# Presentation: 391010

## Follow On Protein WorkshopBackground Concepts & Definitions

- Steven Kozlowski, M.D.
- Acting Director DMA
- OBP/OPS/CDER

## Overview

- History
- Protein Structure & Follow ons
- Possible Parameters, Algorithms & Outcomes
- Complexity & Risk
- Examples & Rules of Engagement

## History: Regulatory Statutes

- PHS Act Section 351
- ...approve...on the basis...that ...the subject of the application is safe, pure and potent...
- FFD&C Act
- 505(b)(1) ...full reports of investigations of safety and efficacy [applicant right of ref]
- 505(b)(2) ...full reports of investigations of safety and efficacy [some without right of ref]
- 505(j) ...a duplicate of a previously approved drug
- Flexibility in PHS Act
- Pre-1962 products DESI process

## History: FFD&C Generics

- Hatch-Waxman, FFD&C 505s, CFR regs
- Scientific principles
- Pharmaceutical Equivalence (PE): same active 	ingredients, dosage form, route, strength
- Bioequivalence (BE): same rate & extent of 	absorbance & availability at site
- Therapeutic Equivalence (TE) =  PE + BE
- Rule for 505(j) need PE + BE without need for 	clinical or pre-clinical studies beyond BE

## Interchangeability (AB Rating) 

- Interchangeability needs Therapeutic Equivalence
- If establishing this requires clinical studies beyond the scope of 505(j), this may occur under 505(b).
- Levothyroxine is an example of a product approved under (b)(2) that has an AB rating.
- Other Examples: Lisinopril

## History: PHS Act 

**Natural Source**
- Albumins
- IVIG
- Allergenic products

**Limited Clinical Data**
- Understood, standardized, controlled processes
- Cohn fractionation; extract.
- Experience w indications
- Experience w products

**Recombinant Proteins & MAb**
- Changes by a single manufacturer
- Improved pharmacology understanding
- Changes in clinical trial requirements

## History: FFD&C Act: Pre-1962 

**Non-glycosylated low MW**
- Insulin (all 505(b)(1) to date)
- Glucagon (recombinants under 505(b)(2) 1998)

**Complex mixtures**
- Hyaluronidase (505(b)(2) 2004)
- Pancreatic Enzymes (505(b)(1) 1996; Guidance 2004)

*Long history product use in indications & routes*

## History: FFD&C Act: Post-1962 

**Non-glycosylated**
- Human Growth Hormone (all 505b(1) to date)
- Some small proteins have had issues with abbreviated pathways (hypersensitivity)

**Glycosylated**
- FSH (all 505(b)(1) to date)
- Menotropin (505(j) 97 not distr; 505b(2) 99 & 04)

*Menotropin only protein approved under 505(j)*

## Historical Context

## Historical Context 

**FDA policy has evolved over many years and continues to evolve based on:**
- the ability of analytical techniques to characterize products
- current manufacturing practices and controls
- clinical and regulatory experience
- legal requirements

## Historical Messages 

**Changes in clinical requirements have occurred for related protein products**
**Increased or decreased depending on findings**
- Have occurred with natural source and recombinant proteins under FFD&C and PHS Acts
- Reductions under FFD&C have generally been via 505(b)(2)
- Significant “within manufacturer” changes have been deemed comparable
- Based on clinical indication, product class or product knowledge
- May be tied to therapeutic index, duration and breadth of experience

## Pharmacological Knowledge

- Knowledge Transferable by
- Similarity of Indication, Product class and/or Product

- Pharmacological Knowledge for Safety & Efficacy

- Knowledge Needed for Follow On

## Role of Comparability

- FDA 1996 Comparability Guidance, ICH Q5E
- Role in follow on proteins
- Regulatory guidance NO
- Scientific principles YES
- Requirements for similarity between different manufacturers should certainly be no less than comparability by the same manufacturer
- Example: Stability to assess differences in degradation profiles (Q5E 2.1)

## EMEA Guideline on Similar Biological Medicinal Products

- Due to complexity of biological/biotechnology products the generic approach is scientifically not appropriate.
- Biosimilar approach
- more likely highly purified products
- more difficult...products...difficult to characterize
- Subtle differences
- to support pharmacovigilance...specific product... clearly identified

- Release for Consultation Nov 2004

## Overview

- History
**Protein Structure & Follow ons**
- Possible Parameters, Algorithms & Outcomes
- Complexity & Risk
- Examples & Rules of Engagement

## Structure & Function

- ICH Q6A specifications for... chemical substances
- does not contain the term potency
- strength and/or content uniformity

- Structure = Function

- Hatch-Waxman
- same API(s) & bioequivalence

## 1 structure
higher order structure
post-translational modifications
heterogeneity

- <date/time>

- 1 structure
- higher order structure
- post-translational modifications
- heterogeneity

**Structure of Proteins**

- Monoclonal Ab MW ~150,000 Da

## How Much of the Iceberg Can We See?

- Characterization

## Definitions for this Discussion

**IDENTICAL**
- The product attributes are the same as those of the comparator drug (difficult for complex products)

**SIMILAR**
- The product attributes are similar enough to establish the same safety and efficacy as the comparator drug

- These determinations assume adequate assays and adequate control of variability

## Evaluation of Similarity

**COMPARATOR(S)**
- Accessible reference DS, API(s)
- Multiple lots
- Multiple source products
- Statistics
- Bracketing

## Evaluation of Similarity

**PHARMACOLOGICAL KNOWLEDGE**
- Molecular MOA(s)
- Structure/function relationships
- Multiple source products
- Clinical** **experience
- AEs
- Biomarkers

## Overview

- History
- Protein Structure & Follow ons
**Possible Parameters, Algorithms & Outcomes**
- Complexity & Risk
- Examples & Rules of Engagement

## Structural Similarity

- Biochemistry
- Peptide mapping (multiple enzymes)
- MS
- Oligosaccharide analysis
- Etc.
- Higher Order Structure
- Absolute (X ray Crystallography, 			Multi-D NMR, etc.)
- Relative (CD, signature assays)
- Percentage of structure evaluable
- Dynamic structure
- Bioactivity

## Heterogeneity Similarity

- Biochemical Analysis
- Sensitivity to variants
- 1% (Orange Book Strength Difference)
- 0.1% (Guide to Inspections of Validation of Cleaning Processes, July 1993, ORA field guide.)
- Case by case (Q3s, ppm)
- Stress conditions
- Higher Order Structure
- Sensitivity to variants
- Stability
- Accelerated, Real Time
- Comparative
- Combinatorics

## Combinatorics?

- 2 x 6 x 4 x 4 x 5 x 5 x 2 = 9600

- (9600)2≈ 108

##  Possible Algorithm

**?**

- Interchangeability ?

- Clinical Pharmacological Knowledge

## (Pharmacological Knowledge)2

- Similarity/
- Complexity

- Clinical
- Pharmacological
-  Knowledge

## Outcomes

- Full safety and efficacy studies
- ICH suggested numbers
- Modified safety
- Targeted for expected AEs
- Smaller numbers
- Immunogenicity
- Limited toxicology
- Indication specific?

- Modified efficacy
- Alternative endpoints/Surrogates
- Biomarkers
- Smaller numbers
- Bioequivalence
- PK study
- Immunogenicity
- Statistical basis for size
- Side by side comparison

## Overview

- History
- Protein Structure & Follow ons
- Parameters for Similarity
- Possible Algorithms & Outcomes
**Complexity & Risk**
- Examples & Rules of Engagement

## Stakeholder Meeting Analogy

- Adapted from Robert Garnick

## The Place In Between

## Risks

- Do complex molecules always have greater risks?
- Hypothetical Example
- Monoclonal antibody targeting infectious agent
- No reactivity with host tissues
- Used at saturation or above
- NOAEL >50X dose in presence of target
- Small molecule anticoagulant
- Adventitous agents - controllable
- Immunogenicity
- Not always associate with AEs

## Overview

- History
- Protein Structure & Follow ons
- Parameters for Similarity
- Possible Algorithms & Outcomes
- Complexity & Risk
**Examples & Rules of Engagement**

## Examples

**Facilitate conference discussions**

*Not defined categories but examples*

## Examples

- Variations on a theme
- Structurally less complex & complicated clinical scenario
- Structurally complex & well understood MOA
- Change in production host
- E coli to CHO
- CHO to transgenic
- Complex formulation buffer (HSA)

## Rules of Engagement

- Specificity of comments
- A) focus on principles
- B) discussion goes from less
-             to more complex
- C) time spent on speaker’s view of the boundaries
- Isolated examples without meaningful denominator are discouraged
- At this meeting, time should not be spent on issues that do not relate to product similarity, such as adventitious agents.
- appropriate testing, validated clearance and cGMPs can deal with this issue.

## Moving Forward

- Averaging into compliance
- Not good practice for lot release
- Not good practice for policy
- Average of polarized innovator and generic views are not the answer
- Science based discussion

## Credits

- Barry Cherney
- Keith Webber
- Chris Joneckis
- Frank Holcomb
- Patrick Swann
- Amy Rosenberg
- Kathleen Clouse
- Dena Hixon

- Helen Winkle
- Paul Rudolf
- Janet Woodcock
- Etc.