# Presentation: 839429

## Examples of Immunohistochemistry Issues

**Nina M. Chace, M.S.**
**Division of**** ****Immunology and Hematology Devices**
**Office of In Vitro Diagnostic**
**   ****Device (IVD) Evaluation and ****	****Safety (OIVD)**
**Center for Devices and**
**   ****Radiological Health (CDRH)**

## Brief History of Immunohistochemistry (IHC) Regulation

**1989 – NIH Workshop on IHC Standardization**
**1991 – Biological Stain Commission (BSC) Established IHC Steering Committee**
**1992 – BSC and FDA Publish Proposed Format  for Package Inserts of IHC Products**

## IHC History (Continued)

**1996 – Proposed IHC and ASR Regulations Published**
**1998 – Draft Compliance Policy Guidance Issued: “Commercialization of IVD’s for Research or Investigational Use Only**
**1998 – Final IHC and ASR Regulations and IHC Guidance Document Published**

## Immunohistochemistry Results are Subjective and Variable Because of:

**Specimen**
**Handling**
**Fixation**
**Stability**
**Sample Processing**
**Washing**
**Drying**
**Temperature**

## Immunohistochemistry Results are Subjective and Variable Because of:

**Embedding**
**Heating**
**Sectioning**
**Antigen Enhancement Procedures**
**Contamination**
**Counterstaining**

## Immunohistochemistry Results are Subjective and Variable Because of:

**Different Antibodies**
**Trapping**
**Stability**
**Freezing and Thawing**
**Inherent Irregularities in the Specimen**

## IHC History (Continued)

**1993 – First issue of Compliance Policy Guideline for “Commercialization of Unapproved IVD Services Labeled for Research and Investigation**
**1994 – FDA Panel meeting to recommend classification of IHC devices**
**1995 – Draft IHC Guidance Issued**
**1996 – FDA Panel Meeting to recommend regulation of Analyte Specific Reagents (ASRs)**

## Definition of Analyte Specific Reagents –[21 CFR 864.4020(a)]

- “**Antibodies, specific receptor proteins, nucleic acid sequences, and similar biological reagents which through chemical binding or reaction with substances in specimen are intended for identification and quantification of an individual chemical substance or ligand in biological specimens”**

## Characteristics of ASRs

**Class I Analyte Specific Reagents (including IHC antibodies) are exempt from 510(k) submission**
**Does not apply to kits**
**Few labeling claims**
**No clinical claims**

## Characteristics of ASRs (2)

**Laboratories are responsible for establishing test performance**
**Non-exempt ASRs**
**Class II: blood banking tests (CMV)**
**Class III: blood banking (hepatitis); contagious diseases, e.g., TB  or HIV; **

## Innovative Aspects of the IHC Regulation

**Modeled after  Radioallergosorbent (RAST) Immunological Test System Regulation **
**Many analytes under one regulation**
**Presented a system for “de novo” classification of IHC antibodies**
**Present**
**Future**

## Class I IHC

**Class I is exempt from 510(k) submission**
**Adjunctive diagnostic information not independently reported by physician**
**Used after tumor diagnosed by  other methods**
**E.g. cytokeratin differentiation markers**

## Class II IHC

**Requires 510(K) Submission**
**Stand alone diagnostic**
**Predictive or prognostic**
**Widely accepted valid scientific claims**
**E.g. hormone receptors in breast cancer**

## Class III IHC

**Requires Premarket Approval Application (PMA)**
**Too little information available to be considered a widely accepted diagnostic**
**Used to choose therapeutic, e.g., Her2/neu, EGFR**

## Highlights of IHC Guidance Document

**Indications for Use**
**Characterization of Antigen/Antibody**
**Characterization of 30 Normal Tissues**
**Reactivity with Clinical Samples**
**Summary of Expiration Studies**
_**Quality Control Release Criteria**_
**Model Package Insert and Checklist**

## Creative Classification of IHC Image Analyzers

**Least Burdensome Approach**
**Accessories to IHC Devices**

## Characteristics of Class II Image Analyzers

**Reagents determine the clinical claims,  not the image analyzers**
**Aid to the pathologist**
**Pathologist enters final result on report form.**

## The Labeling Must State:

**The image analysis system is an adjunctive computer-assisted methodology to assist the reproducibility of a qualified pathologist in the acquisition and measurement of images from microscope slides of .....**

## The Labeling Must State: (continued)

**The accuracy of the test result depends upon the quality of the IHC staining.  It is the responsibility  of a qualified pathologist to employ appropriate morphological controls as specified in instructions for the IHC reagents to assure the validity of the image analyzer score.**

## Performance Must Be Comparable to Manual Determinations:

**Reproducibility**
**Accuracy**

## Submission to FDA

**Software Validation**
**Hazard Analysis**
**http://www.fda.gov/cdrh/ode/57.html**

## Points to Consider for Device-Drug Combos – Lessons from Her2/neufor Breast Cancer

**Use a marketable test for patient selection in the drug clinical trial**
**Save the specimens for validation of future tests**
**Informed consent should consider all future possibilities for use of specimens**

## Lessons Learned from Epidermal Growth Factor Receptor (EGFR) in Colon Cancer

**No relationship between receptor density and patient outcome**
**Need to study drug outcome for test negative as well as test positive patients**

## General Points to Consider for Device-Drug Combos –

**Try to optimize the test before beginning the study**
**Assay cutoff may not be optimized until drug study is analyzed**
**Best way to verify assay and cutoff after the drug study has been completed?**

## General Points to Consider for Device-Drug Combos (2)

**If IHC test makes decisions about the use of a new drug**
**An Investigational Device Exemption (IDE) submission may be required**

## CONTACTS -Division of Immunology and Hematology Devices

**	****	****301-594-1293**
**Maria Chan, Ph. D.**
**	****	****MMC@CDRH.FDA.GOV**
**Nina M. Chace, M. S.**
**	****	****NMC@CDRH.FDA.GOV **

## Office of Combination Products

**Contact early for cross-center coordination of reviews**
**http://www.fda.gov/oc/combination/**