ORFANOS

Meeting Priorities of Biotech & Small Pharma Companies

28 Oct 2015

Dr. Andreas Orfanos, MBBCH,FFPM,MBA

Thrasos Therapeutics Inc. Vice President Clinical Research & Development

ORFANOS 2

• Acute Kidney Injury (AKI)

• Chronic Kidney Disease

• Safety & Efficacy of THR-184 in preventing Cardiac Surgery Associated - AKI

• N = 450+ patients across over 40 sites in NA

Addressing

Compelling Unmet

Needs

Leading Phase II

Study

• Proprietary peptide drugs

• Protect, repair and restore injured tissue

• Fast Track designation (FDA) for Cardiac Surgery Associated - AKI

First in Class Technology

• Private, clinical-stage biotherapeutics company

• Founded (2003) as a research co. by leading Boston based scientists

• Canadian development company since 2010 with over 20 employees

• Research & clinical operations in Montreal; office in Boston

• US and Canadian investors

Montreal Technoparc

ORFANOS

Background

© Andreas Orfanos

ORFANOS

Biotechnology Industry

Need for efficiency follows tight funding environment (global financial crisis and economic downturn)

Venture capital funding has rebounded; but 20% of US companies raising funds garnered 82.6% of capital in 2010

Increased use of milestone-based payments vs. upfront dollars: increased risk sharing

Today’s scientific challenges more complex than those involved in developing earlier generations of biotech technologies and products

Biotech out-license their product after Phase I/II or acquisition, or retaining products and taking them closer to the market

Trials continue to become increasingly complex and global, the competition for access to patients, new investigators &studies

Beyond borders Global Biotechnology Report 2011, Ernst & Young

ORFANOS

Virtual Biotech Model

Biotech company

CRO

Pre-clinical research

CMC

Regulatory Consulting

Legal

Other vendors

Minimal infrastructure

Access to expertise on an as needed basis

Limiting expenditure to what's necessary

Ensure efficiencies

Develop compound(s) to an early clinical data package which can be partnered with pharma

Executive team with significant experience & network

ORFANOS

Outsourcing

Biotech

Often focus on single product or platform

Small team with executive involvement

Need for accessing outside expertise

Transfer of responsibility of many functions

Timelines related to key milestone payments

Pharma

Multi-product: marketed drugs and strong pipeline

Large team with broad and in-depth expertise: “mirrors CRO”

Need to complement several functions that may be in house

Seeing more streamlined business model with strategic CRO partnership

Timelines key with regards to corporate objectives

6

Optimise trial performance: delivery of services in efficiently & effectively

whilst ensuring patient safety & quality of data

ORFANOS

Outsourcing Difficulties in Clinical Development

Clinical Development Outsourcing Models , ISR Report (2nd edition) 2015

Nearly one-third of respondents mention that finding a CRO with strong expertise / capabilities is the most difficult part

Managing timelines, Maintaining quality, and Selecting the best CRO for the project are also difficult.

ORFANOS

Small Medium Enterprise vs. Pharma CRO Needs

Close association between size of sponsor company and the size of the clinical service provider

State of Clinical Outsourcing Survey, Avoca, 2011

ORFANOS

Company Perspective

THR-184-003 Phase II Study - Proof of Concept

• Prevention of AKI in subjects scheduled for cardiac surgery at increased risk for AKI

• Determined likely event rate based on select risk factors e.g. underlying kidney disease, diabetes in a separate prospective observational study; access to hospital database in addition to literature review

• Objectives:

evaluate safety of THR-184

evaluate potential for THR-184 to prevent AKI associated with cardiac surgery in patients with known risk factors for AKI

ORFANOS

Mapping out the Needs & Expectations

•Design

•Protocol

•eCRFs

•Feasibility

•Regulatory approvals

•Data Mx, stats, data entry system, IWRS

•Vendors (central labs, clinical supplies)

•Contracts (CROs; Vendors, sites)

•Study documentation (DMP, SAP, SMP)

Planning

•Site & Investigator identification

•Site & investigator selection

•Informed consent

•IRBs /ECs

•Training & Site initiation visits

•First site(s)

•Investigator Meetings

Site start- up

•FPFV

•Clinical Monitoring

•Safety & PV; medical monitoring

•Site management

•Enrolment

•Quality Assurance

Conduct

•LPLV

•Finalize queries

•Data base lock

•Drug reconciliation

•Archiving

Close-Out

•Analysis

•Reporting

•Publications

Results

Overall expectations: study timelines, quality Needs influenced by study scope

Project Management Study Oversight Commitment & responsibility

ORFANOS

Making the CRO Choice

ORFANOS

Request for Proposal (RFP) sets the stage

Detailed & specific RFP tailored to trial

CRO target group

Share questions applicable to all

Team to review & evaluate

Face-to-face bid presentation with finalists

Reference checks

Budget discussions thereafter

On site visits, audits

Inform all CROs

Contract

Kick off meeting

Company

Clinical trial parameters: stage of study (first in patients)

complexity

clinical setting

geographical area

experience of investigators

Other support e.g. advisors

Therapeutic area knowledge & previous experience (similar practice setting)

Product characteristics & specific needs

Key decisions e.g. EDC, PVP

Company expertise & infrastructure

Evaluation in keeping with RFP

Ability to meet expectations: key timelines, quality

Key Considerations

ORFANOS

Eval

uat

ion

RFP

Mat

rix

A B C D E F G

Strategic …

Experience Nephrology, Cardiac

Surgery, ICU

Medical Advisory; protocol, CRFs

Clinical Project Lead / Manager

Feasibility assessment

Site contact & recruitment / Site

startup & Regulatory

Oversight : DSMB, EAC, SC

Clinical monitoring

Pharmacovigilance

& Drug Safety

Data management

Biostatistics & analysis: ASD, SAP,

Interim & final analysis

Bio-analytical Labs / Central lab

Medical/study report writing

Supply Chain Management

QA

Canadian Presence

Budget & budget Management

ORFANOS

CRO Selection

CRO should meet the needs of the particular project

Therapeutic area expertise & knowledge

Network of centers: access to the targeted patient population

Ability to execute: experience, efficiency & personnel

Relationship: ability to work together

Initial selection criteria Further considerations

May require further company expertise & support

May require access to other consultants & vendors

Budget key but not necessarily initial criterion for decision; need to be detailed & consistent with requirements

Contract: Comprehensive & detailed requirements

Expertise /resources to contract

IP, document & data protection

Subcontracts

Remedies

Non-compete

Strategic Alignment

Contracting

• Contracting – Time vs. Risk – Preferable to work out contract in advance of

work initiated (under LOI)

• The Devil is in the Detail – Sets basis for project

– Avoids Out of Scope charges

– Based on RFP (company needs; comparable)

• Delegation – Responsibility with company even if fully

outsourced

– CRO remedy for defaults

• Take Control and Contract Direction – Contracts with subcontracts (3rd parties)

• Protect Ownership – IP, data & documents

• Insolvency – Sponsor access to data, etc.

• Build a Way Out – Financial consequences of termination

• Less is Not More – Comprehensive & detailed

– Time & resources for contracting

– Thorough assessment

– Define requirements

Confidential 16

Understanding the DNA of the Contracting Parties – Different focus

– Different deliverables

How to Survive Contracting With Contract Research Organizations, Acquisition International 2012

ORFANOS

Managing the Study

ORFANOS

Recent events have highlighted need for sponsor CRO oversight

One out of three FDA inspections linked to CROs & vendor oversight

Responsibility across the board: Sponsor – CRO roles & responsibilities and management key

“Although sponsors can transfer responsibilities for monitoring to a CRO(s), they retain responsibility for oversight of the work completed by the CRO(s) who assume this responsibility.” FDA

Statistics & Data

Management

Sponsor (company)

Participating Centers

Trial Steering Committee

DSMB / DMC

Central Lab & Pharmacokinetic

Analysis CRO(s)

Clinical Project Management Team

Safety & Pharmacovigilance group

Drug Supplies

Trial Governance – Collective Oversight

ORFANOS

Risk Mitigation Strategy: Select Examples

Risk Potential outcome Preventative action Contingency Plan

Study design Challenges in implementation due to design (surgical/ICU study in high risk population)

Observational study to estimate AKI event rate in target population

Access to expertise in renal disease, cardiac surgery , critical care

Access to expertise in ASD

Flexibility built into design ( e.g. regarding dose selection in Stage 2)

Study amendment

Site identification & selection

Risk of meeting study target timelines

Feasibility survey Patient flow chart

(funnel) Sponsor assessment

visits

Additional sites Replace non-contributors

Enrollment Risk of meeting study target timelines

Site selection (past history)

Referrals from other sites

Competitive enrollment

Site-by-site management plan

Increase allocated enrollment at certain sites

ORFANOS

Study Project Management

Dedicated project team; broad membership Leadership throughout trial process Clearly define scope of project Project plan reflecting organization's goals Agreement on timelines & resource planning High intensity periods: start up, Interim Analysis (IA), data

base lock/analysis, close out Regular reports (metrics)

• Site Initiation Reports • Site & Patient Enrollment • Site feedback & satisfaction • Actual vs. Budget • Safety reports • Weekly calls, face-to-face, ad-hoc if necessary

• Issues management

ORFANOS

Site Management Plan

Site selection: advisors, company, CROs

Enrollment projections & tracking

Site Startup Investigators Meeting

SIV

Enrollment targets for sites

Site-by-site plan Track enrollment of sites & patients

Replace & increase number of sites if necessary

Letters to Qualified Investigator & team

Weekly Newsletter

Webinars (target PI/site research coordinator)

Company/ SRO / SC contact with site personnel (email, phone or face-to-face)

In addition to regular CRA activities

ORFANOS

Critical Success Factors

© Andreas Orfanos

ORFANOS

Critical Success Factors

• Working with your vendor to establish your needs and priorities – Clearly define scope of project – Project plan reflecting organization's goal – Collaborative approach on study design, timelines & resource planning whilst recognizing

company needs – Strategic & cultural fit

• Maximizing your investment by promoting innovative planning – CRO market research on sites & enrollment – Identify & agree on sites, selection & site management activities – Requires expertise in therapeutic area & network – Expertise in study design e.g. Adaptive Study Design – Early consultation with regulatory authorities – Carefully identify & allocate necessary resources; streamline costs; based on project scope &

RFP

• Identifying approaches to support sponsors interests – Oversight – Dedicated project management team – Presence throughout trial process

• Ensure strong relationship and allow for productive trial service – Regular meetings, conflict resolution – Clear designation of responsibilities – Regular meetings with sites – Site by site management plan

Strategic Fit & A

lignm

ent

ORFANOS

New CRO Models Evolving

© Andreas Orfanos

ORFANOS

New Small Pharma – CRO Models Evolving

Strategic & cultural fit

Close association between size of sponsor company and the size of the clinical service provider

(State of Clinical Outsourcing Survey Avoca, 2011)

Growth in CRO industry, many options; however seeing consolidation

Furthermore new models evolving – large CROs with dedicated entity

targeting smaller companies e.g. Quintiles’ Emerging Biopharma Solutions

– Partnerships

– Niche providers

The Future of Clinical Development Outsourcing, ISR Reports

ORFANOS

Co

ncl

usi

on

….

© Andreas Orfanos

Value-added approach

Upfront effort key in making a good choice

Early involvement

Leadership & day-to-day management key; particularly if work with multiple CROs

Culture of team: mutual trust & transparency

Issues management -collaborative

“Seamless” approach

Thrasos Therapeutics: Confidential 27

Acute Kidney Injury (AKI)

Thrasos Therapeutics: Confidential 28 ORFANOS

Issues Management (Conflict Resolution)

Develop & agree on an issue management/escalation plan or part of Quality Mx

Identify potential risks & red flags” in clinical trial program (risk mitigation strategy)

Define & utilise metrics

Implement process: rapidly be brought to the attention of senior management at an early stage if not resolved in a timely manner

Also identify issues at site level through site support team

Ensure follow up until issues addressed & resolved (monitor & track)

Sponsor (company)

Clinical Project Mx (CPM) Team

Trial Steering Committee

Metrics

CRO

Site support team

Site personnel

Other vendors