What is HRIPT (Human Repeat Insult Patch Test)?
The Human Repeat Insult Patch Test (HRIPT) is the gold standard clinical method used to evaluate whether a product causes delayed irritation or sensitization after repeated exposure. Unlike a single application test, HRIPT is specifically designed to mimic real-life use scenarios, where patients are exposed to a wound dressing, patch, or aesthetic device multiple times over weeks or months.
Study Design & Phases
An HRIPT (Human Repeat Insult Patch Test) typically follows a three-phase design:
Induction Phase
(Repeated Application)
The investigational product (e.g., wound dressing, patch, topical device) is applied under occlusion to the same site on the back or arm of healthy volunteers.
Applications are repeated several times per week for 3–4 weeks.
The goal is to "prime" the immune system if the product has sensitization potential.
Rest Phase
(Recovery Period)
A break period of 10–14 days allows any short-term irritation to subside.
If the immune system has been sensitized during induction, it will remain "primed" to react when re-exposed.
Challenge Phase
(Re-exposure)
The product is reapplied to a new site (often on the opposite arm or a different patch location).
After the 72 hours grading/assessment, investigators assess whether an allergic-type response occurs upon re-exposure, which would indicate sensitization.
Scoring System: Berger/Bowman Scale
Skin reactions are graded using the Berger/Bowman scale (0–4):
| Score | Definition |
|---|---|
| 0 | No visible reaction |
| 1 | Barely perceptible erythema (mild redness) |
| 2 | Moderate erythema, possible edema |
| 3 | Strong erythema with papules/vesicles |
| 4 | Severe reaction with spreading dermatitis |
This objective system ensures consistency across investigators and helps differentiate normal irritation from clinically relevant sensitization.
| Grade | Score | Definition |
|---|---|---|
| 0 | 0 | No evidence of irritation |
| 1 | 1 | Minimal erythema; barely perceptible |
| 2 | 2 | Definite erythema, readily visible; OR minimal edema; OR minimal papular response |
| 3 | 3 | Erythema and papules |
| 4 | 3 | Definite edema |
| 5 | 3 | Erythema, edema, and papules |
| 6 | 3 | Vesicular eruption |
| 7 | 3 | Strong reaction spreading beyond test site |
Why HRIPT Matters for FDA and Notified Body
Delayed Risk Assessment
Identifies whether repeated use could trigger chronic irritation, scarring, or granuloma formation.
Skin Type Sensitivity
FDA emphasizes that erythema detection varies by Fitzpatrick skin type—redness is easy to spot in lighter skin (I–III), but may be masked in darker tones (IV–VI).
Real-Life Simulation
Human studies are generally requested because animal models may not be fully predictive of the immune, inflammatory, and/or irritation responses in humans.
Regulatory Expectation
FDA often requires HRIPT for wound dressings, adhesives, and skin-contact devices, particularly in the aesthetic and dermatology sectors.
Typical Study Parameters
- Subjects: ~50 healthy adults
- Duration: ~6–8 weeks total
- Endpoints: Incidence and severity of irritation or sensitization, stratified by Fitzpatrick skin type
- Output: Confirmation that the product does not cause clinically significant delayed skin reactions
What is SPT (Skin Prick Test)?
The Skin Prick Test (SPT) is a worldwide recognized clinical method to evaluate whether a product causes immediate hypersensitivity (Type I allergy).
SPT is generally used in allergy and immunology, and regulators such as the FDA require it for wound dressing devices to ensure that products do not trigger fast, immune-mediated reactions in sensitive individuals.
Study Design & Methodology
An SPT follows a simple but highly controlled procedure:
Skin Preparation
- The volar surface of the forearm or the upper back is cleaned.
- Small drops of test solutions (the investigational product or its extracts) are placed on the skin.
Prick Application
- A sterile lancet is used to lightly prick the skin through each drop without drawing blood.
- This introduces trace amounts of the test substance into the epidermis.
Observation Period
- The site is observed after 15–20 minutes.
- Immediate skin reactions (redness, wheals, flare-ups) indicate IgE-mediated hypersensitivity.
Controls
- A positive control (histamine) ensures the skin reacts as expected.
- A negative control (saline) ensures there is no false background response.
Scoring System
SPT results are typically scored based on wheal (swelling) and flare (redness) diameter, compared to the histamine positive control:
| Score | Definition |
|---|---|
| 0 | No reaction |
| +/- | Erythema < 3 mm, no wheal |
| 1+ | Wheal 3–5 mm |
| 2+ | Wheal 5–7 mm |
| 3+ | Wheal 7–9 mm |
| 4+ | Wheal ≥ 9 mm or with pseudopodia (irregular borders) |
This standardized scoring system ensures quantifiable, reproducible data on immediate allergic responses.
Why SPT Matters for FDA
Immediate Risk Detection
Identifies rapid IgE-mediated allergic reactions, which can cause hives, swelling, or in rare cases, anaphylaxis.
Complement to HRIPT
While HRIPT assesses delayed-type hypersensitivity (Type IV), SPT specifically detects immediate-type hypersensitivity (Type I). Both are needed for a full immunological safety profile.
Patient Safety
Early detection of immediate allergy risk prevents serious adverse events in real-world use.
Regulatory Requirement
FDA recommends SPT alongside HRIPT for aesthetic devices, dressings, adhesives, and other long-term skin-contact products.
Typical Study Parameters
- Subjects: ~20 healthy adults
- Duration: ~1–2 weeks (including screening and reporting)
- Endpoints: Incidence and severity of immediate wheal/flare reactions, relative to controls
- Output: Confirmation that the product does not cause clinically relevant immediate allergic responses
HRIPT + SPT Execution Timeline (Gantt Chart)
Here's a typical 6–7 month execution timeline for an FDA-aligned HRIPT and SPT program:
Typical 6–7 Month Execution Timeline
1
Protocol & Regulatory Preparation
Protocol finalization, ethics submission, site selection, recruitment strategy planning
2
Site Initiation & Recruitment Launch
Site training, MILO EDC setup, targeted recruitment campaigns (Fitzpatrick I–III focus)
3–4
HRIPT Induction Phase
3–4 weeks repeated application, photographic documentation, Berger/Bowman scoring in MILO
4
HRIPT Rest Phase + SPT Execution
10–14 days rest period, parallel SPT study (skin prick, 15–20 min observation, wheal/flare scoring)
5
HRIPT Challenge Phase
Re-exposure, 72-hour assessment, final photographic documentation, data lock
6–7
Data Analysis & Final Report
Biostatistics analysis, Fitzpatrick stratification, FDA/EU MDR-compliant final report delivery
Schedule Your Free 15-Minute Consultation
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Skin Type Diversity Required by FDA and Notified Body
When evaluating the safety of aesthetic devices, skin type diversity is important to know that the appearance and detectability of irritation or allergy differ significantly across skin tones and can impact study outcomes.
The Fitzpatrick Skin Type Classification
The Fitzpatrick scale is the international standard used to classify skin types based on pigmentation and response to UV:
| Type | Description |
|---|---|
| Type I | Very fair skin, always burns, never tans |
| Type II | Fair skin, usually burns, tans minimally |
| Type III | Light to olive skin, sometimes burns, tans gradually |
| Type IV | Moderate brown skin, rarely burns, tans easily |
| Type V | Dark brown skin, very rarely burns, tans profusely |
| Type VI | Deeply pigmented dark brown to black skin, never burns |
This classification is directly relevant to HRIPT and SPT studies because erythema (redness)—the earliest visible sign of irritation or allergy—is easier to detect in lighter skin (I–III) and often masked in darker skin (IV–VI).
FDA's Concern
The FDA requires that studies conducted in regions with predominantly darker skin types (IV–VI) may miss early signs of erythema that could correspond to a Berger/Bowman score of 1 or 2. These early reactions, although mild, are clinically relevant because they may:
- Signal an influx of inflammatory cells
- Lead to delayed wound healing
- Increase risk of scarring or granuloma formation
- Conceal early infection signals beneath the device
Thus, FDA recommends at least 10% of participants represent Fitzpatrick skin types I–III to ensure sensitivity in detecting early-stage reactions.
Practical Implications for Clinical Trials
Recruitment Planning
Studies must deliberately recruit lighter skin types (I–III), especially in countries where the population skews toward IV–VI. Recruitment campaigns may need to target specific geographic regions or populations to ensure representation.
Investigator Training
Clinicians must be trained to recognize erythema across different skin types, including subtler signs such as texture changes, edema, or heat in darker tones.
Photographic Documentation
Standardized digital imaging is critical, since erythema may be under-detected visually in darker skin. EDC platforms like MILO allow investigators to capture and centralize high-resolution photos for expert review.
Regulatory Justification
Medical device manufacturers should document Fitzpatrick classification of each subject in their protocol and final report. If lighter skin types (I–III) are underrepresented, additional testing may be required.
Why This Matters for Aesthetic Devices
Unlike systemic drugs, aesthetic devices and dressings are applied directly to the skin, making dermatological safety across diverse populations a priority. Because these products are used in global markets, regulators expect assurance that all skin types are adequately protected.
In short: inclusivity in skin type representation is not just good practice—it's a regulatory expectation.