biomarker assay development based on drug r&d...
TRANSCRIPT
25 Feb. 2015
Biomarker assay development based on drug R&D strategy
Nobuhiro Kobayashi
DaiichiSankyo
The views expressed here are the speaker’s personal perspectives and
do not reflect official policy of DaiichiSankyo Co., Ltd.
2 2
Fit-for-purpose clinical biomarker
assay development based on the
drug R&D strategy
What is biomarker?
What is drug R&D?
What is fit-for-purpose?
3
What is biomarker ? Definition and Classification of Biomarker (FDA)
Definition:
A characteristic that is objectively measured and evaluated as an
indicator of normal biologic processes, pathogenic processes, or
biological responses to a therapeutic intervention. Source: DDT Glossary, FDA
Classification:
•Prognostic biomarker: Indicates future clinical course of the patient with respect to
some specified clinical outcome, in the absence of a Tx intervention
•Predictive biomarker: Measured prior to an intervention / Identifies patients who are
relatively susceptible to a particular beneficial or harmful drug effect versus less
susceptible patients
•Pharmacodynamic biomarker: Response-indicator biomarker / Post Tx measurement
•Efficacy-response biomarker: Efficacy-surrogate biomarker, Surrogate endpoint /
Subset of general pharmacodynamic biomarkers
Source: Marc K Walton, FDA @ MRD in Acute Lymphoblastic Leukemia Workshop (April 2011)
Presentation Name | CONFIDENTIAL
4
My definition and goal of biomarker 1/2
• Pharmacodynamic (PD) biomarker: direct (or indirect)
effector of drug target downstream
• Proof of Mechanism (POM) : verify/validate the evidence based on
the biology in patients/healthy volunteer.
• Efficacy biomarker: efficacy-surrogate biomarker for each
target indication.
• Safety biomarker: target-related or drug related toxic
signs to achieve safe clinical trial for patients.
Evaluate value of drug candidate
compounds appropriately
5
• Pharmacodynamic (PD) biomarker: direct (or indirect)
effector of drug target downstream
• PK/PD : confirm the effective drug exposure in patients.
• Predictive biomarker: contributor of disease phenotype
which has strong link to the drug target to choose right
patients for right drug.
Maximize value of drug candidate
compounds
Realize personalized medicine
My definition and goal of biomarker 2/2
6 6
What is drug Research & Development ?
医薬品・医療機器・医療技術の研究開発(R&D)は、そもそも個人の関心・興味に駆動される、自由な研究ではない。市販に向けて、国際的に法律に基づいて当局からの承認取得を前提として、科学と技術を結集して行なう事業(商品開発)かつ法的プロセスである。
強力なマネージメントが必須 福島 雅典ら、臨床評価 42巻2号P251, 2014より抜粋
Research and development (R&D) for innovative drugs, medical
devices, medical technologies is NOT free research driven by
personal interests. It is business (product development) and a
legal procedure to be challenged calling upon science and
technology, in preparation for launching a new product on the
premise of marketing authorization based on international
specifications .
Need intensive management Adapted from M. Fukushima, et. al. Clinical Eval 42 (2) 251, 2014
7
Typical flow of BM strategy/plan for each project
• Tangible examples : POC plan, Indication selection, Differentiation, etc.
Overall strategy
• How to achieve the goal of overall strategy using BM
• Tangible examples : Stratification of patient, MoA, PK/PD, efficiency, Safety, etc.
BM strategy
• To design over all BM analysis plan in Ph1/2 studies, which facilitate BM implementation
Overall BM analysis plan
• To optimize BM assay and data analysis in each clinical study protocol according to overall BM plan
Each clinical study design based on BM plan
• To implement appropriate BM data analysis to enable decision making
BM data analysis based on BM strategy
Pre
-clin
ica
l Ea
rly c
linic
al p
ha
se
8
This is a primary theme in my today’s presentation.
Presentation Name | CONFIDENTIAL
What is fit-for-purpose for biomarker assay?
9
Case I : Safety marker
Agewall S et al. Eur Heart J 2011;32:404-411
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2010. For permissions please email: [email protected].
Troponin
Troponin has become a major criterion for myocardial infarction
10
Relation between troponin level and possible causes.
Agewall S et al. Eur Heart J 2011;32:404-411
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2010. For permissions please email: [email protected].
99th percentile of normal subject Criteria for MI
11
Joint ESC/ACCC Consensus document J. Am. Coll. Cardiol. 36 958-69 (2000)
Time course of troponin level in human
12
High sensitive troponin-I assay system
13
Human troponin-I assay Comparison
Presentation Name | CONFIDENTIAL
Method Rapid diagnostic
test (PATHFAST TnI)
Electrochemilum
inescence (ECL)
Single molecule
counting (SMC)
Single molecule
arrays (SIMOA)
Cal. range
(pg/mL) 20 - 50000 10 – 50000? 0.4 - 600 0.079 - 300
Detection limit
(pg/mL) 8 1.1-1.9 0.09 0.01
99th percentile
(pg/mL) 28 19.3 10.1 NA
Sample vol.
(minimum) 50 uL/test 150 uL/test?
100 uL/test (50 uL/test)
42 uL/test
Approval US/EU(?)/JA EU/JA None None
14
Case II : PD marker
Peptide X : The PD marker has been validated in preclinical
study using mouse plasma.
A project team wants to confirm response of the marker at SAD/MAD studies.
However, peptide X is unstable in human plasma, and need a cumbersome pre-treatment for assay development.
What will you do then?
15
Case III : PD marker
TRAP-5b : Isozyme of tartrate-resistant acid
phosphatate (TRAP)
TRAP-5b is considered as the most important marker of bone resorption
rate in renal failure patients. Bone metabolism markers like CTX, NTX,
BAP and osteocalcin accumulate in blood because the markers are not
cleared by the dysfunctional kidney. This can lead to elevated marker
levels in renal osteodystrophy, a bone disease affecting the majority of
renal failure patients, causing misinterpretation of bone marker results.
16 16
10. キット
研究用キットを使用する場合には,施設ごとに分析法バリデーションを実施する必要がある.ただし,LC及びLBAガイドラインの内容に従えない場合もあるため,その場合には対応可能な範囲でガイドラインに準じてバリデーションを実施し,その妥当性を確認する必要がある.なお,キットの製造元が確認したキットの有効(使用)期限に関する情報は参照しても良い.
キットのロット変更の際には,ロット間において同一試料中の分析対象物質の定量値に差がないことを確認することが望ましい.
17 17
Summary and Message
Summary : Fit-for-purpose biomarker assay
development should be considered not only
biological characterization of analyte (endogenous
substance), but also objectives based on BM strategy
to implement fit-for-purpose biomarker assay
development.
Massage : Analytical experts (person in charge of BM
assay development) should also join the discussion
on BM strategy/plan, and commit to creation of more
realistic BM plan.
18 18
Acknowledgement
DaiichiSankyo, TMCP
Kazumi Ito
Ryo Atsumi
Taro Tokui
DaiichiSankyo, DMPRL
Tsuyoshi Karibe
JBF Task force of the draft concept paper
Kosuke Iijima, Kyowa Hakko Kirin Co., Ltd.
Chikashi Eguchi, LSI Medience Corp.
Masaaki Kakehi, Takeda Pharmaceutical Co., Ltd.
Yoshitaka Taniguchi, Toray Research Center, Inc.
Noriyuki Danno, JCL Bioassay Corp.
Takahiro Nakamura, Shin Nippon Biomedical Laboratories, Ltd.
Takehisa Matsumaru, Otsuka Pharmaceutical Co., Ltd.
Takashi Miyayama, Chugai Pharmaceutical Co., Ltd.
Itadaki Yamaguchi, Sumika Chemical Analysis Service, Ltd.