Indications for Use

Indications for Use is a regulatory term used by the US Food and Drug Administration (FDA) to describe the specific disease, condition, or patient population for which a medical device is intended. While closely related to "intended use," indications for use is a more precise, FDA-specific statement required in premarket submissions (510(k), De Novo, PMA) that focuses on the clinical indication and target patient group. The indications for use statement is critical for determining substantial equivalence in 510(k) submissions and establishing the regulatory bounds for device marketing.

Regulatory requirements:

FDA 21 CFR 807.87(e) - 510(k) submissions:
The 510(k) submission must include:
"A statement of the intended use of the device, which must include:
- A general description of the disease or condition the device will diagnose, treat, prevent, cure, or mitigate, including a description of the patient population for which the device is intended."

FDA 21 CFR 814.20(b)(3)(i) - PMA submissions:
PMA applications must include:
"A description of the device including... the indications, intended use, and directions for use."

Indications for Use vs. Intended Use:

While often used interchangeably, there are subtle differences in FDA terminology:

Intended Use:
- Broader term encompassing overall purpose and application
- Includes how device is used, by whom, in what setting
- May include mechanism of action
- Example: "The XYZ Surgical System is intended for use by trained surgeons in hospital operating rooms for cutting soft tissue during general surgical procedures."

Indications for Use:
- More specific, clinically focused statement
- Emphasizes disease/condition and patient population
- Required format for FDA submissions
- Example: "The XYZ System is indicated for soft tissue cutting in patients undergoing abdominal, thoracic, or orthopedic surgical procedures."

In practice, FDA often uses these terms together, and the "Indications for Use" statement typically encompasses the clinically relevant aspects of the broader "intended use."

Components of effective Indications for Use statement:

1. Disease or condition:
- Specific medical indication (e.g., "Type 2 diabetes," "osteoarthritis of the knee")
- May include stage or severity if relevant (e.g., "moderate to severe")
- Should align with recognized medical terminology and classifications
- Example: "...for the treatment of symptomatic degenerative disc disease..."

2. Patient population:
- Age range (pediatric, adult, geriatric)
- Gender (if device is gender-specific)
- Other relevant characteristics (e.g., "who have failed conservative treatment")
- Exclusions if applicable
- Example: "...in skeletally mature adult patients..."

3. Treatment goal or diagnostic purpose:
- What the device aims to accomplish
- May include expected clinical outcome
- Example: "...for the relief of symptoms associated with..." or "...for the diagnosis of..."

4. Anatomical location (if relevant):
- Body part, organ, or tissue involved
- May specify laterality or level (e.g., "lumbar spine L1-S1")
- Example: "...at one or two contiguous levels from L2 to S1..."

5. Treatment line or clinical context:
- When in treatment algorithm device is used
- Conditions for use (e.g., "adjunctive therapy," "first-line treatment")
- Example: "...who are candidates for fusion and have failed at least 6 months of non-operative treatment..."

6. Use setting or user (sometimes included):
- Professional use vs. OTC (over-the-counter)
- Healthcare setting vs. home use
- Example: "...for use by healthcare professionals..." or "...for self-testing at home..."

FDA Indications for Use form:

Form FDA 3881 - Indications for Use Statement:
For 510(k) submissions, FDA provides a standard form (FDA Form 3881) that must be completed:

Required information:
- 510(k) Number (assigned by FDA upon submission)
- Device Name (Trade/Proprietary and Common/Usual)
- Indications for Use statement
- Prescription (Rx) or Over-the-Counter (OTC) designation
- Signature and date

Format guidelines:
- Use clear, concise medical terminology
- Avoid promotional language or claims not supported by data
- Be specific enough to differentiate from other devices but not unnecessarily narrow
- Ensure consistency with labeling and other submission sections

Example completed statement:
"The ABC Coronary Stent System is indicated for improving coronary luminal diameter in patients with symptomatic ischemic heart disease due to discrete de novo or restenotic lesions in native coronary arteries with reference vessel diameters of 2.5 mm to 4.0 mm."

Role in 510(k) substantial equivalence:

The indications for use are central to determining substantial equivalence (SE) in 510(k) submissions:

Comparing indications:
- Subject device indications compared to predicate device indications
- Indications must be same or similar for SE
- Different indications can prevent SE determination
- Narrower indications than predicate generally acceptable
- Broader indications than predicate may require clinical data

Impact on SE determination:
- Identical indications support SE (assuming technological characteristics are comparable)
- Similar indications may support SE with appropriate justification
- New or different indications may require De Novo or PMA pathway
- Significantly expanded patient population may require clinical studies

Example scenarios:

Scenario 1 - Identical indications: ✓ Likely SE
Subject: "For measurement of blood glucose in diabetic patients"
Predicate: "For measurement of blood glucose in diabetic patients"

Scenario 2 - Narrower indications: ✓ Likely SE
Subject: "For use in adult patients with Type 2 diabetes"
Predicate: "For use in patients with diabetes"
(Narrower population is generally acceptable)

Scenario 3 - Broader indications: ⚠ May require clinical data
Subject: "For use in patients with Type 1 and Type 2 diabetes"
Predicate: "For use in patients with Type 2 diabetes"
(Expansion requires justification, possibly clinical data)

Scenario 4 - Different indication: ✗ Likely not SE
Subject: "For diagnosis of COVID-19"
Predicate: "For diagnosis of influenza"
(Different disease/condition - SE not appropriate)

Changes to Indications for Use:

When changes trigger new regulatory submission:

Significant changes requiring new 510(k) or PMA supplement:
- Expansion to new disease or condition
- Addition of new patient population (e.g., pediatric extension)
- Change in anatomical site (e.g., from peripheral to coronary use)
- Expansion of treatment line (e.g., from adjunctive to primary therapy)

Example:
Original: "For lumbar spinal fusion in adults with degenerative disc disease"
Changed: "For cervical and lumbar spinal fusion in adults with degenerative disc disease"
→ Requires new 510(k) for cervical indication

Minor changes that may not require new submission:
- Clarifications that don't expand scope
- Corrections of typographical errors
- Translations into other languages
- Format changes without content change

Label changes:
- Device labeling must reflect cleared/approved indications
- Marketing materials must not promote uses beyond cleared indications
- Off-label use discussion by physicians is legal, but manufacturer promotion is not

Indications for Use and clinical evidence:

Evidence requirements:

For initial clearance/approval:
- Clinical data must support all aspects of indications statement
- Patient populations studied must align with indications
- Study endpoints must demonstrate claimed benefit
- Duration of follow-up must be appropriate for claimed use

For indication expansion:
- New clinical studies often required
- May leverage existing data if sufficiently similar
- Post-market data (real-world evidence) may support expansion
- Literature may supplement if robust and applicable

FDA review considerations:
- Does proposed indication match study population?
- Are clinical outcomes clinically meaningful for the indication?
- Is safety profile acceptable for patient population?
- Are there adequate instructions for use for the indicated population?

Common FDA feedback on indications:

"Indications too broad":
- FDA may request narrowing to match demonstrated evidence
- May ask for specific patient characteristics or limitations
- Example: FDA requests "adult patients" instead of "patients" if no pediatric data

"Indications too vague":
- FDA may request more specific disease/condition description
- May ask for clearer patient population definition
- Example: "For improvement of symptoms" may need specification of which symptoms

"Inconsistent with predicate":
- For 510(k), FDA may note indications differ from predicate cited
- May request different predicate or additional data
- May suggest De Novo pathway if no appropriate predicate

Prescription vs. Over-The-Counter (OTC) designation:

The Indications for Use statement must specify whether device is:

Prescription Use (Rx):
- Requires licensed healthcare provider prescription or order
- More complex indications, higher risk, or professional interpretation needed
- Majority of medical devices
- Labeled with "Rx Only" or "Caution: Federal law restricts this device to sale by or on the order of a physician"

Over-The-Counter (OTC):
- Available for consumer purchase without prescription
- Generally lower risk with clear consumer indications
- Must have adequate labeling for lay users
- Examples: certain glucose monitors, pregnancy tests, thermometers

FDA determination based on:
- Risk level
- Complexity of use
- Need for professional supervision or interpretation
- Labeling adequacy for lay users

Indications for Use in PMA vs. 510(k):

510(k) Clearance:
- Indications must be same/similar to predicate
- Substantial equivalence determines acceptable indications
- Can be narrower than predicate without issue
- Broader indications than predicate may prevent SE

PMA Approval:
- No predicate comparison required
- Indications determined by clinical study design and outcomes
- FDA reviews clinical data to determine appropriate indications
- May approve narrower indications than manufacturer requested if data insufficient

De Novo Classification:
- For novel devices without predicate
- Indications based on clinical/performance data provided
- Establishes new predicate for future 510(k)s with same indications

International considerations:

Different terminology:
- EU: "Intended Purpose" is used instead of "Indications for Use"
- Other jurisdictions: "Intended Use" more common globally
- US "Indications for Use" is uniquely FDA-specific terminology

Harmonization challenges:
- US indications format may differ from EU intended purpose descriptions
- Same device may have different indication wording in different jurisdictions
- Must maintain consistency in clinical claims across regions while adapting to local regulatory format

Best practices for drafting Indications for Use:

1. Start with clinical evidence:
- Base indications on populations and outcomes actually studied
- Don't claim beyond what data supports
- Align with study inclusion/exclusion criteria

2. Use clear, specific medical terminology:
- Reference standard disease classifications (ICD codes)
- Use anatomically precise descriptions
- Define patient population characteristics objectively

3. Review predicate devices (for 510(k)):
- Study indications of intended predicate
- Ensure alignment or appropriate narrowing
- Justify any differences

4. Ensure consistency:
- Match indications across all submission sections
- Align labeling, instructions for use, promotional materials
- Coordinate with clinical summary and risk analysis

5. Consider future expansion:
- Initial indications can be strategic (narrower for faster clearance)
- Plan for potential later expansions with additional data
- Balance market opportunity with regulatory feasibility

6. Seek FDA feedback:
- Use Pre-Submission (Q-Sub) to discuss proposed indications
- Clarify FDA expectations before finalizing submission
- Address any FDA concerns early

Indications for Use is a critical regulatory element that defines the clinical scope of a medical device, determines the applicable regulatory pathway, shapes clinical evidence requirements, and establishes the boundaries for device marketing. A well-crafted indications statement, supported by robust clinical data and aligned with FDA expectations, is essential for successful device clearance or approval.