brindley aegate ams 2.2

Medicines Authentication: ‘The New 21st Century Healthcare Model’ David Brindley FRI FRSA DPhil MEng

Amsterdam, Netherlands

20th February 2015

Disclosures

Relevant Disclosures (in addition to grant funding):

D.A.B. is also a stockholder in Translation Ventures Ltd, Charlbury, Oxfordshire, UK, which amongst other services, provides life-science regulation, biomanufacturing and financial services.

D.A.B. is a consultant of Aegate Ltd.

At the time of writing D.A.B. does not have any additional relevant conflicts of interests to disclose.

However, D.A.B. is subject Codes of Practice, Standards and Ethics of the CFA Institute and the CAIA Association, and as such stresses that any opinions presented herein are personal and should not in anyway be construed as an investment recommendation.

A full register of personal interests is available upon request.

20th February 2015

DB Core Academic Affiliations

Medical Sciences Division: Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences

Academic Director CASMI Translational Stem Cell Consortium and Lead Risk Management Programmes

Said Business School: Director of Healthcare Innovation and Entrepreneurship MBA Programme

DB Secondary Academic Affiliations

Research Fellow in Regenerative Medicine

Commercialisation

Senior Research Associate, School of Pharmacy, Centre

for Behavioral Medicine

Stanford-UCSF FDA Centre for Regulatory Science and

Innovation

Myths to be Challenged

FMD Healthcare Industry

UK PilotAuthentication Systems

FMD: Myths to be Challenged



1. Mere compliance to the FMD is a satisfactory outcome for pharmacists, patients and pharma

2. [FMD] statue, regulation, guidance and reimbursement are mutually exclusive

3. Secondary care pharmacists are smaller in number than community, and as such will be easier to achieve FMD compliance

4. Potential ‘exceptions’ to the FMD are well understood

5. FMD compliance is a “huge FTE burden”

Healthcare Industry: Myths to be Challenged

1. A product based business model will continue to

dominate pharma2. The characteristics of patient adherence are

obvious3. Pharmacists feel sufficiently engaged in patient

care4. FMD compliance is a “huge FTE burden”5. The impact of the FMD is likely to be restricted

to Europe6. Only conventional pharmaceuticals are likely to

be impacted by the FMD



Authentication Systems: Myths to be Challenged

1. Our existing scope of an ‘end to end’

authentication system is sufficient2. Authentication systems are likely to represent a

net cost to healthcare delivery3. Systems risk in healthcare is a zero sum game4. Tamper evident packaging is of lesser

importance than the 2D data matrix5. Eventually FMD compliance will require patient

level data



UK Pilot: Myths to be Challenged 1. Secondary care pharmacists are smaller in

number than community, and as such will be easier to achieve FMD compliance

2. Designing a medicines authentication pilot is “easy”

3. Pharmacies are homogenous 4. Clinical engagement is of minimal importance

when the FMD is mandated5. Secondary care pharmacies have well

characterised and optimized workflows6. Pharmacist’s are likely to be robustly supported

by hospital management to implement the FMD 7. “Robots make life easier”



Ecosystem

Types of Healthcare Risks

System Risks

• Clinical Trial Processes

• Healthcare Delivery

• Stakeholders - including patients and pharmacists

• Payer adoption

Technology Risks

• Technology development

• Intellectual Property• Proof of benefit –

including proof of efficacy vs ADR

Financial Risk Management

RISK

BENEFIT

UNCERTAINT

Y

Healthcare Risk Management

Loss

Gain

Unexpected Unpredictable

Efficacy

Adverse Event

\

What is Healthcare Translation?

CASMI Translational Stem Cell Consortium

A Real World Example

Managing System and Technology Risks

US

• NIH NCATS• FDA Breakthrough

Status e.g. CAR-T

Adapted from (Cooksey, D. 2006 and Mason, C. and Manzotti, E., 2010)

Mitigating Healthcare Risks

EU

• National ‘Translation Centres e.g. Francis Crick Institute

• Adaptive Licensing

\

The ‘Forgotten’ Translation Gap

Key Healthcare Trends

• Combinational Diagnostics

• Novel therapeutic technologies

• Value based pricing• Combinational Therapies• Transparency• Patient Adherence• Falsification and

Counterfeiting• Risk:benefit appraisal• Role of patient advocacy

groups and disease specific foundations

• POM - OTC

Future of Healthcare

THERAPEUTICS

Tissue Engineering(Dermagraft)

MEDICAL DEVICES(Stent)Monoclonal

Antibody(Herceptin)

SMALL MOLECULES

(Gleevec)

DEVICES

BIOLOGICS

COMBINATIONAL THERAPEUTICS

REGENERATIVE MEDICINE

Gene Therapy(Glybera)

ImmunoTherapy(CART19)

Cell Therapy

(MSCs)

FMD Statutory Scope 1. Registration with Competent Authority of the Member

State 2. Verification of the authenticity and quality of the active

substances and excipients3. Inform the Competent Authority and marketing

authorisation holder 4. Good Distribution Practice (GDP)5. GMP written confirmation from the competent authority of

the non-EEA country 6. Brokers have to register with the Competent Authority of

the EEA Member State 7. Wholesale dealer's licence for export of medicines to third

countries8. Distance sales of medicines be registered 9. Common internet logo

Beyond ‘Mere Compliance’

Patient Adherence

Effective treatments

Optimum outcomes

BEHAVIOUR

PRESCRIBER

PATIENT -adherence

Behaviour as the rate limiting step between effective treatments and health gain

Neanderthal creativity

The Data

2 REPORTS, 3 POINTS:1. Estimated that between 30

-50% medicines prescribed for long term conditions are not taken as directed

2. If prescription was appropriate then this represents a loss for patients, the NHS and pharma industries

3. Effective interventions are elusive (Haynes et al 1996, 2003)

1World Health Organization Report 2003. 2Horne R et al. Concordance, adherence and compliance in medicine taking. NIHR SDO 2006.

Global Theory : Local Solutions

Need for a general theory to encompass complexity and inform local solutions. Parallel research and evaluation feeds back to refine theory.

Empowering Patient Adherence

Myth 1: Non-adherence is a feature of the disease

Non-adherence is not linked to type of diseaseLow adherence rates are problematic in most

chronic diseases e.g.• HIV1 • Cancer2

• Heart disease3

1. Friedland, Williams. AIDS 1999;13(Suppl 1):S61–72. 2. Lilleyman, Lennard. BMJ 1996;313:1219–1220. 3. Horwitz et al. Lancet 1990;336:1002–1003.4. Cleary et al. Am J Health Syst Pharm 1995;52:1895–1900. 5. Glasgow et al. J Behav Med 1986;9:65–77. 6. Cochrane et al. Respir Med 1999;93:763–769.

Myth 2 The ‘non-compliant’ (deviant) patient

– No clear and consistent links between adherence and age, gender, intelligence, marital status.

– Findings are inconsistent e.g. nonadherence linked to older age in some studies and to younger age in others

Adherence rates vary

Between patients Within the same patient over time and across treatments

Most of us are non-adherent some of the time!Horne R, Weinman J, Barber N, Elliott RA, Morgan M. Concordance, Adherence and Compliance in Medicine Taking: A

conceptual map and research priorities (2005). National Co-ordinating Centre for NHS Service Delivery and Organisation R&D, London,

Myth 3: Simplifying the regimen and reducing ‘pill-burden’ solves the problem of nonadherence

• Simplifying the regimen can be helpful for some patients (Claxton et al, 2001)

• BUT…this alone will not solve the adherence problem

• Complexity per se is not the key issue but how well the treatment fits in with the individual patient’s routine, expectations and preferences (Horne et al, 2006).

Claxton, A. J., Cramer, J., & Pierce, C. (2001). A systematic review of the associations between dose regimens and medication complianceClinical Therapeutics, 23(8), 1296-1310.

Horne R, Weinman J, Barber N, Elliott RA, Morgan M. Concordance, Adherence and Compliance in Medicine Taking: A conceptual map and research priorities (2006). National Co-ordinating Centre for NHS Service Delivery and Organisation R&D, London,

Myth 4: providing clear instructions/information is enough

Horne R, Weinman J, Barber N, Elliott RA, Morgan M. Concordance, Adherence and Compliance in Medicine Taking: A conceptual map and research priorities (2006). National Institute for Health Research Service Delivery and Organisation R&D, London,

The information–action gap

Information ActionxInformation is essential to enable adherence BUT ….Giving more information does not guarantee adherence

BELIEFS

This is a common problem in healthcare – We have an information-action gap

Segmentation: Belief groups and adherence

N = 1871 (A survey of 1 in 10 members of the National Association of Crohn’s and Colitis)

Reported adherence differed significantly between groups with the Accepting group having higher adherence than all other groups (F(3,210.44) = 36.99, p<.001):

Accepting group > Ambivalent group (p<.001) > Sceptical (p<.001) and Indifferent groups (p<.01).

Indifferent

n = 75 (4%)Accepting

n =847 (48%)

Sceptical

n = 110 (6%)

Ambivalent

n = 746 (42%)

High Concerns

High Necessity

Low Necessity

Low Concerns

Parham, R. et al Patients' attitudes to medicines and adherence to maintenance treatment in inflammatory bowel disease. Inflammatory Bowel Diseases, 2014.

Aegate Confidential 32

The Synergy: Execution

http://aegate.com/en/aegate-spoonful-of-sugar-memorandum-of-understanding/

Pharmacist

Patient

Medicine

15,395 Dispensing

Points

200,000

Transactions

Per Hour

3bn

Medicines

To Date

0.25 Secs

Average

Response

Time


The Formula

Depth:

- Understanding of patient behaviour(s)

- Academically rigorous and validated methodologies

- Multi-dimensional ‘bespoke’ approach

Breadth:- Compliance with EU FMD- Real-time business

intelligence (POMs and OTCs)

- Vehicle for messaging: patients and pharmacists

- SAFETY: falsification, expiration & recall


In other words…

Pharmacovigilance

• Accommodating novel regulatory processes

• Convergence with real data

• Retrospective -> real time ->

• ?proactive?• Regulatory

requirement/burden into clinical information tool and business intelligence tool

Risk: Benefit Analysis: Implications

• Decision making vs decision support tool(s)

• Qualitative vs quantitative

• Disparate stakeholder expectations and needs

Background to Healthcare Risk Management Key Drivers of Growth in Healthcare Risk Management:

• General growth in risk management – including in financial services

• Desire for greater transparency in clinical data – FDA and EMA

• Increased risk management initiatives throughout supply chain and delivery to patient e.g. EU Falsified Medicines Directive

• Pharmacovigilance innovation driven by expanded and/or accelerated access schemes e.g. FDA Breakthrough Status and EMA

• Requirement for robust risk management decision support tools under uncertainty e.g. pandemics including Ebola virus disease (EVD)

• Formalisation of risk:benefit appraisal in RCTs

• Growth in range and complexity of combinational therapies

http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM329758.pdf

Combinational Use of Combinational Therapies

Combinational Therapies

Therapeutic + Combinational

Diagnostic

Device + Therapeutic

Device + Transplant

Combinational Therapeutics

Therapeutic + Transplant

UK Pilot

Penicillin and Authentication

Over-Adherence?

Patient Messaging

The Need

Table 1.0: Overview of Notable Examples of Falsified Medicines in the EU Source: Royal Pharmaceutical Society, Policy Statement: “Falsified Medicines Directive (FMD)” September 2013. Data sourced originally from MHRA.

Scope

With thanks to Mark De Simone (Aegate)

Scope

With thanks to Graham Smith (Aegate), Anneke Kramm (CASMI) and Richard Smith (Oxford, NDORMS)

UK Pilot Raison d'être

1. Maximise patient safety throughout pharmaceutical supply chain2. Conduct an academically rigorous, systematic and independent evaluation of Aegate

product(s)3. Efficiently integrate Aegate system into existing pharmacy software4. Support and accelerate compliance of Oxfordshire pharmacies to FMD5. Develop a scalable pilot process that can be applied to validate Aegate software in multiple

markets6. Stimulate multi-stakeholder engagement in FMD compliance7. Yield high-impact peer reviewed publications8. Evaluate application of Aegate product(s) to emerging therapeutic technologies9. Contribute to development of harmonised international governance structures for

pharmaceutical serialisation and authentication10.Support all stakeholders in FMD compliance

Categorisation of Objectives

ValidationAdoption

Operation

Future Opportuniti

es

Work Packages

Integration

Recall

Authentication

StreamliningAdherence

Governance

Stakeholder Evaluation

Key Lessons to Date

1.(Surprisingly) limited awareness of FMD2. Enthusiasm re safety and treatment3.Heterogeneity 4.Selection of representative products5.Types of ‘pharmacist’6.Defining APIs7.Importance of multi-organizational support8.Governance: research and community9.Ethical approval10.Representative ‘tests’11.Security vs confidentiality12.Clinical Engagement

EU Pharmacist Pilot

Core Questionnaire

- Questionnaire evaluating pharmacists’ attitudes to risk:benefit appraisal- Including specific role of pharmacists

Pilot Study

- Questionnaire translated into four languages- N = 494 (Belgium)N= 494 (Italy)Completed

Full Study

- Questionnaire issued to all pharmacists using Aegate system in Belgium and Italy- N ~ 5000Completed

OBJECTIVE

To elicit pharmacists’

attitudes towards risk:benefit appraisal of healthcare

innovations

Pharmacist Pilot Study Key Results

Figure 6.0: Pooled pilot and full study results

Key Findings of Aegate Academic Assessments

• Pharmacists are concerned by the risk of falsified and counterfeit medicines

• Pharmacists believe they have an important role in helping patients evaluate the risks and benefits of medicines – including OTCs

• The PIL alone provides insufficient and/or poorly accessible risk:benefit information to pharmacists

• This is a problem for ‘high risk’ OTCs

FMD: Myths to be Challenged



1. Mere compliance to the FMD is a satisfactory outcome for pharmacists, patients and pharma

2. [FMD] statue, regulation, guidance and reimbursement are mutually exclusive

3. Secondary care pharmacists are smaller in number than community, and as such will be easier to achieve FMD compliance

4. Potential ‘exceptions’ to the FMD are well understood

5. FMD compliance is a “huge FTE burden”

Healthcare Industry: Myths to be Challenged

1. A product based business model will continue to

dominate pharma2. The characteristics of patient adherence are

obvious3. Pharmacists feel sufficiently engaged in patient

care4. FMD compliance is a “huge FTE burden”5. The impact of the FMD is likely to be restricted

to Europe6. Only conventional pharmaceuticals are likely to

be impacted by the FMD



Authentication Systems: Myths to be Challenged

1. Our existing scope of an ‘end to end’

authentication system is sufficient2. Authentication systems are likely to represent a

net cost to healthcare delivery3. Systems risk in healthcare is a zero sum game4. Tamper evident packaging is of lesser

importance than the 2D data matrix5. Eventually FMD compliance will require patient

level data



UK Pilot: Myths to be Challenged 1. Secondary care pharmacists are smaller in

number than community, and as such will be easier to achieve FMD compliance

2. Designing a medicines authentication pilot is “easy”

3. Pharmacies are homogenous 4. Clinical engagement is of minimal importance

when the FMD is mandated5. Secondary care pharmacies have well

characterised and optimized workflows6. Pharmacist’s are likely to be robustly supported

by hospital management to implement the FMD 7. “Robots make life easier”



Collaborative Opportunities

UK Pilot Specific Acknowledgements

Aegate

Mark De SimoneSir David CookseyGraham SmithDamon WitherickCristiano Ressidi CerviaNick CockmanIris Liberloo

University of Oxford

Sir John BellSir Marc FeldmannAndy CarrSue DopsonPeter TufanoAnneke Kramm

Lonza

Jesus Zurdo

Sartorius Stedim

Kim BureOscar Reif

Oxford AHSN/ OUH NHS

Gary FordMike DenisBhulesh VadherDavid TutcherJohn SkinnerWilliam PankSpoonful of Sugar

Andrew MartelloRob HorneSarah Dawson

Principal Project Supporter

Acknowledgements

Direct: [email protected]

Admin: [email protected]

brindley aegate ams 2.2

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