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FDA Guidances

FDA Guidances

All Information was adapted from the Food and Drug Administration website as a service to our readers. The most current versions can be found on the FDA Website.

Contract Manufacturing Arrangements for Drugs: Quality Agreements Guidance for Industry

Contract Manufacturing

Arrangements for Drugs:

Quality Agreements Guidance for Industry

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Veterinary Medicine (CVM)

November 2016
Pharmaceutical Quality/Manufacturing Standards (CGMP)

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Contract Manufacturing

Arrangements for Drugs:

Quality Agreements Guidance for Industry

Additional copies are available from:
Office of Communications, Division of Drug Information Center for Drug Evaluation and Research

Food and Drug Administration th 10001 New Hampshire Ave., Hillandale Bldg., 4

Floor

Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
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http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
and/or
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010
Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and/or
Policy and Regulations Staff, HFV-6
Center for Veterinary Medicine
Food and Drug Administration
7519 Standish Place, Rockville, MD 20855

http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Veterinary Medicine (CVM)

November 2016
Pharmaceutical Quality/Manufacturing Standards (CGMP)

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I. II. III.

IV. A.

B.

V. A.

B.

C. VI.

1. 2.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 DEFINING THE WHO AND WHAT OF CONTRACT MANUFACTURING ........ 2

RESPONSIBILITIES OF PARTIES INVOLVED IN CONTRACT MANUFACTURING........................................................................................................ 3

DOCUMENTING CGMP ACTIVITIES IN QUALITY AGREEMENTS................. 5 What Is a Quality Agreement? ..................................................................................................... 6 Elements of a Quality Agreement................................................................................................. 6 Manufacturing Activities..................................................................................................................7 Change Control Associated With Manufacturing Activities .......................................................... 10 ILLUSTRATIVE SCENARIOS .................................................................................... 11 Owners and Contract Facilities Are Both Responsible for CGMP ......................................... 11 CGMPs Apply to all Contract Facilities, Including Analytical Testing Laboratories...........12 Owners and Contract Facilities Perform Change Control Activities .....................................13 RECOMMENDATIONS................................................................................................ 13

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Contract Manufacturing Arrangements for Drugs: Quality Agreements 1

Guidance for Industry

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This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page.

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I. INTRODUCTION

This guidance describes FDA’s current thinking on defining, establishing, and documenting manufacturing activities of the parties involved in contract drug manufacturing subject to current good manufacturing practice (CGMP) requirements. In particular, we describe how parties involved in contract drug manufacturing can use quality agreements to delineate their manufacturing activities to ensure compliance with CGMP.

For purposes of this guidance, we use certain terms with the following specific meanings:

  • Current Good Manufacturing Practice (CGMP) refers to requirements in the Federal Food, Drug, and Cosmetic Act (FD&C Act), section 501(a)(2)(B), for all drugs and active pharmaceutical ingredients (APIs). For finished human and animal drugs, the term includes applicable requirements under 21 CFR parts 210 and 211. For biologics, the term includes additional applicable requirements under 21 CFR parts 600-680.

  • Commercial manufacturing refers to manufacturing processes that result in a drug or drugs intended to be marketed, distributed, or sold.

  • Commercial manufacturing does not include research and development activities, manufacturing of material for investigational new drug studies (e.g., clinical trials, expanded access), or manufacturing of material for veterinary investigational drugs. Although this guidance does not explicitly apply to the manufacture of investigational, developmental, or clinical trial materials, FDA believes that quality agreements can be extremely valuable in delineating the activities of all parties involved in contract research and development arrangements. Many of the principles described in this guidance could be applied in pre-commercial stages of the pharmaceutical life cycle.

    1 This guidance has been prepared by the Office of Pharmaceutical Quality and the Office of Compliance in the Center for Drug Evaluation and Research in cooperation with the Center for Biologics Evaluation and Research, the Center for Veterinary Medicine, and the Office of Regulatory Affairs at the Food and Drug Administration.

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  • Manufacturing includes processing, packing, holding, labeling operations, testing, and quality unit operations.

  • A manufacturer is an entity that engages in CGMP activities, including implementation of oversight and controls over the manufacture of drugs to ensure quality.2

  • Quality unit is defined as synonymous with the term quality control unit.3

    This guidance covers commercial manufacturing of the following categories of drugs: human drugs, veterinary drugs, certain combination products, biological and biotechnology products, finished products, APIs, drug substances, in-process materials, and drug constituents of combination drug/device products.4 This guidance does not cover the following types of products: Type A medicated articles and medicated feed, medical devices, dietary supplements, or human cells, tissues, or cellular or tissue-based products regulated solely under section 361 of the Public Health Service Act and 21 CFR part 1271.

    In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

II. DEFINING THE WHO AND WHAT OF CONTRACT MANUFACTURING

This guidance describes how contract manufacturing operations fit within the larger scheme of pharmaceutical quality systems. It also presents the Agency’s current thinking on the roles and manufacturing activities of the parties involved in contract manufacturing arrangements. Specifically, this guidance addresses the relationship between owners and contract facilities. For purposes of this guidance, we define owners as manufacturers of APIs, drug substances, in- process materials, finished drug products, including biological products, and combination products. The term owner does not apply to retail pharmacies, drug stores, supermarkets, discount warehouse stores, or other retailers who purchase finished drug products to sell over the counter as a store brand. For purposes of this guidance, we define contract facilities as parties that perform one or more manufacturing operations on behalf of an owner or owners.5

2 See section 501 of the FD&C Act, as amended by the Food and Drug Administration Safety and Innovation Act (Public Law 112-144, title VII, section 711).
3 For quality control unit, see 21 CFR 210.3.
4 Combination product manufacturers can apply this guidance to their quality agreements because they are subject to requirements under 21 CFR part 211 and/or 21 CFR part 820 (see 21 CFR 4.3). In addition to facilitating compliance with requirements under 21 CFR part 211, manufacturers can use quality agreements with contract facilities to demonstrate compliance, in part, with 21 CFR 820.50 (purchasing controls) and with 21 CFR 820.80(b) (receiving acceptance activities) for combination products.

5 A contract facility may also be an owner depending on its role (e.g., when the contract facility is using a subcontractor).

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Drug manufacturing encompasses many discrete operations and activities. One manufacturer may perform all operations and activities or may engage an outside party or parties to perform some or all of the operations and activities under contract. Contract facilities perform a variety of manufacturing operations and activities, including but not limited to:

  • Formulation

  • Fill and finish

  • Chemical synthesis

  • Cell culture and fermentation, including for biological products

  • Analytical testing and other laboratory services

  • Packaging and labeling

  • Sterilization or terminal sterilization

    However, agreements between owners and contract facilities sometimes do not clearly define the CGMP-related roles and manufacturing operations and activities of each of the parties. When all parties clearly understand their CGMP-related roles and manufacturing responsibilities, the owners who use contract facilities, contract facilities that provide services to owners, and, ultimately, patients who take the drugs manufactured under these arrangements may benefit in many ways. Contracting can enhance speed and efficiency, provide technological expertise, and expand capacity.

    We encourage entities that engage in manufacturing related solely to drug distribution (e.g., distributors, brokers, private label distributors, own label distributors) to follow the recommendations in this guidance document, as appropriate. Our focus here, however, is on the roles and manufacturing activities of the owner and contract facility.

III. RESPONSIBILITIES OF PARTIES INVOLVED IN CONTRACT MANUFACTURING

Each party engaged in the manufacture of a drug is responsible for ensuring compliance with CGMP for the manufacturing activities it performs.6 For both owners and contract facilities that conduct manufacturing operations, CGMP “includes the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.”7 Drugs not manufactured in compliance with CGMP are adulterated.8

The FD&C Act also prohibits any person from introducing or delivering for introduction an adulterated or misbranded drug into interstate commerce.9 In addition, it prohibits anyone from the “doing of any ... act with respect to, a ... drug ... if such act is done while such article is held

6 Section 501(a)(2)(B) of the FD&C Act; 21 CFR parts 210 and 211; and 21 CFR part 600.
7 Section 501 of the FD&C Act as amended by the Food and Drug Administration Safety and Innovation Act (Public Law 112-144, Title VII, section 711).
8 Section 501(a)(2)(B) of the FD&C Act.
9 Section 301(a) of the FD&C Act.

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for sale ... after shipment in interstate commerce and results in such article being adulterated or misbranded.”10

FDA’s regulations recognize that owners commonly use contract facilities to perform some drug manufacturing activities.11 When an owner uses a contract facility, the owner’s quality unit is legally responsible for approving or rejecting drug products manufactured by the contract facility, including for final release.12 The regulations require that the quality unit’s responsibilities and procedures be in writing and that they be followed.13

Owners can use a comprehensive quality systems model to help ensure compliance with CGMP. A comprehensive quality systems model anticipates that many owners will use contract facilities and calls for quality agreements between owners and contract facilities. Quality agreements should clearly describe the materials or services to be provided, quality specifications, and communication mechanisms between the owner and contract facility. See guidance for industry Quality Systems Approach to Pharmaceutical CGMP Regulations.14

Owners and contract facilities can review FDA guidance documents for recommendations on achieving compliance with CGMP. Various FDA guidance documents describe how quality management principles relate to contract manufacturing operations, including some of the roles and manufacturing activities of contract manufacturing parties.15

The following three ICH guidances for industry contain relevant and valuable CGMP recommendations with respect to contract manufacturing arrangements:

Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients Q9 Quality Risk Management
Q10 Pharmaceutical Quality System

ICH guidance for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients recommends that owners evaluate contract facilities to ensure that contractor sites comply with CGMP for specific operations.16 It also recommends that owners have approved written agreements with contractors that define the manufacturing responsibilities in detail, including the quality measures, of each party. The written agreements should also define considerations for subcontracting; describe how changes to processes, equipment, methods, and specifications will be managed; and permit the owner to audit its contractor’s facilities for compliance with CGMP.

10 Section 301(k) of the FD&C Act. 11 21 CFR 200.10(b) and 211.22(a). 12 Ibid.
13 21 CFR 211.22(d).

14 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
15 See, e.g., guidance for industry Cooperative Manufacturing Arrangements for Licensed Biologics.

16 In ICH Q7, the term company is used rather than owner and is used to refer to an API manufacturer. 4

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ICH guidance for industry Q9 Quality Risk Management offers a systematic approach to quality risk management as part of an effective quality system. It discusses quality risk management principles such as risk assessment, risk communication, and risk review and provides examples of tools that can be used to make effective and efficient risk-based decisions in, for example, auditing and arranging quality agreements with contract manufacturers.

ICH guidance for industry Q10 Pharmaceutical Quality System states that, as part of a pharmaceutical quality system, the owner is ultimately responsible for ensuring that “processes are in place to assure the control of outsourced activities and quality of purchased materials.”17 It indicates that these processes should incorporate quality risk management and include the following critical activities:

  • Assessing the suitability and competence of potential contractors before outsourcing operations or selecting material suppliers. This could be accomplished through audits, material evaluations, or other qualification criteria.

  • Defining the manufacturing responsibilities and communication processes for quality- related activities of the involved parties. For outsourced activities, these should be in a written agreement.

  • Monitoring and reviewing the performance of the contract facility and identifying and implementing any needed improvements.

  • Monitoring incoming ingredients and materials to ensure they are from approved sources using the agreed-upon supply chain.

    FDA encourages parties engaged in contract manufacturing to implement quality management practices. This guidance is intended to build upon the quality risk management principles and recommendations outlined above and to illustrate key points in developing and executing quality agreements that describe and support contract manufacturing arrangements.

IV. DOCUMENTING CGMP ACTIVITIES IN QUALITY AGREEMENTS

If an owner employs a contract facility for all or part of the manufacturing (including processing, packing, holding, or testing) of a drug or drug product, the owner’s quality unit is responsible for approving or rejecting the contract facility’s product or service.18 The contract facility is also required to comply with statutory CGMP and applicable CGMP regulations, including requirements for its quality unit.19 CGMP regulations require that quality unit activities and procedures be in writing, and that these procedures be followed.20

Implementing a written quality agreement can facilitate compliance with CGMP and, in particular, with 21 CFR 211.22(d), which states that quality unit activities and procedures should be in writing. FDA recommends that owners and contract facilities establish a written quality agreement to describe their respective CGMP-related roles, responsibilities, and activities in drug

17 In ICH Q10, the term company is used rather than owner. 18 Section 501(a)(2)(B) of the FD&C Act; 21 CFR 211.22(a). 19 21 CFR 210.2(b); 21 CFR 211.22(a).
20 21 CFR 211.22(d).

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manufacturing. It is important to note that quality agreements cannot be used to delegate statutory or regulatory responsibilities to comply with CGMP. The following sections describe the Agency’s current thinking regarding the documentation of agreed-upon manufacturing activities in a quality agreement, as well as the basic elements of a quality agreement.

A. What Is a Quality Agreement?

A quality agreement is a comprehensive written agreement between parties involved in the contract manufacturing of drugs that defines and establishes each party’s manufacturing activities in terms of how each will comply with CGMP. In general, the quality agreement should clearly state which party — the owner or the contract facility or both — carries out specific CGMP activities. It should cover activities mentioned in section 501(a)(2)(B) of the FD&C Act and, as applicable, those in 21 CFR parts 210, 211, 600-680, 820, and 1271, as well as all other applicable statutory or regulatory requirements. Representatives from each party’s quality unit and other relevant stakeholders should participate actively in the drafting of quality agreements.

Quality agreements should not cover general business terms and conditions such as confidentiality, pricing or cost issues, delivery terms, or limits on liability or damages. FDA recommends that quality agreements be separate documents, or at least severable, from commercial contracts such as master services agreements or supply agreements. Quality agreements may be reviewed during inspections.21

B. Elements of a Quality Agreement

A quality agreement describes the owner’s and the contract facility’s roles and manufacturing activities under CGMP. A well-written quality agreement will use clear language. It will define key manufacturing roles and responsibilities. It will establish expectations for communication, providing key contacts for both parties. It will specify which products and/or services the owner expects from the contract facility and who has final approval for various activities. Most quality agreements contain the following sections:

  • Purpose/Scope — to cover the nature of the contract manufacturing services to be provided

  • Definitions — to ensure that the owner and contract facility agree on precise meaning of terms in the quality agreement

  • Resolution of disagreements — to explain how the parties will resolve disagreements about product quality issues or other problems

  • Manufacturing activities — to document quality unit and other activities associated with manufacturing processes as well as control of changes to manufacturing processes

  • Life cycle of, and revisions to, the quality agreement
    The owner may consider including the contract facility’s established processes and procedures as

    part of the quality agreement (for example, by incorporating certain standard operating 21 See section 704 of the FD&C Act.

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procedures by reference). Doing so could reduce the risk of misinterpretation or error during manufacturing. The quality agreement should explain how the contractor will report manufacturing deviations to the owner, as well as how deviations will be investigated, documented, and resolved in compliance with CGMP. Quality agreements should state that manufacturing services provided by contract facilities (including laboratories) will comply with CGMP .

From a CGMP perspective, manufacturing activities are the most important element in a quality agreement. The most critical pieces are quality and change control, as described in the following sections.

1. Manufacturing Activities

Quality agreements may document each party’s roles and manufacturing activities with a variety of formats — charts, matrices, narratives, or a combination of these. Regardless of the format, a quality agreement should clearly document which party is responsible for specific activities. No party to a quality agreement may delegate any of its responsibilities to comply with CGMP through the quality agreement or any other means. The quality agreement should cover all of the activities for ensuring compliance with CGMP. Depending on the scope of the contract manufacturing services to be provided, the quality agreement should indicate whether the owner or contract facility (or both) will handle specific activities related to each of the following topics:

a. Quality unit activities

The section of a quality agreement that addresses each party’s quality unit activities should define in detail how the parties will work together to ensure that products are manufactured in compliance with CGMP. Note that assigning quality control or other activities to either the owner or contract facility in the quality agreement does not relieve either party from compliance with applicable CGMP requirements.

In particular, this section of the quality agreement should be clear with respect to product release.

Contract facilities are responsible for approving or rejecting the product or results of their 22 manufacturing operations (e.g., test results, finished dosage forms, or in-process materials). addition, owners are responsible for approving or rejecting drugs manufactured by the contract facility,23 including for final release. In all cases, the owner must not introduce or deliver into interstate commerce, or cause to be introduced or delivered into interstate commerce, any drugs that are adulterated or misbranded.24

Within its quality unit activities, a quality agreement should describe how and when the owner and contract facility will communicate with each other, both verbally and in writing. This includes identifying appropriate contact personnel within the owner’s and contract facility’s organization.

22 21 CFR 211.22(a).
23 Section 501(a)(2)(B) of the FD&C Act; 21 CFR 211.22(a). 24 See section 301(a) of the FD&C Act.

In

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Quality agreements should also cover audits, inspections, and communication of findings. The agreement should allow owners to evaluate and audit contract facilities to ensure CGMP compliance for specific operations. This provision should cover both routine quality audits and for-cause audits. The agreement should also set owner and contract facility expectations regarding FDA inspections (pre-approval, routine surveillance, and for-cause) with consideration for the nature of the products to be manufactured and/or services to be provided. It should include the parties’ agreed-upon provisions for communicating inspection observations and findings, as well as relevant FDA actions and correspondence.

Because contract facilities often provide services to multiple owners, the quality agreement should address when, how, and what information the contractor will report to owners about objectionable conditions observed during inspections and audits of the contract facility.

b. Facilities and equipment

This section of a quality agreement should identify the specific site(s) where the contract facility will perform manufacturing operations, including the address of and specific services to be provided at each site. It should indicate which party will be validating processes and qualifying and maintaining equipment and applicable systems relevant to the contracted operations. These include information technology and automated control systems, environmental monitoring and room classification, utilities, and any other equipment and facilities that must be maintained to perform the contracted manufacturing operations in compliance with CGMP. The agreement also should identify which party will approve equipment validation, qualification, and maintenance activities. In addition, it should indicate how the parties will communicate information about preventing cross-contamination and maintaining traceability when a contract facility processes drugs for multiple owners.

c. Materials management

This section of a quality agreement should indicate which party will establish specifications for components as well as which party will establish processes for auditing, qualifying, and monitoring component suppliers. It should also identify which party will conduct required sampling and testing in compliance with CGMP. This section of the quality agreement should address how the parties will ensure appropriate inventory management, including labeling, label printing, inventory reconciliation, and product status identification (e.g., quarantine). The agreement should address how the contract facility will prevent mix-ups and cross- contamination. FDA does not expect the agreement to contain a complete description of the supply chain for each component. However, the agreement should define responsibility for physical control of materials at different points in the manufacturing process. For example, the quality agreement should cover responsibilities for proper conditions for storing and transporting or shipping materials. It should define each party’s roles in storage and transport — whether from the contract facility back to the owner or to another contract facility for further operations. This includes defining activities for monitoring or validating shipping conditions as appropriate.

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d. Product-specific considerations

A comprehensive quality agreement may address specific considerations related to individual products. The owner and contract facility might opt to include this information in an appendix, or directly in the body of the quality agreement. In either case, if included, this section of the quality agreement should include the parties’ expectations of each other regarding:

  • Product/component specifications

  • Defined manufacturing operations, including batch numbering processes

  • Responsibilities for expiration/retest dating, storage and shipment, and lot disposition

  • Responsibilities for process validation, including design, qualification, and ongoing

    verification and monitoring

  • Provisions to allow owner personnel access to the contract facility when appropriate

    The quality agreement also should indicate how owners will transfer knowledge, such as product and process development information, to contract facilities to ensure a drug can be manufactured in compliance with CGMP, and conversely how contract facilities should share with owners product quality information gained throughout the product life cycle. This applies to knowledge about all drugs, including drugs subject to an approved application (e.g., new drug application) and nonprescription drug products marketed under an over-the-counter drug monograph.

    Owners that hold an approved drug application should be aware of application and approval requirements that could affect manufacturing activities. Both parties to a quality agreement should share relevant information to ensure compliance with CGMP and other applicable requirements of the FD&C Act.

e. Laboratory controls

The owner and contract facility should both have access to adequate laboratory facilities for testing of their drugs. A quality agreement will help each party meet this need by defining roles and responsibilities for laboratory controls. We recommend the following elements:

  • Procedures delineating controls over sampling and testing samples

  • Protocols and procedures for communicating all laboratory test results conducted by

    contract facilities to the owner for evaluation and consideration in final product

    disposition decisions

  • Procedures to verify that both owner and contract facilities accurately transfer

    development, qualification, and validation methods when an owner uses a contract

    facility for laboratory testing

  • Routine auditing procedures to ensure that a contract facility’s laboratory equipment is

    qualified, calibrated, and maintained in a controlled state in accordance with CGMP

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Designation of responsibility for investigating deviations, discrepancies, failures, out-of- specification results,25 and out-of-trend results in the laboratory, and for sharing reports of such investigations

f. Documentation

The quality agreement should define expectations between the contract facility and the owner to review and approve documents. It also should describe how changes may be made to standard operating procedures, manufacturing records, specifications, laboratory records, validation documentation, investigation records, annual reports, and other documents related to products or services provided by the contract facility. The quality agreement should also define owners’ and contract facilities’ roles in making and maintaining original documents or true copies in accordance with CGMP. It should explain how those records will be made readily available for inspection.

The quality agreement also should indicate that electronic records will be stored in accordance with CGMP and will be immediately retrievable during the required record-keeping time frames established in applicable regulations.

2. Change Control Associated With Manufacturing Activities

Either an owner or a contract facility may initiate changes to processes, equipment, test methods, specifications, and other contractual requirements. Both parties should discuss changes and address them in the quality agreement. There are some changes that owners should review and approve before they are implemented and other changes contractors may implement without notifying the owner. How all changes are managed should be outlined in the agreement, including allocation of responsibilities for conducting validation activities as needed before implementing changes. Additionally, both parties should be aware of those changes that need to be submitted to FDA in a supplement or annual report. The owner and contract facility should carefully consider and agree on the types of changes to report to each other and to FDA and the need for approval from each party’s quality unit and FDA, as applicable. The quality agreement should address expectations for reporting and approving changes to the following:

  • Components and/or their suppliers

  • Establishment locations

  • Manufacturing processes

  • Products or product types that use the same production line, equipment train, or facility

  • Testing procedures

  • Major manufacturing equipment

  • Shipping methods

  • Lot numbering scheme

  • Container closure systems

  • Tamper evidence features

    25 Refer to the guidance for industry Investigating Out-of Specification (OOS) Test Results for Pharmaceutical Production.

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Product distribution

Various unexpected events, such as manufacturing deviations, complaints, product recalls, adverse event reports, master label changes, field alert reports, and biological product deviation reports, may necessitate changes to processes and procedures. Process improvement projects, process capability analyses, and trending reports may also necessitate changes to processes and procedures. The quality agreement should include the owner’s and contract facility’s expectations for reporting and communication in case of unexpected events and related changes.

V. ILLUSTRATIVE SCENARIOS

The following hypothetical scenarios illustrate common problems in contract manufacturing arrangements and depict ways in which both owners and contract facilities can affect product quality. These scenarios also demonstrate FDA’s current thinking regarding potential ways to resolve problems. The examples provided are not intended to encompass all drug manufacturing problems related to arrangements between owners and contract facilities. Rather, they provide industry and other stakeholders with patterns FDA investigators frequently encounter and analyses of the facts within these patterns.

A. Owners and Contract Facilities Are Both Responsible for CGMP

Case 1: Facilities and Equipment Maintenance and Upkeep at Contract Facility

An FDA inspection of a contract facility that manufactures an injectable drug product for an owner reveals significant objectionable conditions at the contract facility. Most of the objectionable conditions relate to deficient maintenance of facilities and equipment used to manufacture the injectable drug product. Equipment is broken. Pipes are tarnished, and seals are leaking. In addition, the facility design does not adequately prevent contamination. A quality agreement between the contract facility and the owner states that the owner is responsible for upgrades and maintenance of the facilities and equipment used to manufacture the owner’s product. The owner has failed to provide upgrades and perform maintenance, and the contract facility continues to manufacture the product under non-CGMP conditions with risk of contamination.

Case 2: Documenting Steps in the Manufacturing Process

A contract facility is manufacturing a prescription drug product for an owner. FDA has approved an application from the owner for this drug. On inspection, FDA observes that the contract facility’s batch records do not accurately reflect the actual manufacturing process because the batch records do not document the addition of reclaimed powder. Despite the fact that the batch records are inaccurate and are therefore not compliant with CGMP, the contract facility claims that its batch records comply with expectations set out in the quality agreement with the owner.

In the cases described above, the owners and contract facilities appear to be in violation of CGMP. A quality agreement cannot exempt owners or contract facilities from statutory or

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regulatory responsibilities to comply with applicable CGMP, regardless of whether the quality agreement specifically discusses those CGMP requirements. In case 1, the contract facility violates CGMP requirements by continuing to manufacture on outdated or poorly designed equipment, even though the quality agreement says that the owner is responsible for maintenance and upkeep of the equipment. In case 2, the contract facility violates CGMP by using a batch record that does not accurately reflect the manufacturing process, even though the batch record is consistent with what was set out in the quality agreement.

At the same time, the owner remains responsible for ensuring its products are made in compliance with CGMP even when a quality agreement assigns a particular manufacturing activity to the contract facility. After finding problems at a contract facility, such as the ones described in the cases above, FDA might determine that it is appropriate to inspect the owner. The owner could also be in violation of CGMP related to its failure to oversee the contract facility’s manufacturing activities.

B. CGMPs Apply to all Contract Facilities, Including Analytical Testing Laboratories

Case 3: Unreliable Data in Laboratory Records and Test Results

In this scenario, an owner contracts with a facility for analytical testing services. The contract facility repeatedly reports passing results in its CGMP records when actual analyses indicated failures. The contract facility also fails to report accurate results to the owner, who is the finished drug product manufacturer. When FDA inspects the owner, it finds that despite having a written procedure requiring a site audit of contract facilities every 2 years, the owner has not audited the analytical testing facility.

Case 4: Contracted Analytical Testing Laboratory and Method Validation

An owner contracts with a facility to perform stability testing and other analyses of its newly approved drug. FDA approval and a quality agreement with the owner require the drug to be manufactured using these processes, which are described in the owner’s new drug application (NDA). The contract facility uses an analytical method contained in the NDA but gets several out-of-specification results. Also, the facility’s duplicate sample analyses occasionally point to possible unacceptable variations in drug concentration. The facility investigates the varying results and concludes that the failures are related to the sample preparation techniques but does not clearly identify the problem. Despite this, the contract facility continues to use the noncompliant method to test the product. When FDA inspects the contract facility, it finds that the facility failed to fully investigate the problems and implement corrective actions. The contract facility claims that because it used the owner’s analytical method as specified in the product application, it is not responsible for investigating and implementing corrections related to it.

In both of the cases above, FDA might conclude that the contract facilities are responsible for violating CGMP applicable to the laboratory activities they perform. FDA could also conclude

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that the owners are responsible for CGMP violations. Analytical testing laboratories are responsible for operating in compliance with CGMP regardless of quality agreements they may have with owners. They must employ adequate controls to ensure that data and test results are reliable and maintained in accordance with CGMP requirements. It is the owner’s responsibility to review this information from the contract facility to decide whether to approve or reject product for release and distribution.26

No matter who tests the products, the owners’ quality units are ultimately responsible for ensuring that the products are manufactured in accordance with CGMP. A quality agreement does not change that. FDA could cite the owners in cases 3 and 4 further for failing to evaluate, qualify, audit, and monitor their contract facilities.

C. Owners and Contract Facilities Perform Change Control Activities

Case 5: Approving or Rejecting Changes That Affect Product Quality and CGMP Compliance

A contract facility informed the owner about obvious powder segregation issues. The contract facility had attempted to correct the problem by making changes to the equipment, but then determined that the issues could not be fixed without process redesign and component changes. Under their quality agreement, the contract facility could not implement these changes without the owner’s approval. The owner refused to approve the recommended changes, so the contract facility continued manufacturing the product using the flawed process and is therefore not compliant with CGMP.

Case 5 illustrates the responsibilities of both owners and contract facilities when change control issues are in question. Owners may be reluctant to approve changes recommended by contract facilities, even if changes are necessary to continue manufacturing the drug in compliance with CGMP .

VI. RECOMMENDATIONS

Owners and contract facilities can draw on quality management principles to carry out the complicated process of contract drug manufacturing by defining, establishing, and documenting their activities in drug manufacturing operations, including processing, packing, holding, labeling operations, testing, and quality control operations. Accordingly, FDA recommends that owners and contract facilities implement written quality agreements as tools to delineate manufacturing activities for ensuring compliance with CGMP.

26 See, for example, §§ 211.22(a), 211.68, 211.180, 211.188, and 211.194(a). 13

 

BCG-Unresponsive Nonmuscle Invasive Bladder Cancer: Developing Drugs and Biologics for Treatment Guidance for Industry

BCG-Unresponsive

Nonmuscle Invasive Bladder

Cancer: Developing Drugs

and Biologics for Treatment Guidance for Industry

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this draft document, contact (CDER) V. Ellen Maher at 301-796-5017 or (CBER) the Office of Communication, Outreach, and Development at 800-835-4709 or 240-402- 8010.

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

November 2016 Clinical/Medical

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1152293dft.docx 10/19/16

BCG-Unresponsive

Nonmuscle Invasive Bladder

Cancer: Developing Drugs

and Biologics for Treatment Guidance for Industry

Additional copies are available from:

Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

and/or

Office of Communication, Outreach, and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, rm. 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010; Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www .fda.gov/BiologicsBloodV accines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

November 2016 Clinical/Medical

I. II.

A. B.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 DEVELOPMENT PROGRAM ....................................................................................... 2 Early Phase Development ..............................................................................................................2 Late Phase Development ................................................................................................................3

1. 2. 3. 4. 5. 6. 7. 8. 9.

  1. Accelerated Approval (Subpart H and Subpart E) Considerations.............................................7

  2. Risk-Benefit Considerations.........................................................................................................7

General Considerations ...................................................................................................................3 Trial Population and Entry Criteria.................................................................................................3 Randomization, Stratification, and Blinding ....................................................................................5 Dose Selection ..................................................................................................................................5 Single-Arm vs. Randomized, Controlled Trial Design .....................................................................5 Efficacy Endpoints............................................................................................................................5 Trial Procedures and Timing of Assessments ..................................................................................6 Endpoint Adjudication......................................................................................................................7 Statistical Considerations.................................................................................................................7

C. Other Considerations .....................................................................................................................8

1. Risk Management Considerations....................................................................................................8

2. Nonclinical Safety Considerations ...................................................................................................8

REFERENCES.............................................................................................................................. 9

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 1 BCG-Unresponsive Nonmuscle Invasive Bladder Cancer:

  2. 2 Developing Drugs and Biologics for Treatment

  3. 3 Guidance for Industry1

4 5 6

7 8 9

10 11 12 13

14
15
16
17
I. INTRODUCTION 18

  1. 19  The purpose of this guidance is to assist sponsors in the clinical development of drugs, including

  2. 20  biologics, for the treatment of patients who have bacillus Calmette-Guerin (BCG)-unresponsive

  3. 21  nonmuscle invasive bladder cancer (NMIBC).2 The definition described by Lerner et al. 2015 is

  4. 22  used to identify the patient population with BCG-unresponsive disease. This guidance is

  5. 23  intended for pharmaceutical sponsors, the academic community, and the public and provides a

  6. 24  framework, based on current Food and Drug Administration (FDA) thinking, to facilitate the

  7. 25  development of drugs to treat this patient population.3 The pathological diagnosis and staging,

  8. 26  risk stratification, and trial design, including assessment of appropriate clinical endpoints, are

  9. 27  discussed. These issues were discussed at the Food and Drug Administration/American

  10. 28  Urological Association Bladder Cancer Workshop held on May 6, 2013, and in more recent

  11. 29  publications (Jarow, Lerner, et al. 2014; Jarow, Maher, et al. 2015).

30

  1. 31  Many of the general principles elucidated in this guidance also apply to development of drugs for

  2. 32  other forms of nonmuscle invasive bladder cancer. Nevertheless, the specific recommendations

  3. 33  for trial design and endpoints contained herein may not necessarily apply, and sponsors are

  4. 34  encouraged to discuss development plans with the FDA for drugs intended to treat other forms of

  5. 35  NMIBC or for muscle invasive, locally advanced, or metastatic bladder cancer.

36

1 This guidance has been prepared by the Division of Oncology Products 1 in the Center for Drug Evaluation and Research in cooperation with the Center for Biologics Evaluation and Research at the Food and Drug Administration.

2 For the purposes of this guidance, all references to drugs include both human drugs and biological products unless otherwise specified.

3 In addition to consulting guidances, sponsors are encouraged to contact the division to discuss specific issues that arise during the development of drugs for the treatment of BCG-unresponsive NMIBC.

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This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.

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1

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 37  This guidance does not contain discussion of the general issues of statistical analysis or clinical

  2. 38  trial design. Those topics are addressed in the ICH guidances for industry E9 Statistical

  3. 39 Principles for Clinical Trials and E10 Choice of Control Group and Related Issues in Clinical

  4. 40 Trials, respectively.4

41

  1. 42  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 43  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

  3. 44  as recommendations, unless specific regulatory or statutory requirements are cited. The use of

  4. 45  the word should in Agency guidances means that something is suggested or recommended, but

  5. 46  not required.

47
48
49
II. 50
51
52

  1. 53  Nonclinical studies and early phase development should be conducted to demonstrate antitumor

  2. 54  activity and determine the optimal dose and schedule of the investigational drug. Although six

  3. 55  weekly instillations of intravesical therapy has become a standard approach for the treatment of

  4. 56  NMIBC, there are few data available to support this approach. Antitumor activity may be

  5. 57  demonstrated in animal models and/or in patients with marker lesions or those who are scheduled

  6. 58  for cystectomy.

59

  1. 60  Marker lesions are small areas (less than 3 centimeters (cm)) of low-grade papillary lesions that

  2. 61  are biopsied and left in place. These lesions then can be examined for complete response to the

  3. 62  investigational drug. The number of patients involved in such studies should be small, and these

  4. 63  patients should be closely followed with resection of residual lesions after response has been

  5. 64  determined. In addition to the assessment of drug activity in low-grade disease, sponsors should

  6. 65  consider assessment of activity of the investigational drug in patients with BCG-unresponsive

  7. 66  disease before late phase development.

67

  1. 68  Another option to assess antitumor activity is to administer an investigational drug to patients

  2. 69  who are awaiting cystectomy. This allows examination of activity against higher risk disease

  3. 70  and over the entire surface of the bladder. With this approach, there is only a limited window

  4. 71  available for observation of antitumor activity because surgery should not be delayed. Further,

  5. 72  these studies should not interfere with the use of neoadjuvant systemic chemotherapy whenever

  6. 73  appropriate.

74

4 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

DEVELOPMENT PROGRAM A. Early Phase Development

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2

75 B. 76
77
1. 78

Contains Nonbinding Recommendations

Draft — Not for Implementation

Late Phase Development

General Considerations

  1. 79  A key consideration for the recommended trial design and endpoints used to evaluate

  2. 80  effectiveness for an investigational drug used to treat NMIBC is whether the patient has active

  3. 81  disease at the time of enrollment. The preferred trial design in patients without active disease

  4. 82  (disease was resected at or before trial entry) is a randomized, controlled trial using a time-to-

  5. 83  event endpoint of recurrence-free survival. In contrast, patients with disease at trial entry, such

  6. 84  as patients with carcinoma in situ (CIS), can be studied in either a randomized, controlled trial or

  7. 85  single-arm trial. The natural history of BCG-unresponsive NMIBC (CIS with or without

  8. 86  resected disease) is that, in the absence of a pharmacologic intervention or cystectomy, CIS will

  9. 87  almost always persist. In this setting, a single-arm clinical trial with complete response rate as

  10. 88  the primary endpoint can provide primary evidence of effectiveness to support a marketing

  11. 89  application.

90

  1. 91  The use of systemic, as opposed to intravesical, therapy has been proposed for the treatment of

  2. 92  patients with NMIBC. Given the potential for the increased risks associated with the use of

  3. 93  systemic therapies, initial trials should be limited to patients with few treatment options. Patients

  4. 94  with BCG-unresponsive disease are appropriate because their treatment options are limited and

  5. 95  the current alternative is cystectomy.

96
97
2. Trial Population and Entry Criteria
98
99 The trial entry criteria should be specifically defined in the trial protocol and well documented in

100 the case report forms.
101
102 NMIBC includes the following stages (Edge, Byrd, et al. 2010): 103

  1. 104

  2. 105

  3. 106

107

  1. 108  The 2004 World Health Organization/International Society of Urologic Pathology classification

  2. 109  system is the preferred system for tumor grading. This system categorizes tumors as papillary

  3. 110  urothelial neoplasm of low malignant potential, low-grade, or high-grade (Miyamoto, Miller, et

  4. 111  al. 2010).

112

  1. 113  Tumor stage and grade can be used to categorize an individual patient’s risk of recurrence and

  2. 114  progression. The following risk categories are commonly employed (Persad, Lamm, et al.

  3. 115  2008):

116
117
118
119

Ta: Noninvasive papillary disease
T1: Tumor invades the subepithelial connective tissue Tis: Carcinoma in situ

Low-risk tumors: include all of the following features: small-volume (less than 3 cm), low-grade, pathological Ta lesions with no evidence of CIS

3

Contains Nonbinding Recommendations

Draft — Not for Implementation

Intermediate-risk tumors: include those that cannot be categorized as low-risk or high- risk

High-risk tumors: include any of the following features: T1 lesions, high-grade disease, tumors larger than 3 cm, multiple or recurrent lesions, and CIS

125

  1. 126  For the purposes of this guidance, BCG-unresponsive disease is defined as (Lerner, Dinney, et al.

  2. 127  2015):

128
129
130
131
132
133
134
135

  1. 136  Most patients with intermediate- or high-risk NMIBC are treated with an induction course (six

  2. 137  weekly instillations) with or without maintenance (three weekly instillations at 3 and 6 months

  3. 138  and every 6 months thereafter for 1 to 3 years) of BCG (Lamm, Blumenstein, et al. 2000). Some

  4. 139  tumors recur on therapy or after a short disease-free interval. Patients with BCG-unresponsive

  5. 140  disease are extremely unlikely to benefit from further therapy with BCG and represent a unique

  6. 141  population for study of new therapies.

142

  1. 143  To fully define the extent of disease at study entry, patients with T1 disease should undergo

  2. 144  repeat resection or biopsy of the base of the lesion before study entry to ensure the absence of

  3. 145  muscle-invasive disease (T2). Furthermore, patients with high-risk disease should undergo

  4. 146  pelvic examination under anesthesia and imaging by computerized tomography or magnetic

  5. 147  resonance imaging to rule out locally advanced disease. Patients with BCG-unresponsive

  6. 148  disease can have completely resected disease, resected disease with CIS, or CIS alone at study

  7. 149  entry. Patients should be staged before enrollment. Staging should include the use of bladder

  8. 150  mapping and random biopsies in patients with CIS or high-grade papillary disease (Gudjonsson,

  9. 151  Blackberg, et al. 2012). Urine cytology also should be obtained and evaluated.

152

  1. 153  Data should be collected concerning previous anticancer therapies, the dose and timing of

  2. 154  administration, and the patient’s response to each therapy. Patient sex, age, and race should be

  3. 155  considered when enrolling patients in any clinical trial. In NMIBC, an effort should be made to

  4. 156  include women and patients of all races. Because bladder cancer rarely occurs in children, a

  5. 157  pediatric waiver request may be appropriate.

158

  1. 159  The role of central pathology in establishing patient eligibility should be discussed with the

  2. 160  responsible review division. Fluorescence-guided cystoscopy also may be used to aid in patient

  3. 161  selection. Whether white light or fluorescence-guided cystoscopy is used at baseline, the same

  4. 162  method of assessment should be employed throughout the study of that individual patient.

163

120 121
122
123
124

Persistent high-grade disease or recurrence within 6 months of receiving at least two courses of intravesical BCG (at least five of six induction doses and at least two of three maintenance doses); or

T1 high-grade disease at the first evaluation following induction BCG alone (at least five of six induction doses)

4

Contains Nonbinding Recommendations

Draft — Not for Implementation

164 3. Randomization, Stratification, and Blinding 165

  1. 166  Because the urologist performing the cystoscopy can affect both patient eligibility and outcome,

  2. 167  sponsors should consider randomization by study site. In either a randomized or single-arm trial,

  3. 168  sponsors should ensure that all participating urologists perform and document their examination

  4. 169  of the bladder according to the protocol. Moreover, for either randomized or single-arm trials,

  5. 170  sponsors should provide a plan to examine the effect of the urologist/investigator site on patient

  6. 171  staging and outcome.

172

  1. 173  In a randomized trial that includes patients with CIS and resected papillary disease, patients

  2. 174  should be stratified into patients with CIS alone and patients with CIS and resected papillary

  3. 175  disease. Sponsors also should consider whether fluorescence-guided cystoscopy will be used in

  4. 176  the examination of the bladder and may choose to stratify by this variable as well. Finally,

  5. 177  sponsors should consider whether blinding is feasible in a randomized trial.

178
179
4. DoseSelection 180

  1. 181  Dose selection is critical to optimal patient treatment and to the success of a late phase trial.

  2. 182  Sponsors should consider an exploration of dose and schedule during nonclinical studies and

  3. 183  early phase clinical trials. Systemic exposure assessed in an early phase dose-selection trial may

  4. 184  help evaluate and minimize safety concerns from potential systemic exposure after intravesicular

  5. 185  administration. For investigational drugs administered systemically, it is important to consider

  6. 186  the safety profile, activity, and pharmacokinetics of the drug in patients with nonmuscle invasive

  7. 187  disease. These considerations can help guide selection of various dose levels and dosing

  8. 188  regmimens for study in the trials intended to provide primary evidence of effectiveness. The

  9. 189  doses used to treat nonmuscle invasive disease may be lower than the doses administered for the

  10. 190  systemic treatment of metastatic disease.

191
192
5. Single-Arm vs. Randomized, Controlled Trial Design 193

  1. 194  Single-arm trials are appropriate in clinical settings where a randomized, controlled trial is either

  2. 195  unethical or not feasible. Randomizing patients with BCG-unresponsive disease to a minimally

  3. 196  effective drug as a concurrent control raises ethical concerns. Because effective drugs are not

  4. 197  available and the alternative treatment is cystectomy, single-arm trials of patients with BCG-

  5. 198  unresponsive CIS disease with or without papillary disease are appropriate. In general, these

  6. 199  single-arm trials should use drugs that have shown activity in bladder cancer.

200
201
6. Efficacy Endpoints 202

  1. 203  The primary endpoint we recommend sponsors use in single-arm trials of patients with BCG-

  2. 204  unresponsive disease is the complete response rate of CIS and its 95 percent confidence interval.

  3. 205  The median duration of response also should be assessed. Complete response can be defined as

  4. 206  negative urine cytology and no lesions on cystoscopy. If random biopsies of the bladder and

  5. 207  prostatic urethra are performed, they should be negative. Partial response has not been defined

  6. 208  in this disease setting because the area involved with CIS is difficult to quantitate; therefore,

  7. 209  partial response should not be used as a response criteria in the assessment of patients with BCG-

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Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 210  unresponsive CIS. Furthermore, partial response is not a relevant endpoint because cystectomy

  2. 211  would be indicated in patients with any remaining BCG-unresponsive CIS. Patients with both

  3. 212  CIS and completely resected lesions can be assessed using this endpoint. That is, this endpoint

  4. 213  would be used to assess the response of the remaining CIS. Adequate follow-up should be

  5. 214  provided to establish the duration of response.

215

  1. 216  A delay in cystectomy should not be used as a primary endpoint in patients with BCG-

  2. 217  unresponsive CIS. A delay of cystectomy is considered a direct patient benefit. However, in a

  3. 218  single-arm study, variability in health care provider and patient preference can makes it difficult

  4. 219  to interpret such a delay. Nevertheless, these data should be collected to provide supportive

  5. 220  evidence. Patients with completely resected lesions, in the absence of CIS, also can be included

  6. 221  in these trials but should not contribute to the primary endpoint. These patients should be

  7. 222  included in the safety analysis.

223

  1. 224  Intravesical therapy is unlikely to affect the occurrence of upper tract disease and, therefore, the

  2. 225  development of upper tract disease should not be included as an event in the assessment of the

  3. 226  duration of response. Upper tract disease should be included as an event in systemic therapy

  4. 227  trials. In both settings, the incidence of upper tract disease should be recorded and presented as a

  5. 228  separate analysis. Further, in some situations, it may be reasonable to exclude the development

  6. 229  of low-risk disease as an event. For example, a trial involving patients with BCG-unresponsive

  7. 230  disease could include only high-risk disease as an event. In this clinical setting, low-risk disease

  8. 231  would lead to transurethral resection while high-risk disease would lead to cystectomy, a much

  9. 232  different clinical outcome. Nevertheless, the low-risk recurrences and the development of upper

  10. 233  tract disease should be recorded and reported separately.

234
235
7. Trial Procedures and Timing of Assessments 236

  1. 237  During the conduct of a clinical trial, patients with NMIBC should be followed every 3 months

  2. 238  with cystoscopy, directed biopsies, and urine cytology. The definition of complete response

  3. 239  should be included in the protocol and should include the absence of lesions on cystoscopy or

  4. 240  negative, for cause, biopsies along with negative urine cytology. Random biopsies at a specific

  5. 241  time point(s) are not needed, but sponsors can choose to incorporate these into the study design.

  6. 242  The number of random biopsies and the biopsy sites should be defined in the protocol.

243

  1. 244  With either approach, it is important to ensure that all participating urologists perform and

  2. 245  document their examination of the bladder in a similar manner. A detailed protocol, as well as

  3. 246  investigator meetings and trial initiation visits, can be used to standardize this approach.

247

  1. 248  Follow-up of urine cytology is critical in patients with BCG-unresponsive NMIBC. The clinical

  2. 249  protocol should provide an algorithm for further workup of positive and indeterminate cytology.

  3. 250  In addition, the clinical protocol should provide a statement of what constitutes an event. For

  4. 251  example, the protocol would state whether a patient with no visible lesions, positive urine

  5. 252  cytology (i.e., the presence of malignant cells), and negative random biopsies would still be

  6. 253  considered to have a complete response. Note that the definition of an event used in the clinical

  7. 254  trial setting may differ from the actual management of the patient.

255

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Contains Nonbinding Recommendations

Draft — Not for Implementation

256 8. Endpoint Adjudication 257

  1. 258  Sponsors should consult with the appropriate review division concerning the need for central

  2. 259  pathology review of all patients, or in a representative sample, to assess and adjudicate the

  3. 260  endpoint.

261
262
9. Statistical Considerations 263

  1. 264  For single-arm trials that use complete response rate as the primary endpoint, the lower bound of

  2. 265  the 95 percent confidence interval around the observed response rate should rule out clinically

  3. 266  unimportant complete response rates on treatment. The median duration and lower bound of the

  4. 267  95 percent confidence interval for duration of complete response are also important. A high

  5. 268  complete response rate is not meaningful if the duration is short.

269

  1. 270  Either early phase evidence of effect size or data from historical controls can be employed to

  2. 271  calculate the sample size of the single-arm trial; however, a prespecified response rate

  3. 272  (performance goal) is not required. The natural history of CIS is well understood, and the

  4. 273  complete response rate is negligible in the absence of therapy.

274
275
10. Accelerated Approval (Subpart H and Subpart E) Considerations 276

  1. 277  A development program that assesses complete response rate in a single-arm trial may be

  2. 278  appropriate for traditional approval or it may require a confirmatory trial postapproval.5

  3. 279  A confirmatory, randomized trial in the same population often is not possible (e.g., BCG-

  4. 280  unresponsive patients). It may be possible to provide confirmatory evidence of effectiveness in

  5. 281  a different patient population. For example, a drug that demonstrates a complete response rate in

  6. 282  patients with BCG-unresponsive disease also may be effective in patients who do not develop

  7. 283  a complete response following their initial induction course of BCG. Patients could then be

  8. 284  randomized to additional BCG or additional BCG plus the investigational drug. The need for

  9. 285  a confirmatory trial and its design can be discussed at a separate, end-of-phase 2 meeting held

  10. 286  during the conduct of a single-arm trial. On occasion, long-term follow-up from the same trial

  11. 287  can satisfy a confirmatory study obligation under accelerated approval.

288
289
11. Risk-Benefit Considerations 290

  1. 291  The approval of a marketing application is based on a favorable risk-benefit assessment. The

  2. 292  key elements in the planning and conduct of these trials have been outlined above. For therapies

  3. 293  that have greater toxicity (e.g., systemic therapies), substantially greater efficacy might be

  4. 294  needed to achieve an overall favorable risk-benefit assessment. Sponsors of clinical trials using

  5. 295  either intravesical or systemic therapy are encouraged to meet with the FDA to discuss details of

  6. 296  their trial designs.

297

5 21 CFR part 314, subpart H, and part 601, subpart E
7

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298 C. 299
300
1. 301

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Other Considerations

Risk Management Considerations

  1. 302  The FDA cannot make a decision concerning a risk management plan before it reviews the data

  2. 303  included in a biologics license application or new drug application. Sponsors should provide a

  3. 304  plan to assess the long-term outcomes for patients receiving the investigational drug. For

  4. 305  example, a long-term study or trial to assess bladder capacity may be needed if there was a signal

  5. 306  in premarketing studies that the investigational drug caused bladder fibrosis.

307
308
2. NonclinicalSafetyConsiderations 309

  1. 310  Before initiating clinical trials in patients with NMIBC, we recommend that nonclinical studies

  2. 311  be used to optimize the dose and schedule of intravesicular drugs. The choice and use of

  3. 312  nonclinical models will vary with the investigational drug and should be discussed with the

  4. 313  appropriate review division. Nonclinical studies also can be used to ensure that systemic

  5. 314  therapies are active at the mucosal surface of the bladder and to justify the potential risks

  6. 315  associated with systemic therapies. For drugs intended for intravesicular administration, the

  7. 316  extent of systemic exposure in nonclinical studies following intravesicular administration can be

  8. 317  used to determine the need for evaluation of systemic toxicity. If systemic exposure is low,

  9. 318  histological evaluation may be limited to locally exposed tissues. Similarly, if systemic exposure

  10. 319  of the active substance is equivalent to or less than that of an approved route of administration

  11. 320  for the same active substance, histological evaluation also may be limited to locally exposed

  12. 321  tissues. The recommendations for and timing of additional nonclinical studies depends upon the

  13. 322  available nonclinical and clinical data, the nature of the toxicities observed, and the patient

  14. 323  population (e.g., more advanced NMIBC such as BCG-unresponsive disease). This should be

  15. 324  discussed with the appropriate review division before the conduct of a clinical trial using either a

  16. 325  systemic or intravesicular drug in patients with NMIBC.

326

  1. 327  For recommendations on the substance and scope of nonclinical information needed to support

  2. 328  clinical trials for cell therapy and gene therapy products, see the guidances for industry

  3. 329 Preclinical Assessment of Investigational Cellular and Gene Therapy Products, Clinical

  4. 330 Considerations for Therapeutic Cancer Vaccines, and Recommendations for Microbial Vectors

  5. 331 Used for Gene Therapy.6

332

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6 These guidances are available on the Cellular & Gene Therapy Guidances Web page at
http://www .fda.gov/BiologicsBloodV accines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandG eneTherapy/default.htm.

8

 

Contains Nonbinding Recommendations

Draft — Not for Implementation

333 REFERENCES 334

  1. 335  Edge S, Byrd S, Compton CC, Fritz AG, Greene FL, and Trotti A, editors, 2010, AJCC Cancer

  2. 336  Staging Manual, 7th ed., New York (NY): Springer-Verlag.

337

  1. 338  Gudjonsson S, Blackberg M, Chebil G, Jahnson S, Olsson H, Bendahl PO, Mansson W, and

  2. 339  Liedberg F, 2012, The Value of Bladder Mapping and Prostatic Urethra Biopsies for Detection

  3. 340  of Carcinoma in Situ, BJU Int, 110(2 Pt 2) E41–45.

341

  1. 342  Jarow JP, Lerner SP, Kluetz PG, Liu K, Sridhara R, Bajorin D, Chang S, Dinney CP, Groshen S,

  2. 343  Morton RA, O’Donnell M, Quale DZ, Schoenberg M, Seigne J, and Vikram B, 2014, Clinical

  3. 344  Trial Design for the Development of New Therapies for Nonmuscle-Invasive Bladder Cancer:

  4. 345  Report of a Food and Drug Administration and American Urological Association Public

  5. 346  Workshop, Urology, 83(2):262–264.

347

  1. 348  Jarow J, Maher VE, Tang S, Ibrahim A, Kim G, Sridhara R, and Pazdur R, 2015, Development

  2. 349  of Systemic and Topical Drugs to Treat Non-Muscle Invasive Bladder Cancer, Bladder Cancer,

  3. 350  1:133–136.

351

  1. 352  Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, Sorosdy MF,

  2. 353  Bohl RD, Grossman HB, Beck TM, Leimert JT, and Crawford ED, 2000, Maintenance Bacillus

  3. 354  Calmette-Guerin Immunotherapy for Recurrent Ta, T1 and Carcinoma in Situ Transitional Cell

  4. 355  Carcinoma of the Bladder: A Randomized Southwest Oncology Group Study, J Urol,

  5. 356  163(4):1124–1129.

357

  1. 358  Lerner SP, Dinney C, Kamat A, Bivalacqua TJ, Nielsen M, O’Donnell M, Schoenberg MP, and

  2. 359  Steinberg G, 2015, Clarification of Bladder Cancer Disease States Following Treatment of

  3. 360  Patients With Intravesical BCG, Bladder Cancer, 1(1):29–30.

361

  1. 362  Miyamoto H, Miller JS, Fajardo DA, Lee TK, Netto GJ, and Epstein JL, 2010, Non-Invasive

  2. 363  Papillary Urothelial Neoplasms: The 2004 WHO/ISUP Classification System, Pathol Int,

  3. 364  60(1):1–8.

365

  1. 366  Persad R, Lamm D, Brausi M, Soloway M, Palou J, Bohle A, Colombel M, Akaza H, Buckley R,

  2. 367  and Witjes JA, 2008, Current Approaches to the Management of Non-Muscle Invasive Bladder

  3. 368  Cancer: Comparison of Current Guidelines and Recommendations, Eur Urol, Supplements;

  4. 369  S7(10):637–650.

9

 

ANDA Submissions – Prior Approval Supplements Under GDUFA

ANDA Submissions –

Prior Approval

Supplements Under

GDUFA Guidance for Industry

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

October 2016 Generics

page1image4312

ANDA Submissions —

Prior Approval

Supplements Under

GDUFA Guidance for Industry

Additional copies are available from:
Office of Communications, Division of Drug Information Center for Drug Evaluation and Research

Food and Drug Administration th 10001 New Hampshire Ave., Hillandale Bldg., 4

Floor

Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

and/or

Office of Communication, Outreach, and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010
Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

October 2016 Generics

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Contains Nonbinding Recommendations

TABLE OF CONTENTS

  1. INTRODUCTION............................................................................................................. 1

  2. BACKGROUND ............................................................................................................... 2

  3. IMPACT OF GDUFA PERFORMANCE METRIC GOALS ON PAS

SUBMISSIONS ............................................................................................................................. 3

A. B. C. D. E. F. G.

APPENDIX A – GDUFA SUPPLEMENTS FLOW CHART................................................. 14

Changes to an Approved Application .......................................................................................... 3 GDUFA Performance Metric Goals for PAS Submissions ........................................................ 5 Fee-Related RTR Standards and PAS Submissions under GDUFA.........................................6 Inspections for PAS Submissions ................................................................................................. 7 Amendments to PAS Submissions................................................................................................8 Submission of Supplements......................................................................................................... 11 Other Matters............................................................................................................................... 11

1.
2.
3. Reconsideration of Incorrect Reporting Category Determination ................................................ 13

Grouped Supplements .................................................................................................................... 11 Incorrect Reporting Category........................................................................................................12

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Contains Nonbinding Recommendations

Guidance for Industry1
ANDA Submissions – Prior Approval Supplements Under GDUFA

page4image3784

This guidance represents the current thinking of the Food and Drug Administration (FDA, or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page.

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I. INTRODUCTION

This guidance is intended to assist applicants preparing to submit to FDA prior approval supplements (PASs) and amendments to PASs for abbreviated new drug applications (ANDAs) under section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(j)). The guidance explains how the Generic Drug User Fee Amendments of 2012 (GDUFA) relates to PAS submissions. The guidance also describes the performance metric goals outlined in the GDUFA Commitment Letter that FDA has agreed to meet,2 and clarifies how FDA will handle a PAS and amendments to a PAS for an ANDA subject to the GDUFA performance metric goals.

Specifically, this guidance describes how the GDUFA performance metric goals apply to: A PAS subject to the refuse-to-receive (RTR) standards
A PAS that requires an inspection3
A PAS for which an inspection is not required

An amendment to a PAS Other PAS-related matters

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of

1 This guidance has been prepared by the Office of Generic Drugs in the Center for Drug Evaluation and Research (CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.

2 The performance metric goals were proposed jointly by FDA and representatives of the generic drug industry. See GDUFA Program Performance Goals and Procedures for fiscal years 2015 through 2017 (Commitment Letter), available at http://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM282505.pdf.

3 Section 704 of the FD&C Act (21 U.S.C. 374) authorizes FDA to conduct inspections.

page4image33144 page4image33304

1

Contains Nonbinding Recommendations

the word should in Agency guidances means that something is suggested or recommended, but not required.

II. BACKGROUND

On July 9, 2012, the President signed GDUFA into law.4 GDUFA is designed to speed the delivery of safe and effective generic drugs to the public and reduce costs to industry.

Congress enacted GDUFA based on an agreement that FDA and representatives of the generic drug industry negotiated to address a growing number of regulatory challenges. GDUFA aims to put FDA’s generic drug program on a firm financial footing and ensure timely access to safe, high-quality, affordable generic drugs. GDUFA enables FDA to assess user fees to fund critical and measurable improvements to FDA’s generic drugs program and to bring greater predictability and timeliness to the review of generic drug applications.

GDUFA requires that FDA and human generic drug manufacturers meet certain requirements and commitments. In the Commitment Letter that accompanies the legislation, FDA committed to review and act on a certain percentage of PASs within a specified period from the date of submission for receipts in fiscal year (FY) 2015 through FY 2017. The percentage of PASs that FDA has committed to review and act on increases with each fiscal year; the deadlines for review also depend on whether consideration of a PAS requires an inspection.

GDUFA also establishes application fees (for ANDAs, PASs to ANDAs, and certain drug master files (DMFs)), annual facility fees, and a one-time fee for ANDAs that were pending on October 1, 2012 (referred to as “backlog applications”). As of October 1, 2012, ANDA applicants are required to pay application fees when they submit ANDAs and PASs. Additionally, Type II active pharmaceutical ingredient (API) DMF holders are subject to a DMF fee the first time an initial letter of authorization references that DMF in an ANDA or PAS.5 More information about these fees can be found in the following documents:

Draft guidance for industry Generic Drug User Fee Amendments of 2012: Questions and Answers, Revision 1 (draft GDUFA user fee Q&A guidance)6

4 Public Law 112-144, Title III.
5 Procedures for ANDA and PAS submissions are set forth in FDA’s regulations in part 314 (21 CFR part 314).

6 In the Federal Register of September 10, 2013 (78 FR 55261), FDA announced the availability of the draft GDUFA user fee Q&A guidance. Several other draft guidances are referenced throughout this document. When finalized, these guidances will represent FDA’s current thinking on the respective topics. For the most recent version of a guidance, check the FDA drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, or http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm.

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2

III.

Federal Register notice, Generic Drug User Fee – Abbreviated New Drug Application, Prior Approval Supplement, Drug Master File, Final Dosage Form Facility, and Active Pharmaceutical Ingredient Facility Fee Rates for Fiscal Year 2014 (78 FR 46977, August 2, 2013).

IMPACT OF GDUFA PERFORMANCE METRIC GOALS ON PAS SUBMISSIONS

Contains Nonbinding Recommendations

FDA regulations lay out requirements for making and reporting changes to approved ANDA applications (see 21 CFR 314.70). Under GDUFA and as part of FDA’s commitments under GDUFA, the generic industry and FDA have agreed to certain performance metric goals, including those applicable to PASs. This section describes the specific performance metric goals that apply to PASs and amendments to PASs submitted to ANDAs under GDUFA.

Under the Commitment Letter,7 the GDUFA performance metric goals described in this guidance apply only to holders of an ANDA who electronically submit a PAS on or after October 1, 2014.8 The performance goals do not apply to an amendment to a PAS if the PAS was submitted before October 1, 2014, even if the amendment is submitted on or after October 1, 2014.

The GDUFA performance metric goals also do not apply to new drug applications (NDAs) or biologics license applications (BLAs). Nor do they apply to supplements filed for NDAs or BLAs, changes-being-effected (CBE) supplements, or annual report filings to NDAs, BLAs, or ANDAs. In this guidance, any reference to a PAS refers only to a PAS filed for an ANDA, unless clearly indicated otherwise.

A. Changes to an Approved Application

Section 506A of the FD&C Act (which was added by section 116 of the Food and Drug Administration Modernization Act of 1997) provides requirements for making and reporting manufacturing changes to an approved application and for distributing a drug product made with such changes.9 The following sections of FDA’s regulations set forth the requirements for supplements and other changes to approved applications under section 506A:

  • § 314.70 describes the different reporting categories for changes to an approved application.

  • § 314.71 outlines the procedures for submitting a supplement to an approved application. 7 Supra note 2.

    8 Per the Commitment Letter, prior approval supplements subject to the GDUFA performance metric goals must be submitted in electronic format. Id.

    9 21 U.S.C. 356a.

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3

Contains Nonbinding Recommendations

§ 314.97 provides that supplements and other changes to an approved ANDA must comply with the requirements of §§ 314.70 and 314.71.

Specifically, section 506A of the FD&C Act and § 314.70 of FDA regulations provide for the following reporting categories of changes to an approved application:

1. Major Change: a change that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product. A major change requires the submission of a PAS and approval by FDA before distribution of the drug product made using the change.10

2. Moderate Change: a change that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product. Depending on the nature of the change, one of the following two types of supplements must be submitted to FDA for a moderate change:

  1. Supplement – Changes Being Effected in 30 Days (CBE-30 supplement): A CBE-30 supplement involves certain moderate changes that require the submission of the supplement to FDA at least 30 days before the distribution of the drug product made using the change.11

  2. Supplement – Changes Being Effected (CBE-0 supplement): A CBE-0 supplement involves certain moderate changes that allow distribution to occur as soon as FDA receives the supplement.12

3. Minor Change: a change that has minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product. The applicant must describe minor changes in its next annual report.13

The criteria for submitting information as a PAS, as a CBE, or in an annual report were not changed by GDUFA.14 This guidance does not discuss the various criteria that apply in determining the respective reporting categories for these supplements. For additional information on these reporting categories, refer to § 314.70, as well as related guidances, including but not limited to the Scale-Up and Post-approval Changes (SUPAC) guidance and the Changes to an Approved NDA or ANDA guidance.

10 § 314.70(b).

11 § 314.70(c)(3).

12 § 314.70(c)(6).

13 § 314.70(d).

14 In regard to submissions for modifications and revisions to approved risk evaluation and mitigation strategies (REMS), refer to the guidance for industry Risk Evaluation and Mitigation Strategies: Modifications and Revisions.

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4

Contains Nonbinding Recommendations

B. GDUFA Performance Metric Goals for PAS Submissions

The Commitment Letter outlines the performance metric goals FDA agreed to meet for reviewing and acting on PASs submitted in FY 2015 through FY 2017.15 Specifically, FDA agreed to:

  • Review and act on 60% of complete PASs that do not require inspection within 6 months from the date of submission for receipts in FY 2015.

  • Review and act on 60% of complete PASs that require inspection within 10 months from the date of submission for receipts in FY 2015.

  • Review and act on 75% of complete PASs that do not require inspection within 6 months from the date of submission for receipts in FY 2016.

  • Review and act on 75% of complete PASs that require inspection within 10 months from the date of submission for receipts in FY 2016.

  • Review and act on 90% of complete PASs that do not require inspection within 6 months from the date of submission for receipts in FY 2017.

  • Review and act on 90% of complete PASs that require inspection within 10 months from the date of submission for receipts in FY 2017.

    The Commitment Letter defines submission date as the date an ANDA, ANDA amendment, ANDA supplement, or Type II API DMF arrives in the Electronics Submissions Gateway (ESG) of FDA.16 If a submission arrives in physical media form in eCTD format, it is deemed to be submitted on the day it arrives at FDA’s appropriate designated document room.17 FDA’s performance goal obligations under GDUFA start on the submission date of a PAS or amendment to a PAS. As described in the Commitment Letter, the performance goals identified in this guidance apply only to those PASs, and amendments thereto, submitted electronically to ANDAs and PASs that have been submitted electronically in or after FY 2015 (on or after October 1, 2014).18

    15 Under GDUFA, action on a PAS means issuing a complete response letter, an approval letter, a tentative approval letter, or a refuse-to-receive action (Commitment Letter at 14, supra note 2). The performance metric goals appear on page 12 of the Commitment Letter.

    16 Commitment Letter at 16, supra note 2; see also the guidance for industry Providing Regulatory Submissions in Electronic Format – Receipt Dates (Receipt Dates guidance). These submissions are deemed to be submitted to FDA on the day when transmission to the ESG is completed, except when the submission arrives on a weekend, Federal holiday, or a day when the FDA office that will review the submission is otherwise not open for business. In that case, the submission is deemed to be submitted on the next day when that office is open for business. Additional information concerning the FDA ESG is available at http://www.fda.gov/ForIndustry/ElectronicSubmissionsGateway/default.htm.

    17 21 USC 379j-42(a)(5)(B); see also the Receipt Dates guidance, supra note 16.

    18 Amendment metric goals are added to the original review goal (Commitment Letter at page 10, supra note 2). The adjustment made to the ANDA or PAS review goal assumes that the amendment is amending a submission that has been assigned a goal date (i.e., made electronically, following the eCTD format at the date of submission). If an

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5

Contains Nonbinding Recommendations

Because the Commitment Letter specifies the review period as a number of months “from the date of submission,” FDA counts the submission date as the first day of the review period.19 Also, per the language in the Commitment Letter, FDA calculates the goal date in months. Thus, for example, if a complete PAS that does not require an inspection is submitted on November 3, 2015, its 6-month GDUFA goal date for review and action by FDA becomes May 2, 2016. FDA will provide the applicant with notice of the GDUFA goal date. Filing an amendment to a PAS can revise the existing goal date associated with that PAS, which is discussed in more detail in section III.E of this guidance.

C. Fee-Related RTR Standards and PAS Submissions under GDUFA

FDA regulations in § 314.101 set forth the circumstances in which FDA can refuse to receive a PAS.20 FDA’s performance goal obligations under GDUFA start when a PAS is submitted to21 FDA, which is the day the PAS arrives in the ESG or appropriate designated document room. However, if FDA refuses to receive a PAS, the GDUFA review clock stops. The applicant can submit a corrected or new supplement, but the supplement requires a new GDUFA fee,22 starts a new GDUFA review clock, and results in a new goal date for that PAS.

GDUFA added to FDA’s existing RTR standards for technical deficiencies certain conditions under which outstanding user fee obligations result in FDA refusing to receive a PAS. Under GDUFA, the following fee-related actions can result in FDA refusing to receive a PAS:

applicant submits an original ANDA or PAS that is not in the applicable electronic format and a goal date has not been assigned, any subsequent amendment, even if it is submitted electronically, does not have a goal date associated with it that can be adjusted.

19 FDA follows this approach in implementing provisions that specify a period “from the date of” some triggering event. See, e.g., Mutual Pharm. Co. v. Watson Pharms., Inc., No. 09-5421, 2010 WL 446132 (D.N.J. Feb. 8, 2010) (noting that 7-year orphan drug exclusivity (under section 527(a) of the FD&C Act) for a drug approved on July 30, 2009, ends on July 29, 2016); Letter from FDA to C. Landmon re: Docket No. FDA-2009-N-0184, at 1-2 (Oct. 23, 2009) (5-year new chemical entity exclusivity (under section 505(j)(F)(ii) of the Act) commenced on drug approval date of Feb. 23, 2007, and expired on Feb. 22, 2012).

We note that goal dates agreed to under the Prescription Drug User Fee Act (PDUFA) are calculated differently because the PDUFA Commitment Letter does not specify review periods “from the date of” a triggering event. See PDFUA Commitment Letter, available at http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM270412.pdf.

20 §§ 314.101(d)-(e) and 314.71(c). 21 See supra notes 16-17.

22 If FDA refuses to receive an ANDA or PAS for reasons other than failure to pay GDUFA fees, a refund of 75% of the application fee paid for that application or supplement will be made to the applicant (21 U.S.C. 379j- 42(a)(3)(D)). The resubmission of that application or supplement is subject to a full application fee (21 U.S.C. 379j- 42(a)(3)(E)).

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6

Contains Nonbinding Recommendations

  • An applicant fails to pay the application fee within 20 calendar days of submitting the supplement23

  • A supplement references a Type II API DMF that is not on the public available for reference list because of non-payment of the GDUFA DMF fee24

  • A PAS references a facility on the facility arrears list for failure to pay the GDUFA facility fee(s)25

  • The PAS applicant is the owner of a facility on the facility arrears list26

  • The PAS applicant is affiliated with the owner of a facility on the facility arrears list27

  • The PAS applicant is listed on the backlog arrears list28

  • The PAS applicant is affiliated with an entity on the backlog arrears list29

    In all of these cases, FDA will refuse to receive a PAS until all user fee obligations have been satisfied. If a PAS is substantially complete except for failure to pay the PAS user fee, the PAS will be deemed received as of the date the fee is paid in full. Similarly, if FDA has refused to receive the PAS because it referenced a facility on the arrears list, FDA will receive the PAS once the facility is removed from the arrears list, if the PAS is otherwise substantially complete. Upon satisfaction of all applicable user fee obligations, CDER’s Office of Management issues a formal correspondence indicating the adjusted receipt date (i.e., the date on which all outstanding user fee obligations were satisfied in full) for which the PAS is eligible, assuming all other applicable requirements for receipt of a PAS have been met.30 Adjustment of the receipt date results in a new GDUFA goal date for that PAS.

    FDA can refuse to receive a PAS for other reasons unrelated to the failure to meet GDUFA fee obligations, but those other reasons are not discussed in this guidance. For more information on FDA’s RTR standards, including the timing of RTR decisions, refer to § 314.101 of FDA’s regulations, as well as related FDA guidances for industry.31

D.

23 21 U.S.C.

24 21 U.S.C.

25 21 U.S.C.

26 21 U.S.C.

27 21 U.S.C.

28 21 U.S.C.

29 21 U.S.C.

Inspections for PAS Submissions

379j-42(g)(3). 379j-42(g)(2). 379j-42(g)(4)(A). 379j-42(g)(4)(A)(i). 379j-42(g)(4)(A)(i). 379j-42(g)(1). 379j-42(g)(1).

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30 21 CFR 314.101(d)-(e) and 314.71(c).

31 Related FDA guidances include, but are not limited to, the guidance for industry ANDA Submissions — Refuse-to-

Receive Standards and the draft GDUFA user fee Q&A guidance, supra note 6.

7

Contains Nonbinding Recommendations

As outlined above, the GDUFA goal date for a PAS depends on whether the PAS requires an inspection. If a PAS does not require an inspection, the goal date is 6 months from the date of submission; but if a PAS requires an inspection, the goal date is 10 months from the date of submission.32

Establishments that are required to be registered under section 510 of the FD&C Act (21 U.S.C. 360) and § 207.20 of the FDA regulations (21 CFR 207.20) are subject to inspection to ensure they comply with current good manufacturing practice (CGMP) regulations.33 Determining whether an inspection is required for a PAS is within the discretion of FDA and depends on the nature of the supplement.

Generally, we expect that any submitted PAS that requires an assessment of the need for an inspection, including, for example, a PAS involving a facility not approved in the original ANDA or involving a fundamental change in the manufacturing process or technology, will be treated initially as a PAS requiring an inspection and will be assigned a 10-month GDUFA goal date; however, the GDUFA goal date can be revised to 6 months if it is later determined that an actual inspection is not required for that PAS. Although not typical, an initial goal date of 6 months occasionally may change to a 10-month goal date if, during the review, FDA determines an inspection is necessary.

E. Amendments to PAS Submissions

As noted above, if an amendment is made to a PAS, the GDUFA goal date associated with that PAS may be revised. With limited exceptions, FDA strongly recommends that, at the time of submission, a supplement should be complete and ready for a comprehensive review. Modifications to the supplement, in the form of an amendment, should be made only to clarify part of the already submitted supplement or to answer specific questions raised by the FDA review team. FDA does not recommend that modifications expand or broaden the scope of the already submitted supplement unless the Agency requested them—there may be circumstances in which an amendment must be made to a PAS.

The Commitment Letter outlines FDA’s GDUFA performance metric goals for amendments. They are grouped as Tier 1, Tier 2, or Tier 3.34

Tier1
32 As explained in section III.E of this guidance, filing an amendment to a PAS can revise the goal date associated

with that PAS.
33 See section 510(h) of the FD&C Act; 21 CFR parts 210-216.

34 For more detail on how FDA intends to classify major amendments, minor amendments, and easily correctable deficiencies to original ANDAs and to PASs submitted after October 1, 2014, under GDUFA, see the draft guidance for industry ANDA Submissions – Amendments and Easily Correctable Deficiencies Under GDUFA (Amendments Guidance). Once finalized, that guidance will represent FDA’s current thinking on the tier system and easily correctable deficiencies.

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8

Contains Nonbinding Recommendations

Tier 1 amendments include the first solicited major amendment, the first five minor amendments, and all delaying amendments.35 Delaying amendments address actions by a third party that would cause delay or impede application review or approval timing and that were not, or might not have been initially recognized by FDA as, necessary when the application was submitted.36

Tier2

Tier 2 amendments include all unsolicited amendments not arising from delaying actions as determined by FDA, taking into account the facts and information supplied by the ANDA applicant, excepting those amendments that only remove information from review.

The GDUFA performance metric goals for Tier 1 and Tier 2 amendments vary from 3 months to 12 months, depending on the type of amendment filed.37

Tier3

Tier 3 amendments include any solicited major amendment subsequent to the first major amendment, and any solicited minor amendment subsequent to the fifth minor amendment. There are no GDUFA performance metric goals for Tier 3 amendments.38

As explained in the Commitment Letter, all amendment metric goals are incremental, and the periods specified are calculated from the date of submission. Thus, the performance metric goal for an amendment to a PAS will be added to the original goal date for that PAS.

The Commitment Letter explains in more detail the performance metric goals for each amendment tier; this information is not repeated here. However, the following are some examples of how an amendment to a PAS can have an impact on the GDUFA goal date for that PAS. If an amendment to a PAS is submitted after the issuance of a complete response (CR) letter, this sets a new goal date for the PAS. For example:

35 A solicited amendment is an amendment submitted in response to a complete response (CR) letter. A CR letter refers to a written communication to an applicant or DMF holder from FDA, usually describing all the deficiencies the agency has identified in an ANDA (including pending amendments) or a DMF that must be satisfactorily addressed before the ANDA can be approved. CR letters reflect a complete review and require a complete response from industry to restart the clock. See Commitment Letter at 14, supra note 2; see also § 314.110. An unsolicited amendment is an amendment with information not requested by the FDA except for those unsolicited amendments that are considered routine or administrative in nature and that do not require scientific review. Commitment Letter at 16-17, supra note 2.

36 Commitment Letter at 14, supra note 2.

37 See the Amendments Guidance, supra note 34, for a more thorough description and examples of performance metric goals for Tier 1 and Tier 2 amendments.

38 Id. at 10-11.

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9

If a Tier 1 major amendment with a 10-month metric is submitted on February 1, 2016, in response to a CR letter for a PAS, this establishes a new GDUFA goal date of 10 months from the date of submission of the major amendment for that PAS. The new goal date is November 30, 2016.

If a Tier 1 minor amendment with a 6-month metric is submitted on April 14, 2016, in response to a CR letter for a PAS, this establishes a new GDUFA goal date of 6 months from the date of submission of the minor amendment for that PAS. The new goal date is October 13, 2016.

Contains Nonbinding Recommendations

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CR Tier 1 major 2/1/16

New Goal Date 11/30/16

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CR Tier 1 minor 4/14/16

New Goal Date 10/13/16

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Any subsequent amendments submitted to a PAS after the issuance of a CR letter can also adjust the goal date for the PAS and can add time to the review clock.

If an amendment to a PAS is submitted before the issuance of a CR letter, this can adjust the goal date for the original PAS. For example:

A PAS with a 6-month metric is submitted on January 8, 2016, and given a goal date of July 7, 2016. A Tier 1 delaying amendment with a 3-month metric is submitted in month 5 of the original review cycle on May 19, 2016. Submission of the amendment adjusts the GDUFA review clock and extends the goal date 3 months from May 19, 2016, the date of submission of the amendment for that PAS. The new goal date is August 18, 2016.

10

Contains Nonbinding Recommendations

page14image984 page14image1408 page14image1832 page14image2256

PAS Tier 1 1/8/16 Delay

5/19/16

Goal New

Date Goal 7/7/16 Date

8/18/16

page14image4776

Any subsequent amendments to a pending PAS that are submitted before the issuance of a CR letter can also adjust the goal date for the PAS and can add time to the review clock.

Administrative amendments are routine in nature and do not require scientific review.39 Administrative amendments do not affect the goal dates for the application and, as a result, are considered neither Tier 1, Tier 2, nor Tier 3 amendments.

F. Submission of Supplements

Any PAS to an approved ANDA should identify on the first page of the submission that it is a PAS. To facilitate processing, FDA recommends that the applicant provide the following information on the first page of the submission:

1. 2.

4. 5. 6.

G.

1.

A statement indicating whether the PAS is for a new-strength product
A statement indicating whether the submission is an amendment to a PAS, and if so the corresponding tier classification
A statement indicating whether the PAS contains any manufacturing or facilities changes
A list of the specific review disciplines to review the PAS (Chemistry, Labeling, DMF, Bioequivalence, Microbiology, or Clinical)
If expedited review is requested, the label
Expedited Review Request should be placed prominently at the top of the submission. The submission should include a basis for the expedited review request.

Other Matters

Grouped Supplements

Grouped supplements are multiple supplements submitted to ANDAs by a single applicant for the same chemistry, manufacturing, and controls (CMC) change to each application. For further information on grouped supplements, refer to the Manual of Policies and Procedures 5015.6, Review of the Same Supplemental Change to More than One NDA or ANDA in More Than One Review Division, or its latest revision.

39 For more detail on administrative amendments, see the Amendments Guidance, supra note 34.

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Contains Nonbinding Recommendations

Although the submissions are considered a group, each supplement in the group is considered its own individual submission and therefore would require a GDUFA PAS fee for each ANDA identified in the group.40 Thus, for example, if a group PAS change is submitted to 10 ANDAs, then 10 GDUFA PAS fees should be remitted. Because the grouped supplements are being reviewed together, generally they will have the same GDUFA goal date.

If the applicant identifies a lead ANDA for a group of PASs and only one fee is paid (or fewer than all the fees for the group are paid), the lead supplement and any supplements with the requisite paid fee can be received, but any other supplements without the requisite paid fee cannot be received. If the other fee-deficient supplements are then submitted at a later date, this can result in different GDUFA goal dates for the supplements initially received and the subsequently filed supplements.

There are alternatives to submitting multiple PASs for the same change. For example, for some changes (e.g., widening of an approved specification or introduction of a new API supplier), once a PAS is submitted and approved for the lead ANDA, subsequent supplements for the same change to other ANDAs may be classified as CBE-30s. The Agency recommends that applicants contact the appropriate review division beforehand to ensure the change is appropriate for a PAS followed by a CBE-30, or if there are specific questions regarding this alternative.

Additionally, a comparability protocol submitted in a PAS to an ANDA for a specific drug product, once approved, may justify a reduced reporting category for the same change in subsequent supplements to that ANDA. For further information on a comparability protocol submitted in a PAS, see the draft guidance for industry Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls.

2. Incorrect Reporting Category

If FDA finds that a supplement submitted as a CBE supplement should have been submitted as a PAS, it will notify the applicant. The applicant is not required to withdraw the CBE supplement because when FDA sends a letter explaining that the applicant’s submission is not accepted as a CBE supplement, FDA administratively closes the CBE supplement, and it is considered withdrawn. The applicant may resubmit the supplement as a PAS for FDA approval before distribution of the drug product, along with the required GDUFA user fee.41 The GDUFA performance metric goals and applicable user fees will apply to that PAS.42 As explained in section III.B, the GDUFA review clock will start from the date of submission of that PAS. For example:

An applicant submits a CBE supplement on November 17, 2015. FDA determines that the applicant should have submitted the supplement as a PAS and notifies the applicant that the proposed change was submitted incorrectly as a CBE supplement. Upon issuance

40 21 USC 379j-42(a)(3) (a PAS is subject to a fee “for each such submission”). 41 § 314.70(c)(5)(i).
42 Draft GDUFA user fee Q&A guidance at 13, supra note 6.

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of the letter explaining that the applicant’s submission is not accepted as a CBE supplement, FDA considers the CBE withdrawn. On December 1, 2015, the applicant resubmits the supplement as a PAS that meets all the submission requirements, including payment of the applicable GDUFA user fee. The GDUFA review clock commences on December 1, 2015.

3. Reconsideration of Incorrect Reporting Category Determination

An applicant may request reconsideration of FDA’s supplement reporting category determination. These requests will be reviewed and managed on a case-by-case basis. If an applicant is requesting reconsideration of a supplement reporting category, the applicant must submit a written request for reconsideration within 10 business days of FDA’s notice to the applicant that the applicant’s submission was not accepted as a CBE supplement. If an applicant disagrees with the outcome of the reconsideration, the applicant may initiate a formal appeal.43 Any applicant seeking an appeal above the division level should first seek reconsideration at the division level (21 CFR 314.103).

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43 The process for appeals above the division level is outlined in the draft guidance for industry Formal Dispute Resolution: Appeals Above the Division Level. Once finalized, that guidance will represent FDA’s current thinking on the issue.

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APPENDIX A – GDUFA SUPPLEMENTS FLOW CHART

* If an amendment is filed to the supplement, it may change the goal date. See draft guidance for industry ANDA Submissions – Amendments and Easily Correctable Deficiencies Under GDUFA, flow chart at Appendix A. In addition, the 10-month goal date can change to a 6-month goal date if an inspection is deemed unnecessary, and a 6-month goal date can change to a 10-month goal date if, during the review, an inspection is deemed necessary.

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Sunscreen Innovation Act: Withdrawal of a 586A Request or Pending Request

Sunscreen Innovation Act: Withdrawal of a 586A Request or Pending Request

Guidance for Industry

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

October 2016 OTC

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Sunscreen Innovation Act: Withdrawal of a 586A Request or Pending Request

Guidance for Industry

Additional copies are available from:

Office of Communications, Division of Drug Information Center for Drug Evaluation and Research

Food and Drug Administration th 10001 New Hampshire Ave., Hillandale Bldg., 4

Floor

Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

October 2016 OTC

I. II.

A. B. C.

III. A.

B. IV.

A.

B. C.

1.

2. 3. 4.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 BACKGROUND ............................................................................................................... 2 Regulation of Sunscreen Products ................................................................................................2 Section 586D(a) Guidance on Withdrawal Process .....................................................................4 Related Guidance ...........................................................................................................................5 GENERAL WITHDRAWAL PROCEDURES.............................................................. 5 Request for Withdrawal ................................................................................................................5 Withdrawal Due to Sponsor’s Failure to Take Action................................................................6 EFFECT OF WITHDRAWAL OF 586A REQUESTS AND PENDING

REQUESTS ....................................................................................................................... 7

586A Request — Withdrawal........................................................................................................8

Withdrawal Prior to an Eligibility Determination or After a Determination That a
Request Is Ineligible ........................................................................................................................8 Withdrawal After an Eligibility Determination but Prior to a Filing Determination ......................8 Withdrawal After Filing Determination ...........................................................................................8 Withdrawal After a Proposed Sunscreen Order Under Section 586(7)(C)......................................9
Pending Requests — Withdrawal ...............................................................................................10

New Requests ................................................................................................................................10

Contains Nonbinding Recommendations

I. INTRODUCTION

Contains Nonbinding Recommendations

Sunscreen Innovation Act: Withdrawal of a 586A Request or Pending Request

Guidance for Industry1

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This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page.

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This guidance addresses the process for (1) withdrawal of a request submitted under section 586A (586A request)2 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended by Public Law 113-195 (also referred to as the Sunscreen Innovation Act or SIA)3 and (2) withdrawal of a pending request, as defined under section 586(6) of the FD&C Act.4 The recommendations in this guidance apply to 586A requests and pending requests that seek a determination from FDA of whether a nonprescription sunscreen active ingredient5 or a combination of nonprescription sunscreen active ingredients is generally recognized as safe and

1 This guidance has been prepared by the Office of Regulatory Policy in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.

2 A 586A request is a request submitted to FDA for a determination of whether a nonprescription sunscreen active ingredient or a combination of nonprescription sunscreen active ingredients, for use under specified conditions, is generally recognized as safe and effective (GRASE) and should be included in the sunscreen OTC monograph (section 586A of the FD&C Act (21 U.S.C. 360fff-1)).

3 21 U.S.C. Ch. 9 Sub. 5 Part 1, enacted November 26, 2014.

4 Section 586(6) of the FD&C Act defines a pending request to mean a request for a nonprescription sunscreen active ingredient submitted under § 330.14 (21 CFR 330.14) for consideration for inclusion in the OTC monograph that was determined to be eligible for review and for which safety and effectiveness data were submitted prior to the enactment of the SIA (section 586(6) of the FD&C Act (21 U.S.C 360fff(6)). These pending requests were submitted as time and extent applications (TEAs) under § 330.14 of FDA’s regulations.

5 A sunscreen as defined in the SIA means a drug containing one or more sunscreen active ingredients (section 586(9) of the FD&C Act (21 U.S.C. 360fff(9))), and the term sunscreen active ingredient means an active ingredient that is intended for application to the skin of humans for purposes of absorbing, reflecting, or scattering ultraviolet radiation (section 586(10) of the FD&C Act (21 U.S.C. 360fff(10))).

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effective (GRASE) for use under specified conditions and should be included in the over-the- counter (OTC) sunscreen drug monograph.

The SIA, enacted on November 26, 2014, added new section 586D(a)(1) to the FD&C Act (21 U.S.C. 360fff-4(a)(1)), which directs FDA to issue draft and final guidance on the process by which a request under section 586A or a pending request is withdrawn.6 This guidance is organized as follows:

  • Section II provides background information on the sunscreen OTC monograph process and the new procedures under the SIA (the SIA process) for reviewing 586A requests and pending requests for nonprescription sunscreen active ingredients.7

  • Section III addresses the general withdrawal process for a 586A request or pending request. At certain stages of the SIA process, the sponsor8 who submitted a 586A request or pending request might seek to have it withdrawn, or the request may be withdrawn due to the sponsor’s failure to act on the request and failure to respond to communications from FDA.

  • Section IV addresses the effect of this withdrawal process on key phases of the SIA process.

    In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

II. BACKGROUND
A. Regulation of Sunscreen Products

All sunscreens are regulated as drugs in the United States under one of two processes: The new drug approval process described in part 314 (21 CFR part 314)

6 The draft guidance was issued in November 2015 (80 FR 72970, Nov. 23, 2015).

7 We have previously published Federal Register notices about rulemaking actions for OTC sunscreen monograph products and about actions taken under the SIA. This information can be found on our “Status of OTC Rulemakings” and “Sunscreens” Web sites, respectively. See http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the- CounterOTCDrugs/StatusofOTCRulemakings/default.htm and http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingOver-the- CounterMedicines/ucm239463.htm.

8 A sponsor under the SIA is a person that has submitted a 586A request, a pending request, or any other application subject to the SIA (section 586(8) of the FD&C Act (21 U.S.C. 360fff(8))).

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The OTC drug monograph process (also known as the OTC Drug Review) described in part 330 (21 CFR part 330), as supplemented by the SIA

Products regulated under the new drug approval process may not be marketed without FDA’s prior review and approval of a new drug application (NDA) or abbreviated new drug application (ANDA) for each product.9 Products marketed under the OTC drug monograph process are not individually reviewed and approved prior to marketing. Instead, OTC drug monographs categorize drugs by therapeutic categories, such as sunscreens. For each category, a monograph establishes conditions under which any drug that satisfies those conditions and FDA’s general regulations for OTC drugs is considered to be GRASE and not misbranded when used under the conditions prescribed, recommended, or suggested in the drug’s labeling.10

Active ingredients that were used in U.S.-marketed sunscreens before the OTC Drug Review began are eligible to be included in the OTC sunscreen monograph. An active ingredient or other condition that is ineligible for inclusion in the OTC monograph system is subject to the new drug approval process.

In 2002, before the SIA was enacted, FDA published the “time and extent application” (TEA) regulation in 21 CFR 330.14. The TEA regulation (§ 330.14(c)) has provided a process through which any person may request that FDA amend an existing OTC drug monograph to include an active ingredient or other OTC drug condition, including one not previously marketed in the United States before the OTC Drug Review began.

For OTC sunscreens, the SIA process supplements FDA’s TEA regulation (§ 330.14). The SIA amended the FD&C Act in part by providing new procedures for establishing that nonprescription sunscreen active ingredients or combinations of nonprescription sunscreen active ingredients are GRASE and not misbranded when used under the conditions specified in a final sunscreen order (GRASE determination).11 Active ingredients that are determined to be GRASE under specified conditions of use in a final sunscreen order may be used in U.S.-marketed sunscreens without first obtaining an approved NDA or ANDA. Because the monograph and SIA processes are public, anyone, not just the sponsor who originated the request, may submit data during public comment periods.

As with the TEA process, the SIA process calls for an initial eligibility determination, followed by submissions of safety and efficacy data, and a GRASE determination phase. However, the SIA process also requires FDA to make a filing determination12 and to make proposed and final GRASE determinations in the form of orders rather than the rulemaking required by the TEA

9 See sections 505(a) and 301(d) of the FD&C Act (21 U.S.C. 355(a) and 331(d)). 10 21 CFR part 330.
11 Section 586C of the FD&C Act (21 U.S.C. 360fff-3).

12 The filing determination requires FDA to determine whether the safety and efficacy data submitted to support a GRASE determination are appropriately formatted and sufficiently complete to support a substantive GRASE review (section 586B(b)(2) of the FD&C Act (21 U.S.C. 360fff-2(b)(2))).

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regulation. The SIA process also establishes strict timelines for the necessary administrative actions.

B. Section 586D(a) Guidance on Withdrawal Process

Section 586D(a)(1)(A)(iii) of the FD&C Act requires the Agency to issue guidance on “the process by which a request under section 586A or a pending request is withdrawn.”13 The statute does not address the process by which a sponsor or FDA could withdraw a 586A request or pending request under the SIA. In addition, FDA’s current regulations governing TEA requests do not include a withdrawal process (§ 330.14).14 As directed by the SIA, FDA is issuing this guidance to explain how, at different stages of the SIA process, a 586A request or pending request may be withdrawn.

Although neither the SIA nor the current TEA regulation otherwise discuss the process of withdrawal, we note that in the preamble of the final rule promulgating the TEA regulation, FDA discussed the effect of a withdrawal of a TEA request when a non-GRASE determination for that condition is expected. We explained in the preamble to the 2002 TEA Final Rule that although a sponsor can withdraw its request after receiving a feedback letter indicating that a condition has been determined not to be GRASE, we would still consider the submission, including the data and information submitted, to be a part of the public docket and FDA would still have the 15 discretion to publish the Agency’s non-GRASE decision, notwithstanding the withdrawal. As indicated in the preamble to the 2002 TEA Final Rule, it is the Agency’s view that the OTC Drug Review is a public process, and thus, if a condition is determined to be eligible for review, all information provided to FDA should remain part of the public record, even if a sponsor withdraws its request.16 The SIA process, like the OTC Drug Review, is also a public process. Thus, consistent with the 2002 TEA Final Rule and as explained in Section III of this guidance, the Agency may continue to rely on the data and information that have been submitted in the SIA process after a request is withdrawn.

Based on the requirements of the SIA and the Agency’s prior consideration of a similar issue in implementing the TEA regulation,17 this guidance describes our recommendations for addressing

13 Section 586C(a)(1)(A)(iii) of the FD&C Act (21 U.S.C. 360fff-3(a)(1)(A)(iii)).

14 We note that on April 4, 2016, the Agency issued a proposed rulemaking that proposes to revise section 330.14 of the Agency’s regulations to include provisions regarding the withdrawal of TEAs and safety and effectiveness data submissions (81 FR 19069, April 4, 2016).

15 See “Additional Criteria and Procedures for Classifying Over-the Counter Drugs as Generally Recognized as Safe and Effective and Not Misbranded” (2002 TEA Final Rule), 67 FR 3060 at 3066 and 3067 (January 23, 2002).

16 There may be limited situations in which certain information submitted may be considered confidential. See 2002 TEA Final Rule, 67 FR 3060 at 3067 and 3066; see also section 586B(a)(3) of the FD&C Act (21 U.S.C. 360fff-2(a)(3)).

17 See 2002 TEA Final Rule, 67 FR 3060 at 3067.
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the process for withdrawal of a 586A request or pending request and the effect of a withdrawal on the GRASE review process.

C. Related Guidance

In addition to this guidance, the SIA directs FDA to issue draft and final guidance documents on three other topics.18 These topics include:

  • The format and content of information submitted by a sponsor in support of a 586A request or a pending request;

  • The data required to meet the safety and efficacy standard for determining whether a nonprescription sunscreen active ingredient or combination of nonprescription sunscreen active ingredients is GRASE and not misbranded; and

  • The process by which FDA will carry out section 586C(c) of the FD&C Act as amended by the SIA, including the process for requesting an advisory committee meeting, the circumstances that limit the number and frequency of advisory committee meetings FDA is required to convene, and the number of requests to be considered per advisory committee meeting.

    In November 2015, FDA issued draft guidance on all four topics. As they become available draft or final guidances are posted on the FDA Drugs guidance Web page at

    http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 19

III. GENERAL WITHDRAWAL PROCEDURES A. Request for Withdrawal

A sponsor seeking to withdraw its 586A request or pending request should submit its written or electronic request for withdrawal to the docket with a copy to the Division of Nonprescription Drug Products in the Office of Drug Evaluation IV.20 Written requests should be submitted to:

Division of Dockets Management (HFA-305) Food and Drug Administration
5630 Fishers Lane, Rm. 1061

18 Section 586D(a)(1)(A) of the FD&C Act (21 U.S.C. 360fff-4(a)(1)(A)).
19 When available, FDA will post each final guidance on the FDA Drugs guidance Web page at

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

20 If the Agency has not opened a docket for the proceeding, the sponsor should submit its written request for withdrawal to the Division of Nonprescription Drug Products in the Office of Drug Evaluation IV as described in this guidance.

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Rockville, MD 20852 and

Food and Drug Administration
Division of Nonprescription Drug Products Bldg. 22, Mail Stop 5411
10903 New Hampshire Avenue
Silver Spring, MD 20993

Electronic requests, and electronic copies of written requests, should be submitted to http://www.regulations.gov in the applicable docket. The withdrawal request should include the following information:

submitter
submission date
active ingredient or other condition that is the subject of the submission applicable docket number

A request to withdraw informs FDA of the sponsor’s intent to discontinue its request for a determination from the Agency of whether the sunscreen active ingredient, or combination of active ingredients, is GRASE and should be included in the sunscreen OTC monograph. FDA intends to respond to a request for withdrawal from the sponsor by sending a letter to the sponsor acknowledging the withdrawal of the request. If the withdrawal is made after a docket has been opened for that proceeding, FDA intends to place a copy of the acknowledgement letter in that docket.

As explained in more detail below, generally, if a sponsor submits a request to withdraw its 586A or pending request at any time prior to FDA’s issuance of a final sunscreen order, FDA intends to consider the request withdrawn. If a proposed sunscreen order has not been issued, FDA intends to stop its review of that request. However, similar to FDA’s approach under the TEA regulation, if a proposed sunscreen order has already been issued prior to the withdrawal, FDA may proceed with issuing a final sunscreen order consistent with the SIA and as priorities and resources permit. In addition, FDA intends that the original submission and the data and information submitted in support of the 586A request will remain a part of the public docket for that proceeding, and FDA may continue to rely on such data and information.21

B. Withdrawal Due to Sponsor’s Failure to Take Action

We note that there are several stages in the review process for 586A requests and pending requests at which the Agency will be waiting for the sponsor or other interested parties to submit necessary information or data. With the exception of designated comment periods, the SIA does not require the sponsor or others to submit such information or data within an established

21 See 2002 TEA Final Rule, 67 FR 3060 at 3067. Generally, the Agency will open a docket when the notice of eligibility (NOE) is issued.

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deadline. Based on our past experience with the OTC monograph process, this may create a situation in which the necessary information or data are never submitted.

Accordingly, we recommend that sponsors keep us apprised of the anticipated timing of their data submissions if those submissions are expected to occur more than 1 year from the date of the notice of eligibility (NOE) or the sponsor’s most recent submission. To facilitate the review process and better utilize the Agency’s time and resources, FDA may also request periodic updates from the sponsor on the status of the information or data to be submitted if nothing has been submitted by the sponsor for more than 1 year. If an update is not provided or no information or data are submitted to FDA within 90 days of FDA’s request for an update, the Agency intends to consider the sponsor’s failure to respond to be a request by the sponsor to withdraw the 586A or pending request. By failing to take action, the sponsor will have indicated that it is no longer interested in pursuing a GRASE determination for a particular request. FDA intends to send a letter notifying the sponsor that the request is withdrawn, and FDA intends to place a copy of the letter in the public docket for that proceeding. It is the Agency’s view that this withdrawal process will provide notice to the public of the status of the proceeding and of our intent to stop review of the request due to the sponsor’s failure to take action. As discussed in section IV.C, if a 586A request or pending request is withdrawn, a sponsor can submit a new request for the same sunscreen active ingredient or combination of sunscreen active ingredients.

IV. EFFECT OF WITHDRAWAL OF 586A REQUESTS AND PENDING REQUESTS

As explained above, the SIA process calls for an initial eligibility determination phase followed by the submission of safety and efficacy data, a filing determination by FDA, and a GRASE determination phase, which includes a proposed sunscreen order and final sunscreen order.

If a 586A request is determined to be eligible for review, the Agency opens a docket for the proceeding, publicly posts the NOE and the 586A request,22 and provides interested parties 45 days to submit comments relating to a GRASE determination on the request, including data and other information related to the safety and efficacy of the request.23

A key step in the SIA process requires FDA to determine whether the information and data submitted to support a GRASE determination are appropriately formatted and sufficiently complete to support a substantive GRASE review (filing determination).24 Based on that determination, FDA will either file or refuse to file the request (thus triggering various action timelines).25

22 For information on the treatment of confidential data in 586A requests, see section 586B(a)(3) of the FD&C Act(21 U.S.C. 360fff-2(a)(3)).

23 Section 586B(b)(1) of the FD&C Act (21 U.S.C. 360fff-2(b)(1)). 24 Section 586B(b)(2) of the FD&C Act (21 U.S.C. 360fff-2(b)(2)). 25 Section 586B(b)(3) of the FD&C Act (21 U.S.C. 360fff-2(b)(3)).

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The following sections address the effect that a withdrawal of a 586A request or pending request may have on these and other key phases of the SIA process.

A. 586A Request — Withdrawal

1. Withdrawal Prior to an Eligibility Determination or After a Determination That a Request Is Ineligible

If a sponsor withdraws its 586A request before FDA issues a determination that the request is eligible for review, we intend to stop our review of the request because we no longer have a 586A request upon which to make a determination of eligibility. Similarly, if FDA has made a determination that the 586A request is not eligible for review under the SIA process, the matter may be considered closed without the need for a withdrawal because there is no longer an open matter from which to withdraw. For requests withdrawn prior to an eligibility determination, FDA does not intend to publicly post the withdrawal notification.

2. Withdrawal After an Eligibility Determination but Prior to a Filing Determination

a. Presubmission of Data Package

If a sponsor withdraws its 586A request after FDA has determined that the request is eligible for review and has issued an NOE, but before the data package described in section 586B(b)(1) of the FD&C Act has been submitted, FDA intends to stop its review of the withdrawn request. Upon the sponsor’s withdrawal, there will be no 586A request which may be filed. If a new 586A request is submitted for the same sunscreen active ingredient or combination of sunscreen active ingredients after the withdrawal of the original request, we intend to follow the process for the new request as explained in section IV.C of this guidance.

b. Postsubmission of Data Package

If a sponsor withdraws its 586A request after FDA has determined that the request is eligible for review and has issued an NOE determination, and after the data package described in section 586B(b)(1) of the FD&C Act has been submitted, but prior to FDA’s filing determination, the Agency intends to stop its review of the 586A request. Upon the sponsor’s withdrawal, there will be no 586A request. If a new 586A request is submitted for the same sunscreen active ingredient or combination of sunscreen active ingredients after the withdrawal of the original request, we intend to follow the process for the new request as explained in section IV.C of this guidance.

3. Withdrawal After Filing Determination

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a. Filed 586A Request

If FDA determines that the data and information are sufficiently complete to conduct a GRASE review, the Agency will file the 586A request. If a sponsor withdraws its 586A request after the Agency has filed the request and before the Agency has issued the proposed sunscreen order, the Agency intends to stop its review of the withdrawn request. If a new 586A request is submitted for the same sunscreen active ingredient or combination of sunscreen active ingredients after the withdrawal of the original request, we intend to follow the process for the new request as explained in section IV.C of this guidance.

b. Refuse to File

If a sponsor withdraws its 586A request after FDA refuses to file the request, the Agency intends to stop its review of the withdrawn request. A sponsor can submit additional data or other information in response to a refuse to file. If a sponsor withdraws its 586A request after it has submitted additional data or information, but before FDA has made a new filing determination, the Agency intends to stop its review of the withdrawn request.26 If a new 586A request is submitted for the same sunscreen active ingredient or combination of sunscreen active ingredients after FDA refuses to file the original 586A request, we intend to follow the process for the new request as explained in section IV.C of this guidance.

4. Withdrawal After a Proposed Sunscreen Order Under Section 586(7)(C)

If a sponsor withdraws the 586A request after the Agency has issued a proposed sunscreen order and has made a tentative determination on whether or not an active ingredient is GRASE under certain conditions of use, 27 FDA intends to deem the 586A request withdrawn, but may continue to rely on the information submitted to the docket and may proceed to issuing a final sunscreen order. As explained in section II.B, we consider all data and information submitted (e.g., in response to the NOE, a feedback letter, or tentative GRASE determination) to be part of the public record. Upon submission of such information, the Agency has the data upon which to base its final sunscreen order notwithstanding the withdrawal. If a new 586A request is submitted for the same sunscreen active ingredient or combination of sunscreen active ingredients after the withdrawal of the original request, we intend to follow the process for the new request as explained in section IV.C of this guidance.

26 Section 586B(b)(3) of the FD&C Act provides sponsors with a process to submit additional information and request meetings if FDA refuses to file the request. If FDA makes a new filing determination based on the additional information and accepts the request for filing, then any withdrawal of the request sought thereafter will fall under the approach described in section IV.A.3.a of this guidance.

27 Section 586C(a)(5)(A) of the FD&C Act (21 U.S.C. 360fff-3(a)(5)(A)). Under the SIA, FDA has 300 days to evaluate the information and data submitted to the docket and to issue a proposed sunscreen order on its GRASE determination (section 586C(a)(1) of the FD&C Act (21 U.S.C. 360fff-3(a)(1))). In the proposed sunscreen order, FDA can find that the active ingredient under consideration is GRASE, not GRASE, or not GRASE and more information and data are necessary to allow FDA to determine otherwise (section 586(7) of the FD&C Act (21 U.S.C. 360fff(7))). The sponsor and interested parties will have 45 days to submit comments on the proposed order (section 586C(a)(3) of the FD&C Act (21 U.S.C. 360fff-3(a)(3))).

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B. Pending Requests — Withdrawal

As explained above, a pending request under the SIA is defined to mean a request for a nonprescription sunscreen active ingredient submitted under § 330.14 for consideration for inclusion in the OTC monograph that was determined to be eligible for review and for which safety and effectiveness data were submitted prior to the enactment of the SIA (section 586(6) of the FD&C Act). There are eight pending requests as defined under section 586(6) of the FD&C Act. FDA has issued proposed sunscreen orders for all eight pending requests,28 and the proposed orders tentatively determined that the active ingredients are not GRASE and more data are necessary to allow FDA to determine otherwise.29

Accordingly, FDA intends for the same withdrawal process described in section IV.A.4 to apply if a sponsor of a pending request withdraws the pending request prior to the issuance of the final sunscreen order. If a new 586A request is submitted for the same sunscreen active ingredient after the withdrawal of the pending request, we intend to follow the process for the new request as explained in section IV.C of this guidance.

C. New Requests

The same or a different sponsor can submit a new 586A request for the same sunscreen active ingredient or combination of sunscreen active ingredients after the original request has been withdrawn. If FDA has already made a determination that the active ingredient is eligible for further review under the SIA process, FDA intends for the existing NOE to remain in effect and the sunscreen active ingredient or combination of active ingredients to remain eligible for consideration under the SIA. The sponsor of the new 586A request may rely on the existing NOE for that active ingredient; but, thereafter, we intend to treat the new submission as a new 586A request under the SIA process, and the sponsor should submit a new and complete data submission package for its request. The data package may include data and other information that were submitted as part of a prior 586A or pending request for that ingredient under the SIA. If there is no existing NOE or the active ingredient has been found ineligible, then we intend to treat the submission of another 586A request for this ingredient as a new 586A request subject to the full SIA process, including an eligibility determination.

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28 Section 586C(b)(3) of the FD&C Act (21 U.S.C. 360fff-3(b)(3)).

29 See http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingOver- the-CounterMedicines/ucm239463.htm.

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Sunscreen Innovation Act: Section 586C(c) Advisory Committee Process

Sunscreen Innovation Act: Section 586C(c) Advisory Committee Process

Guidance for Industry

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

October 2016 OTC

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Sunscreen Innovation Act: Section 586C(c) Advisory Committee Process

Guidance for Industry

Additional copies are available from:

Office of Communications, Division of Drug Information Center for Drug Evaluation and Research

Food and Drug Administration th 10001 New Hampshire Ave., Hillandale Bldg., 4

Floor

Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

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U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

October 2016 OTC

I. II.

A. B. C.

III.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 BACKGROUND ............................................................................................................... 2 Advisory Committees and the Nonprescription Drugs Advisory Committee...........................2 Regulation of OTC Sunscreen Products.......................................................................................4 Related Guidance ...........................................................................................................................5 SECTION 586C(c) OF THE FD&C ACT ...................................................................... 6

IV. PREPARATION AND PUBLIC AVAILABILITY OF INFORMATION GIVEN
TO ADVISORY COMMITTEE MEMBERS..................................................................... 8

Contains Nonbinding Recommendations

Sunscreen Innovation Act:
Section 586C(c) Advisory Committee Process

Guidance for Industry1

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This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page.

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I. INTRODUCTION

This guidance addresses the process by which the Food and Drug Administration (FDA or Agency) intends to carry out section 586C(c) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 360fff-3(c)), as amended by Public Law 113-195 (also referred to as the Sunscreen Innovation Act (SIA)).2 Under the SIA, the Agency may convene the Advisory Committee (also referred to in this guidance as the Nonprescription Drugs Advisory Committee or NDAC)3 to provide recommendations on requests submitted to FDA for a determination of whether a sunscreen active ingredient or combination of sunscreen active ingredients, for use under specified conditions, is generally recognized as safe and effective (GRASE) and should be added to the over-the-counter (OTC) sunscreen drug monograph system. However, section 586C(c) of the FD&C Act provides specific circumstances under which FDA is not required to convene or submit requests to the NDAC. The SIA also added section 586D(a)(1) to the FD&C Act (21 U.S.C. 360fff-4(a)(1)), which directs FDA to issue a draft guidance and a final guidance on the process by which FDA will carry out section 586C(c) of the FD&C Act, including with respect to how FDA will address the total number of requests received under section 586A (21 U.S.C. 360fff-1) and pending requests, as defined by the SIA.4

The recommendations in this guidance apply to section 586A requests and to pending requests. A 586A request seeks a determination from FDA on whether a nonprescription sunscreen active

1 This guidance has been prepared by the Office of Regulatory Policy in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.

2 21 U.S.C. Ch. 9 Sub. 5 Part 1, enacted November 26, 2014.

3 The SIA defines “Advisory Committee” to mean the Nonprescription Drugs Advisory Committee of the Food and Drug Administration or any successor to such Committee (section 586(1) of the FD&C Act (21 U.S.C. 360fff(1))).

4 The draft guidance was issued in November 2015 (80 FR 72972, Nov. 23, 2015). 1

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Contains Nonbinding Recommendations

ingredient,5 or a combination of nonprescription sunscreen active ingredients, is GRASE for use under specified conditions and should be included in the OTC sunscreen drug monograph (section 586A of the FD&C Act). Section 586(6) of the FD&C Act (21 U.S.C. 360fff(6)), as amended by the SIA, defines a “pending request” to mean a request for a nonprescription sunscreen active ingredient submitted under § 330.14 (21 CFR 330.14) for consideration for inclusion in the OTC monograph that was determined to be eligible for review and for which safety and effectiveness data were submitted prior to the enactment of the SIA.6

We have published a number of Federal Register notices about rulemaking actions for OTC sunscreen monograph products and about actions taken under the SIA. Information on these notices can be found on our “Status of OTC Rulemakings” 7 and “Sunscreen”8 Web sites.

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

II. BACKGROUND
A. Advisory Committees and the Nonprescription Drugs Advisory Committee

FDA has established advisory committees “to secure independent professional expertise in accomplishing its mission and maintaining the public trust.”9 FDA's advisory committees provide independent expert advice to the Agency on a range of complex scientific, technical, and policy issues. An advisory committee meeting also provides a forum for a public hearing on important matters. Although advisory committees provide important advice and

5 A “sunscreen,” as defined in the SIA, means a drug containing one or more sunscreen active ingredients (section 586(9) of the FD&C Act (21 U.S.C. 360fff(9))), and the term “sunscreen active ingredient” means an active ingredient that is intended for application to the skin of humans for purposes of absorbing, reflecting, or scattering ultraviolet radiation (section 586(10) of the FD&C Act (21 U.S.C. 360fff(10))).

6 These pending requests were submitted as time and extent applications (TEAs) under section 21 CFR 330.14 of FDA’s regulations.

7 The “Status of OTC Rulemakings” Web site is available at

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the- CounterOTCDrugs/StatusofOTCRulemakings/default.htm.

8 The “Sunscreen” Web site is available at

http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingOver-the- CounterMedicines/ucm239463.htm.

9 See guidance for industry, Advisory Committees: Implementing Section 120 of the Food and Drug Administration Modernization Act of 1997 (Advisory Committee Guidance), at 1, available at http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm079765.pdf.

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Contains Nonbinding Recommendations

recommendations to FDA, the Agency has sole discretion concerning action to be taken and policy to be expressed on any matter considered by an advisory committee.10

The NDAC was established under the Federal Advisory Committee Act11 (in addition to other statutory and regulatory provisions), which sets forth requirements for the formation and utilization of advisory committees. Part 14 (21 CFR part 14) describes the procedures and rules that govern the Agency’s use of advisory committees (such as the NDAC).

The NDAC reviews and evaluates available data concerning the safety and effectiveness of OTC drug products for use in the treatment of a broad spectrum of human symptoms and diseases and advises the Agency on the requirements for monographs establishing conditions under which these drugs are GRASE and not misbranded.12 The NDAC consists of approximately 10 voting members selected from among specialists knowledgeable in the fields of internal medicine, family practice, pediatrics, statistics, clinical toxicology, clinical pharmacology, pharmacy, and related specialties.13 The Agency may call upon individuals to supplement the core membership on an ad hoc basis so that the group considering an issue presented to an advisory committee may also include members who are specialists with expertise in the particular disease or condition for which the drug product under consideration is proposed to be indicated.14 For example, NDAC committees considering matters related to sunscreens may be supplemented with dermatologists.

FDA recognizes that advisory committee meetings impose significant resource commitments on advisory committee members, sponsors, and other public participants, as well as on the Agency itself, and therefore FDA seeks to limit use of such meetings to important matters. In general, FDA has discretion to decide whether to present a matter to an advisory committeehere, to the NDACfor consideration. In making this decision, FDA generally considers several factors, including the following:

  1. (a)  Is the matter at issue of such significant public health importance that it would be highly beneficial to obtain the advice of an advisory committee as part of the Agency’s regulatory decision-making process?

  2. (b)  Is the matter at issue so controversial that it would be highly beneficial to obtain the advice of an advisory committee as part of the Agency’s regulatory decision-making process?

10 Id.
11 Public Law 92-463 (5 U.S.C. Appendix).

12 See the NDAC Charter, available at

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/NonprescriptionDrugsAdvisoryCom mittee/ucm105992.htm.

13 Id.
14 Advisory Committee Guidance, supra note 9, at 2.

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Contains Nonbinding Recommendations

(c) Is there a special type of expertise that an advisory committee could provide that is needed for the Agency to fully consider a matter?

If one or more of these factors are met, FDA generally refers the matter at issue to an advisory committee. Conversely, FDA generally refrains from referring a matter to an advisory committee if none of the factors are met. By prioritizing matters according to these factors, FDA helps ensure that the finite resources of the advisory committee program are devoted to consideration of the most important matters, including those matters in which the Agency would most benefit from the advice of outside experts.

Specifically for the NDAC, if FDA determines that it would be useful to convene a meeting to discuss sunscreen active ingredients being considered through the SIA process, the Agency would generally make the following preparations, including, but not limited to: (1) identifying additional members, if necessary, for each NDAC meeting who are specialists on the issue(s) to be considered, as well as determining their availability and screening them for conflict-of- interest; (2) preparing FDA briefing information and presentations; (3) publishing notice of the NDAC meeting in the Federal Register; and (4) organizing the logistics of setting up and holding the NDAC meeting. Based on the Agency’s experience with past NDAC meetings, it may take 4 to 6 months to prepare for an NDAC meeting.

B. RegulationofOTCSunscreenProducts

All sunscreen products are regulated as drugs in the United States under one of two processes:

  • The new drug approval process described in 21 CFR part 314

  • The OTC drug monograph process (also known as the OTC Drug Review) described in part 330 (21 CFR part 330), as supplemented by the SIA

    Products regulated under the new drug approval process may not be marketed without FDA’s prior review and approval of a new drug application (NDA) or abbreviated new drug application (ANDA) for each product.15 Products marketed under the OTC drug monograph process are not individually reviewed and approved prior to marketing. Instead, OTC drug monographs categorize drugs by therapeutic categories, such as sunscreens. For each category, a monograph establishes conditions under which any drug that satisfies those conditions and FDA’s general regulations for OTC drugs is considered to be GRASE and not misbranded when used under the conditions prescribed, recommended, or suggested in the drug’s labeling.16

    Active ingredients that were used in U.S.-marketed sunscreens before the OTC Drug Review began are eligible to be included in the OTC sunscreen monograph. An active ingredient or other condition that is ineligible for inclusion in the OTC monograph system is subject to the new drug approval process.

    15 See sections 505(a) and 301(d) of the FD&C Act. 16 21 CFR Part 330.

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Contains Nonbinding Recommendations

In 2002, before the SIA was enacted, FDA published the “time and extent application” (TEA) regulation in 21 CFR 330.14. The TEA regulation (§ 330.14(c)) has provided a process through which any person may request that FDA amend an existing OTC drug monograph to include an active ingredient or other OTC drug condition, including one not previously marketed in the United States before the OTC Drug Review began.

For OTC sunscreens, the SIA process supplements FDA’s TEA regulation (§ 330.14). The SIA amended the FD&C Act in part by providing new procedures for establishing that nonprescription sunscreen active ingredients or combinations of nonprescription sunscreen active ingredients are GRASE and not misbranded when used under the conditions specified in a final sunscreen order (GRASE determination).17 Active ingredients that are determined to be GRASE under specified conditions of use in a final sunscreen order may be used in U.S.-marketed sunscreens without first obtaining an approved NDA or ANDA. Because the monograph and SIA processes are public, anyone, not just the sponsor who originated the request, may submit data during public comment periods.

As with the TEA process, the SIA process calls for an initial eligibility determination, followed by submissions of safety and efficacy data, and a GRASE determination phase. However, the SIA process also requires FDA to make a filing determination18 and to make proposed and final GRASE determinations in the form of orders rather than the rulemaking required by the TEA regulation. The SIA process also establishes strict timelines for the necessary administrative actions. At certain stages in the SIA process, FDA has the discretion to convene the NDAC for the purpose of reviewing and providing recommendations on a 586A request or on a pending request.

C. Related Guidance

In addition to this guidance, the SIA directs FDA to issue draft and final guidance documents on three other topics.19 These topics include:

  • The format and content of information submitted by a sponsor in support of a 586A request or a pending request;

  • The data required to meet the safety and efficacy standard for determining whether a nonprescription sunscreen active ingredient or combination of nonprescription sunscreen active ingredients is GRASE and not misbranded; and

    17 Section 586C of the FD&C Act (21 U.S.C. 360fff-3).

    18 The filing determination requires FDA to determine whether the safety and efficacy data submitted to support a GRASE determination are appropriately formatted and sufficiently complete to support a substantive GRASE review (section 586B(b)(2) of the FD&C Act (21 U.S.C. 360fff-2(b)(2))).

    19 Section 586D(a)(1)(A) of the FD&C Act (21 U.S.C. 360fff-4(a)(1)(A)). 5

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Contains Nonbinding Recommendations

The process for withdrawing a 586A request or a pending request.

In November 2015, FDA issued draft guidance on all four topics. As they become available, draft or final guidances are posted on the FDA Drugs guidance Web page at

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 20

III. SECTION 586C(c) OF THE FD&C ACT

Section 586D(a)(1)(A)(iv) of the FD&C Act (21 U.S.C. 360fff-4(a)(1)(A)(iv)) requires FDA to issue guidance on the process it will use to carry out section 586C(c) of the FD&C Act, including with respect to how FDA will address the total number of requests received under section 586A and pending requests.21 Section 586C(c) of the FD&C Act states that:

  • FDA is not required to convene the NDAC “more than once with respect to any request under section 586A or any pending request.”

  • FDA is not required to convene the NDAC “more than twice in any calendar year with respect to the review under this section.”

  • FDA is not required to “submit more than a total of 3 requests under section 586A or pending requests to the Advisory Committee per meeting.”22

    Below, we describe how we intend to carry out section 586C(c), including how we intend to handle the total number of 586A requests and pending requests.

    As an initial matter, a sponsor can request that FDA convene the NDAC to consider certain issues related to the sponsor’s 586A request or pending request. (An NDAC meeting is not meant to take the place of the public feedback meetings with CDER, which are provided for elsewhere in the SIA.23) To provide adequate time for the parties to prepare for an NDAC meeting, we recommend that (1) sponsors of 586A requests that are interested in seeking an NDAC meeting submit their request for such a meeting at the time they submit their initial data package, or no later than at the time of the filing determination; and (2) sponsors of pending requests that are interested in seeking an NDAC meeting submit their request for such a meeting at the time they submit their supplemental data package.

    20 When available, FDA will post each final guidance on the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

    21 Section 586D of the FD&C Act (21 U.S.C. 360fff-4). 22 Section 586C(c) of the FD&C Act.

    23 See, e.g., sections 586B(b)(3)(A) and 586C(a)(4) and (b)(7) of the FD&C Act (21 U.S.C. 360fff-2(b)(3)(A) and 21 U.S.C. 360fff-3(a)(4) and (b)(7)).

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The request for an NDAC meeting should be sent as a letter (either by hard copy or electronically) to the Division of Nonprescription Drug Products (DNDP). If there is an applicable docket,24 a duplicate letter should be sent (either by hard copy or electronically) to the Division of Dockets Management as well. Both addresses are as follows:

Food and Drug Administration
Division of Nonprescription Drug Products
Bldg. 22, Mail Stop 5411
10903 New Hampshire Avenue
Silver Spring, MD 20993
Electronic letters should be sent to the following e-mail address:
This e-mail address is being protected from spambots. You need JavaScript enabled to view it

Food and Drug Administration
Division of Dockets Management (HFA-305)
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852
Electronic letters should be submitted at
http://www.regulations.gov in the applicable docket.

We recommend the sponsor submit the following information as part of a request for an NDAC meeting:

  1. The subject line should be prominently labeled: “SIA (586A Request/Pending Request) - Request that FDA Convene the Nonprescription Drugs Advisory Committee.”

  2. The body of the letter should contain the following:

    • - A statement that the sponsor requests FDA to convene the NDAC for review and recommendations regarding a 586A request or a pending request for a sunscreen active ingredient or combination of sunscreen active ingredients under specified conditions of use.

    • - Information about the specific sunscreen active ingredient or combination of sunscreen active ingredients and specified conditions of use to be the subject of the requested NDAC meeting.

    • - The name of the specific sponsor that will present information to the NDAC.

    • - A statement of the specific matter proposed for discussion at the NDAC meeting.

    • - A statement explaining why the specific matter warrants NDAC discussion and why it should be considered at the particular time of the request.

      24 If no docket has been opened for the matter, the request should be sent only to the DNDP. 7

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- As applicable, the statement should refer to the factors discussed above in Section II.A in support of the request for an NDAC meeting.

3. The name, title, address, telephone number, and e-mail address of the sponsor’s contact person should be included.

Upon receipt of the NDAC request,25 DNDP intends to review the letter. FDA intends to consider an NDAC request to have been made when the Agency acknowledges receipt of the request letter. DNDP intends to provide an acknowledgment letter to the sponsor within 30 days of receipt. Acknowledgment of the receipt of the request does not constitute an agreement by FDA to convene the NDAC. If FDA decides that the NDAC will be convened, FDA will notify the sponsor.

Under the SIA, FDA may decide whether to convene an NDAC for any particular 586A request or pending request regardless of whether the sponsor has made an NDAC request. FDA intends to address and prioritize the total number of 586A requests and pending requests received by using the factors described in Section II.A above to determine whether and when to refer such a request to the NDAC. For example, FDA would be more likely to convene a meeting for matters that are dissimilar to those discussed at a previous NDAC and for which a clear path forward had not already been determined. In addition, FDA may convene an NDAC on its own initiative, using similar criteria as those factors used to determine whether to present sponsor requests to an NDAC.

As explained above, referring a matter to the NDAC involves a substantial expenditure of the Agency’s limited resources and time. Accordingly, depending on the total number of 586A requests and pending requests to be considered by the NDAC, FDA intends to limit the number of NDAC meetings per year and the number of requests to be considered per meeting as discussed in section 586C(c) of the FD&C Act.

IV. PREPARATION AND PUBLIC AVAILABILITY OF INFORMATION GIVEN TO ADVISORY COMMITTEE MEMBERS

For each advisory committee meeting, the sponsor should provide briefing materials to be considered by the members of the NDAC. For most meetings, these materials should consist of the sponsor’s briefing document which addresses the issues to be considered by the NDAC. The briefing document should include all information relevant to the matters to be discussed at the NDAC meeting, presented in a concise summary. Information on briefing material preparation, timelines, and public availability of briefing material is included in the guidance for industry

25 The official date of receipt of the letter may be assigned by FDA and may not necessarily be the date of mailing or of delivery by a delivery service.

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Contains Nonbinding Recommendations

Advisory Committee Meetings —Preparation and Public Availability of Information Given to Advisory Committee Members.26

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26 Available at http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-afda- gen/documents/document/ucm125650.pdf.

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