# Presentation: 331838

## Clinical Safety and Efficacy Studies: Report

- David Orloff, M.D.
- Marc Walton, M.D.
- Dorothy Scott, M.D.
- Dawn Viveash, M.D.
- Yafit Stark, Ph.D.

## Outline

- Brief overview of general approaches proposed in the plenary (reiterated by presenters in breakout session)
- Discussion of questions
- Summary

## Approach to the problem

- Non-clinical testing is never all-informative.  How do we decide when/what clinical studies are [absolutely] needed?
- Depends on level of concern of significant inferiority after non-clinical (including chemical characterization, PK/PD) product workup.
- How likely or unlikely is the possibility of inferior safety or efficacy?
- How inferior might it be (worst-case scenario)?
- Morbid/mortal
- Immunogenicity
- True toxicity
- Inferior efficacy in serious condition

## Approach-2

- Quantity of evidence needed to conclude clinical comparability varies across the “complexity” spectrum of protein products.
- Clinical safety and efficacy studies (excluding issues of potential immunogenicity) not needed for low complexity products.
- Targeted clinical studies to address residual uncertainties (based on non-clinical workup or experience with innovator product or class)
- Post-marketing safety surveillance as for all marketed products

## Breakout Questions

- In which situations would clinical safety/efficacy studies be needed and why?
- What factors should be considered in designing appropriate/relevant clinical studies?
- What concerns can be addressed via postmarketing surveillance as part of risk management?

## Q1. When are clinical studies needed?

- “Experience” [problems of variable safety, efficacy, immunogenicity] informs judgment concerning need for clinical studies (institutional memory)
- manufacturing processes (critical steps/parameters)
- history of product development
- marketing history
- [History of manufacturing using multiple processes and long-term marketing of multiple similar products without clinical safety or efficacy issues may dictate that studies not needed.]

## Studies when?-2

- Major process change (e.g., change in cell line) from innovator
- e.g., Epo products: based on product history (public domain)
- Difference in PK from innovator
- But if rigorous PK/PD shows similarity, may not need efficacy (safety)
- Perhaps a lower threshold for requiring safety and efficacy studies for chronic-use products
- Inability to predict immunogenicity based on non-clinical studies raised repeatedly

## Q2. Appropriate/relevant clinical studies

- Chemical complexity and knowledge of specificity/mechanism(s) of action important to level of study required
- No definitions of:
- “well-characterized”
- “complexity”
- Studies to qualify major process changes should [at a minimum] be those to “qualify” follow-ons
- Few, if any specifics given

## What studies?

- Surrogates/biomarkers/intermediate PD measures useful and often sufficient for efficacy
- Validation *per se* not needed
- Raising Hgb in CRF improves outcomes
- Lowering glucose of benefit in DM
- In some instances may need to bridge to multiple separate indications with separate studies
- Knowledge of mechanism(s) of action
- Mechanism(s) shared or not shared across indication(s)/clinical effects

## Issues addressed via post-marketing surveillance

- Should post-marketing surveillance “replace” pre-market safety studies?
- Surveillance *per se* not informative of efficacy for most products
- Only means of detecting rare events (i.e., not detectable in small pre-market programs)
- Surveillance *per se* not adequate for assessment of causality by drug of common AEs
- [Spontaneous reporting not well-suited to comparisons across products]

## Post-marketing-2

- Detecting emerging safety issues with follow-ons
- Concerns about spontaneous reporting in a world with multiple follow-ons: tendency to not report brand
- Concerns about switching and inability to determine culprit agent in drug-caused AEs
- e.g., Epo experience

## Registries

- Registries often conceived and designed to address specific questions
- If innovator has registry, so should follow on
- Plenty of experience with registries and surveillance by all parties
- Should safety of all new products (innovator or follow on) be “tracked”?

## Summary

- When
- Limits to info from chem characterization, PK/PD, etc., though parameters not defined
- Complexity, characterization
- Knowledge of mechanisms of action
- “Experience” as the guide to what constitutes a “major” change

## Summary-2

- Which
- Complexity, knowledge dictates study requirements
- Study standards and thresholds should mirror those for innovators after major changes
- Post-marketing
- Challenge of identifying culprit products for reported AEs