# Presentation: 532893

## Scientific Considerations Related to Follow-On Biologics

- Kenneth B. Seamon, Ph.D.
- Vice President, Regulatory Affairs

## Core Principles	

- Follow-on biologics are unique products, and must be held to the same high standards of safety, purity, and potency as the innovator to ensure patient safety
- Immunogenicity presents a serious concern for all biologics and should be studied through controlled trials pre-approval and monitored using robust post-approval surveillance
- Follow-on biologics cannot be considered therapeutically equivalent to the innovator product and require unique labeling

## Identity of Follow-On Product with Reference Product Cannot be Demonstrated

**Limitations in Analytical Methodology for Determining Identity**
- Product Characterization
- Reference product is purified drug substance which is not available
- Methods are defined for each product and process
- Product and Process Impurities
- Methods for detection and quantitation are not standard or compendial
- These occur in low abundance with significant potential to affect product’s immunogenicity or activity
- Identity of tertiary structure cannot be determined

## “Generic” Epoetin Alfas From Other Regions Differ From U.S. and European Approved Epoetin Alfa

- “Generic” Epoetin Alfas From Other Regions Differ From U.S. and European Approved Epoetin Alfa

- Source: Schellekens H, EJHP, 3/2004, Scientific Section, pp 43-47.

## Safety Considerations

*Each product has a unique safety profile which is dependent on its mechanism of action and its unique manufacturing process and composition.  Consequently, follow-on biologics need to have appropriate pre-clinical and clinical pre-approval safety data, in addition to robust pharmacovigilance*

## Safety Concerns are Related to both Product and Low Level Impurities and Species

**Pharmacology due to Product Activity**
- Pleiotropic activity or complicated mechanism of action
**Low Level Species and Impurities**
- Product related species
- Enhanced activity or clearance
- Elicit immunogenicity
- Process related impurities
- Enhance immunogenicity
- Conformational differences
- Increased activity
- Enhanced immunogenicity
- Difficult to standardize or compare products from different manufacturers

## Immunogenicity Needs to be Assessed Both Pre-Approval and Post-Approval

- Immunogenicity of follow-on biologics cannot be predicted with preclinical or non-human studies.  Clinical data is required.
- Factors affecting immunogenicity include:
- Structural alterations
- Production/purification steps
- Formulation
- Route, dose and frequency of administration
- Immune status of patient
- Genetic background of the patients
- Significant Consequences of Immunogenicity
- Loss of activity of product
- Loss of activity of endogenous molecules
- Serious, disabling, and potentially permanent

## Pre-Approval Detection of Immunogenic Adverse Event - MGDF

- Amgen product designed to mimic thrombopoietin
- Phase II clinical study identified several subjects that developed antibodies
- Bound to the drug
- Neutralized the drug
- Neutralized endogenous thrombopoietin
- Resulted in loss of platelet production in these patients
- Immunogenicity resulted in the abandonment of this clinical program

## Post-Approval Detection of Rare Immunogenic Adverse Event - Eprex®

- Johnson & Johnson’s erythropoietin
- Removal of human serum albumin stabilizer from epoetin alfa and associated manufacturing changes (outside USA)
- Increase in cases of Ab-mediated PRCA since 1998
- Serious hematologic disorder that has been recently described in some patients receiving ESAs for anemia associated with chronic kidney disease
- This condition caused by the development of circulating anti-EPO antibodies that cross-react with all commercially-available erythropoietic products as well as endogenous erythropoietin
- 	As a result:
- Erythropoietic treatment is discontinued
- Therapy to decrease or eliminate the neutralizing Abs must be initiated
- Blood transfusions are generally required to control severe anemia

## Qualifying Changes in Manufacturing

|  | Same Manufacturer |  | Follow-On Biologic |
| --- | --- | --- | --- |
| Manufacturing Step | Discrete Change | Significant Change | New Process |
| Cell Production | Same | Different | DifferentNo comparison to original |
| Unit OperationsScale Location | Different | Different | DifferentNo comparison to original |
| Methods | Same | Same | Different: No comparison to original |
| Data Requirements | Quality Data | Quality Data
Comparative pharmacokinetic data if needed
Clinical to confirm safety and efficacy | Quality Data
Comparative pharmacokinetic data
Clinical to establish efficacy and safety |

## Data Requirements for Significant Changes

- Characteristics of Significant Change
- Changes in fundamental process technology
- Product profile substantially comparable
- Manufacturing and development history
- Data to support change
- Quality data, characterization and comparability
- Product Specific Assessment depending on Molecule and Clinical Setting
- Pre-clinical data
- Pharmacokinetic comparison
- Efficacy data
- Safety data including exposure and immunogenicity

## Safety

- Preclinical studies in animals consistent with ICH S6 document
- Pharmacokinetic profile, acute toxicity, and immunogenicity
- Safety data consistent with ICH Guideline “Extent of Population Exposure to Assess Clinical Safety”
- Immunogenicity data to detect differences
- Determination of frequency and type of serious adverse events
- Pharmacovigilance
- Large number of patients for an extended period of time (~4000 patients for a year)
- Size, duration, and type of study should depend on size of patient population and known safety risks associated with treating disease.

## Efficacy

- Pharmacokinetics
- Comparative bioavailability trial between original and follow-on biologic
- Clinical Efficacy
- A comparative pharmacodynamic study using surrogate markers only if these have been well established and accepted
- Demonstration of clinical efficacy in the absence of accepted surrogate markers
- Multiple studies if there are multiple indications that are significantly different with regard to biology or site of action

## Summary

- Discussion of scientific, legal, and regulatory issues relating to follow-on biologics must include a transparent process and public comment.
- Follow-on biologics must be held to the same high standards as the original to ensure safety and efficacy for patients.
- An appropriately sized pre-approval safety database, including pre-clinical and clinical trials, in addition to robust pharmacovigilance, should demonstrate adequate safety.  Immunogenicity testing may never be left to the post-approval phase.
- Small differences in the production process of biologics can yield different products. Thus, follow-on biologics can never be considered “copies” of the innovator products, and cannot be deemed therapeutically equivalent to the innovator product.
- Follow-on biologics should have unique names (USAN).  They will need original labeling based on their own clinical experience for each indication.  Class specific safety information should be included.