Fundamentals of Medical Device Regulations: US Submissions
User Fees
Goal: Augment FDA resources, improve approval process efficiency and timelines, hold FDA accountable, increase interaction, enhance transparency.
Origin: Frustration from consumers, industry, and FDA in the late 1980s.
FDA reported an average of 29 months from submission to decision.
Each month delay cost manufacturer estimated .
Congress authorized User Fees to supplement federal funds.
Most submissions require User Fee payment before processing.
Resources involve hiring staff, generating guidance, public outreach, and training programs.
User Fee Acts
Prescription Drug User Fee Act (PDUFA)
Enacted in 1992.
Agreement on:
Target completion times/performance goals.
User fees supplement, not replace, congressional funding.
Reauthorized every 5 years with new goals.
Medical Device User Fee Act (MDUFA)
Enacted in 2002.
Goal: Ensure adequate submission reviews for timely market access.
Generic Drug User Fee Amendments (GDUFA)
Designed to speed access to generic drugs and reduce industry costs.
Aimed to endorse consistency and increase inspection frequency.
Biosimilar User Fee Act (BsUFA)
Created an abbreviated licensure pathway for biosimilar products.
Animal Drug User Fee Act (ADUFA)
Authorized FDA to collect fees to modernize animal drug review.
Animal Generic Drug User Fee Act (AGDUFA)
Provided quicker access to animal drugs at lower cost.
Other Fees
Color Additive Certification Fee
For color additives used in FDA-regulated products requiring batch certification.
Export Certificate Fee
For US companies exporting FDA-regulated products and needing certification.
Family Smoking Prevention and Tobacco Control Act Fee
Granted authority to regulate tobacco products.
Food Safety Modernization Act Fee
Goal of preventing food safety problems before they occur.
Freedom of Information Act Fee
For disclosure of previously unreleased information.
Human Drug Compounding Outsourcing Facility Fees
For drugs compounded in outsourcing facilities not exempt from GMP.
Mammography Quality Standards Act Fee
To regulate mammography facilities quality and ensure compliance.
User Fee Requirements
Definition: Fees paid to FDA for services related to medical product regulation.
Authorized under PDUFA, MDUFA, BsUFA, and ADUFA.
Intent: To help FDA protect public health and advance medical innovations by supplementing funds.
How to pay: Create a cover sheet with necessary information. Pay online (credit card/electronic check) or via mail.
Medical Device Classification
Definition: Instrument, apparatus, implement, machine, implant, in vitro reagent, or similar article.
Recognized in the official National Formulary, US Pharmacopeia, or any supplement.
Intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease.
Intended to affect the structure or function of the body without achieving its primary intended purposes through chemical action or being metabolized.
Classification
Class I: General controls (low risk).
Safety and effectiveness well established.
Exemptions to specific general controls exist (e.g., not subject to premarket notification (510(k))).
Class II: General & special controls (intermediate risk).
General controls (premarket notification (510(k) clearance).
Special controls.
Class III: General controls, relevant special controls, and premarket approval (PMA) (high risk).
Life-sustaining, life-supporting, or implantables.
Devices with new intended use or new unique technology not substantially equivalent to a predicate are automatically Class III.
Subject to expert panel review (review is non-binding).
US Food, Drug, and Cosmetic Act (Section 201(h)) created the definition of medical devices.
FD&C Act established the risk-based medical device classification system.
Examples:
In vitro diagnostics (reagents and instruments) – COVID test.
Combination products (drug, biologic, medical device) – drug eluting stent.
Companion Diagnostic (in vitro or imagine tool) – genetic test, x-ray machine.
Software (programs and apps) – glucose monitoring app linked to continuous glucose monitor.
Accessories (used with parent device or has a unique standalone function) – cryoablation temperature sensor.
Requirements
General Controls
Adulteration and misbranding.
Registration and listing.
Notification (recalls).
Records/reports (adverse events, tracking, removals, corrections).
Special Controls
Performance standards, special labeling, guidelines, postmarket surveillance.
Premarket Approval
Valid scientific evidence (IDE-clinical investigation) showing the device is reasonably safe and effective.
*Device Examples
*Class I
*Bandages, hospital beds, laboratory equipment, surgical instruments, arm sling
*Class II
*PTCA catheters, cardiac devices, blood pressure cuffs, ELISAs, hemodialysis
*Class III
*Heart valves, breast implants, IOLs implants, orthopedic implants, tubal occlusion devices
Submission Types (CDRH)
Request for Information (Q-Submission Program)
For all submission types.
Ask FDA broad range of questions (submission risks due to novel technology, feedback on clinical trials prior to commencing, where guidance's aren’t clear).
Investigational Device Exemption (IDE)
Allows devices not cleared or approved to be distributed for conducting clinical research.
Study must be approved by Institutional review board (IRB) or ethics committee.
Studies with “significant risk” require FDA approval (Based on study risk, not device class).
Non-Significant Risk (NSR) or exempt devices do not require FDA approval (IRB approval still required).
510(k) Premarket Notification
Premarket notification demonstrating device is safe and effective (S&E), substantially equivalent to a legally marketed Class II device.
Substantial equivalence is not a determination of S&E (like in a PMA) but is a determination the device is at least as S&E as the predicate device (Clearance, not approval).
Traditional 510(k)
Original or for modification to any previously cleared device.
Includes performance data (bench, clinical trials, clinical studies, DV, human factors, etc).
Special 510(k)
Modifications to own device (not claiming substantial equivalence to competitor).
Results can be reviewed in a summary or risk analysis format (performance data not necessary to be submitted – testing must still occur).
Abbreviated 510(k)
Summary reports (no test data) based on guidance docs and conformity to recognized standards.
Premarket Approval Application (PMA)
FDA's application process for scientific and regulatory review of Class III medical device safety and effectiveness.
Several ways to gain Class III device marking approval.
Traditional PMA
requires all testing and results (Clinical info required).
Modular PMA
Same as traditional but broken up when submitted (framework typically agreed upon in a Pre-sub).
Humanitarian Device Exemption (HDE)
For rare diseases or conditions affecting <8,000 people.
Similar in form and content to a PMA but is exempt from PMA effectiveness requirements.
No clinical investigation is required.
Application contains info to show no unreasonable or significant risk.
De Novo
Process created for classifying certain low- to –moderate risk devices for which there are no predicates.
Previously lower class devices had to go through the 510(k) process and receive a not substantially equivalent (NSE) determination before applying for risk-based determination.
Today, devices can go straight to the De Novo pathway without receiving a 510(k) NSE determination.
Devices classified under De Novo petitions may serve as predicates for future devices.
Supplements
180 days – significant changes to safety and effectiveness.
Special – change enhances or increase device safety.
30 day – modifications to manufacturing that impact safety and effectiveness. Can be converted to 135 day if 30 day found to be inadequate.
Manufacturing Site change – different facility to manufacture, process or package device. 180 day required if manufacturing site of a finished device is moving.
Annual Report – all other changes not captured in a supplement (think letter- to-file but for Class III).
FDA Communication During Submission Review
Pre-submission meeting Types
Informal Meeting:
Ask FDA for advice on gathering pre- clinical data or for investigational plan.
Formal Meetings:
Determination Meeting: Discuss types of valid scientific evidence necessary.
Agreement Meetings: Reach agreement regarding investigational plan (clinical protocol).
Refuse to Accept Policy for 510(k)s
Guidance doc (checklist) that lays out criteria FDA uses in assessing whether a 510(k) meets minimum acceptability threshold and will be accepted for a review.
FDA has 15 days to complete its review and notify if the file is administratively complete.
If not complete, FDA will reject, and process starts over. 15-day clock starts over as well.
FDA substantive review clock begins on receipt of acceptance or on receipt of most recent information (their clock stops when we are answering questions).
Acceptance Reviews for PMAs
15 days to complete acceptance review (application completeness).
45 days to complete filing review (basic adequacy of PMA technical elements).
FDA substantive review clock begins on receipt of acceptance or on receipt of most recent information (their clock stops when we are answering questions).