FDA Pre-Market Interaction StrategiesBethany J. Hills JD/MPH

Agenda:

• Standard and Expedited Pathways Overview

• Types of Pre-Submission Interactions • Key Communication Strategies • Follow Up Recommendations • Handling Challenges – Options for Appeal

Device Classification Review • 513(g)

– Regulatory filing with FDA making the determination of classification

– 513(g) determination is final – Device reviewers not involved in 513(g) review

• Pre-Submission for either 510(k) or PMA – Sponsor must proffer device classification – FDA will react but may not be comprehensive in response – Allows more interaction with FDA review staff than 513(g)

• Request for Designation (Combo Products) – FDA Office of Combo. Products will determine lead

review based on product’s primary mode of action (PMOA)

Product Pathway Options • Devices

– Exempt – 510k – PMA (Pre-Market Approval)

• Drugs – NDA, ANDA, 505(b)(2) (New Drug Application,

Abbreviated New Drug Application, bioequivalent)

• Biologics – BLA, PMA, 510k, NDA (Biologics License

Application) • Dietary Supplements

– NDIN (New Dietary Ingredient Notification) • Combination Products

– RFD (Request for Designation)

Expedited Device Pathways

• Expedited Access for Premarket Approval (PMA) Medical Devices Intended for Unmet Medical need for Life Threatening Irreversible Debilitating Disease or Conditions (4/23/14)

• Balancing Premarket and Postmarket Data Collection for Devices Subject to Premarket Approval (4/23/14)

– Building on Innovation Pathway and Innovation Pathway 2.0

Incorporated Guidance Documents• “Factors to Consider When Making Benefit-Risk

Determinations in Medical Device Premarket Approvals and De Novo Classifications.” FINAL (3/28/12)

• “Priority Review of Premarket Submissions for Devices “ FINAL (5/17/13)

• “In Vitro Companion Diagnostic Devices” DRAFT (7/14/11)

• “Medical Device Development Tools” DRAFT (5/27/14)

• “Quality System Information for Certain Premarket Application Reviews” DRAFT (2/3/2003)

• “Procedures for Handling Post-Approval Studies Imposed by PMA Order” FINAL (6/15/2009)

• “Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with FDA Staff” FINAL (2/18/14)

4-Step Voluntary EAP Process 1. Request for designation as an EAP Device (“EAP Designation”) 2. Agreement upon a Data Development Plan 3. Review of a PMA application for an EAP Device 4. If conditionally approved, postmarked data collection and evaluation

Final Approval

Expedited Drug & Biologic Pathways• Guidance for Industry: Expedited

Programs for Serious Conditions – Drugs and Biologics

• May 2014 • http://www.fda.gov/downloads/drugs/

guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

Building an FDA Interaction Strategy

Pre-Submission Meetings • Formal or Informal • Purpose?

– Obtain needed designations – Confirm Classification and

Pathway – Receive FDA feedback on

proposed studies, indications, and other submission questions

Device Pre-Submission • Guidance History

• Pre-IDE Program March 1999 • Draft Pre-Sub Guidance July 2012 • Final February 2014 entitled,

“Requests for Feedback on Medical Device Submissions: the Pre-Submission Program and Meetings with Food and Drug Administration Staff”

Definition of “Pre-Submission”• A formal written request from an applicant for

feedback from FDA provided in the form of: – a formal written response or – a meeting or teleconference in which the

feedback is documented in meeting minutes • When FDA’s feedback on specific questions is

necessary to guide product development and/or application preparation (i.e., prior to intended submission of an IDE or marketing application)

• Request must include specific questions regarding review issues relevant to a planned IDE or marketing application (e.g., questions regarding pre-clinical and clinical testing protocols or data requirements).

• http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM29 5454.pdf

Pre-Submission Meeting• Intended to be specific to the questions

posed, however, if other deficiencies or concerns are noted during review, they may be included in FDA’s feedback.

• Generally meant to be a one-time process per topic (i.e., not iterative) but can be utilized at different times and/or for multiple topics for the same device (e.g., prior to IDE submission for bench testing and clinical protocols, then prior to PMA submission regarding data presentation).

• If significant changes are made to sponsor’s proposal in response to initial FDA feedback, may be appropriate to engage in repeat interaction on the same topic.

Submit a Pre-Sub request? • Voluntary, but encouraged • Prior to initiating long term preclinical studies • When planning a study that does not require an

IDE (Studies that are outside the US, exempt, or NSR)

• Before submission of an IDE to: – Discuss nonclinical data and clinical study

design • Before submission of a marketing application to:

– Apprise FDA review team on specifics of device and clinical study if there have been changes since initiation of the IDE

– Obtain feedback on preferred data presentation

– Gain insight into potential hurdles for approval or clearance

• When preparing a submission for a new device that does not clearly fall within an established regulatory pathway

Rely on Pre-Sub Feedback • FDA intends to stand behind its feedback

unless: – Information in subsequent submission is not

consistent with Pre- Sub (e.g., change in proposed indication for use or device design)

– Data in the subsequent submission raise important new issues related to safety and effectiveness (e.g., a study is conducted as recommended by FDA, but results raise new safety concerns)

– Feedback given previously does not adequately address important new issues materially relevant to a determination of safety or effectiveness that have emerged since the time of the Pre-Sub (e.g., new alternative therapies/diagnostics have emerged since discussion of the clinical protocol making the previously recommended study design unethical)

Pre-Sub for De Novo Review? • Pre-Submission (Pre-Sub). A Pre-Sub is not required in order to

obtain FDA review of a de novo, but is a useful way for submitters to facilitate early feedback from FDA. A Pre-Sub would allow FDA to provide feedback on whether a device may be suitable for the de novo process and/or to advise you on the documentation needed in a subsequent de novo. The primary advantage of a Pre- Sub is that it provides an opportunity to obtain our preliminary perspective on the likely regulatory controls necessary to provide a reasonable assurance of safety and effectiveness as well as feedback on the evidence, including performance and/or clinical data, that will likely be necessary to support the de novo. By obtaining this feedback, you are more likely to optimize your resources in collecting safety and effectiveness evidence needed to support a de novo, without the need to perform additional tests. This should also facilitate the review of a subsequent de novo.

• Aug 2014 - http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM273903.pdf

Pre-Submission Meeting TIPS • Prepare a stellar briefing package

– Impress FDA – RTA policy in Appendix 2 of Guidance

• Prepare specific goals and questions – Q-Sub Acceptance Criteria

• Anticipate and prepare responses – Team experts; dry-runs

• LISTEN – Designate a note taker whose only job

is to listen • Be Direct and Get Clarification

– Ask clear questions; push FDA to be clear in responses

FDA Comments• Process Driven • Understand FDA limitations • Demonstrate Sophistication and

Advocacy • Written Communication – Create a

Record • Oral Communications – Opportunity to

Impress • Need for “translator” – Company detail

translated to FDA terms/needs

Post Interaction TIPS • Draft meeting minutes immediately

– even before company “debrief” • Identify how information impacts

submission strategy • Manage changes from pre-

submission to submission – any unexpected changes?

What if things go badly…?• Formal CBER/CDER Dispute Resolution

– FDA regulations (§§ 10.75, 312.48, and 314.103), sponsor should initially seek resolution of any scientific or procedural dispute at the division level before making an appeal to the next higher management level. Sponsors can do this by holding a post-action meeting with the division or asking the division for reconsideration.

– For example, if there is a dispute regarding a deficiency cited in a complete response letter, the sponsor should first request a post-action meeting with the division to discuss the issue. Or, if an IND has been put on clinical hold, the sponsor should first ask the division to reconsider the issue.

– No new information can be submitted – Written file matters!

– FORMAL DISPUTE RESOLUTION REQUEST – FDA internally reviews the FDA decision

Administrative Appeals• 21 CFR 10.75 Supervisory Review (60 days) • 21 CFR 10.33 Reconsideration • 21 CFR Part 16 Informal Regulatory Hearing • Section 517A – Review of Significant

Decisions • Section 515(g) Appeal of a PMA Approval or

Denial • Section 562- Dispute Resolution – Scientific

Controversies where no other appeal paths

Judicial Review • No one really wants to get to this point

(Section 517) – Classification, Reclassification or

Performance Standard Regulations – Regulation Requiring PMAs for

Preamendment Devices – Order Approving or Denying a PMA

(After an Administrative Appeal) – Order Approving or Denying a GMP

Exemption or Variance – NSE or SE Order

Other Appeal Options • Filing a Citizen Petition per 21 CFR

§§ 10.30 and 10.20 — this process may be used by any person to appeal any FDA action or decision. These petitions must include, among other things (a) a statement of the factual and legal grounds for taking the requested action, (b) information on any environmental impact, and (c) a certification that the petition includes all information and views relied upon.

Office of the FDA Ombudsman • Assists aggrieved parties when problems/

concerns are not or cannot be addressed at center or district level, or when concerns exist about raising issues at those levels. Problems addressed by the FDA Ombudsman might include import/export issues, as well as responses from FDA district, center, division, or office, FDA action/inaction. The FDA Ombudsman’s Office also provides guidance on the course of action to resolve problems, and how a product will be regulated.

• Laurie Lenkel and Andrew Moss • http://www.fda.gov/AboutFDA/

CentersOffices/OC/OfficeofScientificandMedicalPrograms/ucm197508.htm

Thank you!