gcp meets glp- the sponsor perspective

Peter van Amsterdam

Head Bioanalytics, Abbott Healthcare Products

DARQA themadag ‘When GCP meets GLP’, 30 Jan 2015, Utrecht

The views and conclusions presented in this slide deck are

those of the author/presenter and do not necessarily reflect

the representative affiliation or company's position on the

subject.

Exaggeration is often chosen as a style model to emphasize

the similarities or differences between various situations.

The focus is on the bioanalytical arena

30-Jan-2015 GCP meets GLP @DARQA 2


1. Some history lessons

2. Outsourcing

3. Perspective / Perception

4. GCP in the BA lab

5. Anomalous results

6. Case studies

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

1978: 21 CFR 58

1982: OECD 1 o Both are General GLP guidelines (preclinical safety)

o Quality system ensure the uniformity, consistency, reliability, reproducibility, quality, and integrity pre-clinical safety tests.

Eighties (flowing over in the Nineties) o Increased focus on Bioequivalence studies (including paragraphs on

bioanalytical methodology to be applied)

o EU, FDA, Australia, Canada to lead

BMV workshop – (Crystal City-I) o < 1990 = lack of uniformity in industry wrt validation bioanalytical methods

o Crystal City-I was first international conference with focus on Bioanalytical method validation and sample analysis

o Resulted in Shah paper (Pharm Res. 1992;9:588-592).



Crystal City I Shah

2001 FDA

Guidance

CC-I CC-II CC-III Crystal City

Conferences

Conference papers

Regulatory

Guidance

Additional white

papers

CC-IV

(ISR)

CC-IV Fast

1990 2000 2010

CC III Viswanathan

CC II Shah (chrom.)

Miller (LBA)

DeSilva


2020 1960 1970 1980

1965:

65/65/EEC

1979:

US 58cfr21

1982:

OECD GLP

A B C

Anvisa RDC 899

HC removes ISR

1988:

Australian draft

CO6: 7581c

EMA draft

Anvisa update

Open letter to

FDA & EMA

GBC

formed

More countries or

regions likely to issue

Guidelines

D

E

1990 2000 2010

Thalidomide

A. scientist adopting home designed quality

systems

B. scientist shopping for inspiration in other areas

– peers, DIN, EPA,..

C. scientist regrouped around Shah paper

D. multiple countries issuing regulations of BA included in BE

guidelines

E. Industry increase meeting frequency (e.g. APA, EBF, CVG)

recommendation papers after (broad) internal discussions

EMA final

MHLW chrom

MHLW LBA

CFDA draft


A bucket full of other

adjacent regulations:

21 CFR 58 (GLP), OECD-

GLP, 21 CFR 11 (CSV),

ICH-S3A (TK), ICH-E6

(GCP), ICH M3 (MIST),

MHRA GCLP, EMA GCLP,

21 CFR 320.29 (BE), …,

…, …,

1963 FDA drafting the GMP concept

1964 Declaration of Helsinki

1973 New Zealand draft GLP concept

1978 FDA GLP final

1978 FDA GMP final

1981 OECD GLP

1982 MHLW GLP

1983 EPA GLP

1989 Revised EPA GLP

1989 ICH global standards for Clinical Research

1997 21 CFR 11

1997 Revised OECD GLP

1997 ICH GCP

2001 EU Clinical Trials directive

2005 EU GCP directive

2009 MHRA GCP for laboratories

2009 WHO GCLP

2012 EMA 'GCLP' reflection paper


Hmmm….

~1980 GLP

~2000 GCP

~2010 GCLP

Within Pharma, bioanalytical departments are often part of

DMPK/Research.

o Basically a pre-clinical (GLP) area

o Science & technology driven

o High attrition rate

Within CROs, bioanalytical departments are often core

business.

o Can cover all R to D area’s (GLP and)

o Science & technology driven

o Client focus, costs & timelines driven




2. Outsourcing




6. Case studies

By design, e.g.:

Corporate strategy

o Science in house

o Operational external

Flexible workforce

o Cope with peaks in workload

o No redundancies in slow periods

Excess or shortage of money

o R&D expenditures as % of sales

Improvement of deliverables, e.g.:

Better suited then own labs

o Better equipped

o GxP compliant

o Right location

Faster then own labs

o Larger workforce

o More instruments

o Routine power

Specific expertise


CRO selection

Oversight

Monitoring


Sponsor Clinical QA Stats Bioanalytical Operations Trial managers CRAs Supplies Contracting Legal Data management Regulatory Marketing

CRO Project manager Recruitment CRAs Data management Pharmacokinetics Statistics Legal Regulatory QA Medical writers Archives, TMF


Central Lab

Project manager

Logistics

o Kits

o Samples

Kit building

Safety analysis

Data basing

Reconciliation

QA

Reporting

Bioanalytical Lab(s)

Study lead

QA

Management

Sample receipt

Archives



Other Ethical Committee Safety Review Board Health Authorities

And Public disclosure Share holders Senior management Financial analists

Clinical sites Investigators Hospital staff Recruitment Inclusion / Exclusion Medical history Dosing Observations Sampling

Pharmacists



2. Outsourcing




6. Case studies

In the Bioanalytical (‘GLP’) Environment

BioAnalysis Man Knows BMV Guidelines

Knows (OECD) GLP

Knows (a bit) CSV

Knows the (relevant) SOPs

Knows his science

Can handle equipment

Can perform validations

Can run samples

Can report the results

23 GCP meets GLP @DARQA 30-Jan-2015

In the Research (GLP) environment

BioAnalysis Man

Knows bioanalysis

Knows (OECD) GLP

Knows a bit about DMPK

Knows a bit about the study

Takes care of the PK/PD samples

Part of team

Report appendix

24 GCP meets GLP @DARQA 30-Jan-2015

In the Clinical (GCP) environment

25 30-Jan-2015 GCP meets GLP @DARQA

BioAnalysis Man

Knows bioanalysis

Knows some GCP

Knows a bit about DMPK

Knows a bit about the study

Takes care of the PK/PD samples

May be part of sub-team

Report appendix / part of the reported data

In the BA lab, bioanalytical objectives o “You can do anything you want“

• Change method, amend something, redo an experiment, ….

• (as long as you follow some SOPs and QA and management rules)

In a GLP study o “You can mostly do what you want“

• Change method, amend something, redo an experiment, BUT …

• (as long as you follow the SOPs, protocol, SD input/agreement and QA and management rules)

In a GCP study o “You can hardly do what you want“

• NO to change of method, amend something, redo an experiment, UNLESS ..

• (and follow the SOPs, protocol, sponsor input/agreement, patient rights, and QA and management rules, ….)




2. Outsourcing




6. Case studies


From: Principles and Practice of ICH GLP

Rebecca Luk, Pfizer (2012)


EMA:

EMA BMV: The validation of bioanalytical methods and the analysis of study samples for clinical

trials in humans should be performed following the principles of GCP. Further can be found in

the “Reflection Paper for Laboratories That Perform The Analysis Or Evaluation Of Clinical Trial

Samples.” (EMA/INS/GCP/532137/2010).

EMA BMV: The validation of bioanalytical methods used in non-clinical pharmaco toxicological

studies that are carried out in conformity with the provisions related to Good Laboratory Practice

should be performed following the Principles of GLP.

EMA BE: The bioanalytical part of bioequivalence trials should be performed in accordance with

the principles of GLP. However, as human bioanalytical studies fall outside the scope of GLP, the

sites conducting the studies are not required to be monitored as part of a national GLP

compliance programme.

Note: OECD GLP

Draft FDA: Pre-clinical adhere to GLP (21 CFR 58), Clinical adhere to 21 CFR 320.29

ANVISA: Not addressed

MHLW: Not clearly addressed

Availability of the clinical protocol

Central lab between clinic and BA lab

Lab manual

Sample roster ≠ sample tube label

Data base (LIMS) requirements

Timelines

Reporting final data before issuing final report

Who to report what to (communication plan)

Patients and IC

CRFs



From: Unexpected Results in a Bioanalytical Laboratory – a Safety and Compliance Issue?

Silke Luedtke, Boehringer Ingelheim (2011)

Excerpt from the MHRA "Guidance for the notification of serious breaches of GCP or the trial protocol", released 2006, update Jan 2013

non-compliance with GCP or the protocol If this non-compliance has a significant impact on the integrity of trial subjects in the UK or on the scientific value of the trial, this will constitute a serious breach. For example, widespread and uncontrolled use of protocol waivers affecting eligibility criteria, which leads to harm to trial subjects in the UK or which has a significant impact on the scientific value of the trial. Another example would be an investigator repeatedly failing to reduce or stop the dose of an IMP in response to a trigger defined in the protocol (for example, abnormal laboratory results).

Examples of Serious Breaches Notified to MHRA Investigator site failed to reduce or stop trial medication, in response to certain laboratory parameters, as required by the protocol. This occurred with several subjects over a one year period, despite identification by the monitor of the first two occasions. Subjects were exposed to an increased risk of thrombosis.




2. Outsourcing




6. Case studies

Is the bioanalytical laboratory (CRO) able to:

o Identify significant deviations from the protocol?

o Identify misdosing?

• Overdosing

• Underdosing

• Wrong medication

o Identify differences in drug clearance (a subjects ability to metabolise or excrete an investigational drug)?

o Identify sloppy conduct at a clinical site?

o Report in a timely manner?

o Report to the right parties involved?


Yes, e.g. in a non-placebo controlled trial with cross-over

design some subjects had normal PK profiles for treatment

1 but hardly any profile for treatment 2

subjects did not take medication in treatment cycle 2

clinic did not notice as e.g. no vomiting etc was reported

Could be a compliance issue due to misconduct


Yes, e.g. placebo or reference drug and active treatment

mixed-up

may not be a safety issue for subject if the dose was

approved for the trial

Compliance issue as it demonstrates that procedures at

the clinic are prone to error


Yes, e.g. some or all subjects show much higher plasma

levels than expected (e.g. from sponsor info or literature or

comparison to historic data)

may be a safety issue for the subject(s)

Could be a compliance and safety issue as it indicates

that the study is not executed according to protocol and

subjects may have been overdosed


Yes, e.g. some or all subjects show much lower plasma

levels than expected (e.g. from sponsor info or literature or

comparison to historic data)

may be a safety issue for the subject(s): undertreatment

of patients

Could be a compliance and safety issue as it indicates

that the study is not executed according to protocol and

patients may have been underdosed


Yes, but may need help from a DMPK scientist (from the

sponsor)

e.g. profile differs significantly from others, no hint for

analytical problem like matrix effect

Could be a safety issue


Yes, e.g. sample mislabeling, wrong collection tubes, wrong

matrix, large volume variations, strongly hemolyzed, …

may not be a safety issue

sloppiness/errors in sample collection and handling can

be indicative of bigger compliance issues

Compliance issue as it demonstrates that procedures at

the clinic are prone to error


Not always but very often, i.e. for clinical trials were the

bioanalyst is unblinded and sample analysis is performed

while the trial is still ongoing


Yes, if there is a communication plan

Maybe yes, with known contact details of key (sponsor)

people

Likely not in cases of ‘thrown over the fence’




2. Outsourcing




6. Case studies

In een multiple ascending dose study met een NCE worden plasma monsters direct na de 1e en na de 7e dag geanalyseerd door een CRO BA-lab. Gebaseerd op de PK (plasma spiegels) en de klinische observaties wordt door de sponsor de beslissing genomen wat de volgende (hogere) dosis gaat worden of dat de studie gestopt moet worden. Wanneer de sponsor de resultaten van de eerste (laagste) dosering krijgt valt op dat er 1 subject is met 5-10x hogere plasma spiegels dan de overige 5 subjects op drug.

Hebben we een probleem?

Wat had het BA lab (eerder) moeten doen?

Wat moet de sponsor doen?

Kan de volgende hogere dosering volgens plan plaatsvinden?


Om een op tijd belangrijke beslissing te kunnen nemen in een fase III programma is het gewenst dat de resultaten van een zeer grote fase I dubbelblinde DDI studie halverwege de bioanalyse pharmacokinetisch verwerkt en geëvalueerd worden. Hiervoor wordt een derde onafhankelijk partij gecontracteerd zodat de sponsor en de onderzoeker en biometrie van de CRO blind kunnen blijven. Het lab stuurt de data en randomisatielijst naar de 3e partij en de sponsor …



Wat moet het BA lab doen?

Wat moet de 3e partij doen?


Bij de pharmacokinetische verwerking en statische analyse

van een dubbelblinde PK studie blijken 3 subjects zeer

vreemde PK curves te laten zien. De sponsor wordt gevraagd

wat met deze subjects te doen. De bioanalyticus van de

sponsor ontdekt dat er bij deze 3 subjects zeer waarschijnlijk

de data van de QCs tussen de monster data is gekomen

waardoor ‘alles is opgeschoven’

Curve 1: QC-HI ipv t=0, QC-ME ipv t=1, QC-LO ipv t=2, t=0 ipv t=3 …

Curve 2: t=n-21 ipv t=02, t=n-11 ipv t=12, t1=n1 ipv t=22, t=02 ipv t=32 …


Wat had het BA lab (eerder) moeten doen?



Na 3 succesvolle fase I studies wordt een bioanalyse methode

enigszins aangepast: ander merk HPLC kolom en wordt bij de

MS/MS overgegaan van API-CI naar ESI (zachtere ionisatie).

De methode wordt prachtig gevalideerd en toegepast bij studie

nummer 4. De chromatogrammen van vrijwel alle subject

samples laten onverwacht in meer of mindere mate een

schouder zien op de analyte piek.



Wat moet het BA lab doen?


DARQA for giving me the opportunity to present at their

meeting.

The regulators and inspectors for stimulating us to

continuously improve our work

Philip Timmerman (JnJ) for some of the ‘History’ slides

Silke Lüdtke (BI) for some of the ‘Anomalous’ slides

You, for your attention


gcp meets glp- the sponsor perspective

Health & Medicine