Damian o'connell - Transformation of the global clinical trials footprint in a big Pharma company -...

Case Study

Transformation of the global clinical trials footprint in a big Pharma company

Key Learnings as to How International BioPharma views Ireland

Damian O’Connell MD PhD BSc

VP Clinical Research

Pfizer

Company

logo here 1

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Overview

  Rationale for change

  Baseline status and end game vision

  Country selection process

  The new foot print

  Why Ireland is Non-Core

  Developing a Functioning Clinical Research System

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Rationale for change   Drug development costs are increasing dramatically

although output is flat or declining

  It takes more trials and more patients per trial to get a new drug application approved;

  New approaches e.g. pharmacogenomics, and reduced attrition is resulting in increased expenditure on development operations activities

  Study start up and subject recruitment are major challenges

  Speed, Quality and Cost reduction are strategic imperatives

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Rationale for change: Length of Protocols is Increasing

Length of Protocol incl. Appendix vs. Median FAP-LSFV Cycle Time

Median Length of Protocol incl. Appendix Over Time

•  Median length of Pfizer protocols grew 18 pages

•  This trend is not phase or TA dependent

•  Protocols longer than 100 pages have FAP-LSFV cycle time medians 97% > than with < 60 pages

•  This is not driven by phase of study or TA

Med

ian

FAP-

LSFV

Cyc

le T

ime

•  (n=1, 9, 10)

Length of Final Protocol incl. Appendix in Pages •  (n=8,

11, 15) •  (n=6, 5,

10)

Med

ian

Leng

th o

f Fin

al P

roto

col i

ncl.

App

endi

x

•  (n=18) LSFV Year

•  (n=26) •  (n=32)

* Source: Data manually extracted from 76 protocols that span all Phases and CVMED, GU, Neurology, Oncology, and Pain Therapeutic Areas

•  (Phase I, II, III)

5 5

Rationale for Change: Number of Eligibility Criteria is Increasing

Number of Eligibility Criteria vs. Median FAP-LSFV Cycle Time Median Number of Eligibility Criteria Over Time

•  Median # of eligibility criteria (sum of inc/exc) grew most b/w 2005 and 2006

•  Trend is not phase or TA dependent

•  # of eligibility criteria has some impact on FAP-LSFV cycle times; most often with >30 criteria

Med

ian

FAP-

LSFV

Cyc

le T

ime

•  (n=3, 7, 4)

Number of Eligibility Criteria •  (n=3,

15, 6) •  (n=12,

10, 14) •  (n=18) LSFV Year

•  (n=26) •  (n=32)

Med

ian

Num

ber o

f Elig

ibili

ty C

riter

ia



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Rationale for Change: Number of Protocol Procedures is Increasing

Number of Procedures/Protocol vs. Median FAP-LSFV Cycle Time Number of Procedures/Protocol Over Time

•  Number of procedures are increasing by year •  Trend consistent with industry data (Tufts

CSDD, Getz) •  Trend consistent across all phases and in the

Oncology and Pain TAs.

•  Increase in the number of procedures correlates with increase in cycle times; especially if > 60 procedures

Med

ian

FAP-

LSFV

Cyc

le T

ime

•  (n=3, 5, 3)

Number of Procedures/Protocol Criteria •  (n=1, 8,

10) •  (n=2, 3,

12)



Med

ian

Num

ber P

roce

dure

s pe

r Pro

toco

l

LSFV Year •  (n=18) •  (n=25) •  (n=29)

20%

19%

11%

2%

24%

5% 9%

2%

1%

18%

2% 10% 3%

3%

52

41 35

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Rationale for Change: Number of CRF Enterable Fields is Increasing

# of Enterable Fields Over Time

•  Median # of enterable fields increased by 103%

•  Pfizer protocols require investigators to collect more data per protocol

•  Upward trend seen across all phases and TAs

•  Increase in the number of enterable fields appears to increase cycle times

# of Enterable Fields vs. Median FAP-LSFV Cycle Time

•  (n=15) LSFV Year

•  (n=20) •  (n=31)

Med

ian

Num

ber o

f Ent

erab

le F

ield

s

Med

ian

FAP-

LSFV

Cyc

le T

ime

•  (n=2, 6, 10)

Number of Enterable Fields •  (n=2, 3,

6) •  (n=4, 4,

4) •  (n=1, 8,

5) •  (n=4, 4,

4)



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Baseline Country Clinical Trials Footprint

Indicates country where an R&D based office is located

Indicates country where R&D studies are being conducted, but no office

62 Country Clinical Operations groups 20+ additional countries where clinical studies are performed

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Europe Asia Can/Africa/Middle East

Study Distribution - September 2008

Canada Protocols 88 22% Patients 3871 4%

US Protocols 308 78% Patients 34599 32%

EU Non EM Protocols 165 42% Patients 26590 24%

LA/AFME Protocols 83 21% Patients 13386 12%

Global Protocols 395 Patients 109256

Asia (excl. AU, KOR) Protocols 43 11% Patients 6776 6%

Korea Protocols 50 13% Patients 2573 2%

Australia Protocols 53 13% Patients 2155 2%

EU EM Protocols 71 18%

Patients 19306 18%

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Baseline Status Pfizer patient recruitment cycle times (FAP to LSFV) exceed industry benchmarks and inhibit Pfizer’s ability to quickly bring drugs to market

•  Not in Scope: Phase 1 volunteer, Ph 3b/4 regional and country sponsored studies

•  Baseline Data Set included: 273 protocols, 75 countries, 8313 total sites, 5666 unique sites, 89,587 patients across 11 therapeutic areas

465

441

Pfizer Actual - All patient studies, all TAs, phases I, II, III and globally sponsored IV, with LSFV on or after 01-Jan-2005

Pfizer Targets – “Best in class” cycle time

CMR Industry Benchmark - Centre for Medicines Research Global Clinical Programmed Rpt v1.0 (May 2007)

FAP to FSFV FSFV to LSFV

Cycle Time Performance 2005 – 2008*

Project and Data Analysis Scope * Calendar Days

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Country Selection •  Recommendations from root cause analysis:

–  ≥50% reduction in number of countries with Pfizer has infrastructure/staff •  Assumed a significant reduction in global clinical trial volume •  Assumed reduction in relative allocation of EU patient volume •  Anticipated shift of clinical trial placement to lower cost and/or high speed regions

(NB quality maintained) •  Classified country operations into core and non core countries

Definitions

Non Core

•  No interruption to ongoing, committed studies that will be performed by Pfizer staff

•  Attrition of staff until all commitments accomplished •  New studies (by exception) to be conducted by CROs in these

countries

Core •  No interruption to ongoing, committed studies •  Place studies actively and increase staff accordingly

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Country Selection Quality and risk filter

1

Core

Non Core

All countries

  Countries with high political instability and/or environ-mental risk are excluded

  Population is defined as ages 15 – 65

  Countries with population ≤ 3M are excluded

  Performance-based metrics include startup speed, cycle time (regulatory to LSFV), subjects /site, recruitment reliability, MBR*, and subjects/ FTE**

  Metrics were grouped into three categories: high, medium, and low

Population filter

2 Evaluate countries based on performance metrics

3 Prioritize based on quantitative and qualitative analysis

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*Monitor Burden rate

** FTEs include both permanent and contracted staff at all levels

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Country Selection Quality and risk filter

All countries

1

• Political stability – Economist Intelligence Unit • Availability of qualified, experienced Investigators • Adequacy of Pfizer in-country clinical research/monitoring infrastructure • Audit performance history

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Country Selection Population filter

Remaining countries

2

•  Population is defined as ages 15 – 65 years

•  Countries with population ≤ 3M are excluded

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Country Selection

•  Country performance is assessed against evaluation criteria broken down into three categories: good, acceptable, and poor performance for each metric

Assessment of performance metrics

3

Startup Speed

Cycle Time

Subjects per site

Recruitment Reliability

MBR ($000)

Pts/FTE

Good Acceptable Poor

≤90 90-135

>135

≤270 270-360 ≥360

≥12 8-12 ≤ 8

≥115 75-115 ≤75

≤ 150 150-250 ≥250

≥55 40-55 ≤40

Start up speed – median #days from receipt of protocol package to latter of regulatory approval or ethics approval Cycle time – median #days from regulatory approval to LSFV Recruitment reliability - # actual subjects randomised as percentage of # planned per study Monitor Burden Rate (MBR) – Fully loaded annual cost of a monitor/CRA

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Ranges for Performance Metrics

Clinical Trial Metrics & Ranges

Metric Range Average Startup Speed 57 – 656 days 154 days Final approved protocol to last subject first visit

109 – 1508 days 373 days

Subjects /site 4 – 83 subjects 15 subjects

Recruitment reliability

9 - 494 % 133 %

Monitoring Burden Rate*

$26K – $363K $141K

Subjects/ FTE 6 – 284 subjects 60 subjects

Performance metrics

*Monitoring Burden Rate is the fully loaded cost of supporting a monitor in a country.

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Recruitment Reliability

(Actual Patients * Planned Recruitment Period)

(Planned Patients * Actual Recruitment Period)

Actual Patients = Number of randomized patients in the study in the country (RighTrack II)

Planned Recruitment Period = Study planned last subject first visit (EPM) – country planned first subject first visit (eCPM via initial CMA)

Planned Patients = Number of planned patients in the study in the country (eCPM via initial CMA)

Actual Recruitment Period = Study actual last subject first visit (EPM) – country actual first subject first visit (RighTrack II or ClinrepNet)

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Ranges for Performance Metrics

Clinical Trial Metrics & Ranges

Metric Range Average Startup Speed 57 – 656 days 154 days (206) Subjects /site 4 – 83 subjects 15 subjects (5)

Recruitment reliability

9 - 494 % 133 % (69%)

Performance metrics

*Monitoring Burden Rate is the fully loaded cost of supporting a monitor in a country.

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Country Selection

Low volume cohort <1,600 patients

High volume cohort ≥1,600 patients

Core

Non core

Core

Non core

Prioritize based on quantitative and qualitative analysis

4

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Europe – 14 Core countries

Asia – 9 Core countries

Can/LA/Africa/Middle East – 10 Core countries

New Country Clinical Trials Footprint

US

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Why is Ireland Non-Core

• Fragmented – research infrastructures not connected and hard to find. The key opinion leaders and researchers are there and are performing at individual level with individual companies. This activity is not collated, communicated and connected to showcase Irelands capacity as a country level. • Ireland is “person dependent” – you need to know individuals in order to get connected to the right chain of knowledge – it is not a “system” • Performance - not predictable – research approval processes – especially ethics, protracted negotiation process for trial cost negotiation as each facility has different costs for the same service, access to patient populations in quite diffused with lack of connectivity between the various points of care e.g. hospital, GP interface

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• Cost of patients – for the number of patients Irelands can contribute – the cost is too high to justify the effort. Coupled with the fact that Ireland has a limited patient population and also a limited market for the sale of products – the cumulative effect of the investment risk is not a positive one •  For a number of companies there have been more findings (and of a more serious nature) in regulatory inspections in Irish sites compared to sites in the UK which colours views when it comes to allocating clinical research between sites in the UK & Ireland • Industry has been evaluating cost cutting and productivity enhancement for several years – this means decisions are made on countries to involve in trials is not as it used to be “who the medical director knew”. It is now in the hands of procurement departments, operational departments whose bonuses are based on performance of countries chosen. Ireland has not evolved from the person based influencing strategy.

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• In recent times – the issue of hiring freezes of nurses has impacted. This has already been heard in the corridors of BioPharma and once this message starts to move – the perception is very hard to shake. The fact that the Irish economic status and actions are communicated at global level will not add to confidence in this area

• Communication strategy for what Ireland has to offer is fragmented and does not have a strategic lead. Ireland is NOT the right country for EVERYTHING and an uncoordinated communication plan just adds to the perception of confusing, complicated and not joined up

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Conclusions •  Robust root cause analysis as part of a Lean six sigma

continuous improvement process identified a reduction in the country clinical trials foot print as an imperative to increase study execution speed and reduce costs while maintaining quality.

•  Analysis of performance data with consideration of cost and risk factors led to proposed core county foot print of 34 countries representing an approximately 50% reduction.

•  Ireland did not make core country footprint

•  Ireland has many of the clinical trial jigsaw pieces in place – but they are not joined to form a picture of a good research country.

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Developing a Functioning Clinical Research System

• The development of a functioning clinical research system is fundamental to the evolution of LifeSciences in Ireland. • Healthcare practitioners play a vital role in identifying unmet medical needs and giving direction and support to LifeSciences research. • The Strategy for Science, Technology & Innovation, 2006 – 2013 (SSTI), highlighted the relatively low levels of translational and/or clinical research underway in Ireland and stated that “the introduction of an R&D culture within mainstream health service has been relatively slow (and) there is a need to strengthen considerably the health services research and policy research capacity nationally” • The reality today is that the resource pressures faced by the hospital system means that research has tended to take ‘second place.’

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Summary

•  If Ireland is to become a core site for clinical trials everyone must be committed to making Ireland a beacon for clinical research and we are currently far from that

•  There is no national vision on how we want to partner as a country with biopharma re research

•  A shared vision would help us focus on what each part of the chain needs to deliver whilst maintaining their independence

•  All parts of the chain must be working correctly from hospitals, universities, ethics committees to IMB etc.

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Summary Clinical Trial Research is not a commodity, but a

sophisticated element of technology in a very competitive environment. Countries wishing to attract high-level clinical research must offer: –  sophisticated healthcare environment –  professional investigational environment - doctors need explicit

incentives to conduct research (ie "good investigators are good doctors”)

–  institutions should have explicit objectives to engage in CR; they often charge overheads, so this is a revenue stream, but may be poorly organized

–  countries need to offer access to modern diagnostics and treatments, so that data generated will have relevance in a rapidly developing healthcare environment ("future compatibility")

–  comprehensive, integrated information systems are very valuable – they enable effective review/follow up of patients on new treatments with critical evaluation of new treatments.

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Acknowledgements

•  Pfizer: – Dennis Joseph – Rory O’Connor – Anthony Chan – John Farrell

•  Amgen: – Charles Brigden

•  MMI: – Marie Mellody

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Damian o'connell - Transformation of the global clinical trials footprint in a big Pharma company -...

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