

-veterinary pharmaceuticals, including prescription and nonprescription drugs, with the exclusion of veterinary immunologicals (Under 9 CFR 101.2 "veterinary immunologicals" are referred to as "veterinary biologicals"); -premixes for the preparation of veterinary medicated feeds (EC), Type A medicated articles for the preparation of veterinary medicated feeds (United States); -intermediate products and active pharmaceutical ingredients or bulk pharmaceuticals (United States)/starting materials (EC).

APPENDIX D TO SUBPART A OF PART 26CRITERIA FOR ASSESSING EQUIVALENCE FOR POST- AND PREAPPROVAL

I. Legal/Regulatory authority and structures and procedures providing for post- and

preapproval:

A. Appropriate statutory mandate and jurisdiction.

B. Ability to issue and update binding requirements on GMP's and guidance documents.

C. Authority to make inspections, review and copy documents, and to take samples and collect other evidence.

D. Ability to enforce requirements and to remove products found in violation of such requirements from the market.

E. Substantive current good manufacturing requirements.

F. Accountability of the regulatory authority.

G. Inventory of current products and manufacturers.

H. System for maintaining or accessing inspection reports, samples and other analytical data, and other firm/product information relating to matters covered by subpart A of this part.

II. Mechanisms in place to assure appropriate professional standards and avoidance of conflicts of interest.

III. Administration of the regulatory
authority:

A. Standards of education/qualification and training.

B. Effective quality assurance systems measures to ensure adequate job performance. C. Appropriate staffing and resources to enforce laws and regulations.

IV. Conduct of inspections:

A. Adequate preinspection preparation, including appropriate expertise of investigator/ team, review of firm/product and databases, and availability of appropriate inspection equipment.

B. Adequate conduct of inspection, including statutory access to facilities, effective response to refusals, depth and competence of evaluation of operations, systems and documentation; collection of evidence; appropriate duration of inspection and completeness of written report of observations to firm management.

C. Adequate postinspection activities, including completeness of inspectors' report, inspection report review where appropriate, and conduct of followup inspections and other activities where appropriate, assurance of preservation and retrieval of records.

V. Execution of regulatory enforcement actions to achieve corrections, designed to prevent future violations, and to remove products found in violation of requirements from the market.

VI. Effective use of surveillance systems:

A. Sampling and analysis.

B. Recall monitoring.

C. Product defect reporting system.

D. Routine surveillance inspections. E. Verification of approved manufacturing process changes to marketing authorizations/approved applications.

VII. Additional specific criteria for
preapproval inspections:

A. Satisfactory demonstration through a jointly developed and administered training program and joint inspections to assess the regulatory authorities' capabilities.

B. Preinspection preparation includes the review of appropriate records, including site plans and drug master file or similar documentation to enable adequate inspections. C. Ability to verify chemistry, manufacturing, and control data supporting an application is authentic and complete.

D. Ability to assess and evaluate research and development data as scientifically sound, especially transfer technology of pilot, scale up and full scale production batches.

E. Ability to verify conformity of the onsite processes and procedures with those described in the application.

F. Review and evaluate equipment installation, operational and performance qualification data, and evaluate test method validation.

APPENDIX E TO SUBPART A OF PART 26— ELEMENTS TO BE CONSIDERED IN DEVELOPING A TWO-WAY ALERT SYS

TEM

1. Documentation

-Definition of a crisis/emergency and under what circumstances an alert is required -Standard Operating Procedures (SOP's) -Mechanism of health hazards evaluation

and classification

-Language of communication and transmission of information

2. Crisis Management System

-Crisis analysis and communication mechanisms

-Establishment of contact points
-Reporting mechanisms

3. Enforcement Procedures

-Followup mechanisms
-Corrective action procedures

4. Quality Assurance System -Pharmacovigilance programme —Surveillance/monitoring of implementation of corrective action

5. Contact Points

For the purpose of subpart A of this part, the contact points for the alert system will be:

A. For the European Community: the Executive Director of the European Agency for the Evaluation of Medicinal Products, 7, Westferry Circus, Canary Wharf, UK London E14 4HB, England. Telephone 44-171-418 8400, Fax 418-8416.

B. For the United States :

Biologics: Director, Office of Compliance and Biologics Quality (HFM-600), 1401 Rockville Pike, Rockville, MD 20852, phone: 301-8276190, fax: 301-594-1944.

Human Drugs: Director, Office of Compliance (HFD-300), MPN I, 7520 Standish Pl., Rockville, MD 20855-2737, phone: 301-594-0054, fax: 301-594-2114.

Veterinary Drugs: Director, Office of Surveillance and Compliance (HFV-200), MPN II, 7500 Standish Pl., Rockville, MD 20855-2773, phone: 301-827-6644, fax: 301-594-1807.

Subpart B-Specific Sector Provisions for Medical Devices

§ 26.31 Purpose.

(a) The purpose of this subpart is to specify the conditions under which a party will accept the results of quality system-related evaluations and inspections and premarket evaluations of the

other party with regard to medical devices as conducted by listed conformity assessment bodies (CAB's) and to provide for other related cooperative activities.

(b) This subpart is intended to evolve as programs and policies of the parties evolve. The parties will review this subpart periodically, in order to assess progress and identify potential enhancements to this subpart as Food and Drug Administration (FDA) and European Community (EC) policies evolve over time.

§ 26.32 Scope.

(a) The provisions of this subpart shall apply to the exchange and, where appropriate, endorsement of the following types of reports from conformity assessment bodies (CAB's) assessed to be equivalent:

(1) Under the U.S. system, surveillance/postmarket and initial/

preapproval inspection reports;

(2) Under the U.S. system, premarket (510(k)) product evaluation reports;

(3) Under the European Community (EC) system, quality system evaluation reports; and

(4) Under the EC system, EC type examination and verification reports.

(b) Appendix A of this subpart names the legislation, regulations, and related procedures under which:

(1) Products are regulated as medical devices by each party;

(2) CAB's are designated and confirmed; and

(3) These reports are prepared.

(c) For purposes of this subpart, equivalence means that: CAB's in the EC are capable of conducting product and quality systems evaluations against U.S. regulatory requirements in a manner equivalent to those conducted by FDA; and CAB's in the United States are capable of conducting product and quality systems evaluations against EC regulatory requirements in a manner equivalent to those conducted by EC CAB's.

§ 26.33 Product coverage.

(a) There are three components to this subpart each covering a discrete range of products:

(1) Quality System Evaluations. U.S.type surveillance/postmarket and ini

tial/preapproval inspection reports and European Community (EC)-type quality system evaluation reports will be exchanged with regard to all products regulated under both U.S. and EC law as medical devices.

(2) Product Evaluation. U.S.-type premarket (510(k)) product evaluation reports and EC-type-testing reports will be exchanged only with regard to those products classified under the U.S. system as Class I/Class II-Tier 2 medical devices which are listed in Appendix B of this subpart.

(3) Postmarket Vigilance Reports. Postmarket vigilance reports will be exchanged with regard to all products regulated under both U.S. and EC law as medical devices.

(b) Additional products and procedures may be made subject to this subpart by agreement of the parties.

§ 26.34 Regulatory authorities.

The regulatory authorities shall have the responsibility of implementing the provisions of this subpart, including the designation and monitoring of conformity assessment bodies (CAB's). Regulatory authorities will be specified in Appendix C of this subpart. Each party will promptly notify the other party in writing of any change in the regulatory authority for a country. § 26.35 Length and purpose of transition period.

There will be a 3-year transition period immediately following the date described in § 26.80(a). During the transition period, the parties will engage in confidence-building activities for the purpose of obtaining sufficient evidence to make determinations concerning the equivalence of conformity assessment bodies (CAB's) of the other party with respect to the ability to perform quality system and product evaluations or other reviews resulting in reports to be exchanged under this subpart.

§ 26.36 Listing of CAB's.

Each party shall designate conformity assessment bodies (CAB's) to participate in confidence building activities by transmitting to the other party a list of CAB's which meet the criteria for technical competence and

independence, as identified in Appendix A of this subpart. The list shall be accompanied by supporting evidence. Designated CAB's will be listed in Appendix D of this subpart for participation in the confidence building activities once confirmed by the importing party. Nonconfirmation would have to be justified based on documented evidence.

§ 26.37 Confidence building activities.

(a) At the beginning of the transitional period, the Joint Sectoral Group will establish a joint confidence building program calculated to provide sufficient evidence of the capabilities of the designated conformity assessment bodies (CAB's) to perform quality system or product evaluations to the specifications of the parties.

(b) The joint confidence building program should include the following actions and activities:

(1) Seminars designed to inform the parties and CAB's about each party's regulatory system, procedures, and requirements;

(2) Workshops designed to provide the parties with information regarding requirements and procedures for the designation and surveillance of CAB's;

(3) Exchange of information about reports prepared during the transition period;

(4) Joint training exercises; and (5) Observed inspections.

(c) During the transition period, any significant problem that is identified with a CAB may be the subject of cooperative activities, as resources allow and as agreed to by the regulatory authorities, aimed at resolving the problem.

(d) Both parties will exercise good faith efforts to complete the confidence building activities as expeditiously as possible to the extent that the resources of the parties allow.

(e) Both the parties will each prepare annual progress reports which will describe the confidence building activities undertaken during each year of the transition period. The form and content of the reports will be determined by the parties through the Joint Sectoral Committee.

§ 26.38 Other transition period activities.

be

(a) During the transition period, the parties will jointly determine the necessary information which must present in quality system and product evaluation reports.

(b) The parties will jointly develop a notification and alert system to be used in case of defects, recalls, and other problems concerning product quality that could necessitate additional actions (e.g., inspections by the parties of the importing country) or suspension of the distribution of the product.

§ 26.39 Equivalence assessment.

(a) In the final 6 months of the transition period, the parties shall proceed to a joint assessment of the equivalence of the conformity assessment bodies (CAB's) that participated in the confidence building activities. CAB's will be determined to be equivalent provided they have demonstrated proficiency through the submission of a sufficient number of adequate reports. CAB's may be determined to be equivalent with regard to the ability to perform any type of quality system or product evaluation covered by this subpart and with regard to any type of product covered by this subpart. The parties shall develop a list contained in Appendix E of this subpart of CAB's determined to be equivalent, which shall contain a full explanation of the scope of the equivalency determination, including any appropriate limitations, with regard to performing any type of quality system or product evaluation.

(b) The parties shall allow CAB's not listed for participation in this subpart, or listed for participation only as to certain types of evaluations, to apply for participation in this subpart once the necessary measures have been taken or sufficient experience has been gained, in accordance with § 26.46.

(c) Decisions concerning the equivalence of CAB`s must be agreed to by both parties.

§ 26.40 Start of the operational period.

(a) The operational period will start at the end of the transition period after the parties have developed the list of conformity assessment bodies (CAB's)

found to be equivalent. The provisions of §§ 26.40, 26.41, 26.42, 26.43, 26.44, 26.45, and 26.46 will apply only with regard to listed CAB's and only to the extent of any specifications and limitations contained on the list with regard to a CAB.

(b) The operational period will apply to quality system evaluation reports and product evaluation reports generated by CAB's listed in accordance with this subpart for the evaluations performed in the respective territories of the parties, except if the parties agree otherwise.

§ 26.41 Exchange and endorsement of quality system evaluation reports. (a) Listed European Community (EC) conformity assessment bodies (CAB's) will provide FDA with reports of quality system evaluations, as follows:

(1) For preapproval quality system evaluations, EC CAB's will provide full reports; and

(2) For surveillance quality system evaluations, EC CAB's will provide abbreviated reports.

(b) Listed U.S. CAB's will provide to the EC Notified Body of the manufacturer's choice:

(1) Full reports of initial quality system evaluations;

(2) Abbreviated reports of quality systems surveillance audits.

(c) If the abbreviated reports do not provide sufficient information, the importing party may request additional clarification from the CAB.

(d) Based on the determination of equivalence in light of the experience gained, the quality system evaluation reports prepared by the CAB's listed as equivalent will normally be endorsed by the importing party, except under specific and delineated circumstances. Examples of such circumstances include indications of material inconsistencies or inadequacies in a report, quality defects identified in postmarket surveillance or other specific evidence of serious concern in relation to product quality or consumer safety. In such cases, the importing party may request clarification from the exporting party which may lead to a request for reinspection. The parties will endeavor to respond to requests for clarification in a timely manner.

Where divergence is not clarified in this process, the importing party may carry out the quality system evaluation.

§ 26.42 Exchange and endorsement of product evaluation reports.

(a) European Community (EC) conformity assessment bodies (CAB's) listed for this purpose will, subject to the specifications and limitations on the list, provide to FDA 510(k) premarket notification assessment reports prepared to U.S. medical device requirements.

(b) U.S. CAB's will, subject to the specifications and limitations on the list, provide to the EC Notified Body of the manufacturer's choice, type examination, and verification reports prepared to EC medical device requirements.

(c) Based on the determination of equivalence in light of the experience gained, the product evaluation reports prepared by the CAB's listed as equivalent will normally be endorsed by the importing party, except under specific and delineated circumstances. Examples of such circumstances include indications of material inconsistencies, inadequacies, or incompleteness in a product evaluation report, or other specific evidence of serious concern in relation to product safety, performance, or quality. In such cases, the importing party may request clarification from the exporting party which may lead to a request for a reevaluation. The parties will endeavor to respond to requests for clarification in a timely manner. Endorsement remains the responsibility of the importing party.

§ 26.43 Transmission of quality system evaluation reports.

Quality system evaluation reports covered by $26.41 concerning products covered by this subpart shall be transmitted to the importing party within 60-calendar days of a request by the importing party. Should a new inspection be requested, the time period shall be extended by an additional 30-calendar days. A party may request a new inspection, for cause, identified to the other party. If the exporting party cannot perform an inspection within a specified period of time, the importing