GLOBAL BIOANALYSIS CONSORTIUM

Regulated Bioanalysis

A Proposed Global Harmonization Process

presented by Peter Van Amsterdam and Rafael Barrientos, for GBC

at 1st Latin American Meeting on Bioanalysis,

May 2012, São Paulo - Brazil

1. Historic perspective on the evolution of Regulated Bioanalysis (Peter Van Amsterdam )

2. Recap on GBC goals and structure (Rafael Barrientos )

3. Harmonization team activities – GBC sessionsLatin America members presentation (Rafael Barrientos )

Outline

2

1. Historic perspective on the evolution of Regulated Bioanalysis

3

The early years of regulations

� 1965: EEC 65/65 (reaction to Thalidomide)• No real focus on bioanalysis

� 1978: 21 CFR 58 � 1982: OECD 1

• Both are General GLP guidelines (preclinical safety)• quality system ensure the uniformity, consistency, reliability, reproducibility,

quality, and integrity pre-clinical safety tests.

� Eighties (flowing over in the Nineties)• Increased focus on Bioequivalence studies (including paragraphs on bioanalytical

methodology to be applied• EU, FDA, Australia, Canada to lead

� BMV workshop – (Cristal City-I):• < 1990 = lack of uniformity in industry wrt validation bioanalytical methods• Cristal City-I was first international conference with focus on Bioanalytical method

validation and sample analysis• Resulted in Shah paper (Pharm Res. 1992;9:588-592).

4

Bioanalysis regulations >1990: simplified

Crystal City I CP(Shah Paper)

2001 FDA

Guidance

CC-I CC-II CC-IIICrystal City Conferences:

Conference papers (CP):

Regulatory Guidance:

Additional white papers:

CC-ISR

CC-ISR CPFast

1990 2000 2010

CC III CPViswanathan

CC II CPShah (chrom.)

Miller (LBA)

DeSilva

5

The broader and global context

20201960 1970 1980

1965:65/65/EEC

1979:US 58cfr21

1982:OECD GLP

A B C

A. scientist adopting home designed quality systemsB. scientist shopping for inspiration in other areas – peers, DIN, EPA,..C. scientist regrouped around Shah paperD. multiple countries issuing regulations of BA incl uded in BE guidelinesE. Industry increase frequency on coming together (e .g. APA, EBF, CVG)

some issue recommendation papers after (broad) inte rnal discussions

Anvisa RDC 899HC remove ISR

1988: Australian draft

CO6: 7581c

EMA draftAnvisa update

Open letter to FDA /EMA

GBC formed

More countries or regions likely to issue Guidelines

D

E

1990 2000 2010

Thalidomide

6

1995-2010A bucket full of other adjacent regulations:

Cfr 21 part 11ICH S3A, ICH-E6

ICH M3 (R2)MHRA GcLP

Etc…

20201960 1970 1980

1965:65/65/EEC

1979:US 58cfr21

1982:OECD GLP

A B C

Anvisa RDC 899HC remove ISR

1988: Australian draft

CO6: 7581c

EMA draftAnvisa update

Open letter to FDA /EMA

GBC formed

More countries or regions likely to issue Guidelines

D

E

1990

The broader and global context: more detail

2000 2010

Thalidomide

A. scientist adopting home designed quality systemsB. scientist shopping for inspiration in other areas – peers, DIN, EPA,..C. scientist regrouped around Shah paperD. multiple countries issuing regulations of BA incl uded in BE guidelinesE. Industry increase frequency on coming together (e .g. APA, EBF, CVG)

some issue recommendation papers after (broad) inte rnal discussions7

Technology developments

20201960 1970 1980 1990 2000 2010

TLC, GC(LC-UV)immunoassays

Sub mcg/mL

GC2, GC-MSGC-NPD/ECDHPLC-UV/flimmunoassays

ng/mL

TLCImmunoassaysbioassays

mcg/mL

GC2, GC-MSGC-NPD/ECDHPLC-UV/flLC-MS/MS,Old school Immunoassays

Sub ng/mL

LC-MS/MS,New generationBinding assays

pg/mL

New generationLC-MS/MS andBinding assays, other?

Sub pg/mL?

?

8

Highlights from technology

Manual low throughputMcg limits of quantification

Chromatography: Multiple assay formatsLBA: Limited assay formats

Paper raw dataPK of unchanged drug

� automated high throughput� sub-pg limits of quantification� 1 single assay format (LC-MS/MS)� multiple (and novel) assay formats� electronic raw data� PK/PD, TK, metabolites, biomarkers,..

20201960 1970 1980 1990 2000 2010

a lot happened

9

Other factors…Evolutions in the Pharma landscape around the turn of the century and how it (may have) impacted regulated bioanalysis across industry:

�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

�Patent expirations (of multi-billion 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

• CROs growing their business exponentially (also outside EU/US)– More people involved = more difference in how quality is achieved and documented– More regions involved

10

Back to Bioanalysis…

11

Crystal City I to…………………………………………………………..Crystal City II

patent expiry

technology developments

CRO booming

portfolio changes

2001

FDA

1990

2000

(Re-)united at last, or??See next slide

On the way from CC-I to

CC-II, a lot of bioanalytical

experience was built

12

> 2001……• Individual interpretations of Guidance � ambiguity

(individual flavors both from industry + HA inspectors (483))• Technology developments not covered in Guidance• Added value of new regulatory insights sometimes poorly

understood (ISR, FDC,…)• Regulatory awareness in an increasing number of regions

leading to multiple interpretations of FDA guidance • Some regions felt need for own guidelines (EMA, ANVISA)• More bioanalysis is performed in more areas (metabolites,

tissue, biomarkers, immune response, ..) requires new guidance

• More bioanalysis preformed outside EU/US, i.e. APAC, LA urging scientist to re-unite

From the FDA guidance onwards

Ligand Binding community didn’t feel their science was fully recognized in FDA Guidance (Findlay-2000, DeSilva-2003)

Industry united around one Guidance

2001

2010

Increasing number of bioanalysis meetings in all regions, sparking peer discussions

Open letter to the Health Authorities from EBF, AAPS, CVG and APA (Bioanalysis, 2010)

13

14

2010OR

2001

> 2012

Can GBC re-unite towards a harmonized understanding and

application of bioanalysis guidelines and convince the world?

15

… or will we all be playing the game differently?

Cooperation, team work, building bridges toward a g lobal harmonization in Bioanalysis

17

2. Recap on GBC goals and structure

18

Mission StatementMission Statement

Create an all inclusive Global Bioanalysis Global Bioanalysis ConsortiumConsortium (GBC) consisting of represented

scientific associations with world wide influence to merge existing or emerging bioanalytical guidance to create one, unified consensus unified consensus

documentdocument that can be presented to the regulatory bodies/health authorities in various countries.

19

GBC: Goals and ObjectivesGBC: Goals and Objectives

• To bring together stakeholders from the pharmaceutical industry, contract research organizations and academia to share current understanding of bioanalysis current understanding of bioanalysis guidelines,guidelines, identify differences in these guidelines or differences in the interpretation or application thereof to routine regulated bioanalysis.

• To come forward with recommendationsrecommendations 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.

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• To invite relevant stakeholders, from industry, academia, Health Authorities and regulatory bodies, to jointly discuss the GBC recommendations at a global global conference(s)conference(s) in order to achieve globally agreed guidelines on bioanalysis.

• Going forward, to serve as a pivot pointpivot point on the continued harmonized interpretation and/or updates of globally agreed guidelines.

GBC: Goals and ObjectivesGBC: Goals and Objectives

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Organization Chart

Harmonization Team # 1

Harmonization Team # 2

Harmonization Team # ‘n’

Steering Committee ( GBCGBC--SCSC)

Scientific Leadership Team ( GBCGBC--SLTSLT)

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North America (US + Canada)

• Mark Arnold (AAPS)

• Binodh DeSilva (AAPS)

• Fabio Garofolo (CFABS)

Latin America (South America + Mexico)

• Rafael Barrientos (Acbio)

Asia Pacific (Asia + Pacific area)

• Shinobu Kudoh (JBF)

• Shrinivas Savale (APA-India)• Daniel Tang (SBDG&BBDG)

Europe (Europe + Africa/Middle East)

• Peter van Amsterdam (EBF)• Michaela Golob (EBF)• Philip Timmerman (EBF)

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Steering Committee Members

P.Timmerman D. Tang, S. Kudoh, P. van Amsterdam, S. Savale, M. Golob. F. Garofolo, B. DeSilva, R. Barrientos, M. Arnold,

Live Live

EBF: European Bioanalysis ForumAAPS: American Association of Pharmaceutical ScientistsCFABS Canadian Forum for Analytical and Bioanalytical Sciences ACBio: Assosiacao BRASILEIRA DOS CENTROS DE BIODISPONIBILIDADE E BIOEQUIVALENCIA BBDS/SBDS:Beijing Bioanalytical Discussion Group/Shanghai Bioanalytical Discussion Group

Active Harmonization TeamsA ll

Top ics C om m on

to a ll m olecules

A

A 1

Scope and regula tionsA 2

Tie red approaches

for m ethod valida tion

A 3

M ethod Transfer,

partia l/ cross valida tions

A 4

R e ference standards

and reagents

A 5

Sam ple M anagem ent

A 6

Stab ility

A 7

R epeat ana lysis

and ISR

A 8

D ocum enta tion

A 9

A na lytica l Instrum ent

Qualification

A10

New Frontie rs

A 11

B iom arkers

L arge M olecule

L

L1

L arge m olecule

specific run acceptance

L2

L arge m olecule

specif ic assay opera tion

L3

A ssay form ats

L4

Reagents and

their Stab ility

L5

Autom ation practices

in LM b ioana lysis

L6

Im m unogenic ity

e ffect on Pk

Sm all M olecule

(Chrom atographic

A ssays)

S

S1

Sm all m olecule

specific run acceptance

S2

Sm all m olecule

specific assay operation

S3

Chrom atographic

R un Qua lity A ssessm ent

24

Team Leaders SC Sponsor Team Leaders SC Sponsor

A1: A2: A4: A6:A11:

Surendra BansalSteve LowesJoseph BowerNico van den MerbelRuss Weiner

Philip TimmermanEBF, Europe

Daniel Tang BBDS &

SBDS , Asia Pacific

Shinobu Kudoh JBF, Asia Pacific

L1: L2: L3: L4: L5: L6:

Marian KelleyLauren StevensonSherri Dudal Lindsay KingScott DavisJeff Sailstad

Michaela Golob EBF , Europe

Fabio Garofolo CVG, N America

Binodh DeSilva AAPS , N America

A3: A5: A7: A8:

Ray Briggs Mike Redrup Eric FluhlerTom Verhaeghe

Peter van Amsterdam EBF , Europe

Shrinivas SavaleAPA-India, Asia Pacific

A9: Chad Briscoe A10: Bob Bethem/

Chad Ray S1: Douglas FastS2: Eric WoolfS3: Stuart McDougall

Rafael Barrientos ACBio, L America

Mark Arnold AAPS , N America

SC Sponsorship of Harmonization Teams

Latin America , 11

A1 Myriam Salvadori A11 -

A2 Vinicius Resende L1 -

A3 Paulo Galvinas L2 Mario Dominguez

A4 Katia Pastre L3 -

A5 Thales Cardoso L4 -

A6 M. Francesca Riccio

L5 -

A7 Vinícius Resende L6 -

A8 Myriam Salvadori S1 Maristela Andraus and Gabriel Marcelín

A9 Katia Pastre S2 Miguel Vago and Gabriel Marcelín

A10 - S3 M. Francesca Ricio

APAC China, 7 A1 1 A11 -

A2 - L1 1

A3 1 L2 -

A4 - L3 -

A5 - L4 -

A6 1 L5 -

A7 1 L6 -

A8 - S1 -

A9 1 S2 -

A10 - S3 1

APAC India , 21A1 1 A11 -

A2 1 L1 2

A3 1 L2 1

A4 - L3 1

A5 1 L4 -

A6 1 L5 -

A7 2 L6 1

A8 1 S1 1

A9 1 S2 3

A10 1 S3 2

APAC, 20A1 1 A11 1

A2 1 L1 1

A3 1 L2 1

A4 1 L3 1

A5 1 L4 1

A6 1 L5 1

A7 1 L6 1

A8 1 S1 1

A9 1 S2 1

A10 1 S3 1

Europe , 55A1 1 A11 3

A2 3 L1 3

A3 3 L2 2

A4 2 L3 4

A5 3 L4 2

A6 3 L5 2

A7 3 L6 1

A8 3 S1 3

A9 2 S2 2

A10 7 S3 3

N. America , 87

A1 4 A11 4

A2 5 L1 4

A3 3 L2 4

A4 2 L3 5

A5 3 L4 6

A6 3 L5 5

A7 4 L6 11

A8 3 S1 5

A9 4 S2 3

A10 5 S3 4

HT Leaders Objectives •Remove concepts of company or region from your thinking - you’re leading a global effort.•Facilitate discussion, don’t push your personal agenda

Teams are to develop science-based best practices•Recognize that consensus may not be possible. People with different views will spark vigorous discussion. •Prevent bullying by the loudest voice. Allow and stimulate less extrovert people to share their opinion and experience•Recognize that some governments /regions may have regulations that are outdated or inconsistent with a science-based approach. Be prepared to defend proposals that conflict with existing regulations.

80:20 Rule •Not all items within the Scope of the Team need to be redone, in fact 80% may already have industry-regulatory consensus

Harmonization Team Objectives

27

HT activities

Compile regional information on regulations and practices related to the Team’s scope

• Share regulations with other Team • A lot of prework has been done

Evaluate scope list to categorize those that: • Are fully agreed to • Are generally agreed to • Have no agreement

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HT activities

• For those that are agreed to write science-based language as proposed position

• For those that are generally agreed to , discuss differences and develop science-based position, write science-based language as proposed position

• For those that are not generally agreed to , prioritize the list to enable discussion on those with the greatest impact to the bioanalytical community• Have internal team discussions and where possible, develop recommendations• Where no consensus is achieved, provide arguments on both sides

• Utilize GBC SC and other HT leaders for input

Team members should reach back to regional organizations for input• Query regional organization membership on positions on a topic(s)

• Coordinate across Teams. Regional memberships will lose interest if frequently bombarded with requests.

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HT activities

Proposals and outcome

• Write proposals in a clear and concise manner that are suitable for publication, include references to existing literature and regulations

• As noted above, where proposal conflicts with existing regulations, additional details and discussion may be needed

• Create slide deck for communication of proposals that go into greater depth and may contain data. This will be foundation of

• Presentations at regional meetings

• Presentation at international meeting• Publications in international journals• Note: timing of publications in relation to the Global Meeting

• Where no consensus is achieved, provide arguments on both sides

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New insights developed at GBC-SC meetings

Potential win-win

• Connect GBC better with the regions � Reconnection with supporting organizations as our day to day supporters� All regions get expanded opportunity to be involved

• Engage and inform a broader scientific community in advance of the global meeting� Allow BA community to comment within the comfort zone of their region � Allow BA community to comment to their regional organizations

• Provide the opportunity to publish a summary of thinking in advance of the global meeting � Allow global community of practice to know what’s coming � Be more engaged in the global meeting and not be caught by surprise

• Create visibility, recognition and connectivity in regions � for HT-L and HT members� for SC members

• Create flexibility to present on topics in need of influencing current thinking of regulators or on emerging guidelines

LA representative activities within GBCLA representative activities within GBC

• TCs:– SC only meetings (every 2 weeks)

– HTLs meetings (as needed)

– Sponsored HTLs (every 3rd Monday of each month)

– LA HT members: as needed

• Face-to-face meetings:– SC only: Barcelona/Spain – Nov. 11

– SC + HTLs: San Antonio/USA – Mar. 12

• Reporting news:– Every meeting @ Acbio bioanalysis focus group

– Acbio´s Board meetings

– Emails throughout the RLABB (Rede Latinoamericana de Bioequivalência)

– Meetings with Cobio/Anvisa

How to move forward?How to move forward?

What triggered this change?What triggered this change?• FDA plan/communication to release draft of updated

guidance in summer. As follow up, AAPS/FDA will organize a Cristal City V (CC-V) meeting in Washington DC area within 90 days of draft guidance release

• Consequence for GBC meeting:

– CC-V and GBC meeting involve the same audience separated potentially by only few weeks or months

– Travel restrictions in industry will limit delegates to travel to two similar meetings in 2 different regions

– Attendance to CC-V may be prioritized by industry over GBC meeting

– By connecting the GBC meeting in time and place, GBC and delegates can participate in both meetings;

• Provide consolidated feedback to and get input from the Global Community on draft recomendations (=original intenten of GBC meeting)

• At the CC-V meeting, share this consolidated GBC as input into FDA draft Guidance (=impact as per GBC Mision and Vision)

Additional reflectionsAdditional reflections• GBC needs to ensure their global mission is not

redirected to only providing input on draft FDA guidance but maintains it global perspective

– Scope and agenda of GBC remains unchanged

– Upon release of the draft FDA guidance, Harmonization Teams (not L) needs to ensure that the scope and content of the team discussions does not change relative to FDA guidance

• Nevertheless, major discussion points can be identified in preparation for discussion @CC-V

– By intensifying the feedback from other regional meetings and earlier publication of our draft recommendation slides on the GBC website from April onwards, scientist in all regions should feel invited to also intensify their input.

UpdatedUpdated Proposed way forwardProposed way forward

HT- L identification

2011

Start up phase

2012

HT identification

HT working on content

working close with SLT

Identified regional meetings

• Invite 4-5 topics to present the progress of their teams and to share.

• Present high level progress on other topics and Get input

SLT f-2-f

Consolidation

and joint

discussion of

all topics in

preparation

of Global

Meeting

Global Meeting

2-day

Conference in

Washington DC

(USA), 2 days

before Crystal

City V

Other regional meetings

SLT f-2-f

Consolidation

and joint

discussion of

all topics in

preparation

of Global

Meeting

Global Meeting

2-day

Conference in

Washington DC

(USA), 2 days

before Crystal

City V

UpdatedUpdated Proposed way forwardProposed way forward

Zoom inZoom in

Proposed way forward Proposed way forward -- detailsdetails

Global

Meeting

‘Recommendation

Slides’

on GBC website for

all to read, in

preparation of

Global Meeting

March e.o. June

max. 90 days

post release

of FDA draft

Guidance.

Current

exact date

unknown

2012

HT-L/SC F2F

San Antonio (Tx)Consolidation and

joint discussion of

all topics in

preparation of

Global Meeting

Crystal City V

April

draft slides

Consolidatio

n of slides

from all HTs

from SA (Tx)

on GBC

website

Intensify consolidation

and consultation from

teams and from regional

meetings, building on

slides presented at HT-L

in San Antonio

APAC

CPSA

e.o.

April

LA

ACBio

mid

May

EU

EBF

mid

June

APAC

JBF

mid

Aug.

2 days prior

to CC-V

NA

NBC

mid

May

US

LoL

e.o.

July

Continued slide iterations, based on HT team

meetings and input form the regions

3. Harmonization team activities – GBC sessionsLatin America members presentation

GBC sessions at the GBC sessions at the I Latin American Meeting in BioanalysisI Latin American Meeting in Bioanalysis

Day 1Day 1

13:30 13:35 OpeningRafael Barrientos (LA GBC-SC

member)

13:35 14:05Regulated Bioanalysis: A Proposed Global

Harmonization ProcessPeter Van Amsterdam (on behalf

Steering Committee GBC)

14:05 14:20 GBC update Rafael Barrientos (LA GBC-SC member)

14:20 14:40 HT A1 - Scope and Regulations Myriam Salvadori

14:40 15:00 HT A2 - Tiered approach Vinícius Rezende15:00 15:20

15:20 15:40 HT A3 - Method transfer Paulo Galvinas15:40 16:10

Coffee break

Roundtable

GBC session - I

GBC session - I

GBC sessions:GBC sessions:-- 3 sessions during the meeting3 sessions during the meeting-- 11 presentations (20 minutes) from activities of HT s11 presentations (20 minutes) from activities of HT s-- 3 roundtables (30 minutes each)3 roundtables (30 minutes each)

GBC sessions at I Latin American Meeting in Bioanal ysisGBC sessions at I Latin American Meeting in Bioanal ysisDay 2Day 2

09:50 10:20HT A4 - Reference standards and reagents /

A9 - Analytical Instrument QualificationKatia Pastre

10:20 10:40 HT A5 - Sample Management Thales Cardoso10:40 11:00

11:00 11:20 HT L2 - Assay operations Mario Dominguez11:20 11:40 HT A6 - Stability M. Francesca Riccio

11:40 12:00 HT A7 - Repeat analysis and ISR Vinícius Rezende12:00 12:20

12:20 13:5013:50 14:10 HT A8 - Documentation Myriam Salvadori

14:10 14:30 HT S1 - Specific run acceptance Maristela Andraus

14:30 14:50 HT S2 - Assays operations Miguel Vago

14:50 15:10 HT S3 - Chromatographic run quality M. Francesca Riccio

15:10 15:40

Lunch

Roundtable

Roundtable

GBC session - II

GBC session - II

GBC session - III

Coffee break