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Background of the Q-Submission program; IVDs; nonclinical ... preparation and submission of a Pre-Sub request ... Using the Pre-Sub Guidance, answer the.
INSTRUCTOR’S GUIDE Seeking Early Feedback from FDA through the Pre-Submission Program LEARNING OBJECTIVES 1. To understand how to use the Q-Sub program to seek FDA feedback on specific topics. 2. To identify when a Q-Sub would be useful for applicants and study sponsors.

3. To review the unique process applicable to a Pre-Sub using a fictional in vitro diagnostic (IVD) device. 4. To review the general considerations for conducting nonclinical studies on an IVD using a fictional IVD device. 5. To prepare a partial Pre-Sub request in a team project.

TOPICS

Background of the Q-Submission program; IVDs; nonclinical study design

ASSUMPTIONS

Users of the case study are instructors who have some basic knowledge about FDA processes and the scope of regulatory oversight. Instructors may spend at least three class periods to teach the materials, including student presentations.

SUGGESTED APPROACH

1. Preparing Students (Session 1): Students are required to review the appendices, the glossary, and the background of the case before class lecture(s).

2. Engaging Students (Session 2): This session is the main lecture on the requirements associated with preparation and submission of a Pre-Sub request using an IVD device as an example. 3. Immersing Students (Session 3): This is a team project focused on the preparation of a partial mock Q-Sub request.

The case study is based on the following assumptions: Target audience is undergraduate and graduate students with little to no experience in medical device development or regulatory affairs.

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Seeking Early Feedback from FDA through the Pre-Submission Program: Instructor’s Guide continued Student Activities Instructors should direct students to review all of the materials before the first class session and may elect to test students at the beginning of this session on their preparation via a quiz. Alternatively, the case study could be used as a unit review with activities serving as a summative content assessment.

SESSION 1

I. Review the following materials before Session 1: 1. Information on Multiple Myeloma, Immunoglobulins, and Nephlometry

The following links are intended to familiarize students with multiple myeloma and the technology described in this case study. Instructors should not spend too much time or effort on the technology or the disorder, but instead emphasize how FDA’s regulatory process can be applied to the various devices.

a. Mayo Clinic: Multiple Myeloma

http://www.mayoclinic.org/diseasesconditions/multiple-myeloma/basics/ definition/con-20026607

b. American Cancer Society: Multiple Myeloma

http://www.cancer.org/cancer/ multiplemyeloma/detailedguide/multiplemyeloma-key-statistics

c. Structure and Function of Immunoglobulins http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3670108/pdf/nihms469957.pdf

2. CDRH Learn Materials

The following materials provide an overview of the Pre-Submission program process, the key concept for students to learn in this case study.

a. Webinar audio file: “Requests for Feedback on Medical Device Submissions: The PreSubmission Program and Meetings with Food and Drug Administration Staff” http://www.fda.gov/downloads/Training/ CDRHLearn/UCM387649.wmv

b. Slides

http://www.fda.gov/downloads/Training/ CDRHLearn/UCM387291.pdf

c. Transcript

http://www.fda.gov/downloads/Training/ CDRHLearn/UCM387646.pdf

3. Mandatory Reading

a. Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff

http://www.fda.gov/downloads/Medical Devices/DeviceRegulationandGuidance/ GuidanceDocuments/UCM311176.pdf

b. Guidance for Industry and FDA Staff: In Vitro Diagnostic (IVD) Device Studies— Frequently Asked Questions

http://www.fda.gov/downloads/Medical Devices/DeviceRegulationandGuidance/ GuidanceDocuments/ucm071230.pdf

d. Nephelometry and Turbidimetry

http://www.britannica.com/EBchecked/ topic/409243/nephelometry-and-turbidimetry

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Seeking Early Feedback from FDA through the Pre-Submission Program: Instructor’s Guide continued 4. Optional Reading

The following materials may help students understand other concepts related to the case study. Instructors are encouraged to teach these concepts as time permits.

a. Early Collaboration Meetings Under the FDA Modernization Act (FDAMA)

http://www.fda.gov/MedicalDevices/ DeviceRegulationandGuidance/ GuidanceDocuments/ucm073604.htm

b. The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)] Guidance for Industry and Food and Drug Administration Staff http://www.fda.gov/downloads/ medicaldevices/deviceregulationandguidance/ guidancedocuments/ucm284443.pdf

c. eCopy Program for Medical Device Submissions

http://www.fda.gov/downloads/ MedicalDevices/DeviceRegulationandGuidance/ GuidanceDocuments/UCM313794.pdf

d. Video: How to Create and Submit an eCopy

(Approximately 27 minutes)

http://www.accessdata.fda.gov/cdrh_docs/ presentations/eCopy/index.html

II. Answer the following questions before Session 1—Fundamental concepts:

1. Describe the following items for the IVD device discussed in the case study: a. Device Description

b. Proposed Intended Use c. Indications for Use

2. Using the Pre-Sub Guidance, answer the following: a. What is a Pre-sub?

A Pre-Submission request is defined as a formal written request from an applicant/sponsor for feedback from FDA to be provided in the form of a formal written response or, if the manufacturer chooses, a meeting or teleconference in which the feedback is documented in meeting minutes. A Pre-Submission is appropriate when FDA’s feedback on specific questions is necessary to guide product development and/or application preparation.

b. Name three types of Q-subs and describe what they are. Informational Meeting request: A sponsor or applicant may request a meeting in which the intent is to share information with FDA without the expectation of feedback. Specifically, an informational meeting may be appropriate to:

1. Provide an overview of ongoing device development when there are multiple submissions planned within the next 6 to 12 months, or 2. Familiarize the review team about a new device(s) with significant differences in technology from currently available devices.

Study Risk Determination request: The IDE regulations (21 CFR Part 812) describe three types of device studies: significant risk (SR), non-significant risk (NSR), and exempt studies. For studies that are not exempt, sponsors are responsible for making the initial risk determination (SR or NSR) and presenting it to an Institutional Review Board (IRB).

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Seeking Early Feedback from FDA through the Pre-Submission Program: Instructor’s Guide continued FDA is available to help the sponsor, clinical investigator, and IRB in making the risk determination. FDA will review written requests from sponsors planning a device clinical study and provide a risk determination in writing.

Early Collaboration Meeting request: The FD&C Act, as amended by FDAMA, provides for two early collaboration meetings: determination meetings and agreement meetings. These meetings are intended to facilitate interaction between FDA and applicants and provide clear direction for testing and development of those devices requiring clinical investigations to support marketing. A determination meeting, as described in Section 513(a)(3)(D) of the FD&C Act, is available to anyone anticipating submitting a PMA or product development protocol (PDP) and is intended to provide the applicant with the Agency’s determination of the type of valid scientific evidence that will be necessary to demonstrate that the device is effective for its intended use. As a result of this meeting, FDA will determine whether clinical studies are needed to establish effectiveness and, in consultation with the applicant, determine the least burdensome way of evaluating device effectiveness that has a reasonable likelihood of success. The other type of early collaboration meeting is an agreement meeting, described in Section 520(g)(7) of the FD&C Act, which is open to any person planning to investigate the safety or effectiveness of a Class III device or any

implant, including submitters of 510(k)s for eligible devices. The purpose of this meeting is to reach agreement on the key parameters of the investigational plan (see 21 CFR Part 812.25), including the clinical protocol.

Submission Issue Meeting request: A sponsor or applicant may request a submission issue meeting to discuss deficiencies identified during premarket review of a 510(k), de novo, IDE, HDE, PMA, IND, or BLA application or CLIA Waiver by Application, including associated amendments or supplements, whether these deficiencies were communicated in writing (e.g., additional information, major deficiency, or not approvable letter) or through email, telephone, or fax (e.g., telephone hold). Such a meeting is intended to provide clarification of FDA’s questions and/or to discuss an approach to responding to complex issues.

Day 100 Meeting request: A PMA applicant may request a day 100 meeting to discuss the review status of their PMA application. As outlined in FDAMA, FDA will meet with an applicant no later than 100 days after the receipt of a PMA application that has been filed. Prior to the meeting, FDA is to inform the applicant in writing of any identified deficiencies based on an interim review of the entire application and what information is required to correct those deficiencies.

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Seeking Early Feedback from FDA through the Pre-Submission Program: Instructor’s Guide continued SESSION 2

It is recommended that instructors spend time going through relevant sections in class. Instructors may choose the level of detail students are required to provide for the project and which aspects of the PreSub request students are required to prepare. Other information recommended for inclusion in a PreSub request also could be prepared according to the resources available to the class.

In-class discussion should focus on answering the before class questions (Session 1, Section II) with student participation. Further details from the guidance should be given to ensure that students fully understand the varied applications of Q-subs and are prepared to complete the team project.

I. In-class discussion (instructor guidance required):

Instructors are encouraged to review the specific recommendations from the Pre-Sub guidance for determining if appropriate information has been included and the quality of questions being raised by the students in their projects. Instructors may use the acceptance checklists used by FDA reviewers as outlined in Appendix 2 of the guidance while reviewing the quality of student assignments.

1. Discuss the different types of Q-Sub requests: a. Pre-Submission (Pre-Sub) b. Informational Meeting

c. Study Risk Determination

d. Early Collaboration Meeting e. Submission Issue Meeting f. Day 100 Meeting



2. Discuss the requirements for an IVD Pre-Sub request.

Refer to Appendix 1F “Pre-Sub for an IVD” in the “Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff” guidance

SESSION 3: Project and Presentation

Instructors should be familiar with Section III.A.5 “Recommended Information for Pre-Sub Packages” and Appendix 1C “Pre-Sub for a 510(k)” in the “Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff” guidance.

Note: This project may be used to satisfy, in part, a senior or graduate project or other special academic requirement.

I. Review the following material before beginning the project:

Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff http://www.fda.gov/downloads/MedicalDevices/ DeviceRegulationandGuidance/GuidanceDocuments/ UCM311176.pdf

II. Prepare a Pre-Submission Team Project

1. Prepare a Pre-Submission for a 510(k) medical device. This device can be one you have focused on in class, the IgTope device discussed in the case study, or a device of your choice.

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Seeking Early Feedback from FDA through the Pre-Submission Program: Instructor’s Guide continued

The following sections should be included in your project as recommended by the Pre-Sub guidance: a. Cover Letter

b. Table of Contents

c. Device Description

d. Proposed Intended Use/Indications for Use e. Overview of Product Development f. Specific Questions to ask FDA g. Method for Feedback

Further information can be included in the projects based on the questions being raised by the students and the specific type of PreSub being prepared. Appendix 1 of the PreSub guidance has further suggestions for additional information for Pre-Subs dealing with the regulator pathways listed below.

2. Review Appendix 1 of the Pre-Sub guidance. Based on the information in Section C (page 35), list two to three criteria applicable to submitting a Pre-Sub for your medical device. Assume it is a Pre-Sub for a 510(k) device.

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