GLOBAL BIOANALYSIS

CONSORTIUM Updates

Shinobu Kudoh/工藤 忍

on behalf of GBC steering committee: P. Timmerman フィリップ ティンマーマン,

M. Arnold マーク アーノルド,

F. Garofolo ファビオ ガロフォロ,

P. van Amsterdam ピーター ヴァン・アムステルダム,

M. Golob ミカエラ ゴロブ,

B. DeSilva ビノー デシルバ,

P. Singhal プーラン シンガール,

D. Tang ダニエル タン,

M.F. Riccio マリア・フランチェスカ リッキオ

Lead to

Candidate

Candidate Selection to

FTIH

FTIH* to PoC PoC** to

Commit to

Phase III

Phase III File &

Launch

Lifecycle

Management

Phase II Phase III Phase IV Phase I *FTIH: First time in Human **PoC: Proof of Concept

Discovery

Pre-Clinical Clinical

Post Launch

Regulated Bioanalysis • PK / TK • ADME in tox species • Metabolite identification • In-vitro metabolism/enzymology • Protein binding • PK/PD • Drug-Drug interactions

• Identify routes of human metabolism • Compare human & animal metabolism • Human radiolabel study • Bioanalysis for Clinical & Toxicity Studies

• Bioanalysis for Clinical, Toxicity & Oncogenicity Studies • ADME for reprotox & oncogenicity species • Placental & milk transfer • BE

• Bioanalysis for Clinical Studies • ADME support of alternative • administration routes • TDM

Gene-

function-

target

association

Phase III

Target to

tractable

hit

File and

launch

Life cycle

management

FTIM

to

PoC

PoC to

commit to

Phase III Pre-clinical

Tractable

hit to

candidate Target family

selection

Disease selection

Commit

to Product Type

Commit to

Target Tractable Hit Candidate

Selection First Time

in Man

Proof of

Concept

Commit to

Phase III

Commit to

Launch/

NDA filing

NDA Approval

& Launch

Decision

points

• Bioanalysis defined by EMA Guideline

• is measurement of drug concentrations in biological matrices in animal toxicokinetic studies and of clinical trials, including bioequivalence studies.

• should be well characterised, fully validated and documented to a satisfactory standard in order to yield reliable results. • Determination of Specific endogenous compounds as biomarkers may be in it ??

Bioanalysis through Drug R & D

Assay [Quantification] •Instrument management・System suitability •Weighing •Calibration standard・QC samples preparation/store •Determination・incurred samples •Evaluation with Acceptance & rejection criteria, Reanalysis

•PK/PD analysis/Evaluation, Stat •Documentation and raw data Management & Archiving •Sample storage & discard

Report/Documentation Raw data management Work sheet Sample stability

Study type/Objective Human or animals (cells) Healthy sub/Patients Ethnicity, Special pop, sex, Fast/non-fasted Specimen: Blood, Urine, feces, cerebrospinal fluid, lymph, (Broth) etc.

Bioanalysis: Method Development & Validation

GMP・GLP/GCP

Compound inf.

Assay Method Development Technique：HPLC, LBA, LC-MS(/MS), GC-MS Sample Process: (pre-)treatment: PPT, SPE, LE, Derivatization, Enrichment

Specimen sampling (Blood, Urine, Tissue) Identification information, Storage/carriage, etc.

Regulated Bioanalysis

Non-Clinical/Clinical study

Method Validation Calibration range, Selectivity, LLOQ, Calibration curve, Accuracy and precision, Matrix effect, Carry-over, Dilution integrity Stability, etc.

• FDA’s Guidance for Industry on Bioanalytical Method Validation in May 2001

based on the outcomes from CC-I & II and their conference reports

giving the regulatory framework for bioanalytical method validation and the application with the method in clinical and preclinical studies.

has been referred worldwide for a long time.

• FDA tried to catch up the rapid technological advancements in separation sciences.

• They also continued to dialogue with the bioanalysis communities to try to provide assistance and supplementary explanations

esp., on those for emerging biologics, which were not sufficiently covered in the guidance.

Two additional white papers were published to cover LBA aspects in bioanalysis.

At Crystal City III, a controversial topic “Incurred Sample Reanalysis (ISR) “ was raised (discussion continued to the next CC IV)

Before GBC

1982: OECD GLP

1990

C.City I CP (Shah Paper)

C.City I C.City II CC II CP

Shah (chrom.) Miller (LBA)

a lot of bioanalytical experience was built

2001

F

D

A

2001: Guidance for Industry Bioanalytical Method

CRO

booming

2001

11

Portfolio changes in industry: new targets, new disease models

Increased development time for small molecule scaffold less NCE

Increased emphasis on peptides and proteins more NBE

Enabling also faster development from Discovery to market

Creating a boost in (new and innovative) LBA developments. e.g. α-LISA, Gyros, Luminex,

Patent expirations (of multi-billion dollar/euro selling drugs):

R&D optimise life cycle management

More Bioequivalence (BEQ) studies filed from R&D Pharma

Generic Pharma boosting

More BEQ studies (with bioanalysis often outsourced) filed from generic Pharma

Economic pressure on R&D Pharma calling for re-organisations resulting in

more (bioanalytical) outsourcing

more bioanalysis began to be accomplished in many countries besides the US, EU

and Japan, where R&D for NCEs were mainly done.

Bioanalytical data obtained elsewhere are used for drug approvals in many countries.

CROs growing their business exponentially (also outside EU/US)

More people involved / More regions involved

⇒ more difference in how quality is achieved and documented

Landscape changeｄ it impacted regulated bioanalysis across industry

Bio-Pharmaceuticals

New Formats/Technology

Newly Emerging Countries/Communities

2001

FDA

2001: Guidance for Industry Bioanalytical Method Validation

Before GBC

around 2000

The need for harmonization of the bioanalytical

guideline was gradually recognized

• Multiple BMV Guidance exist • More BWV guidelines published around the world (EMA,

ANVISA, JAPAN, China coming …) • Majority of the guidelines are similar, at least in small molecule

BA. But still some discrepancies.

Bioanalysis has become Global but • Harmonized/Common Guidance is missing • Majority of the guidelines are similar, at least in small molecule BA. But still some discrepancies. • Discordant regulations or Variations between guidelines increase effort and cost

Additional burden on Bioanalysts/Mangers and regulators, with little improvement in data quality in some cases Duplicity of data, causes confusion and no value addition nobody's benefit

• (New areas such as LBA, biomarker, new technologies are still to be defined)

with the initiative of the EBF, AAPS, APA and CFABS

Harmonizing currently available guidelines and guidance into one for the best bioanalytical practices was requested to the FDA and the EMA.

– The formation of the GBC was proposed and established in 2011 • in which bioanalytical experts came together, as balanced representation from

– North America (AAPS & CFABS)

– Latin America (AcBio)

– Europe/Middle East/Africa (EBF) and,

– Asia-Pacific (APA-India, CBF & JBF)

– to discuss potential/facing problems, share practical solutions and exchange views/thoughts on regulated bioanalysis.

– Finally, bioanalytical best practices were proposed; standing on the reached consensus based on the currently available sciences and technologies.

• The proposal could be a foundation for a harmonized guidance to be established.

GBC: Mission & Objectives

to Deliver new/better/safer medicines to patients

in need faster to meet unmet medical needs

GBC Mission statement: Create an all inclusive Global Bioanalysis Consortium (GBC) consisting of represented scientific associations with world wide influence to merge existing or emerging bioanalytical guidance to create one, unified consensus document that can be presented to the regulatory bodies/health authorities in various countries.

GBC: Mission & Objectives

to Deliver new/better/safer medicines to patients

in need faster to meet unmet medical needs

GBC ‘s objectives have 4 pillars

1.

• To bring together stakeholders from the pharmaceutical industry, CROs and

academia to share current understanding of bioanalysis guidelines.

• To identify differences in these guidelines or differences in the interpretation

or application thereof to routine regulated bioanalysis.

2. To come forward with recommendations to Health Authorities and regulatory

bodies worldwide on globally agreed best practices for Bioanalytical Method

Validation (BMV) and application of such methods/technologies to the analysis

of drugs of all molecular sizes in support of clinical and nonclinical studies.

3. To invite relevant stakeholders, from industry, academia, Health Authorities

and regulatory bodies, to jointly discuss the GBC recommendations at a global

conference(s) in order to achieve globally agreed guidelines on bioanalysis.

4. Going forward, to serve as a pivot point on the continued harmonized

interpretation and/or updates of globally agreed guidelines.

Timeline of activities

9

Decision not to

have global

meeting and

start publication

HT working on

content

SC & HT

f-2-f

touching base

2015

today

HT preparing

for FB

(most) HT

publishing in

AAPS-J

2013 2012 2014 2011 2010

Open Letter

to the

regulators

Defining mission,

vision, teams

and strategy

Preparing execution of agreed

strategy (i.e. publication, global

meeting,..) and intense

communication at global

meetings

Understanding

impact of delayed

release of draft

FDA guidance

and adapt

strategy

Prepare

next steps

of GBC

strategy

Under

discussion in

GBC-SC

Start up phase: Steering Committee

(SC) identification

Harmonization Team Lead

(HTL) identification

HT team members

identification

Harmonization Teams’ Themes & Leaders

A1: Scope and regulations

Surendra Bansal, NA

A2: Tiered approaches for method validation

Steve Lowes, NA

A3: Method Transfer, partial/cross validations

Ray Briggs, EU

A4: Reference standards and reagents

Joseph Bower, NA

A5: Sample Management

Mike Redrup, EU A6: Stability

Nico van den Merbel, EU

A7: Repeat analysis & ISR

Eric Fluhler, NA

A8: Documentation

Tom Verhaeghe, EU

A9: Analytical Instrument Qualification

Chad Briscoe, NA

A10: New Frontiers

Bob Bethem, NA

A11: Biomarkers

Russell Weiner, NA

A:All Molecules / All Techniques

L1: Large molecule specific run acceptance

Marian Kelley, NA

L2: Large molecule specific assay operation

Lauren Stevenson, NA

L3: Assay formats

Sherri Dudal, EU

L4: Reagents & the stability Link with tiered approach

Lindsay King, NA

L5: Automation practices in LM bioanalysis

Scott Davis, NA

L6: Immunogenicity (effect on PK)

Jeff Sailstad, NA

L:Large Molecules / Ligand Binding

S1: Small molecule specific run acceptance

Douglas Fast, NA

S2: Small molecule specific assay operation

Eric Woolf, NA

S3: Chromatographic Run Quality Assessment

Stuart Mc Dougall, EU

S:S.Molecules/Chromatographic

Steering Committees

• Bring together a global community of bioanalytical scientist and stimulate regional discussions on bioanalytical guidance

• Visualize the challenges of different global Guidance

• Highlight the need/desire for a harmonized (view on) Bioanalytical regulations

• Stimulate best practices, considering science and regulations

• Decision not to have a global meeting and start publication

• Instead;

Webinars Harmonization teams (most not all) published best practice

recommendation articles Presentations by SC and HT members at many regional

conferences. Significant attendance at CCV

Report on GBC Activities:

fruits of intensive discussions by 20 GBC harmonization teams (HTs)

should be recognized as just proposals for the best practices identified by the HTs.

can serve as the best information source internationally when authorities in the world need to define criteria for regulated bioanalysis

GBC publications: best practice recommendation articles

HT Title Authors

SC Introduction to the Proposals from the Global Bioanalysis Consortium Harmonization Team P. Timmerman, M. Arnold, B. DeSilva, F. Garofolo, M. Golob, P. van Amsterdam, S. 工藤, P. Singhal, D. Tang, M.F. Riccio, R. Barrientos, S. Savale, T. Kurokawa

A2

Tiered Approaches to Chromatographic Bioanalytical Method Performance Evaluation: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team

S. Lowes, R. Hucker, M. Jemal, J.C. Marini, V.M. Rezende, R. Shoup, P. Singhal, P. Timmerman, T. 米山, N. Weng, D. Zimmer

A3 Method Transfer, Partial Validation, and Cross Validation: Recommendations for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team

R.J. Briggs, R. Nicholson, F. Vazvaei, J. Busch, M. 間渕, K.S. Mahesh, M. Brudny-Kloeppel, N. Weng, P.A.R. Galvinas, P. Duchene, Pei Hu, R.W. Abbott

A4 Recommendations and Best Practices for Reference Standards and Reagents Used in Bioanalytical Method Validation

J.F. Bower, J.B. McClung, C. Watson, T. 大住, K. Pastre

A6 Stability: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team

N. van de Merbel, N. Savoie, M. Yadav, Y. 大津, J. White, M.F. Riccio, K. Dong, R. de Vries, J. Diancin

A7 Repeat Analysis and Incurred Sample Reanalysis: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team

E. Fluhler, F. Vazvaei, P. Singhal, P. Vinck, W. Li, J. Bhatt, T. Boer, A. Chaudhary, M. 谷口, V. Rezende, D. Zhong

A8 Recommendations from the Global Bioanalysis Consortium Team A8: Documentation T. Verhaeghe, H.H. Barton, H. 原, R. Hucker, M. Kelley, F. Picard, K.S. Reddy, M.C. Salvadori, E. Woolf

A10 New Frontiers - Accelerator Mass Spectrometry (AMS): Recommendation for Best Practices and Harmonization from Global Bioanalysis Consortium Harmonization Team

G.C. Young, M. Seymour, S.R. Dueker, P. Timmerman, A. Arjomand, K. 野沢

L1 Large Molecule Run Acceptance: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team

M. Kelley, C. Beaver, L.F. Stevenson, R. Bamford, P. Gegwich, K. 山本 , D. Li, S. Little, A. Muruganandam, D. Stoellner, R.K. Trivedi

L2 Large Molecule Specific Assay Operation: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team

L. Stevenson, M. Kelley, B. Gorovits, C. Kingsley, H. Myler, K. Österlund, A. Muruganandam, Y. 南出, M. Dominguez

L3 Assay Formats: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team

S. Dudal, D. Baltrukonis, R. Crisino, M.J. Goyal, A. Joyce, K. Österlund, J. Smeraglia, Y. 谷口, J. Yang

L4 Ligand Binding Assay Critical Reagents and Their Stability: Recommendations and Best Practices from the Global Bioanalysis Consortium Harmonization Team

L.E. King, E. Farley, M. 今里, J. Keefe, M. Khan, M. Ma, K.S. Pihl, P. Sriraman

L5 Automation Practices in Large Molecule Bioanalysis: Recommendations from Group L5 of the Global Bioanalytical Consortium

A. Ahene, C. Calonder, S. Davis, J. Kowalchick, T. 中村, P. Nouri, I. Vostiar, Y. Wang, J. Wang

L6 A White Paper-Consensus and Recommendations of a Global Harmonization Team on Assessing the Impact of Immunogenicity on Pharmacokinetic Measurements

J.M. Sailstad, L. Amaravadi, A. Clements-Egan, B. Gorovits, H.A. Myler, R.C. Pillutla, S. Pursuhothama, M. Putman, M.K. Rose, K. 曽根原, L. Tang, J.T. Wustner

S1,2,3

Small Molecule Specific Run Acceptance, Specific Assay Operation, and Chromatographic Run Quality Assessment: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Teams

E.J. Woolf, S. McDougall, D.M. Fast, M. Andraus, M. Barfield, M. Blackburn, B. Gordon, D. Hoffman, N. 井上, G. Marcelin-Jimenez, A. Flynn, R. LeLacheur, S. Reuschel, R. Santhanam, P. Bennett, B. Duncan, R. Hayes, B. Lausecker, A. Sharma, K. 富樫, R.K. Trivedi, M. Vago, S. White, H. Barton, J.A. Dunn, R.H. Farmen, K. Heinig, C. Holliman, J. 駒場, M.F. Riccio, E. Thomas

• Some countries may be issuing their own guidelines on regulated bioanalysis in the near

future in addition to the ones from FDA, ANVISA, EMA, and MHLW.

• The biggest achievement as a result of GBC activities;

having energized and facilitated sharing or exchanging information and ideas on

bioanalysis among bioanalysts and between bioanalytical communities irrespective of

countries.

Reduced of information deviations on available guidelines, their rationale and background

Minimize biased interpretation of conveniently selected guidelines.

• Regional interactions via continued communication and referencing to the GBC publications in the themed issue are to stimulate harmonization

• Having this greater common understanding, the hurdle of establishing a unified

guideline seems to have been much lowered.

• Technology will evolve and it may affect the way of regulated bioanalysis that needs to be changed in the near future.

GBC is aware that

2013 2012 2014 2011 2010

And now…

FDA – 2001

CC-III/IV?

FDA – 2001

CC-III/IV?

EMA

FDA – 2001

CC-III/IV?

EMA

Anvisa

FDA – 2001

CC-III/IV?

EMA

Anvisa

MLHW

FDA – 2001

CC-III/IV?

EMA

Anvisa

MLHW

FDA-2013??

FDA – 2001

CC-III/IV?

EMA

Anvisa

MLHW

FDA-2013??

SFDA?

today

Defining

mission, vision,

teams and

strategy

Preparing execution of agreed

strategy (i.e. publication, global

meeting,..) and intense

communication at global

meetings

Understanding

impact of delayed

release of draft

FDA guidance

and adapt

strategy

Prepare

next steps

of GBC

strategy

14

Open Letter to

the regulators

Applicable Guidance

• GBC as an International scientific bioanalytical communities influences domestic regulations

– goal achieved or being achieved

• International scientific bioanalytical communities influence cross-regional regulations such as ICH and WHO

– Next step?

• Strengthen scientific exchanges among bioanalytical and regulatory communities to achieve harmonization

Full consensus amongst regulators on a number of ambiguities.

– Next step?

• One harmonized Guidance on Bioanalysis?

What is still in front of us?

15

‐ “All what we have to do is dream?”‐

Perspectives on the harmonization of regulated bioanalysis in general

What is our goal (if it exists), How we can achieve it, What are the difficulties and Their overcoming ways towards our goal

♣ What is our goal (if it exists) ? Deliver new medicines to patients in need

one global guideline or at least globally harmonized guidelines for BMV (large & small)

Harmonization of Guidelines ≠ One Guideline Only/Harmonization of Guidelines = Similar

Guidelines

Build common understanding of regulated bioanalysis all over the globe

Ideally, one shared guideline

♦ How we can achieve it ? by continuing to champion:

• The cause of good science,

• Fit-for-purpose (tiered approaches) and

• Harmonization

Discuss & agree on scientific basis for BMV globally within BA community, but also with

agencies

Why don't we all follow EMA & MHLW?

Eliminate ‘Not invented here syndrome’

Legislation

Not discuss the superiority between scientifically-valid ways

Establish harmonized guidance/guidelines applicable to worldwide pharmaceutical

industries & regulatory agencies

Have a platform for scientific discussion on regulated bioanalysis

Like JBF, EBF, AAPS, CFABS, CBF, APA-India, ACBio... & GBC!

♠ What are the difficulties ? Not differentiating between studies with PK as primary endpoint (i.e.,

bioequivalence) and studies with PK as secondary endpoint; Do these require

the same quality and effort?

Many guidelines that have different specific requirements

Mindset –

Stake holders (Doers & Regulators), additional work

Un-availability of common platform

Diversified ideas (balancing act)

Bringing everyone on same platform

How to send a common message to community

“There is more than one right answer”

Bioanalysts have already established their own protocols/SOPs from their

past experiences

Gap between MHLW & Japanese industry

What do you expect from a Guideline?

A basic principle or detailed experimental procedure?

Change in the way of thinking in industries (although it is easy to follow a

guideline describing detail procedures)

♥ Their overcoming ways towards our goal Primarily intended to share scientific mind (not detail estimation

procedures)

Regulatory understanding of bioanalysis

Scientists to box-checkers

Good science that supports the questions being asked to drive new

drug development

Escalate to ICH, OECD, WHO, …!?

Workable Approaches like GBC to be thought off and executed

GBC created a good platform for discussions and collective

recommendations

GBC Recommendations published as white papers need to be

referred

Target to have a common BMV guidance like ICH-GCP

Information sharing among bioanalysts

Continued dialogue between regulators & industry

GBC and the regions:

• Bring more ownership of discussions to regions

Acknowledge that regional organizations are closer to the

scientists and can connect better to the regional regulators.

Regional organizations can become or continue to be:

• First point of contact for (regional) regulators

• Interface between bioanalytical community and other (regional)

communities (e.g. QA, PK, toxicology, pharmacology)

• Can GBC grow to become glue between regional BA

organizations, and if so, what is needed?

Building a global community

20

What about harmonization? • There may be 2 ways to realize:

one harmonized regulated bioanalysis guideline to be established

to accept bioanalytical data obtained according to one of guidelines for filing

in multiple regulatory bodies,

2010

Future vision

2001: FDA Guidance

GBC Present

2015 thereafter

Consideration of future of GBC

Should we take up biomarkers?

potential consequences of promoting an ICH guideline. • Highlights are:

Realistic and wider aspiration Harmonize regional differences; propose best global practices

Clarifications on ambiguities in different Guidelines

Clarify the scope of regulations (e.g. when is a validated assay required and when can other criteria be applied)

Encourage and promote discussions in BA community prior to stepping to ICH

If the idea of the harmonization is supported:

1. liaise with ICH parties to bring a proposal to the ICH Steering Committee 2. Transfer GBC’s activities to an ICH-type discussion 3. In practice, Philip Timmerman assigned within GBC to coordinate with

Harmonization Team leaders (and if needed other interested parties) the preparation of an ICH guideline development conversation

4. GBC may play a role in bringing scientist together, as part of existing teams or by forming new teams.

Continue Regular GBC Steering committee meetings to keep and stimulate connectivity of scientists and

regional professional organizations GBC continues to put our every effort into open communication for sharing information and interpretation of

guidelines and newly evolved science and technologies in bioanalytical practices.

Future Activities

GBC-SC is aware ICH doesn’t represent all regions/countries

But ICH Guidance is often used as reference in industry or Regulatory Authorities in non-ICH countries

ICH is seeking to renew its governance and frame work (quot. from HP)

Membership: More countries & regions

Coping with emerging countries & generic drugs

Increasing the role of regulators in ICH & improving transparency & openness of ICH and its processes

Increasing the involvement of other regulators as well as those global industry sectors that are affected by ICH guidelines

Identifying an alternative funding model that would make ICH less dependent in the future of the current form of industry funding

Setting up ICH as a legal entity as continuing activities in the current informal setting wil be difficult in the changed environment, with more members

Perspective, ICH?

23

‐ “All what we have to do is dream!”‐

GBC Steering Committee Mark Arnold (AAPS/BMS),

Binodh DeSilva (AAPS/BMS), Michaela Golob (EBF/Merck Serono),

Peter van Amsterdam (EBF/Abbott),

Philip Timmerman (EBF/J&J),

Fabio Garofolo(Algopharma, C-FABS)

Maria F. Riccio (ACBio)

Puran Singhal (APA-India/Alkem Labs)

Daniel Tang (CBF/ICON),

Shinobu Kudoh (JBF/Shimadzu Techno)

JBF the 6 Symposium

25 Feb., 2015

Pursuing a Dream 夢を追いかけて ! Boldly go where no one has gone before, for an early delivery of safer and efficacious

medicines and medications to patients and medical practices.

GBC Steering Committee

Thanks all the scientists having contributed to the GBC’s activities.