Public Hearing FDA Regulation of Combination Products

November 25, 2002

Risk Classification of Combination Products (Biologic/Device)

Zorina Pitkin, Ph.D.Vice President, Regulatory Affairs & Quality Systems

Nephros Therapeutics, Inc., Lincoln, RI

Nephros Therapeutics,

Inc.

Overview

1. Renal Assist Device (RAD) System – biologic/ device combination product

2. Critical issues in RAD development3. Risk-based classification of combination

products

Nephros Therapeutics,

Inc.

Renal Assist Device (RAD) Biologic/device combination

product

Human cells—no modifications

Renal cell isolation and expansion

Extracorporeal system based on hollow fiber membrane technology

Relatively short-term exposure

Conventional instrumentation and equipment (CVVH)

Nephros Therapeutics,

Inc.

RAD Regulatory Status

Regulated as Biologic by CBER with CDRH consults

Two physician-sponsored INDs Phase I/II Clinical Study – ongoing

Targeted population: Acute Renal Failure (ARF) – high predicted mortality 10 patients enrolled and treated

Nephros Therapeutics,

Inc.

Critical Issues in RAD development

Quality systems Product/system characterization and assurance of its safety Reproducible and consistent delivery of viable and functional

cells in a system to patients

Unique biologic/device issues Complex interactions between the material and cellular

processes

Regulatory issues Applicability of specific regulations to various components of the

RAD

Nephros Therapeutics,

Inc.

Regulatory issues in development of combination products

Combination products do not fit adequately into existing statutory definitions

Issues that are unique to combination products Which GMP regulations are applicable to the

manufacturing of combination products and inspection by the FDA? How will the assigned Center handle reported changes in manufacturing of combination products?

Lack of consistency in assigning to a Lead Center

Nephros Therapeutics,

Inc.

Recommendations for Regulation of Combination Products

Risk-Based ClassificationPurpose

Identify the component of the combination product that potentially presents the highest risk

Create one quality system which will encompass the most appropriate regulation that could be applicable to all components of a combination product

Establish a common approach to similar issues

Nephros Therapeutics,

Inc.

Risk Classification of Combination Products (Biologic/Device)

Main assumptionRisk of combination product increases with direct long- term exposure  

Factors contributing to risk assessment: Use: extracorporeal vs. implanted Type of contact: through barrier vs. direct

exposure Exposure Time: short-term vs. long-term

Nephros Therapeutics,

Inc.

Risk Classification of Combination Products

Limitations

Existing classification of devices (Classes I-III) was employed

Assessment of mode of action was not considered No distinction was made between novel and “off the

shelf” components No distinction was made between autologous and

allogeneic sources of cells/tissues No distinction was made between human and

xenogeneic sources of cells/tissues

Nephros Therapeutics,

Inc.

Proposed Risk Classification of Combination Products (Biologic/Device)

Biologics Risk Score (1 to 12) + Device Class (1 to 3)= Combination Product Risk Score (2 to 15)

Risk Classes of Combination Products:

Risk score from 2 to 5 – combination product risk class IRisk score from 6 to 10 - combination product risk class IIRisk score from 11 to 15 - combination product risk class

III

Nephros Therapeutics,

Inc.

Biologics Risk Scoring

Risk Factors Risk Score

Implanted - direct contactLong-term 12Mid-term 11

Short-term 10

Implanted with barrier Long-term 9Mid-term 8

Short-term 7

Extracorporeal, direct contact

Long-term 6Mid-term 5

Short-term 4Extracorporeal, contact through barrier

Long-term 3Mid-term 2

Short-term 1

Nephros Therapeutics,

Inc.

Classification Chart for Risk Assessment of Combination Products (CP)

1 2 3Long-term 12 13 14 15 IIIMid-term 11 12 13 14 IIIShort-term 10 11 12 13 IIILong-term 9 10 11 12 IIIMid-term 8 9 10 11 IIIShort-term 7 8 9 10 IILong-term 6 7 8 9 IIMid-term 5 6 7 8 IIShort-term 4 5 6 7 IILong-term 3 4 5 6 IIMid-term 2 3 4 5 IShort-term 1 2 3 4 I

CP Risk ClassDevice Class

Risk score

Implanted - direct contact

Risk Factors

Biologics

Implanted with barrier

Extra-corporeal,

direct contact Extra-

corporeal, contact

through barrier

Exposure Time

Type of Contact

Nephros Therapeutics,

Inc.

Summary

A risk assessment classification for combination products has been proposed based on risk factors associated with both biologics and device components.

The classification was developed under the assumption that the risk for a patient and for the public at large increases with long term direct exposure of a combination product.

Risk classification might eliminate the ambiguity of combination product regulation.

This classification system might be helpful in the decision-making process for the characterization, designation and regulation of combination products.