Public Hearing

1

• 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

2
Overview

• Renal Assist Device (RAD) System biologic/
  device combination product
• Critical issues in RAD development
• Risk-based classification of combination products

3
Renal Assist Device (RAD) Biologic/device
combination product

• Human cellsno modifications
• Renal cell isolation and expansion
• Extracorporeal system based on hollow fiber
  membrane technology
• Relatively short-term exposure
• Conventional instrumentation and equipment (CVVH)

4
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

5
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

6
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

7
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

8
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

9
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

10
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

11
Biologics Risk Scoring
12
Classification Chart for Risk Assessment of
Combination Products (CP)
13
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.