CLINICAL TRIAL MANAGEMENT BOOT CAMP Taryn Losch-Beridon and Maureen Cleaver Sucampo Pharma Americas, LLC

The information presented and discussed represents the opinions of the author/presenter and, although descriptive of general activities, do not necessarily reflect the views of Sucampo Pharma Americas, LLC

Disclaimer

Site Selection and Feasibility

Importance of Site Selection and Project Success Investigative site payments and patient costs generally

comprise 20-25% of a given clinical project budget Cost of identifying, qualifying, contracting, obtaining IRB

approval for site, as well as issuance of upfront non-refundable payments and investigator meeting attendance, can exceed $20,000 dollars to achieve just one SIV-ready site This investment, on a study of 100 clinical sites where 30% of

sites do not perform, could amount to over $600K wasted

Investigative sites impact data quality, enrollment timelines, and overall study budget more so than any other study-related expense

Planning for Site Identification

Create a process and plan for Site ID Process commences with initial site search and outreach and

ends with establishment of final list of qualified sites

Consider utilizing in-house site ID team who will later become point of contact for sites and field monitors

Consider planned sources of clinical sites, e.g., CenterWatch, scientific meetings and congresses, ClinicalTrials.gov, literature searches, referrals from KOLs

Planning for Site Identification (cont’d)

Define the types of sites are you seeking Consider the patients seeking for treatment and the types of

treating physicians for condition, i.e., PCP or specialist…in some cases, multiple specialist types may be viable

Who are high prescribers in this therapeutic area, i.e., what does market research tell us?

Include assumptions for ratio of academic/VA hospitals to private practice or clinical research specialty clinics If these assumptions change during feasibility, may need to

adjust budget and/or timeline assumptions to account for more local vs central IRBs, longer contracting timeframes, and lower enrollment rates

Site ID Plan Content

Named team member roles and responsibilities Document process so all team members, as well as stakeholders reviewing plan,

can understand the process in detail. Pre-feasibility/feasibility questions CDAs and process for establishing

Consider at what point during site ID process protocol synopses will be shared Tracking tools for process activities Goal dates/timelines for each stage of process culminating with final Site

ID list Documentation of each stage of Site ID and review/decision-making for

site funnel Timeline for conduct of SQVs Target site locations, including countries

During site ID process, maintain map of potential sites to ensure wide distribution of site locations and avoid overlap in certain areas within a country/region

List of relevant SOPs

Advantages to Comprehensive Feasibility Validate protocol enrollment potential Refine forecasts of trial enrollment, costs, and timing Obtain practical, early feedback on trial design Establish rapport with site staff early to begin building

partnership Involve sites in protocol, eClinical System, site manual

development, etc. Sites are more engaged during study implementation when

their opinions are considered during study start-up Take the opportunity to listen to and respond to site needs

on an individual basis

Trial/Site Feasibility

Earliest possible opportunity to assess site quality before a large financial investment

It is not just a questionnaire and does not substitute for site qualification visit

Telephonic feasibility interviews vs. paper questionnaires Greater ability to gauge site enthusiasm, organization, staff

involvement … all drivers for site success in enrollment Allows for immediate clarification of unclear responses

unlike written responses to mailed questionnaires

Content of Feasibility Interviews

Investigator interest and capability Appropriateness of protocol requirements

Specifically ask PI and coordinator to comment on list of procedures and protocol visit schedule

Regulatory considerations and assessment of operational capacity of site (i.e., resources, processes)

Success (or failure) on similar studies previously and contributing factors

Determine how the site typically identifies potential patients and discuss the types of recruitment efforts may work best based on what has worked in the past If site asks a lot of questions regarding provision of budget for

recruitment/advertising, it may be a sign that site does not have adequate access to patient population for protocol

Site Qualification

Prior to an on-site qualification visit, ensure that the proposed investigators have been checked against applicable local debarment lists

Consider whether use of research naïve sites/PIs will be allowed and include a plan for additional training and oversight in the clinical monitoring plan

Maintain thorough documentation regarding site selection or reasons for non-selection

Waivers of qualification should only granted in unique circumstances such as current or recent participation in a Company-sponsored trial (e.g., within past 6 months)

If PI is replaced, must re-qualify

Other Recommendations for Success

Ensure clear lines of communication for site Always inform sites proactively regarding delays Consider one point of contact for contract negotiation and

another for budget negotiation For good sites who you want on your “team”, be

flexible For example, may not be able to offer payment more

frequently than quarterly, but can increase upfront subject payment that will be earned back as patients are screened/enrolled

Minimize site burden in setup of eClinical systems; ensure simplicity and organization of site tools and documents; streamline supply request and re-supply processes

…and a Few More

Maintain list of issues raised during feasibility for medical and clinical development team to consider before protocol finalization

Generate and maintain FAQ list amongst feasibility and clinical project mgmt teams, refining throughout site ID process

Don’t be afraid to label sites as back-up or decline for participation on a particular program….hitting target number of ID’ed sites means nothing if 30% or more of them underperform or don’t perform at all, wasting investment of precious time and resources to get them up and running

Outsource/Resource Planning

Outsourcing Drivers

Pharma/biotech increasing R&D budgets to “tap” into additional product pipeline, leading to increased reliance on CROs1

Increased regulatory, political, and scientific scrutiny on both investigational and marketed products

Generic product encroachment on market share and revenue Outsourcing solutions offering lower costs, better use of

internal/external resources, and high quality results are desired Smaller pharma/biotech do not have infrastructure to conduct a

full development program from nonclinical to marketing approval

1 Moody’s Global Corporate Finance, August 2008

Decision to Outsource

Why should a Sponsor outsource activities to a CRO Define strategy

Benefits of strong outsourcing partnership Supplement expertise of Sponsor, especially in new

therapeutic areas Resourcing flexibility / managing internal resources Utilize industry best practices

Assessing CRO Fit

Identify CRO(s) to partner with Conduct RFI (Request for Information) Provide general strategy Obtain general CRO capabilities and pricing

Conduct RFI meetings Identify which CRO(s) align best with company strategy

o Do therapeutic areas / strengths of CRO align o CRO strengths supplement Sponsor needs

CRO Evaluation

Request for Proposal (RFP) Provide template to prospective CROs, including as much

detail on study as possible Provide budget template if possible in order to assist in

comparing proposals Provide point of contact at Sponsor

o As questions are asked regarding RFP, provide responses to all CROs

Prepare an RFP

Group Exercise A

Workshop Exercise Background

You are a Clinical Project Manager at, CBI Pharmaceuticals, a small sized pharmaceutical company. In October 2014 you are assigned a phase 2/3 study to manage. The protocol has been fully developed and is handed over to you in a final version. The company has set a goal of FPFV in March 2015. As a small sized company you do not have the internal resources to manage the study. You will need to fully outsource the study to a CRO. A list of potential CROs has been provided to you and the next thing you need to do is to send out RFPs.

Site Contract & Budget Negotiation

Considerations when Outsourcing Site Selection Caution against blanket acceptance of CRO-suggested sites and

against waiving qualification for sites used by CROs recently Often CROs have sites they’ve used on different studies and have

established working relationships but NOT with the population you are studying.

What a CRO considers a good site (high speed enrollment) may be negligible in terms of quality.

CROs may recommend countries that are not feasible from a regulatory or patient population perspective simply because they have operational presence there

Budget negotiation by CROs on Sponsor behalf can result in higher investigative costs (~10% on average)

Sponsor is ultimately responsible for ensuring use of quality sites…you cannot outsource oversight of selection of qualified sites/investigators!

Site Contracting

Consider negotiation of master clinical service agreements for multiple studies at a single center

Document/understand relationships between study staff and clinical research unit Beware in contracting private research entities…ensure that

proposed PI is full-fledged site employee and the site can be held accountable for his/her performance on trial

Make certain to have strong language regarding PI replacement, notification thereof, and transfer of obligations/training

Include provisions regarding maintenance of documentation

Draft Budget

Site Budget Negotiation

Site Negotiation Final Budget

Site Budget Negotiation

Site Negotiation Final Budget

Site Budget Negotiation

Site Negotiation Final Budget

Site Payment Details

Type Criteria for Payment Payment Details

Start Up Contract execution Start-up fees

Monthly Payments Per completed subject visits and screen failures, based upon site's entry of data on all required eCRF screens for each completed visit at the time of month close

Total visit costs for enrolled patients and/or fees for each screen failure less 10% holdback

Final Payment Issued upon database lock, return of unused study materials, and receipt of copies of site's notification to IRB regarding study completion/termination

Payment for remaining subject visits and screen failures 10% holdback payment Archiving fee Close Out

Ad-Hoc & Other Contracted Fees

Invoice from site required Payment for IND safety reports, SAE processing, Reconsenting

Site Budget and Payment Summary

Accept increased subject/visit fees over other contracted fees such as start up

Where possible include “per subject fees” within grid

Keep sites within the standard budget template If paying by procedure avoid site specific line items

within visit schedule Avoid accepting changes to payment terms Require invoicing for items outside of standard

template and terms

Review/Negotiate CRO Proposals

Group Exercise B

Selecting CRO for Study / Evaluating RFPs

Review all proposals and budgets Address any discrepancies / clarify differences Conduct face to face bid defense meetings

Provide agenda and list of attendees Provide CRO opportunity to discuss their approach to

conduct study Provides study team members to meet proposed

counterparts and ensure team cohesion

CRO Selection

Determine rating system What is most important? Therapeutic expertise, global

expertise, resourcing

Decision made on considering all factors (i.e. not choosing CRO based solely on price)

Sample CRO Evaluation Grid

Master Services Agreement

Establish framework for relationship – preferred provider / general MSA

Govern legal and business terms Negotiate all legal terms Includes operational expectations

Scope of Work Define study specific details Delegation of responsibilities Transfer of Obligations Payment terms Timeline expectations

Study Oversight

Establish expectations upfront Conduct kick off meeting with CRO and Sponsor teams Review study details, changes since RFP Define communication plan, including escalation Define roles and responsibilities – utilize detailed RACI

Ongoing Study Management

Set standard meeting schedule Weekly? Telecons? Face to Face?

Periodic milestone reviews Identify when timelines are in jeopardy

Proactively address issues

Factors for a Successful Partnership

Trust is the foundation! Pairing of sponsors and vendors who are in

alignment on objectives and have a strong commitment to a successful outcome

Build effective lines of communication Put governance committees and executive oversight

mechanisms in place Ensure sufficient resources on both sides to

effectively collaborate and manage the relationship

Factors for a Successful Partnership (cont’d)

Early discussion of shared vision for relationship, goals, etc.

Open dialogue to ensure assumptions are valid and agreed upon amongst stakeholders

Common understanding of communication channels and expectations for reporting/monitoring of progress to upper management in both organizations

Factors for a Successful Partnership (cont’d) Ensure that teams mesh well; if foundation is not

sound, relationship will likely falter and goals will not be achieved Match experience levels; step in if major turnover

occurs on either side of relationship Develop issue escalation and contingency plans Conduct regular business performance evaluations

(two-way) Ensure roles and responsibilities are clearly defined

(e.g., detailed RACI charts)

Projecting Project Spend

Group Exercise C

Risk Management Plan/Grid

Contact us

Maureen Cleaver

Director, Clinical Operations

Sucampo Pharma Americas

4520 East-West Hwy, Ste 300

Bethesda, MD 20814

mcleaver@sucampo.com

240-223-3618

Taryn Losch-Beridon

VP, Clinical Development

Sucampo Pharma Americas

4520 East-West Hwy, Ste 300

Bethesda, MD 20814

tberidon@sucampo.com

240-223-3604