RAC Study Group 2025 Week 3: Regulatory Strategy

US FDA Communications and Meetings with CDRH

  • Four basic types:
    • Administrative Meetings and Communications
    • Regulatory Communications: FDA and company-initiated
    • Product application meetings: Sponsor and Office of Device Evaluation (ODE) at CDRH
    • Public administrative proceedings

Product Application Meetings (Q-sub Program)

  • Pre-submission:
    • Obtain formal feedback before submitting.
    • FDA meeting (60-75 days) or written feedback (about 70 days).
  • Informational:
    • Sponsor shares info with FDA without requesting feedback.
    • Meeting 90 days from request.
  • Study Risk Determinations:
    • Advice on IDE study risk (SR, NSR, or exempt).
    • Feedback in formal letter.
  • Formal Early Collaboration:
    • Agreement or determination meetings.
    • Results are binding; meeting time frame is 30 days.
  • Submission Issue Request (SIR):
    • Sponsor requests discussion of items identified by FDA during submission review.
  • PMA Day 100:
    • Discuss PMA review status.
    • FDA feedback by 90 days or at least 10 days prior to the meeting.
  • Breakthrough Device Designation Requests:
    • Prioritized review; FDA responds within 60 calendar days.

Advisory Committee Panel

  • SMEs provide recommendations to the agency.
    • Classification or PMA review.

Public Regulatory Hearing

  • 21 CFR 16 called by commissioner to obtain additional info prior to taking regulatory action.

Public Workshop

  • Held by FDA to share and gather information.
    • Notification via Federal Register (FR).

Board of Inquiry

  • Called by commissioner to review medical or scientific issues.
    • Not a legal trial, published in FR.

Evidentiary Hearing

  • Can be required by law, called by Congress or FDA commissioner to discuss a product’s public health concerns.

Regulatory Communications

  • Private 2-way Conversations:
    • Formal or ad-hoc, phone/email/in-person, discussions on missing submission information or disagreements.
  • Public FDA Meetings:
    • Notices posted in Federal Registrar.
  • FDA Regulations:
    • Published in Federal Register.
    • Comment Period: 30-60 days.
  • FDA Guidance Documents:
    • 90-day comment period.
  • Citizen Petitions:
    • Formal requests to FDA to take or refrain from taking administrative action.
    • FDA must respond within 180 days.

FDA Meeting Preparation Tips

  • Step 1: Know the Audience, the Issues, and the Environment
    • Research FDA personnel.
    • Be aware of recent FDA actions, workshops, public meetings, or publications.
  • Step 2: Set a Goal and Determine the Company’s Position
    • Determine meeting objectives and ensure team alignment.
  • Step 3: Anticipate Concerns and Interests
    • Draft likely FDA questions and responses.
    • Anticipate FDA opinions/recommendations and proactively provide resolutions.
  • Step 4: Provide Pertinent Meeting Materials in a Timely Manner
    • For Pre-Sub: All information should be provided with the original request.
    • Streamline to obtain essential feedback for development or submission.
    • Develop an agenda and provide it to FDA prior to the meeting.
  • Step 5: Assemble the Right Team
    • Choose knowledgeable team members who can clearly communicate data and the sponsor’s position.
    • Consider including key opinion leaders if necessary.
  • Step 6: Practice with the Meeting in Mind
    • Practice with the team and ensure everyone is aligned and technology works.
    • Practice likely questions and establish discussion boundaries.
  • Step 7: Manage the Meeting
    • Stay on topic to ensure all necessary topics are discussed.
    • Seek agreement on main issues and specific feedback or commitment if possible.
  • Step 8: Listen Carefully
    • Listen to who says what and how they say it.
    • Note when direct advice is not given, a topic is avoided, or FDA mutes the phone, indicating indecision or disagreement.
    • Immediately correct any FDA misinterpretations or misconceptions.
  • Step 9: Document Feedback
    • Strive for clear agreement on critical decisions and document in sponsor-driven meeting minutes.
    • Note ongoing issues and how often they are brought up.
  • Step 10: Foster a Flexible, Collaborative, and Non-Adversarial Relationship
    • Keep the lines of conversation open and keep your composure.
    • Try to resolve issues before they become obstacles to approval.
    • Be ready to adapt.

Regulatory Strategy Definition

  • Intent: Align business strategy with regulatory activities and quality compliance to bring a new or modified product to market in a desired timeframe.
  • Provide overall direction to the project team and define key milestones.
  • Proactively identify risks as well as alternative approaches and mitigations.

Market Considerations

  • What is the business objective?
  • What business problem will the product solve?
  • What are the competitor products?
  • Which regulatory pathway did the competitor product take, and what was the time to market?
  • Work with the cross-functional project team to determine if outside experts are needed to determine critical milestones and high-level deliverables.

Information Sources for Regulatory Strategy Development

  • Product Database Content Description

    • Combination Devices
      • Drug Establishments
        • Current Registration
          • Site Establishment locations of manufactures, repackers, and relabelers; lists products produced for commercial distribution
    • Drugs@FDA
      • Approval materials (including review) for original new drug applications (NDA) and biologics license applications (BLA) reviewed by CDER; limited info on supplements also
    • Clinicaltrials.gov
      • Registry and results database of clinical studies conducted globally, study design and clinical endpoints
    • Daily Med
      • Label information for prescription and OTC drugs including artwork and other drug listing-related info
    • Devices
      • FDA Device Registration and Listing
        • Locations of medical device establishments and the devices manufactured at the establishments
      • 510(k) Premarket Notification
        • 510(k) premarket notification submissions cleared by FDA
      • Premarket Approval (PMA)
        • Medical device approval materials and labels approved under the PMA pathway including supplements.
      • Manufacturer and User Facility Device Experience (MAUDE)
        • Medical device reports (MDRs) submitted to FDA
      • Total Product Life Cycle (TPLC)
        • Premarket and post market medical device data including information about classification codes, PM, 510(k) clearances, MAUDE adverse event reports, CDRH recalls, and data about device problems
    • All
      • FDA Inspection Classification
        • Final inspection classifications of many firms and project areas including those from CBER,CDER, CDRH

Key Considerations During Development and Lifecycle Management

  • Device Classification - Review 21 CFR Parts 862-892
  • What interactions with CDRH are planned?
  • Are Clinical studies required?
  • Does an IDE need to be filed?
  • What other studies/testing is required?
  • What is the best regulatory pathway and its requirements?
  • Does the device qualify for expedited review?
  • What are the specific quality compliance requirements for the deliverables?
  • Will a pre-approval inspection be required?
  • Know target populations and risks.
  • Device Classification Panels, if de novo classification process appropriate
  • Any prior communication required?

EU Regulatory Strategy

  • Align regulatory and quality compliance activities with business strategy.
  • Bring a new or modified product to market in desired regions within desired timeframes.
  • Provide overall direction to project team and define key milestones.
  • Proactively identify challenges and alternative approaches.

EU Specific Market Considerations

  • What national requirements will impact product development? (e.g., translation, costs)
  • Regulatory Application Fees and reimbursement strategy for each country/region.
  • Do any countries require another country's prior approval?
  • Does the potential revenue justify the costs of pursuing regulatory approval?

Developing and Implementing a Regulatory Strategy (EU)

  • Start with the end in mind; development program driven by product’s end use.
  • Project plan breaks down regulatory strategy into critical deliverables and identifies actions and key stakeholders.
  • Create a plan and examine potential pitfalls, mitigating risks, challenges, or issues.
    • Cross-functional project team to determine if outside experts are needed for critical milestones.
    • Gather and interpret regulatory intelligence data and challenge assumptions.
    • Assess the regulatory plan with all desired geographies in mind to avoid duplication.
    • Create a timeline and account for submission requirements, including timing and fees.
    • Gain stakeholder acceptance and ensure appropriate funding and support.
    • Identify any desired claims and required support.
  • Document everything and confirm the strategy with the cross-functional team.
  • Consider confirming the strategy with the Notified Body (NB).
  • Be prepared to modify the strategy as conditions and requirements change.
  • If you fail to plan, you can plan to fail.

Information Sources for EU Regulatory Strategy Development

  • European Commission provides guidance documents adopted by the Medical Device Coordination Group (MDCG) to assist in implementing EU MDR (2017/745).
  • Objective: Ensure uniform application of regulations within the EU.
  • Guidance documents are not legally binding and cover topics like:
    • Unique Device Identifiers (UDI)
    • Qualification and Classification of software
    • Cybersecurity
    • Summary of Safety and Clinical Performance

Key Considerations During Development and Lifecycle Management (EU)

  • Conformity Assessment
    • Required NB involvement and NB availability
  • Economic Operators have been identified and formal agreements set.
    • Have manufacturers, authorized reps, importers, and distributors been identified?
  • Quality Management System Requirements
  • Marketing Authorization Procedure
    • Are there additional requirements beyond the CE mark?
  • Promotion and Advertising
    • What are the country requirements, and what claims are being made?

International Counterfeit and Regulation

  • Falsified and counterfeit medicinal products pose a risk to public health and have been increasing.
  • WHO (2017): 10% of medical products are counterfeit.
  • Medicinal products account for 60-80% of counterfeit medical products.

Definitions

  • Falsified Medical Products: Deliberately or fraudulently misrepresent their identity, composition, or source.
  • Substandard Medical Products: Authorized medical products that fall outside of their quality standards and/or specifications.
  • Falsified Medicine: Medicinal Products with a false representation of its identity, source, or history.
  • Counterfeit Medicine: Any medicinal product that does not comply with intellectual property rights and/or infringes on trademark law.
  • Falsified Device: Any device with a false presentation of its identity and/or source and/or its CE marking certs or documents.

Regulations

  • US DSCSA
    • Aims to provide an electronic system solution to identify and trace selected prescription drugs for human use throughout the legitimate US pharmaceutical supply chain.
    • “Track and Trace” measures from manufacture through supply to patients
  • Falsified Medicines Directive (FMD)
    • Intended to tighten medicinal product distribution chain control and protect consumers from falsified, recalled, and expired medicines.
    • Falsified medicines regulation harmonization across the EU
  • WHO Global Surveillance and Monitoring System
    • To improve quantity, quality, and analysis of accurate data concerning SF medical products, and to use that data in the better prevention, detection, and response to those products, in order to protect public health.
    • Due to be implemented by 2027

Unique Device Identifier (UDI) Frameworks

  • US UDI System Rule
    • An electronic system solution intended for medical device distribution’s identification and traceability
    • Protect the public from unsafe devices including counterfeits, Ensure only safe and effective products reach patients by facilitating their identification, access to attribute information, providing a clear means to document their use in electronic health records clinical information systems, and registries.
  • EU UDI System
    • Improve public health by ensuring medical devices’ safe use by enabling unambiguous identification during distribution, use, vigilance reporting, during recalls, and other FSCAs.
    • Not specifically developed to combat counterfeiting Improve traceability and transparency and strengthen PMS
  • IMDRF Guidance
    • To set standards for countries to establish their own UDI frameworks to eventually reach global counterfeit product control.
    • Implementation set for 2027.

Stakeholder Requirements

  • FMD
    • Implementation of tamper-evident packaging
    • Unique identifier in a 2D barcode (product code, serial/lot #, expiry date, reimbursement #)
    • All unique packs must be decommissioned upon distribution.
    • Risk-based inclusion for requirements.
  • DSCSA
    • Phase I: Supply Chain participants must comply with product tracing requirements by providing transaction documentation upon ownership transfer.
    • Manufacturers and Repackagers must affix ‘product identifiers’ to each package and case.
    • Wholesale distributors and dispensers may take ownership if they have the required product identifiers.
    • Phase II: traceability requirements extend to the individual package level; transaction documentation and pharma pedigree info must be exchanged.
  • US UDI
    • Manufacturers print codes on labels, packages, and/or devices.
    • Code includes device identifier (DI) – mandatory (medical device version and model) and production identifier (PI) – optional and variable (lot/batch/serial number, expiry/manufacture dates, distinct codes).
    • Submit required information to the Global UDI Database (GUDID).
    • Healthcare community to adopt and implement UDI System.
  • EU UDI
    • "Basic UDI-DI” = DI (primary identifier of a single device or group of devices)
    • Must be on the label, contain UDI-PI (product identifier)
    • EUDAMED – Publicly available database containing medical device lifecycle information
    • EU MDR requires legal manufacturers to submit their devices UDI’s to EUDAMED

Challenges in Implementing Regulations

  • FMD
    • Costs could make medicines unaffordable and negatively impact trade and availability.
  • DSCSA
    • Complexity of supply chain and dispensers’ operability.
    • Confidentiality of patient or commercially sensitive information due to the exchange of transactional history
    • Distributors may not have required hardware or software.
  • US UDI
    • Substantial costs for FDA and Manufacturers; unclear requirements for convenient kits or some combination products.
  • EU UDI
    • Substantial costs for industry.

Third Countries Covered by FMD

  • Countries with equivalent public health protection:
    • Australia
    • Brazil
    • Canada
    • Israel
    • Japan
    • New Zealand
    • Singapore
    • South Korea
    • Switzerland
    • United States

International Regulations and Timelines

  • India
    • Medicines: Track and trace system and central data portal (April 2021); barcoding in place; serialized records maintained until 6 months after expiry.
    • Medical Devices: 2017 risk-based classification; UDI compliance required by Jan 2022.
  • Argentina
    • Medicines: GS1 traceability system; start with initial list.
    • Medical Devices: GS1 traceability system (2015 for first two groups); FDA-aligned UDI accepted.
  • Brazil
    • Medicines: 2015 and 2016 implementation for manufacturers and supply chain members.
    • Medical Devices: IMDRF UDI to be implemented for hip, knee, implants, and stents.
  • South Korea
    • Medicines: Barcode or RFID tag required for selected drugs (2012) and prescription drugs (2013).
    • Medical Devices: UDI framework compliance (2019 for Class IV - highest risk, 2020 Class III, 2021 Class II, 2022 Class I - lowest risk).
  • Turkey
    • Medicines: Unit level serialization and centralized government portal (2009).
    • Medical Devices: UDI-like repository (2007) for reimbursement; GMDN, GS1, GTIN, or HIBC accepted.
  • China
    • Medicines: Full serialization due by 2015.
    • Medical Devices: NMPA published UDI rules in 2019; Class III devices must comply by Jan 2021.