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 development 3. 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 Classification Purpose 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 assumption Risk 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 I Risk score from 6 to 10 - combination product risk class II Risk score from 11 to 15 - combination product risk class III

Nephros Therapeutics, Inc. Biologics Risk Scoring Risk FactorsRisk Score Implanted - direct contact Long-term12 Mid-term11 Short-term10 Implanted with barrier Long-term9 Mid-term8 Short-term7 Extracorporeal, direct contact Long-term6 Mid-term5 Short-term4 Extracorporeal, contact through barrier Long-term3 Mid-term2 Short-term1

Nephros Therapeutics, Inc. Classification Chart for Risk Assessment of Combination Products (CP)

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.