Multicentre P Animal - University of Edinburgh Funding.pdf · Grant Agreement n°HEALTH-F2-2013-603043 Multi-PART: A new paradigm for translational medicine Practical aspects of organising

Multi-PART: A new paradigm for translational medicineGrant Agreement n°HEALTH-F2-2013-603043

Multicentre Preclinical Animal Research Team

Multi-PART – WP1

Project management, training, and dissemination


Practical aspects of organising multicentre studies:

• Establish a model Consortium agreement;

• Recruit, train and approve participating sites;

• A framework to attribute intellectual property;

• A dissemination strategy to include engagement with researchers working in other disease models (e.g. the EUROPAIN consortium, MS-START);

• Develop framework for financial management.

WP1 Specific tasks


Opinions of international experts

most important characteristics of study sites for a multi-centre trial

Delphi technique

2 rounds of questionnaires

2 rounds of open discussion (Barcelona + Utrecht) aimed to reach consensus

Task: Define requirements for study sites


Countries 85 persons invited

Response rates

#1: 49 (58%)

#2: 36 (42%)

Questionnaires


1. ≥ 3 years of expertise in stroke modelling

2. ≥ 3 original articles reporting animal stroke studies in the previous 5 years

3. adherence to ethics regulations, assessed by a review of statements thereof in articles from in the previous 5 years

4. willingness to be trained in study methodology

Requirements for study sites – 1


5. ≥ 2 fte scientific staff

6. ≥ 1 fte technician

7. ≥ 25 stroke inductions in previous 2 years by each participating individual

8. ≥ 100 stroke inductions in previous 2 years at study site



9. able to assess– body temperature during surgery

& follow-up– blood gases– blood pressure



10. undergo training in behavioural testing, without exam but with central assessment of quality of testing

11. PI ≥ 3 years of experience in stroke modelling

12. PI ≥ 3 articles reporting original stroke research in animals in previous 5 years



PubMed Search Strategy (To find papers on modelling ischemic stroke in experimental animals)

The purpose of this search was to provide a systematic and unbiased approach to identify research groups likely to have the expertise to join the MultiPART consortium. In this first instance the search has been performed to identify laboratories with experience modelling ischemic stroke. Other disease models such as epilepsy, SCI, trauma, MS, etc can also be identified this way.

Exploratory searching began by probing PubMed's different fields for potentially relevent citation numbers but yielded dramatically different results

Stroke - All Fields = 232751Stroke - Text Word = 198215Stroke - Title & Abstract = 162239Stroke - Title = 66095Stroke - MESH Major Topic = 69330

Comparing this text word search with a Mesh search with the same limits of duration (10 years) and species (other animals) using PubMed's built in limiters gave dramatically different results

e.g. Stroke - MESH Major Topic - Limit 10 years + other animals = 5760Stroke + cerebral ischemia - Text and Abstract - Limit 10 years + other animals = 16083

Secondary manual screening in EndNote

This left a dataset of 7891 references highly enriched for studies of ischemic stroke in experimental animals


Sorting in MS Excell

First Author Number of Publications

Wang, Y. 31

Zhang, Y. 28

Zhang, L. 27

Li, J. 26

Chen, J. 20

Li, L. 18

Lapchak, P. A. 17

Li, H. 17

Liu, Y. 17

Liu, Z. 17

Sun, L. 17

Wang, J. 16

Wang, L. 16

Wang, X. 16

Zhao, Y. 16

Zhang, X. 15

Koh, P. O. 14

Li, Y. 14

Wang, Z. 14

Yang, Y. 14

Zhao, H. 14

Chen, Y. 13

Wang, Q. 13

Zhang, J. 13

Cui, X. 12

Zhang, H. 12

Chi, O. Z. 11

Chen, X. 10

Liu, X. 10

Liu, X. S. 10

Last Author Number of Publications

Chopp, M. 99

Won, M. H. 47

Abe, K. 39

Chen, J. 38

Wang, Y. 37

Zhang, G. Y. 35

McCullough, L. D. 31

Hara, H. 27

Ding, Y. 26

Xiong, L. 26

Chan, P. H. 24

Dore, S. 24

Lo, E. H. 23

Steinberg, G. K. 23

Zhang, Z. G. 23

Li, H. 21

Veltkamp, R. 21

Zhao, H. 20

Wang, X. 19

Yang, G. Y. 19

Chen, L. 18

Fujiwara, M. 18

Hermann, D. M. 18

Islam, F. 18

Wei, E. Q. 18

Corbett, D. 17

Zhang, J. H. 17

Chen, Z. 16

Jolkkonen, J. 16

Liu, X. 16

"FIrst Author Sort" and "Last Author Sort" revealed that there were 4981 individual first authors and 3751 individual last authors in the 7891 record data set.

There are 119 first authors and 233 last authors with > 5 publications each.

The 138 last authors with >8 publications each and the corresponding publication details including addresses are provided in the Senior Authors >8 Publications Tab. It is recommended that the most recent address provided be used and in the few instances where multiple addresses have been retreived from PubMed that a google search be performed to resolve any conflict.


A searchable laboratory dataset

../Projects/MultiPART/Literature searching/Stroke_Cerebral ischemia_10 years_Non-human_Title_Abstract_Cleaned_Author counts.xlsx

../Projects/MultiPART/Literature searching/Stroke_Cerebral ischemia_10 years_Non-human_Title_Abstract_Cleaned_Author counts.xlsx


No agreements that prevent the academic reporting of results

Study protocol published on Multi-PART website

specific details may be masked

Results published independent of outcome

Data dissemination strategy


Authorship according to ICMJE principles

Individual-animal dataset in public repository after 18 months

Adhere to relevant clauses in consortium and copyright agreements

Data dissemination strategy


MultiPART Research / Business Plan

Principle of Operation:• MultiPART is a not for profit research consortium.

• The purpose of MultiPART is to assess candidate drugs for

efficacy before the commencement of clinical trials.

• The aim is to perform this preclinical assessment with the

same methodological rigor as the best clinical trials to avoid

introduction of bias by randomisation, allocation

concealment, intention to treat analysis and blinded

assessment of outcome.

• To ensure provision of appropriately powered experiments in

a timely fashion, workload will be distributed across

multinational laboratories subject to centralised monitoring

and quality control by the consortium.

• Efficiency will be ensured by provision of centralised

randomisation and blinding schedules and raw data collection

for distributed primary outcome analysis using a web-based

data engine. Using this data,

• The MultiPART scientific Advisory Committee will provide

advice to investigators on clinical trial go/no-go decisions.


Funding sources

• MultiPART is not a contract research organisation (CRO).

• Its purpose is to advance the research interests of the consortium.

• As such it is expected that core funding will come from public and philanthropic granting bodies.

• The competitive advantage for the consortium will be the ability to provide world-leading expertise to address

the specific scientific requirements of each research project. The very best CV’s and methodological expertise

for each experimental aim.

• The primary mode of engagement with the pharmaceutical industry will be formation of a multiPART-PHARMA

precompetitive sub-consortium. The level of investment can vary depending on the size of the Pharma (e.g.

large multinational vs start-up).

• Testing of compounds proposed by MultiPART-PHARMA precompetitive sub-consortia members will be subject

to the same prioritisation and experimental planning schedule and application of the same go/no-go criteria as

for academically proposed drug candidates.

• The MultiPART SAC may allow Pharma who are not members of the pre-competitive consortia one-off access

to the MultiPART research infrastructure for a mutually agreed program of research, for this the MultiPART SAC

will be expected to consider team capacity, reputation and willingness of >70 % of team members to engage

with that entity.

• Academic researchers who lack the expertise to be consortium members can engage with the MultiPART SAC

to develop grant proposals to jointly fund their research. The SAC will accept brief outlines of proposals for

consideration as collaborative research projects.


Research Prioritization

Multi-PART will receive more research proposals than the consortium has capacity to process.

• Prioritization will be required.

• Process must be evidence-based rather than dependant on force of personality.

• Able to adapt to disease specific circumstances and to evolve as MultiPART grows and develops.

• Bench-mark against the best in the field

• Start with a systematic review of the existing data

• what relevant data is known

• what are the gaps in this knowledge.

• Where possible, meta-analysis will be performed.

• biologically plausible

• Is data consistent with a biased or an unbiased evaluation of the merits of the compound.

• rank the point estimate of effect size against known translational successes for the field.

Comparison of blinded and non-blinded stroke preclinical data sets for the

candidate treatment hypothermia with the effective human therapy tPA

and the ineffective human therapy NXY-059.


Depending on quality and breadth of evidence gathered, a decision will be made to determine where a

candidate drug enters the MultiPART research pipeline.

Different drug candidates can enter the research pipeline at different points.

A) Choices made in determining the purpose of the proposed experiments, B) Illustration of the range of experiments possible and their purpose in stroke drug testing.


Illustrative program and costs

Multi-PART• Thread occlusion dose response 4x8 rats

Control + 4x8 rats Drug =64 rats @ €58,000

• Time to no effect (5x8x2=80 rats)• ± Reperfusion (2x8x2=32 rats)• Young vs Old (2x8=16 rats)• Normotensive (33x2=66 rats)• Diabetic (33x2=66 rats)

=260 rats @ €238,000

Repeated in 260 female rats = €238,000

• Repeated in thromboembolic model=260 rats €238,000

Overall cost to assess one drug = €773,358.37

Multi-PART• Thread occlusion dose response 4x8 rats

Control + 4x8 rats Drug =64 rats @ €58,000

• Time to no effect (5x8x2=80 rats)• ± Reperfusion (2x8x2=32 rats)• Young vs Old (2x8=16 rats)• Normotensive (33x2=66 rats)• Diabetic (33x2=66 rats)

=260 rats @ €238,000

Repeated in 260 female rats = €238,000

• Repeated in thromboembolic model=260 rats €238,000

Overall cost to assess one drug = €773,358.37


• Governmental and charitable funds will be made available to the MultiPARTconsortium in accordance with standard granting practices.

• Funds from pre-competitive consortia members will be paid to MultiPART annually in advance with the ability to withdraw from the agreement with 6 months notice.

• Other commercial collaborators will pay 6 monthly in advance with the ability to give 3 months notice of withdrawal from the agreement.

• Funds held by MultiPART will be paid to investigators quarterly in advance but with the provision that payment can be withheld if agreed deliverables have not been reached.

• If agreed deliverables are not achieved for 2 consecutive quarters, planned workload will be redistributed to other consortia members where possible and the teams on-going MultiPART involvement reviewed by the SAC.

Distribution of funds

Data Collection

../../../Desktop/2013 MultiPART/Multi-Part Financial Management Framework Version 3.xlsx

../../../Desktop/2013 MultiPART/Multi-Part Financial Management Framework Version 3.xlsx


Practical aspects of organising multicentre studies:

Recruit, train and approve participating sites;

Establish a model Consortium agreement;

A framework to attribute intellectual property;

A dissemination strategy to include engagement with researchers working in other disease models (e.g. the EUROPAIN consortium, MS-START);

Develop framework for financial management.

WP1 Specific tasks

Still Need

• To understand whether UK and EU costings for staff include superannuation and leave on-costs. In Australia this requires and extra ~31.5%.

• Whether to apply highest rather than average cost for some items egOccluding threads (Melbourne and Glasgow €1, Berlin €39.80).

• Build a cost model for immunohistochemistry that is sophisticated enough to account for different primary and secondary antibody costs and slice density plus associated analysis costs. (Probably not needed for current report).

• Build a cost model for different types of MRI sequence per animal per number of repetitions that takes into account high cost of equipment depreciation. (Probably not needed for current report).

• Costing for diathermy model (Needed for current report, have data from Glasgow).

Documents

Multicentre P Animal - University of Edinburgh Funding.pdf · Grant Agreement n°HEALTH-F2-2013-603043 Multi-PART: A new paradigm for translational medicine Practical aspects of organising