biosimilar fda clinical pharmacology draft guidance: … · 2014-11-04 · confidential © 2014...

CONFIDENTIAL © 2014 PAREXEL INTERNATIONAL CORP.

BIOSIMILAR

FDA CLINICAL

PHARMACOLOGY

DRAFT GUIDANCE:

INDUSTRY

PERSPECTIVE

Date: November 4, 2014

Sally Choe, Ph.D.

© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 2 Bayer Core w EU & Sum 08-OCT-2014.pptx

OUTLINE

• Regulatory Framework and Expectations

• Role and scope of comparative PK, PD and PK/PD data

• Accepted examples of PK and PD in biosimilarity demonstration

• Future applications - Greater acceptability and integration of

PK/PD

• Conclusions


UNDERLYING REGULATORY FRAMEWORK AND

EXPECTATIONS

• Data requirements for a Biosimilar application will be less than a

full complement of product-specific preclinical and clinical data

required for an original BLA application

• FDA may waive any of these data requirements if it finds the

data are “unnecessary”

• FDA has a “longstanding policy of permitting appropriate reliance

on what is already known about a drug, thereby saving time and

resources…and avoiding ethical concerns associated with

unnecessary duplication of human or animal testing.”


HIGHLY SIMILAR ANALYTICAL AND PK / PD DATA =

LOWER RISK OF CLINICAL DIFFERENCES

Risk-Based, Stepwise, Totality

of Evidence

Analytical Characterization is

the foundation

PK/PD is a key component of

initial clinical assessment

Comparative Immunogenicity

assessment expected

Clinical

PK/PD

Nonclinical

Analytical

PK/PD

Nonclinical

Analytical

Clinical

Sim

ilarity

Ass

ess

ment

with R

efe

renc

e

Reduc

ing

Unc

ert

ainty

Clinical efficacy and safety

studies

Additional Clinical studies, if

needed


QUALITY ATTRIBUTES THAT IMPACT PHARMACOKINETICS

AND PHARMACODYNAMICS

Attributes Impact on PK, PD

Primary amino acid sequence, Fc

receptors

Ligand binding impacts distribution and

elimination

FcRn binding Alters elimination rate

Folding, disulfide bridges Misfolding is associated with faster clearance

Oxidation Can impact FcRn binding

Glycosylation Impacts immunogenicity and has the potential

to impact PK

Degradation Degraded products have faster clearance

Adopted from Windisch J. DIA Biosimilars Meeting, Washington DC, 2014


PK AND/OR PD STUDY CONSIDERATIONS

• Cross-over vs. Parallel

• Healthy volunteers vs. patients

• Dose (s) and routes of administration

• Sensitive and relevant assays

• PK parameters, i.e. Cmax, AUC

• Alternate data analysis strategy to deal with PK variability

• When you do not meet the similarity (80-125%) margin:

Unlikely that PD and/or clinical endpoint can rescue the PK similarity evaluation


PD AND PK/PD EVALUATION – TOTALITY OF EVIDENCE

Prior knowledge from drug and disease including the reference product and

therapeutic class

Mechanistic basis for drug action

Relevant to disease process related to effectiveness and safety

Sensitivity to detect clinically meaningful differences between the two

products, i.e. dynamic range

Can be assessed after a sufficient period of time after dosing, and with

appropriate precision

Multiple PD parameters generate relevant fingerprinting and reduce residual

uncertainty


UTILITY OF POPULATION PHARMACOKINETICS AND

PHARMACOMETRIC APPROACHES TOWARDS

BIOSIMILARITY EVALUATION

Population PK alone is not adequate to demonstrate PK similarity; it is

additional supportive data towards a totality of the evidence approach to

achieve an overall demonstration of biosimilarity

M&S tools can be useful when designing a PK and/or PD study

• Selection of an optimally informative dose (s) for evaluating PD similarity

• Evaluating an Exposure (or Dose) – Response relationship

• Developing acceptable limits for PD similarity based on biomarker-clinical endpoint

relationship

Modeling exercise to compare relevant PK parameters, such as clearance

and volume of distribution following multiple routes of administration following

single and multiple-dose administration


PK, PD, PK/PD ARE KEYS TO EXTRAPOLATION TO

OTHER INDICATIONS NOT STUDIED IN THE PROGRAM

Indication 3 Indication 2

Robust CMC

Data

Keys to Extrapolation

Fewer Indications

All Indications

Pivotal PK/PD/Phase 3 in Core Indication

Agency Negotiation

MOA/PK/PD/Biodistribution

Toxicity


PK SIMILARITY DEMONSTRATED BETWEEN NEUPOGEN

AND FILGRASTIM BIOSIMILAR (ZARZIO)

PK parameter Day Ratio (90% CI)

Cmax 1 95.91 (88.73 - 103.67)

AUC 1 95.87 (90.31 - 101.78)

Cmax 7 80.05 (70.19 - 91.30)*

AUC 7 86.90 (80.90 - 93.35)

Single-dose conc-time curves

superimposable between 5 mg/kg

IV Neupogen and Zarzio – PK

similarity achieved

Exploration of PK similarity for 5

mg/kg after single and multiple

dose administration between SC

Neupogen and Zarzio

IV route

SC route

* Outside the standard equivalent limits

Ref: McCamish M and Woollett G (2012) Clinical Pharmacology & Therapeutics

Ref: CHMP Assessment for Zarzio, 2008


PD (ANC AND CD34+) SIMILARITY DEMONSTRATED

BETWEEN NEUPOGEN AND FILGRASTIM BIOSIMILAR

ZARZIO

PD parameter Ratio (90% CI)

AUEC0-216h

(103.h/mL) 99.37 (96.30 – 102.54)

PD parameter Ratio (90% CI)

CD34+ (h/mL) 102.11 (93.53 – 111.47)

McCamish M and Woollett G (2012) Clinical

Pharmacology & Therapeutics


ANALYTICAL PK PD SIMILARITY

ABBREVIATED CLINICAL PROGRAM

Demonstration of highly similar physicochemical and functional characteristics

between the potential biosimilar and the reference biologic is the foundation

on which biosimilarity stands

Following analytical similarity, step-wise demonstration of PK and PD

similarity based on the 80-125% equivalence margin was sufficient (w.r.t.

efficacy) for approval per CHMP

The sponsor undertook a supportive clinical study designed as a single-arm,

open-label, parallel, safety, tolerability and immunogenicity study in breast

cancer patients treated with myelosuppressive chemotherapy


TYPICAL GLOBAL CLINICAL PROGRAM :

CAN WE DO BETTER THAN THIS?

Products Phase 1

(3-way PK)

Phase 3

(Equivalence trial)

Estimated Costs

Trastuzumab

(Herceptin)

~100 HVs 600 - 800 pts $40 million

Bevacizumab

(Avastin)

~100 HVs 800 – 1200 pts $60 million

Etanercept

(Enbrel)

~80 HVs 500 – 600 pts $40 million

Rituximab

(Rituxan)

~300 patients 500 – 1000 pts $50 million

Adopted from Nick C. DIA Biosimilars Meeting, Washington DC, 2014


TRADITIONAL CLINICAL ENDPOINTS ARE BLUNT

INSTRUMENTS TO DETECT ANALYTICAL DIFFERENCES

Adopted from Windisch J. DIA Biosimilars Meeting, Washington DC, 2014


LOOKING FOR A SENSITIVE PD/SURROGATE

Clinical Endpoint PD Marker /

Clinical Surrogate

Clinical endpoint with which the reference product was approved is

often not sensitive enough to identify clinically meaningful differences

Human PK and PD data may be able to substitute a large Phase 3 study in

order to support a demonstration of biosimilarity in some cases

Adopted from Nick Holford


PROBABLE PK/PD APPROACHES THAT MAY

ABBREVIATE CLINICAL PROGRAMS FOR

MONOCLONAL ANTIBODIES

Biologics PK/PD metrics Outcome

Omalizumab

(Anti-IgE)

PK – free & total IgE – asthma

exacerbation

Support for the approved BW

and IgE-based dosing table (ref: Xolair USPI 2014)

Tocilizumab

(Anti-IL-6) PK – DAS28 response model

Dosing regimen justified (ref: Clinical Pharmacology review of

BLA125472, 1/29/2013)

Adalimumab

(Anti-TNF)

PK – remission and time to response

in the induction treatment phase in

moderate to severe UC

Support for optimal dosing (ref: FDA Gastrointestinal AdCom

meeting for Adalimumab, FDA Clinical

Pharmacology slide presentation,

08/28/2012)


CONCLUSIONS

• Clinical Pharmacology data is a critical part of the totality of evidence to

support a demonstration of biosimilarity to a Reference product

• PK and PD data has been utilized as pivotal clinical data to support

clinical similarity between the biosimilar product and the reference

product

• Exposure-Response evaluation has the potential to substantially

abbreviate a biosimilar clinical development

• Can PK/PD ever replace a Phase 3 therapeutic equivalence study for

biosimilars?


ACKNOWLEDGEMENT

• Partha Roy, Ph.D.

Principal Consultant, PAREXEL

• Biosimilar Experts at PAREXEL


THANK YOU

© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 19

For more information, please contact:

Sally Choe, Ph.D.

Senior Director

PAREXEL Consulting

[email protected]

mailto:[email protected]

biosimilar fda clinical pharmacology draft guidance: … · 2014-11-04 · confidential © 2014...

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