Clinically Relevant Specifications: Case Study and Summary ... · •Simulation of bioequivalence study •DS (10% total oligomannose) similar to that used in Ph3 study •Hypothetical

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Clinically Relevant Specifications: Case Study and Summary of Discussion at BioPhorumDevelopment Group MeetingTaro Fujimori AbbVie

© BioPhorum Operations Group Ltd 2

• Introduction

• Case Study mAb-X

• Summary of Discussion at Biophorum Development Group Face Meeting

Outline

2


“Clinically relevant specifications can be defined as a

set of criteria and acceptance ranges to which drug

products should conform in order to deliver the

therapeutic benefit indicated in the label.”

“Clinically relevant specifications increase flexibility

within the pharmaceutical manufacturing sector while

maintaining quality by establishing acceptance criteria

based on clinical relevance, instead of process

capability or manufacturing process control.”

Excerpt from “FDA Pharmaceutical Quality Oversight: One Quality Voice”

https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM442666.pdf


Overarching question for this section: What are the expectations for a company to establish and utilize clinically relevant specifications?

4

Q: Why are we still talking about clinically relevant specifications?

A: Although we are aligned on the concept, we still have practical questions about what is expected

Case Study: mAb-X


mAb-X• mAb-X is an IgG1 antibody binds to and neutralizes a Ligand-X (soluble ligand)• Binding of mAb-X to ligand prevents binding of Ligand-X to its cell surface receptor• Mechanism of action for mAb-X is inhibition of Ligand-X signaling via receptor

• mAb-X prevents binding of Ligand-X to its receptor• ADCC and CDC are not observed with mAb-X

Development in two different indications• Indication #1:

• Loading dose: 200 mg, subcutaneous, weeks 0 and 4 • Maintenance dose: 100 mg, subcutaneous, q4w

• Indication #2: • 700 mg dose, iv infusion, q4w

CMC Development• Process A: Phase 1 and Phase 2 for Indication #1• Process B: Phase 2 for Indication #2• Process C: Phase 3 for Indication #1

Case Study: mAb-X

6


Changes in Oligomannose Profile during Process Changes

• Change in glycoform profile for mAb-x due to changes in cell culture process

• CQA designation: Literature reports that IgG1 antibodies with Oligomannose have faster clearance relative to FBOs


mAb-X Glycoform Clinical PK Study

• 700 mg iv dose on Day 0• PK samples collected 0 to 14

days• Capture mAb-X from PK

sample using Ligand-X affinity column

• Analysis using optimized oligosaccharide method (2-AB label with NP-HPLC)

Leslie Alessandri MAbs. 2012 Jul 1; 4(4): 509–520.


mAb-X Glycoform Pharmacokinetic Data

• Based on pharmacokinetic modeling, it is appropriate to categorize the glycoforms into the two groups: FBO and oligomannose species

• Slightly faster clearance observed for oligomannose species• Mean clearance rate and observed variability used for PK simulations (next

slide)

Fucosylated Biantennary Oligosaccharides Oligomannose

Solid line: Mean; Dashed line: 95% CI

Correia, 2012, US Patent Application: 0195885 A1


Population PK Simulations

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• Simulation of bioequivalence study• DS (10% total oligomannose) similar to that used

in Ph 3 study • Hypothetical DS with 0% to 40% total

oligomannose• Two arm study with N=75 per arm

• The simulations results demonstrate that varying the total oligomannose percentage from 0% to 30% would have minor impact on the pharmacokinetics of total mAb-X

• Support ≤ 20% total Oligomannose as a clinically relevant specification


• Objective: demonstrate comparable bioavailability for drug supply used throughout clinical development

• Single 100 mg subcutaneous (SC) dose of mAb-X from one of the following processes:• Process A: 4% Oligomannoses• Process B: 9% Oligomannoses• Process C: 9% Oligomannoses

• Clinical readouts:• PK was comparable for mAb-X Process A, B, and C after a 100 mg subcutaneous

dose• The percentage of subjects with at least one positive anti-drug antibody (ADA)

measurement following single dose mAb-X administration was similar across all regimens.

Clinical Comparability Study

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• GLP Toxicology studies• Chronic tox (39w): 100 mg/kg/wk NOAEL dose x 4.2% = 4.2 mg oligomannoses/kg/wk• SegIII: 200 mg/kg/wk dose x 8.8% = 17.6 mg oligomannoses/kg/wk

• Clinical Experience• Phase 3 (indication #1): 200 mg loading sc dose x 9% = 19 mg oligomannoses or 0.27

mg oligomannoses/kg*• Phase 2 (indication #2): 700 mg iv dose x 9% = 60 mg oligomannoses or 0.88 mg

oligomannoses/kg*

• Glycoform PK study• PK simulations: oligomannoses percentage up to 30% would have only minor impact

on the pharmacokinetics of total mAb-X

• Clinical comparability PK study• Comparable clinical pharmacokinetics and ADA (immunogenicity) for Process A (4%

oligomannoses), Process B (9% oligomannoses), and Process C (9% oligomannoses)

• Proposed clinically relevant specification of Oligomannoses ≤ 20% supported by:• Maximum patient exposure for loading dose: 200 mg x 20% = 0.57 mg

Oligomannoses/kg*• Clinical experience up to 0.88 mg Oligomannoses/kg• Toxicology studies up to 17.6 mg oligomannoses/kg

Summary for Case Study

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Summary of Discussionon Clinically Relevant Specifications at Biophorum Development GroupFace to Face Meeting #24Oct 30 – Nov 1, 2018

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BioPhorum Development Group (BPDG) – Mission and Scope


BPDG Member companies

Company Company

AbbVie* Lonza

Alexion* Merck MSD*

Bayer EMD Serono*

Biogen* Pfizer

BMS* Regeneron*

Celgene Roche*

Eisai Inc* Sanofi*

Ferring* Samsung Biologics*

GSK* Samsung Bioepis*

ImmunoGen* Shire*

Janssen* Takeda

KHK* UCB*

The content in the following slides represents the collated view of the companies* who contributed to and/or attended the BPDG24 meeting. The views are not attributable to any individual company.


Process C

(Ph 3 supp

ly)

Clinical Exp

erience (Ph 1 ‐ 3

)

% Total Oligom

anno

seClinical Experience Based on Percentage of Product Related Variants

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Are there challenges for companies to include the range of product quality used in all clinical studies (Ph1-3) assuming no adverse events (safety / lack of efficacy) are associated with any particular batch?

BPDG Feedback• Depends on clinical protocol

• Ph 1 is typically for safety only and may not be informative about efficacy

• Might be challenging to leverage clinical experience in different indications and/or different modes of administration (iv, sc)

• Efficacy biomarker might help bridge these gaps

• May be challenging to compare product quality from Ph1 to commercial• Assay comparability for early development and commercial QC assays• Back-lot testing of early clinical material with commercial release assays

• Consider use of aged drug supply and/or alteration of manufacturing process to generate a range of product quality used in clinical studies

5%

0%

10%

15%


.

.

Indicatio

n #1

, Ph 3, sc

, 200

mg

Indicatio

n #2

, Ph 2, iv,700

mg

39w Tox, iv/sc, 100

mg/kg

SegIII GL

P To

x, sc

, 200

mg/kg

Total O

ligom

anno

se Dose, m

g/kg

For 7

0 kg patient and

accep

tance crite

ria of ≤

20% Total Oligom

anno

seAbsolute Dose of a Product Related Variants in Clinical/Non-Clinical Studies

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Are there challenges for companies to consider the absolute dose (mg/kg) of a Product Related Variant from non-clinical and clinical studies in setting commercial acceptance criteria?

BPDG Feedback• Can be challenging depending on the risks associated with that

particular CQA:• Immunogenicity• Adverse events• Less efficacious• Infusion reactions

• Different modes of administration (iv and sc) and different indications may present challenges

• Helpful to have preclinical and clinical SMEs provide input for a robust discussion on risks and appropriate acceptance criteria

4.2 17.6

0

0.5

1.0

*Red line represents maximal absolute dose of Total Oligomannose for a 70 kg patient and acceptance criteria of ≤20%

*


Process C

(Ph3

supp

ly)

Justified

based

on Glycoform PK

Stud

y / PK

Mod

eling

% Total Oligom

anno

se“In Vivo CQA” Study to Justify Acceptance Criteria for Product Related Variants

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Are there challenges for companies to use “in vivo CQA” (clinical or non-clinical) studies of Product Related Variants in setting commercial acceptance criteria?

BPDG Feedback• Challenges

• Ideally, would want to leverage multiple studies:

• Animal models: What is consistent between animal and human?

• Clinical PK study with analysis of drug recovered from serum

• Clinical PK/PD modeling/simulations

• Utilizing data from an iv study for setting specification for subcutaneous administration might be challenged

• Discuss proposed approaches with Health Authorities as early as possible

10%

0%

20%

30%

* Proposed Acceptance Criteria of ≤20% Total Oligomannose

*

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Life Cycle Management for Clinically Relevant Specifications

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Clinically Relevant Specifications Under Regulatory ControlProcess Capability Monitored By Local Quality

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Are there challenges for companies implementing and maintaining clinically relevant specifications for commercial manufacturing and using Continued Process Verification to ensure process consistency?

BPDG Feedback

• Challenges could include:

• Residual risk due to limited clinical experience

• Potential incomplete confirmation of Mechanism of Action and impact of CQAs on efficacy

• Solutions could include:

• Increased understanding of MoA

• Increased understanding of post-translational modifications / degradation pathways and impact of these modifications on clinical efficacy

*Clinically Relevant Specifications**Safety Margin


Specifications for Lifecycle Management: New Manufacturing Process

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If justified by clinical relevance, can specifications for a new manufacturing process or site be broader than current commercial specifications?• Increased product understanding after approval, may result in a broader range

for clinically acceptable levels of a product attribute.• A new manufacturing process or site, may have a new range of process

capability for a product attribute.

BPDG Feedback• How can we justify broadening the specs at the new site when the original site

can meet the current specs? • Two specs would lead to logistical challenges in supply chain & in general, not

acceptable• No one wants to touch filed specs – viewed as unchangeable• One specification for all sites/process

Acceptab

le Lev

els B

ased

on

Clinical Relev

ance

Process C

apab

ilitie

s

Prod

uct A

ttrib

ute Levels

*Acceptance criteria based on Process Capability at original site

*

*


Concluding Thoughts

• All companies are struggling with clinically relevant specifications

• Clear definition of clinical experience for setting specs is still missing

• Clinically relevant specifications is still evolving

• There is no one strategy for establishing clinically relevant specifications. Several factors have to be considered – previous molecule experience, in vivo studies, mechanism of action, etc.

• Clinical and tox/preclinical SME input on setting clinically relevant specifications is valuable

• Leverage in vivo CQA studies and modeling to support clinically relevant specifications


AcknowledgmentsAbbVie (Case Study)• Protein Analytics

• Leslie Alessandri• David Ouellette• Aima Acquah• Czeslaw Radziejewski• Ivan Correia

• DMPK/Bioanalysis• Mathew Rieser• Mary Saltarelli

• Statistics• David LeBlond

• Clinical PK/Pharmacometrics• Matt Hruska• Susan Paulson

BioPhorum Development Group (Clinically Revelant Specifications Subteam)• Veronique Bailly, Biogen • Neha Franz, Biogen• Rahul Godawat, Alexion• Michele Lastro, Regeneron • Shawn Lawrence, Regeneron• John Mattilla, Regeneron• Francis Poulin, Sanofi• Rachel Thornton, UCB• Yuki Yagi, Kyowa Hakko Kirin• Jack Yu, Alexion


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Documents

Clinically Relevant Specifications: Case Study and Summary ... · •Simulation of bioequivalence study •DS (10% total oligomannose) similar to that used in Ph3 study •Hypothetical