Pre-Submission

The Pre-Submission (Pre-Sub) program, also known as Q-Submission (Q-Sub), is a formal mechanism established by FDA's Center for Devices and Radiological Health (CDRH) that allows manufacturers to request feedback from FDA before submitting a marketing application such as 510(k), Premarket Approval (PMA), or De Novo request.

Purpose and benefits:
Pre-Submission allows manufacturers to:
- Clarify regulatory requirements and pathway selection
- Obtain FDA feedback on proposed testing protocols
- Discuss clinical study design and endpoints
- Resolve classification questions
- Address novel technology or unique device issues
- Reduce likelihood of application deficiencies
- Establish agreement on regulatory strategy
- Save time and resources by identifying issues early

Types of Pre-Submission interactions:

1. Pre-Submission (Pre-Sub)
The most common type, addressing:
- Testing protocols and methodologies
- Clinical study design, endpoints, and sample size
- Regulatory pathway selection (510(k) vs. PMA vs. De Novo)
- Predicate device selection and substantial equivalence strategy
- Device classification questions
- Biocompatibility and sterilization approaches
- Software validation and cybersecurity considerations
- Non-clinical and clinical data requirements

2. Informational Meeting (Info Meeting)
Used for:
- Early stage device development discussions
- General regulatory strategy conversations
- Understanding FDA's perspective on novel technologies
- Exploring potential pathways before significant investment
- Less formal than Pre-Sub, typically used when questions are broader

3. Study Risk Determination (SRD)
Specifically for determining whether a clinical study presents:
- Significant risk (requires IDE approval)
- Non-significant risk (may proceed with IRB approval only)
- Clarification on whether FDA will exercise enforcement discretion

Pre-Submission process steps:

1. Determine appropriate Pre-Sub type
Evaluate whether your questions are suited for Pre-Sub, Info Meeting, or SRD based on device development stage and question specificity.

2. Prepare Pre-Sub submission package
Include:
- Cover letter with meeting request and preferred dates
- Device description and intended use
- Regulatory history and classification information
- Specific questions for FDA (clearly numbered and prioritized)
- Background information and supporting data
- Proposed study protocols or testing plans (if applicable)
- References to relevant standards and guidance documents
- Draft labeling (if appropriate)

3. Submit to FDA
- Submit through electronic Submission Template and Resource (eSTAR)
- FDA acknowledges receipt within 5 days
- Assigned to appropriate review division and reviewers

4. FDA review and response
- FDA reviews submission materials
- May request additional information if needed
- Provides written feedback or schedules meeting

5. Pre-Sub meeting (if requested)
- Typically 60-75 days after submission
- FDA issues preliminary written response before meeting
- Meeting conducted via teleconference or in-person
- Manufacturer presents questions and proposals
- FDA provides verbal feedback and discussion
- Meeting typically 60-90 minutes

6. Official FDA response
- FDA issues official written response within 75 days of submission
- Summarizes FDA's recommendations and conclusions
- Addresses all submitted questions
- May include action items or requests for additional information

Pre-Submission content requirements:

Device description:
- Detailed technical specifications
- Intended use and indications for use
- Device design and operating principles
- Materials and manufacturing processes
- Comparison to predicate devices (if applicable)

Regulatory background:
- Product classification (if known)
- Predicate device identification (for 510(k))
- Previous FDA interactions or submissions
- Regulatory pathway considerations

Specific questions:
- Clear, focused, numbered questions
- Prioritized by importance
- Sufficient background for FDA to understand context
- Proposed approaches or options for FDA consideration

Supporting data:
- Non-clinical test results
- Preliminary clinical data
- Literature references
- Risk analysis
- Design validation data

Strategic considerations:

When to submit a Pre-Sub:
- Before initiating expensive clinical studies
- When regulatory pathway is uncertain
- For novel devices without clear predicates
- When proposing alternative test methods
- If previous submissions raised unresolved questions
- Early in development to establish regulatory strategy

When NOT to submit a Pre-Sub:
- For routine, well-established device types
- When standard testing approaches apply
- If questions can be answered through existing guidance
- Very early concepts without sufficient detail
- After substantial testing is already complete

Pre-Sub submission timing:
Optimal timing varies by situation:
- Early development - Informational meetings for pathway discussion
- Protocol development - Pre-Sub for clinical or testing protocol feedback
- Pre-market submission preparation - Pre-Sub 6-12 months before planned 510(k)/PMA submission
- Clinical trial planning - SRD before initiating studies

Meeting types:

Written feedback only:
- No face-to-face or teleconference meeting
- Faster turnaround (75 days)
- Appropriate for straightforward questions with clear proposed approaches

Teleconference:
- Most common meeting format
- Efficient use of time
- Suitable for most Pre-Sub discussions
- Screen sharing available for presentations

In-person meeting:
- Reserved for complex issues requiring detailed discussion
- Hands-on device demonstrations
- Multi-stakeholder discussions
- Must justify need for in-person format

FDA response timeline:
- Acknowledgement: 5 days after submission
- Preliminary written feedback (if meeting requested): Before scheduled meeting
- Meeting: Typically 60-75 days after submission
- Final written feedback: 75 days after submission (MDUFA performance goal)

Pre-Sub vs. other FDA interactions:

| Aspect | Pre-Submission | Q-Submission | Breakthrough Device Program |
|--------|----------------|--------------|----------------------------|
| Purpose | Pre-market feedback | Same as Pre-Sub | Expedited review for innovative devices |
| Eligibility | Any device | Any device | Breakthrough devices only |
| Timeline | 75 days | 75 days | 60 days for Pre-Sub |
| Frequency | As needed | As needed | More frequent interactions |

Fees:
As of 2024, Pre-Submission meetings for certain device types may be subject to user fees under the Medical Device User Fee Amendments (MDUFA). Fee requirements depend on:
- Type of device
- Submission type (initial vs. follow-up)
- Company size (small business exemptions may apply)

Pre-Sub feedback binding vs. non-binding:
- FDA feedback is generally non-binding unless explicitly stated otherwise
- Represents FDA's current thinking based on information provided
- Not a guarantee of marketing application approval
- FDA may change position if new information emerges
- Manufacturer should document reliance on FDA feedback in subsequent submissions

Documentation and follow-up:
- Maintain complete records of all Pre-Sub communications
- Reference Pre-Sub in subsequent marketing applications
- Explain how marketing application addresses FDA feedback
- If deviating from FDA recommendations, provide clear rationale
- Consider follow-up Pre-Sub if significant changes occur

Common Pre-Sub topics:

Testing and validation:
- Biocompatibility testing protocols
- Sterilization validation approaches
- Software verification and validation
- Electrical safety and EMC testing
- Shelf life and stability studies
- Performance testing methodologies

Clinical considerations:
- Clinical study design and endpoints
- Sample size and statistical analysis plans
- Patient selection criteria
- Comparator device selection
- Clinical data sufficiency
- Literature-based 510(k) strategies

Regulatory strategy:
- 510(k) vs. De Novo vs. PMA pathway
- Predicate device appropriateness
- Device classification questions
- Special controls compliance
- Combination product jurisdiction
- Breakthrough Device Designation eligibility

The Pre-Submission program is a valuable tool for reducing regulatory uncertainty, aligning manufacturer plans with FDA expectations, and ultimately increasing the likelihood of successful marketing authorization. Strategic use of Pre-Sub can save significant time and resources in the device development process.