Addressing the Food-Fuel Balance: Applying the Analysis of Life Science Innovation Systems Approach to the

Agricultural BioeconomyBy Michele Mastroeni

Joyce Taitm.mastroeni@ed.ac.uk

Innogen, University of Edinburgh

Biofuel Development: Multiple Challenges in Multiple Areas

• Biofuel development presents many different challenges in different spheres of debate.

– Reality of climate change (i.e. Political and scientific p.o.v.)– Fuel security (i.e. Ease of use versus long-term sustainability)– Food security (what are the direct and indirect factors?)– Economic development (e.g. Clean tech as new sector vs switch

from fossil fuel and potential loss)– Alternative technologies (Gen 2, or non-biofuel)– Genetic Modification of crops (e.g. Precautionary principle)– Land use (How do previous two points impact land use?)– The need for and utility of public engagement (i.e. be wary)

• The challenges are therefore not only scientific and technical. Some of the hardest challenges are economic, social and political.

• Require an approach that can present to the analyst (and decision-makers) how the different challenges interact, and how they impact a particular path of development.

• Not sufficient to use Life Cycle Assessment (whether attributional or consequential)

• And normative standpoints must be examined and problematized, to ensure that unseen barriers are not ignored.

Analysis of Life Science Innovation Systems (ALSIS): Approach and Definitions

Value systemEmbeds one or more value chains in the wider economic, regulatory and political contexts.

Value chainCovers all activities needed to bring a product from conception to end use. Depending on the opportunity and the route to exploiting it, the value chain can encompass several business models operating in sequence or in parallel.

Business modelApplies to a class of firms that play a common role within a value chain - describes the rationale for how the firms create, capture and deliver value.

Value System(external constraints and enablers)

ALSIS Methodology

Business Model

Business Model

Business Model

Business Model

Business ModelValue Chain

RegulationFunding

Markets

Data from

interviews

Data fr

om

workshops

Data from

published sources

Scenario 1

Scenario 2

Stakeholders

Nuffield Council on Bioethics: 6 Principles

• Biofuel Development should not be at expense of human rights

• Biofuels should be environmentally sustainable• Biofuels should contribute to net reduction of

GHG and not exacerbate climate change• Biofuel should develop with fair trade principles• Equitable distribution of costs and benefits• A duty not to do nothing

Case Studies Originally Used to Develop ALSIS:

Let me put ALSIS in context

•Human Embryonic Stem Cells•Red Blood Cells•Liver Device

Red Blood Cells from Stem Cells – Business Model Map (simplified)

Obtain startingMaster cell bank of

cell lines toclinical grade GMPstandards (hesc atfirst but eventually

IPS)

Use NHS and bloodtransfusion service

for supply anddistribution chain

Develop nucleatedRBCs

Differentiatecultured rbcs fortherapeutic use

Generate revenuefrom nucleated RBCs

... consider them aproblem

Scale up productionfor preclinical

testing (10_13)

Test on animals

Decide type ofanimal model and

test protocols

Meet regulatoryrequirements for

animal testing (HomeOffice Approval)

Conduct combinedPhase1 + Phase 2Clinical trials with

thalassemia patients

Meet regulatoryrequirements for

MHRA, EMA and localethics committees

Scale up GMPmanufacture forphase 3 (10_16)

Conduct phase 3clinical trials

Meet traceabilitystandards and

establish length ofpatient follow-up

period

Devise procedure forfurther scale up of

RBC manufacture forfinal market

Re-appraise route tomarket

Decide location/typeof manufacture for

final market

Deliver to patients

Locate new sourcesof funding for

further clinicalstudies

Locate additionalsources of fundingincluding buy-out

and licending (tensof millions at this

stage)

Implementpharmacovigilance

plan andtraceability

criteria

Establish qualitystandards for the

cell product(including level of

enucleation)

Source animals fortoxicity testing

(GLP compliant)

Meet clinical gradeGMP requirements for

cells and facilities(HTA, HFEA, MHRA)

Collect and submitall preclinical data

Evaluate competitorproducts, such as

haemoglobin basedblood substitutesand enucleated in

vitro rbcs

Continue to derivenew pluripotent celllines for improved

performance(including searchfor good O- (ideally

including minorblood group

appropriate) line

Establish benefit ofin vitro producedrbc over donated

blood

Explore patentlandscape for

relevant constraints

establish survivaland recovery ofrbcs, safety and

efficacy; andabsence of any

detrimental effects

Submit in vitro datato CAT to obtainclassification of

rbc as ATMP

Secure IMP licencefrom MHRA

Optimised prototypescale up manufacture

for Phase 1 and 2studies (10_15)

Develop marketingstrategy

Consider economicviability of the

range of potentialmarkets and decideon market type and

scale

Implement marketingstrategy

Implement storageand distribution

plan

Implement finalscale up process

(10_18?)

Develop therapy forthalassemia as first

market

Conduct equivalencytests with

conventional donorrbcs (safety and

efficacy)

Prepare phase 1/2clinical Trial

application for MHRAincluding IMPD (all

animal data,preclinical and QC

testing)

Integrateinformation and

design phase 3 study

Use patients ...than healthyvolunteers

Recoup revenue fromcore assets and

onsite IP

Provide contractmanufacturing

services

Decide manufacturingprocess and

distribution/storage

Consider setting upnew commercial

company

Develop Working CellBank (WCB)

Make case foralternative approach

to safety testing,including animalmodels and/or

alternatives

Decide point ofmanufacture forenucleated rbcs

Incorporate newdata/information on

manufacturingtechniques

MARKETS ANDCOMMERCIAL OUTCOMES REGULATORY ISSUES

SCIENCE ANDTECHNOLOGY

MANUFACTURINGRED ARROWS = VALUE

CHAIN IP RELATED

Secure relevant IP

Consider impact ofBrustle patent

decision if HESC

Select appropriatere-programming

method for IPS cells(example, Sendai

virus)

Ideally source animmortalised

progenitor cell linethat is expandable

and candifferentiate only

into rbcs for use asstarting material

Provide rbcs fordiagnostic-reagents

testing - bloodscreening

Consider level ofenucleation that is

acceptable formanufacturing andscale up (50%?)

If manufacturingtechnique is changedsubstantially securenew IMP license and

update IMPD

Agree to anintegrated andcoordinated

regulatory plan andsecure approval

Secure clinicaltrials license

Submit applicationto EMA for Marketing

Authorisation

Discuss with EMA andMHRA proposals for aregulatory plan and

agree standards

Define QC assays

Define a clearbusiness plan

EMA/CAT team -approval on

harmonisationapproach

Prepare scienticicrationale andjustification for

appropriateness ofpreclinical data

Conduct phase4/5clinical trials if

required

Consult withregulators about new

markets andpotential need foradditional clinical

trials (perhaps withhealthy volunteers)

Test equivalency ofscale up process

Test storage anddistributionapproach

Conduct in vitrotesting

Obtainclassification of

rbc as ATMP from CAT

Securematerial/supply of

reagents andconsider scale up

implications

Ensure equivalencyof product

Red Blood Cells from Stem Cells – Critical Decision Points

Use NHS and bloodtransfusion service

for supply anddistribution chain

Develop nucleatedRBCs

Differentiatecultured rbcs fortherapeutic use

Scale up productionfor preclinicaltesting (10_13)

Conduct combinedPhase1 + Phase 2Clinical trials with

thalassemia patients

Meet regulatoryrequirements

Scale up GMPmanufacture forphase 3 (10_16)

Conduct phase 3clinical trials

Devise procedure forfurther scale up of

RBC manufacture forfinal market

Re-appraise route tomarket

Decide location/typeof manufacture for

final market

Deliver to patients

Locate additionalsources of fundingincluding buy-out

and licending (tensof millions at this

stage)

Implementpharmacovigilance

plan andtraceability

criteria

Establish qualitystandards for the

cell product

Secure relevantlicenses

Optimise prototypescale up manufacture

for Phase 1 and 2studies (10_15)

Develop marketingstrategy

Consider economicviability of the

range of potentialmarkets and decideon market type and

scaleImplement marketing

strategy

Implement storageand distribution

plan

Implement finalscale up process

(10_18?)

Prepare phase 1/2clinical Trial

application for MHRAincluding IMPD (all

animal data,preclinical and QC

testing)

Integrateinformation and

design phase 3 study

Decide manufacturingprocess and

distribution/storage

Develop Working CellBank (WCB) fromstarting material(ips or hesc line)

MARKETS ANDCOMMERCIAL OUTCOMES

REGULATORY ISSUESSCIENCE ANDTECHNOLOGYMANUFACTURING

RED ARROWS = VALUECHAIN IP RELATED

Provide rbcs fordiagnostic-reagents

testing - bloodscreening

Agree to anintegrated and

coordinatedregulatory plan and

secure approvalfollowing

discussions wth EMAand MHRA

Submit applicationto EMA for Marketing

Authorisation

Conduct phase4/5clinical trials if

required

Test storage anddistribution

approach

Securematerial/supply of

reagents andconsider scale up

implications

Ensure equivalencyof product

Sell nucleated rbcs

Conduct all animaland in vitro testing

and submitpreclinical data

Scenario Development

HESC lines:•Impact of variation in demand from different markets

Red Blood Cells:•Step change in manufacturing technology•Impact of regulatory requirements regarding animal models

Bio-artificial Liver Device:•Impact of manufacturing decisions on product delivery

The Innogen Triangleand Methodologies

Markets/customers

Regulation

Political influence

Innovators:ALSIS

Governance:AGIT

Stakeholders:Critical

Engagement