Team 3 UW Biotechnology Project Management Capstone

Team 3, Inc.

Biosimilars Product Development Plan

Notebook Deliverables for:

Biotechnology Project Management

(BIOPROJ 450 and 455)

August 4th, 2013

Team Members:

Elizabeth Oseid Jim Hancock Marie Beltran

Matthew Skallet Todd Lester

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Biosimilar Project / Notebook Deliverable

Table of ContentsTABLE OF CONTENTS........................................................................................21. TEAM OPERATING RULES..............................................................................32. TEAM PROCESS AND COMMUNICATIONS PLAN.................................................53. PROJECT OVERVIEW STATEMENT (POS)..........................................................84. PROJECT STRATEGY....................................................................................105. PROPOSAL PRESENTATION...........................................................................126. CONTRACT MANAGEMENT PLAN..................................................................157. RISK MANAGEMENT PLAN..........................................................................228. WORK BREAKDOWN STRUCTURE (WBS).......................................................249. NETWORK DIAGRAM:.................................................................................3210. PROJECT SCHEDULE (GANTT):....................................................................4611. COST AND BUDGETING PLAN....................................................................5312. CHANGE MANAGEMENT PLAN...................................................................5913. VISIBILITY AND CONTROL PLAN..................................................................6314. BIOPROJIMAB CLOSEOUT PLAN..................................................................66A. APPENDIX A – BIOPROJIMAB PRODUCT DEVELOPMENT PLAN...........................68B. APPENDIX B – TOTAL COSTS (PIVOT SOURCE)................................................80

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1. Team Operating RulesTeam Operating Rules

Personal Behavior

Maintain high standard of professional conduct and accountability

Critique ideas rather than criticize people

Keep an open mind and a positive attitude

Participate in discussions and ask for clarification as needed

Encourage effort and continuous improvement

Assignments

Team member responsible for Team Deliverable will post draft to the Team 3 Google docs site before weekly teleconference

Team members will review Team Deliverable before the teleconference and be ready to discuss

Notebook Deliverables will follow formatting guidelines decided on by team

Team comments can be made to Team 3 Discussion Forum until midnight Friday before the due date

Final comments can be made to the gdocs site no later than 7pm PDT Saturday before the due date. Note changes made, to avoid confusion.

After 7 pm PDT, Saturday before the due date, only the responsible person for that deliverable can make changes to the current deliverable.

Team members are responsible for assignments as per Assignment Calendar (see below)

Encourage team involvement: request ideas from every member, select the best among them

Notify team via Team 3 Discussion Forum if for any reason you cannot participate in a team activity/assignment

Participation and Decision Making

Decisions regarding Team Project will be made by vote during Teleconference or on the Team 3 Discussion Forum.

Develop consensus on major decisions

Decisions require a 3/5 majority

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Participate in discussions by explaining your vision and any issue you may have.

Bring up any issues as soon as possible – don’t wait until the deadline

Team members are responsible for reviewing minutes and responding with any questions or comments if they cannot make a teleconference for any reason.

Respect and follow team decisions

All topics up for vote will be discussed until no one has anything more to add

Communication between team members

General communication via Team 3 Discussion Forum. Start new thread when appropriate.

Teleconferences on Thursday from 7-8pm PDT, additional teleconferences as needed

o 206-315-1785 or 800-379-6841, Participant code 34699346

Standard templates for Teleconference Agenda and Minutes will be used. (see below)

If there is reason to believe that more than an hour will be needed, team members will be notified 24 hours in advance

If an additional meeting is needed, post a meeting request to the Team 3 Forum. Allow at least 24 hours’ notice.

In the unlikely event that the UW system is down, contact via e-mail

o Marie Beltran.....................................................mariegbeltran@gmail.com

o Jim Hancock........................................................softwareexec@gmail.com

o Elizabeth Oseid..............................................elizabethoseid@earthlink.net

o Todd Lester.................................................................wtlester@gmail.com

o Matthew Skallet..........................................................mskallet@gmail.com

Let the team know if you have scheduling issues.

Stay focused and clear in communications

Seek participation and clarification from others

Check Team 3 Discussion Forum frequently

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2. Team Process and Communications Plan

Description of Communications Plan

This high level Project Communications Plan lists the project stakeholders and the general groups they belong to. It also lists the various forms of communication with them, including methods, format, frequency, etc. This plan may be updated during the life of the project at the discretion of the Project Manager.

RACI Matrix

The core part of the Communications Plan is the matrix on the following page.It uses a tool called the RACI Matrix to determine interaction between stakeholders as defined below.

RACI Definitions

R Responsible for leadership and delivery.

A Approval of Deliverable.

C Consulted, often a SME or other expert.

I Informed

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Communication Plan RACI Matrix

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3. Project Overview Statement (POS)Project Overview Statement

Project Name: Product Development Plan for Biosimilar Compound

Project No:

2013-BSC420

Project Managers:Marie BeltranJim HancockTodd LesterElizabeth OseidMatt Skallet

Problem/Opportunity

The biotechnology revolution has changed the face of pharmaceutical research since the first biopharmaceutical drug first was approved in 1982. As more companies jumped onboard in the research and release of new biotherapeutics, patients received life-changing treatment albeit with costs ranging up to hundreds of thousands of dollars for a treatment cycle. With the patent on Herceptin expiring in six years, Team3 Inc. has managed to produce a molecule with comparability to that of Herceptin, and the intent of the company is to bring this biosimilar molecule to market to directly compete with Herceptin. In doing so, Team3 Inc. will be the first U.S. company to bring a biologics drug to market.

Goal

The primary goal of Team 3 Inc. is to create and follow a pharmaceutical development plan (PDP) by end of Q4 of 2013 that will allow Team 3 Inc. to have a set of guidelines, milestones, and a timeline to introduce the biosimilar drug BIOPROJ4078 to market as the patent for Herceptin expires in order to aggressively compete for treatment of the breast cancer.

Objectives

1. Perform phase 1 and 3 clinical trials with the expectation the phase 2 trials may be unnecessary. Demonstrate safety, efficacy, and comparability to Herceptin. Phase 1 will be expected to be complete in 1.5 years, and phase 3 trials are expected to be complete in 4 years, with final review and approval by FDA 6 years after phase 1 trials begin.

2. Set and maintain a budget of no more than 10% of Team 3 Inc.’s expected 6-year profit margins.3. The company will use in-house groups consisting of, but not limited to quality control and

assurance, validation, process engineering, regulatory, manufacturing, and research. Consultants and outsourcing will be used as needed for issues such as data processing and troubleshooting.

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Project Overview Statement

Project Name: Product Development Plan for Biosimilar Compound

Project No:

2013-BSC420

Project Managers:Marie BeltranJim HancockTodd LesterElizabeth OseidMatt Skallet

Success Criteria

Phase 1 and 3 data will prove the all characterization assays of the biosimilar will be comparable to Herceptin. Safety will also be demonstrated throughout all phases. Phase 1 and 3 will both be completed by Q3 of 2019.

Production and marketing costs will be at or under budget, allowing sales prices to be in the 65-85% range of drug X’s costs.

In-house groups will operate under project operating rules, with turnover rate <10% throughout the project lifecycle.

Assumptions, Risks, Obstacles

Assumptions Market demand will remain steady or increase by the time the biosimilar hits the market. Validation of process will go smoothly, with no lot flags delaying release to test groups. Manufacturing will run smoothly, with no lost runs.

Risks QC assays could show that drug is not comparable to Herceptin. Poor results could cause investment from executive committee to cease, ending the project. As this is a new and unproven process, there could be unexpected delays, causing unwanted

increases to time and budget.

Obstacles FDA bottleneck due to manpower and review period Lack of experience personnel with this type of unproven process, e.g. regulatory and what data

is needed

Prepared by:Team 3

Date:5/4/2013

Approved By: Date:

4. Project StrategyProject Strategy for the Product Development of Bioprojimab

Stakeholder analysis

The following groups maintain a critical stake in the development of Bioprojimab:

Stakeholder Position Influence

Executive Management Internal

– Promote objective analysis of all information available– Acknowledge input from product development team– Challenge business-as-usual with innovative mind-set

Product Development Team

Internal

– Responsible and accountable to all parties for future of the product– Responsible for optimizing product to the maximum possible within confines

of the market place– Responsible for meeting all applicable regulatory requirements

Regulatory Authorities External – Will make final decision based on totality of the 351(k) submission package

– Decision will be based on claims of safety, efficacy and comparabilityIRB, physicians, patients External – Expect a safe product

– Expect a product that addresses needs effectively

Analysis of strengths/weaknesses/opportunities/threats

Strengths

– Existing infrastructure necessary to produce high quality biologic compounds

– Extensive expertise in development and approval of biologic compounds

– Established relationships with investigators, CROs, regulators

– Established marketing force

Weaknesses

– Ambiguous regulatory expectations surrounding biosimilars

– Lack of in-house expertise specific to biosimilar development

– Patient recruitment may prove challenging

– Procurement of Herceptin may prove difficult

Opportunities

– Percentage of breast cancer market share following patent expiration of Herceptin

– Potential market exclusivity period of 1 year if approved as first biosimilar for Herceptin

– Possibility to extrapolate approved indications

Threats

– Competition may obtain approval before we do, eliminating opportunity for exclusivity

– Regulators may shift expectations prior to our submission of 351(k) package

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Development and production of high quality biologic therapeutics requires extensive knowledge and infrastructure. With a portfolio consisting of five FDA-approved biologics, Team 3 Inc. has proven success bringing monoclonal antibody-based drugs to market. Team 3 Inc. will leverage this knowledge and organizational process assets (e.g. step-wise planning, templates, quality by design, design of experiments) to help ensure achievement of the project’s objectives.

Since the FDA’s expectations are still ambiguous and Team 3 Inc. lacks in-house expertise specific to biosimilar development, proactive communication with the FDA will be critical to ensuring approval of the 351(k) submission. Identification and consultation of key biosimilar subject matter experts will further ensure appropriate design of clinical trials to allow for the necessary comparability assessments. Previous experience supporting biosimilar development will be a driving factor behind selection of investigators, sites and CROs throughout all stages of the project.

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5. Proposal Presentation

Executive SummaryGlobal Sales of Herceptin are currently in excess of 5 billion annually. Because the innovator’s patent is set to expire in 2019, TEAM 3 Inc. began investigating potential biosimilar molecules in order to further our mission of bringing the best treatments to consumers at reduced prices. We have discovered a molecule that is very promising Team 3 Inc. believes that our drug can easily capture 30% of the market share

The goal of this project is to develop a plan to bring this new compound, Bioprojimab through clinical trials and complete further characterization as necessary in order to gain market approval, making use of the abbreviated licensure pathway afforded by a 351(k) application. This will give us a competitive edge in bringing our compound to market.

BackgroundMarket conditions for biosimilar pharmaceuticals have never been better. Patents are set to expire on a number of Biologics and current health care legislation; in particular, the Biologics Price Competition and Innovation Act (BCPIA), favors the creation of market competition in this area due to the high cost of treatment with biologics. It has been estimated that enabling generic options on just the top 12 categories of biologic treatments with expired patents would save Americans between $236 and $378 billion over 20 years--an average of some $31 billion a year.1 This creates a prime opportunity for companies possessing the right capabilities to enter the follow-on biologic market.

Team 3, Inc. has expressed a commitment to entering the biosimilar market with its R&D plan to develop a biosimilar compound that, if approved, would compete directly with Herceptin. The R&D team has completed preliminary characterization of a very promising compound that is ready to begin the process of obtaining FDA approval.

ObjectiveThe Bioprojimab team will create a product development plan to bring Bioprojimab to market. This will include further characterization to demonstrate similarity, including successful completion of phase 1 and 3 clinical trials, and gaining FDA approval. The goal is successful completion of clinical trials by Q3 of 2019 with product introduction in early 2020. Development of the post-marketing safety program is out of scope for this project.1 http://www.forbes.com/2009/12/03/kramer-health-care-intelligent-investing-pharmaceuticals.htmlprocess

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Overview of Approach

Working closely with the FDA via Biosimilar Product Development meetings and using the various regulatory steps as go/no-go gates will best allow us to navigate the uncertain regulatory landscape – see Project Strategy Document for more details.

We will scale up manufacturing to accommodate clinical trials and file paperwork necessary to initiate human studies. QA/QC will continue to be handled in-house, as will process engineering and validation. After human studies are complete, assuming FDA approval, the drug will be marketed. Based on characterization of our drug, we believe that we will be able to reduce time to market by avoiding Phase 2 trials. Minimize risk by working closely with FDA and ensure place in the market by keeping costs down.

Statement of Work

Phase 1 clinical trial 18 months from initiation of project

Phase 3 clinical trial 6 years from initiation of project

Manufacturing scale up 1 year, during late stage of Phase 3 trial

QA/QC/Validation During Preclinical and Phase 1 clinical trial

Filing of regulatory paperwork At appropriate intervals

Product launch Q3 2022

Time and Cost SummaryBioprojimab’s total cost estimate: $800 million over 6 years. Profitability by Y4 post introduction.

YearBioprojimab's % of market

Revenue

ROIAnnual Cumulative2022 10% $160,000,000 $160,000,000 -80%2023 15% $240,000,000 $400,000,000 -50%2024 20% $320,000,000 $720,000,000 -10%2025 30% $480,000,000 $1,200,000,000 50%2026 30% $480,000,000 $1,680,000,000 110%

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SWOT Analysis - Analysis of strengths/weaknesses/opportunities/threats

Strengths – Existing infrastructure necessary to produce high quality biologic compounds

– Extensive expertise in development and approval of biologic compounds

– Established relationships with investigators, CROs, regulators

– Established marketing force

Weaknesses – Ambiguous regulatory expectations surrounding biosimilars

– Lack of in-house expertise specific to biosimilar development

– Patient recruitment may prove challenging

– Procurement of Herceptin may prove difficult

Opportunities – Percentage of breast cancer market share following patent expiration of Herceptin

– Potential market exclusivity period of 1 year if approved as first biosimilar for Herceptin

– Possibility to extrapolate approved indications

Threats – Competition may obtain approval before we do, eliminating opportunity for exclusivity

– Regulators may shift expectations prior to our submission of 351(k) package

Rationale for contracting out the Phase 3 clinical trials for

Bioprojimab

Team 3, Inc. has identified a need to contract out the Phase III portion of the Bioprojimab clinical study. This will allow Team 3, Inc. resources to be better utilized during the timeframe Q1 2017 to Q4 2019 in anticipation of the 351(k) submission for regulatory review.

Team 3, Inc. has maintained consistent and well-established business relationships with a key group of CROs during the first two decades in the field of oncology biologics. This joint expertise has established Team 3, Inc. in its current role as a market innovator. We intend to expand further with our lead biosimilar, Bioprojimab, and be poised for market launch as the patent for Herceptin expires in 2019.

With assistance from our in-house legal and regulatory affairs divisions, we have selected two CROs with clinical study expertise both in the United States and Europe.

This is important since the EMA has established biosimilar guidelines with 13 currently on the EU market. The FDA has issued draft guidance on biosimilars in February 2012, but with no entity in the US market, tapping into key expertise will assist with meeting key project milestones while working closely with the FDA transitioning from Phase I to Phase III.

Transparent and timely communication channels with our partners will be required to reach the targeted 351(k) submission. Vetted breadth, depth and quality of the technical, clinical and compliance competencies are also highly valued to accomplish a landmark filing. Global Therapeutics will be the primary CRO, while Cascade Innovation will be the secondary CRO.

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6. Contract Management Plan

Request for Quotation (RFQ) from Global Therapeutics

Background Provide CRO services to Team 3, Inc.to complete Phase III clinical trials.

Purpose and Scope Phase III clinical study design and execution to determine safety and efficacy of Bioprojimab against Herceptin as conventional chemotherapy targeting both early stage and metastatic Her2+/estrogen and progesterone negative breast cancer. Patient delivery will be via intravenous route.

Tasks Confirm availability to partner with Team 3, Inc. by Q3 2018.

Complete on-site audit of Global Therapeutics training proficiencies and related study protocols.

Deliverables Identification of Global Therapeutics personnel to work with Team 3 Inc. project team.

Approval of clinical study design via executive management (sponsor), quality and regulatory teams, and regional IRB prior to the FDA biosimilar product development Type 3 meeting.

Identification of clinical sites and complete logistics for patient identification, enrollment and site monitoring for Phase III initiation and launch.

Milestone for data acquisition, analysis, and report completion with quality and regulatory approval prior to the FDA biosimilar product development Type 4 meeting and 351(k) submission.

Cost and Schedule Team 3, Inc. project proposal stated that Phase III trials would take approximately 4 ½ years to complete. The total time frame to bring Bioprojimab for approval and market launch would take approximately six years and at a projected total cost of 800 million.

6 months for initiation / enroll and consent subjects 67 million3 ½ years to gather and analyze clinical data 600 million6 months to close out or extend Phase III trial 67 million

Note: Cost is in US dollars.

Dependencies Regional CRAs and site monitors weekly updates with project manager.

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Scheduled availability with key personnel for site visits.

Total quality management is the expectation for all clinical study tasks

Project Team Executive Management (sponsor)Project ManagerRegulatoryQuality AssuranceQuality ControlClinicalCRAs, site monitors, study physicians, support staff (Global Therapeutics)IRB/Drug Safety BoardR&D/product developmentManufacturingIT/Validation

Management Approach Timely and transparent communication channels across all cross functional teams.

Oversight is shared by Team 3, Inc. (80%) and Global Therapeutics (20%)

Project manager or designee conducts site visits on a rotational basis to meet with CRAs, site monitors and study physicians.

Patient adverse events and/or site deviations triggers an immediate IRB meeting at Team 3, Inc. corporate headquarters.

Maintain ongoing dialogue with the FDA and remain attuned to market trends with EMA during Phase I and Phase III clinical trials of Bioprojimab.

Proposal Specifications The Service Level Agreement will outline what we expect and when regarding progress, using metrics such as:

PK and clinician observations to determine efficacy and immunogenicity/adverse events to determine safety in the Phase III trials.

The CRO will provide the following:

Web portal where we can see all data generated by the CRO on an ongoing basis, updated weekly

Interim reports at regular intervals (weekly, monthly, quarterly)

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Transparency reports Adverse event reporting to be reviewed by IRB/ethics

committee as needed

Evaluation Criteria Intent to use known CROs, both with extensive experience in US and EU. The primary CRO, Global Therapeutics, meets criteria based on audit findings and completed and successful clinical trials addresses quality and expertise to mitigate specific threats and weaknesses from the initial project proposal (SWOT chart)

Appendix New biosimilar developments, citations, regulations filed here for reference (FDA, EMA, journal papers)

Copy of waterfall timeline for reference

Contact matrix for project team and clinical sites

Based on the above and previous business relationship, the payment style would be a combination of a fixed price contract (based on a defined, fixed budget) and progress payments for meeting key milestones ahead of schedule and under budget (i.e.10% above negotiated cost). If successful, this business arrangement would be mutually beneficial with its high visibility and notoriety of being the first biosimilar on the US market.

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Team 3, Inc. Legal and Regulatory Evaluation Criteria Results for Global Therapeutics

References Evaluation of references - audited study summaries 2009-2014

Reputation Debarment history – none cited Fraudulent activity – none cited Successful contracts – average 3 to 6 per year Failed contracts – 3, attributed to sponsor’s loss of funding Time in business – 22 years in US, 18 in EU

Past Performance Types of projects performed – PK/PD, tox studies, viral clearance, preclinical to Phase IV

Projects similar to the work packages – N/A Bonding status and cost – active Union/nonunion status – non union

Financial Stability Credit rating – A+ Banking arrangements – verified Financial statements – verified, 10K statements filed

Current Workload Under contract – Q4 through Q4 2016 Bid backlog – 4 in US, 2 in EU Capacity of contractor to do your work when you need it done - TBD

Technical Expertise Officers and key personnel – staffed, audited technical proficiency records and licensures

Past work performance - excellent Company policies and procedures – documented corporate handbook Project control procedures – audited completed

Project-Specific Criteria Milestone payments negotiable, case-by-case

Contract Management Process

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Create an online web portal to allow access for all parties the ability for real time monitoring between sponsor and clinical sites

Provision for an interim report compiled from each clinical sites to report on collective data used to determine overall progress and quality (weekly, monthly, quarterly basis)

Schedule ongoing meetings at designated time points to discuss compiled data and whether key objectives are being met. Metrics such as PK (efficacy), immunogenicity via biomarker results (safety), site clinician observations.

Any adverse events are reviewed per designated protocol by IRB and triggers the decision process for resolution

Establish matrix of all parties involved between sponsor and contract entities and detailed responsibilities via service level agreement

Watchful observation of market trends and advances by potential competing companies or organizations with interests with biosimilar development in the area of breast cancer therapies.

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Project Kick-off Meeting Agenda

Introductions: Identification of Roles and Responsibilities (Day 1)

Executive Management (sponsor)Project ManagerRegulatoryQuality AssuranceQuality ControlClinicalCRAs, site monitors, study directors/physicians& support staff (Global Therapeutics)

Study Director (Cascade Innovation)IRB/Drug Safety BoardR&D/product developmentManufacturingIT/ValidationAdministrative Support Team

Contractual authorities (Day 1)

o Primary – Global Therapeutics

o Secondary – Cascade Innovation

Contractual communications—especially integration

of schedules (Day 1)

o Project Manager (Team 3, Inc.) triage communication between executive

management and project directors from Global Therapeutics and Cascade

Innovation (bi-monthly, quarterly)

o Project Manager with key departmental heads at Team 3, Inc. (monthly)

o Project directors (CROs) meet with site monitors and/or study

directors/physicians (bi-weekly, immediate with IRB with identified

deviations/AEs), communicated to Project Manager (Team 3, Inc.)

Deliverables acceptance process (Day 2)

o Deliverables as stated with above RFQ

Payment process (Day 2)

o Completion of fixed priced project items and milestones and signed off by Project

Manager, CRO Project Directors, and Executive Management.

o 10% bonus when completed on time and within established budget

Change control and problem resolution processes (Day 2)

o Key departmental heads, project manager, project director with IRB

o Any deviations documented with timely investigations and CAPA closure by QA

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Closeout process (Day 2)

o Clinical data reviewed, QA data packages audited, and archive study materials,

completed payments, close down clinical sites

o Project Manager, CRO Project Directors, QA and Regulatory prepare for future

FDA biosimilar product development Type 4 meeting and 351(k) submission

Re-assignment of internal staff, completion of project milestones – terminate contract with CRO staff

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Event Potential Failure

Potential Failure Effect Cost S Potential Causes O Current Controls D RPN Actions Recommended

Responsible Party

Actions Taken

Phase 1 Trials Trial results not as expected

Phase 2 trials may be needed, path to approval is jeopardized

$400M 3 Improper practices by contractor, data errors, dosage errors

Patients selected with incorrect disease indication

2 Large patient population

Data from current marketed drug

2 12 Audit trials procedures and expect routine updates

PM, Clinical regulatory

AVOID

Project Costs Costs are beyond 10% of expected budget

Request for budget increase, cutting costs needed

$80M 2 Costs go unreported Unexpected

expenditures are needed (e.g. retests, patients not showing up for appointments, patient death)

2 Aggressive oversight on expenditures

Approval needed for expenditures >$5000

1 4 Routine monitoring of budget

PM, Business Analysts, Senior Management

ACCEPT

Competitors with biosimilar development

Competitor is first to market

Loss of profits due to saturated market

$Billions 3 Competitor contribute more funding to project

Unforeseen delays with our approval process

2 Tight deadlines with phase 1-3 trials

Be aware of industry progress

1 6 Stick to schedule, be aware of industry speed

Core Team, Business Analysts

MITIGATE

7. Risk Management Plan

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Risk Quantification and Mitigation

Where: Severity (S) = amount at stake (3 = unfit for use/illegal, 1 = unnoticed or does not affect

performance) Occurrence (O) = probability event may happen (3 = very likely, 1 = unlikely) Detection (D) = how quickly event may be detected (3 = never, 1 = obvious) RPN = Risk priority number (Sev*Occ*Det). High number = high priority to address RPN: 1-4 = Accept, 5-8 = Mitigate, 9-12 = Avoid

Risk Response and Action Plan

1. Our top three potential risks will be monitored and reassessed biweekly in our project update meetings.

a. At this time each risk will be reassessed for severity to the project health, occurrence it is happening or may happen, and the likelihood we have procedures in place to detect it.

b. Risks will also be retired or downgraded out of our tracker depending on how the project is progressing. For example, after Phase 1 trials are complete, we will know if we can retire the risk of having to perform phase 2 trials.

c. If >2 factors (S, O, or D) score a 1, the risk will be downgraded out of the top three risks to track.

d. If factors of new risks obtain a score of >5, they will be added to the tracker.e. Each week, the top three risks will be assessed in detail addressing why they are

in our top three risks, their impact to the business, and plans in place to address them.

2. Action items to do and actions taken will also be addressed biweekly.a. Actions taken and to do will be updated in the matrix and play a role in

updating our risk assessment.b. The project manager and the core team will be updated from the team on any

new risk factors and assign action items as necessary.

If a tracked risk is likely to happen where the project could be in jeopardy of failing, risk

management meetings will occur twice weekly until a plan is in place to effectively contain the

risk.

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8. Work Breakdown Structure (WBS)

WBS Task Name Duration Person Hours Resource Names Predecessors Start Finish

1Project Initiation 114 days 780 hrs Mon 6/3/13 Thu 11/7/13

1.1 Evaluation -> Identify Project Focus - Biosimilar 14 days 100 Project Management Mon 6/3/13 Thu 6/20/13

1.2 Approval/Execution -> Management initiation (approval) 7 days 40 Project Management 2 Fri 6/21/13 Mon 7/1/13

1.3Create -> WBS 5 days 10 Project Management 3 Tue 7/2/13 Mon 7/8/13

1.4 Create -> Project plan / Completed budget - monthly, quarterly, annually 60 days 300 Project Management 4 Tue 7/9/13 Mon 9/30/13

1.5 Regulatory awareness -> Updated regulatory expectation report 5 days 20 Regulatory Affairs 3 Tue 7/2/13 Mon 7/8/13

1.6 Approval/Execution -> Assemble team members 22 days 250 Project Management 5 Tue 10/1/13 Wed

10/30/13

1.7 Approval/Execution -> Management project approval. 6 days 60 Project Management 7,6 Thu

10/31/13 Thu 11/7/13

2CMC Dev. & Pre-Clinical Study 208 days 24940 hrs 1 Fri 11/8/13 Tue 8/26/14

2.1 Identify candidate biosimilar -> Candidate biosimilar 5 days 1000 R&D 8 Fri 11/8/13 Thu 11/14/13

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2.2 Determine structural similarity -> structural data 30 days 5000 R&D 10 Fri 11/15/13 Thu 12/26/13

2.3 Create Study Design -> Animal testing protocols - dosage, safety, efficacy 25 days 1000 PreClin and Regulatory 10 Fri 11/15/13 Thu 12/19/13

2.4Investigational New Drug (IND) Application -> Info on biosimilar, how manufactured, testing

plan in humans70 days 5000 PreClin and Regulatory 12,11 Fri 12/27/13 Thu 4/3/14

2.5 Determine pharmacological similarity -> PK/PD (animals) 60 days 3500 R&D 12 Fri 12/20/13 Thu 3/13/14

2.6Phase planning -> Clinical study protocol 20 days 1000 Clinical Development 14 Fri 3/14/14 Thu 4/10/14

2.7Phase closeout -> Pre-clinical study report 30 days 4000 Clinical Development 15,13 Fri 4/11/14 Thu 5/22/14

2.8 IND Review -> Discussion and approval by FDA/regulatory agencies 10 days 200 PreClin and Regulatory 16 Fri 5/23/14 Thu 6/5/14

2.9 FDA Initial Advisory Meeting -> Meeting report 10 days 20 Regulatory Affairs 17 Fri 6/6/14 Thu 6/19/14

2.10 Scale up Manufacturing -> Material for use in clinical trials 30 days 5000 Manufacturing 18 Fri 6/20/14 Thu 7/31/14

2.11 Regulatory awareness -> Updated regulatory expectation report 5 days 20 Regulatory Affairs 19 Fri 8/1/14 Thu 8/7/14

2.12 Biosimilar Initial Advisory Meeting -> Data to support IND filing 7 days 100 Project Management 20 Fri 8/8/14 Mon 8/18/14

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2.13 Report to Management -> Approval to continue 6 days 100 Project Management 21 Tue 8/19/14 Tue 8/26/14

3Phase I Clinical Trial 615 days 16440 hrs 9 Wed

8/27/14 Tue 1/3/17

3.1Investigational Review Board (IRB) monitoring -> Timely meetings for adverse events, safety

issues80 days 1000 Cross Functional 22 Wed 8/27/14 Tue 12/16/14

3.2Patient eligibility criteria and safeguards ->

Establish specific criteria and patient protection/privacy

15 days 500 3.2 24 Wed 12/17/14 Tue 1/6/15

3.3Phase planning -> Clinical study protocol 20 days 500 Clinical Development 25 Wed 1/7/15 Tue 2/3/15

3.4Audit staff training and records -> Report

completion, identify training deficiencies/proficiencies

10 days 500 Clinical,QA 26 Wed 2/4/15 Tue 2/17/15

3.5Design Phase 1 clinical trials -> IRB application 20 days 1000 Project Team 27 Wed 2/18/15 Tue 3/17/15

3.6 Identify sites, PI/Study Director and Staff -> Completed in target regions 40 days 1000 Clinical 28 Wed 3/18/15 Tue 5/12/15

3.7 Submit Clinical Trial Design to IRB for approval -> Approval to begin P1 25 days 100 Project Management 29 Wed 5/13/15 Tue 6/16/15

3.8Recruit subjects -> Pool of potential subjects 35 days 5000 CRO-PM 30 Wed 6/17/15 Tue 8/4/15

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3.9 Consent and enroll subjects -> Subjects screened, consented and enrolled - start of P1 35 days 1000 CRO-PM 31SS Wed 6/17/15 Tue 8/4/15

3.10 Phase 1 clinical trial monitoring and completion -> Completed P1 data set 300 days 20 CRO-PM 32SS Wed 6/17/15 Tue 8/9/16

3.11R&D assay transfer to GXP - Quality -> Assay

transfer and validation/stability/comparability studies

70 days 100 QC, QA, IT, Validation 22 Wed 8/27/14 Tue 12/2/14

3.12 Regulatory awareness -> Updated regulatory expectation report 5 days 100 Regulatory Affairs 34 Wed 12/3/14 Tue 12/9/14

3.13 Review of Completed Data -> safety, safe dosage range, and side effect 30 days 1000 Project Team 33 Wed 8/10/16 Tue 9/20/16

3.14FDA BPD Type 3 Meeting -> Meeting report 15 days 20 Regulatory Affairs 36 Wed 9/21/16 Tue 10/11/16

3.15Phase closeout -> Clinical study report 45 days 4000 Clinical Development 35,36,37 Wed

10/12/16 Tue 12/13/16

3.16 Report to management -> Approval to continue 15 days 100 Project Management 38 Wed

12/14/16 Tue 1/3/17

4Phase III Clinical Trial 690 days 31340 hrs 23 Wed 1/4/17 Tue 8/27/19

4.1Phase planning -> Clinical study protocol 50 days 1000 Clinical Development 39 Wed 1/4/17 Tue 3/14/17

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4.2 Design of Phase 3 clinical trials -> IRB application 50 days 2000 Project Management 41 Wed 3/15/17 Tue 5/23/17

4.3 Submit Clinical Trial Design to IRB for approval -> Approval to begin P3 45 days 100 Project Management 42 Wed 5/24/17 Tue 7/25/17

4.4CRO site selection -> Request for bids 50 days 40 Project Management 43 Wed 7/26/17 Tue 10/3/17

4.5CRO site selection -> Evaluation of bids 30 days 40 Project Management 44SS Wed 7/26/17 Tue 9/5/17

4.6CRO site selection -> Audit report 50 days 40 Project Management 45 Wed 9/6/17 Tue 11/14/17

4.7CRO site selection -> Contract with CR 15 days 40 Project Management 46 Wed

11/15/17 Tue 12/5/17

4.8CRO site selection -> Statement of work 15 days 40 Project Management 47 Wed 12/6/17 Tue 12/26/17

4.9Scale up study -safety and efficacy -> Collect

data on target populations, dosage, drug interaction

200 days 10000 Cross Functional 48 Wed 12/27/17 Tue 10/2/18

4.10Scale up patients in process, release, stability

studies -> Evaluate data/trends regarding identity, stability and potency

50 days 10000 Cross Functional 49 Wed 10/3/18 Tue 12/11/18

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4.11Review of data -> effectiveness, side effects, compare it to commonly used treatments,

and collect information that will allow it to be used safely

45 days 3000 Project Team 50 Wed 12/12/18 Tue 2/12/19

4.12 Regulatory awareness -> Updated regulatory expectation report 5 days 20 Regulatory Affairs 51 Wed 2/13/19 Tue 2/19/19

4.13FDA BPD Type 4 Meeting -> Meeting report 15 days 20 Regulatory Affairs 52 Wed 2/20/19 Tue 3/12/19

4.14 Report to management -> Approval to submit 351(k) 30 days 1000 Project Management 53 Wed 3/13/19 Tue 4/23/19

4.15Phase closeout -> Clinical study report 90 days 4000 Clinical Development 54 Wed 4/24/19 Tue 8/27/19

5351(k) to FDA for Review 495 days 7900 hrs 40 Wed

8/28/19 Tue 7/20/21

5.1Review submission -> Quality report 60 days 6000 QA 55 Wed 8/28/19 Tue 11/19/19

5.2Study sponsor meet with FDA/regulatory ->

Complete biosimilar label information for med staff/consumer

30 days 500 Regulatory 57 Wed 11/20/19 Tue 12/31/19

5.3Draft submission -> 351(k) package 180 days 500 Regulatory Affairs 58 Wed 1/1/20 Tue 9/8/20

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5.4 File New Drug Application (NDA) -> Complete 60 day review for safety and efficacy 60 days 200 Cross Functional 59 Wed 9/9/20 Tue 12/1/20

5.5Manufacturing facility inspection -> Complete inspection with approval or issued response

letter (483)75 days 400 Cross Functional 60 Wed 12/2/20 Tue 3/16/21

5.6 NDA Review -> Discussion and approval by FDA/regulatory agencies 60 days 200 Cross Functional 61 Wed 3/17/21 Tue 6/8/21

5.7Request FDA/advisory board approval ->

Regular, fast tracked or accelerated approval for market

30 days 100 Regulatory 62 Wed 6/9/21 Tue 7/20/21

6Project Closure 237 days 700 hrs 56 Wed

7/21/21 Thu 6/16/22

6.1 Close out contracts associated with this project -> completion of final payments 30 days 50 Project Management 63 Wed 7/21/21 Tue 8/31/21

6.2Reimbursements and payments -> Financial

records review, payments completed, archived docs

75 days 50 Clinical, Finance 65 Wed 9/1/21 Tue 12/14/21

6.3 Site Debrief and inactivate status -> Issue final report, archive study data and materials 45 days 100 Clinical 66 Wed

12/15/21 Tue 2/15/22

6.4Affected staff notified of project/study end ->

Reassignment of staff to other projects or departments

30 days 100 Cross Functional, HR 67 Wed 2/16/22 Tue 3/29/22

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6.5 Ensure necessary filings complete -> All filings are complete 30 days 50 Project Management 68 Wed 3/30/22 Tue 5/10/22

6.6Archiving -> Archived report 5 days 50 Project Management 69 Wed 5/11/22 Tue 5/17/22

6.7Hand off pertinent information to marketing

team and post marketing team -> End of Project

22 days 100 Project Management 70 Wed 5/18/22 Thu 6/16/22

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9. Network Diagram:

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10. Project Schedule (Gantt):

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11. Cost and Budgeting Plan

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Assumptions made in building the Budget and Spending Plan:

1. Activity costs are based on the WBS hours submitted previously, timeframes based on the Gantt Chart.

2. Hourly rates are based on Salary.com median salaries converted to hourly and then fully burdened at 200% (PTO, medical, retirement, taxes, etc.).

3. Indirect costs were calculated based on estimates per person per month and then extrapolated for the total "person months" in each phase.

4. The first two tabs are the budget and spending plan. The third tab is the data source for the first two tabs. The remaining tabs are data gathering, but will not be included in the final plan.

5. Since this is a multi-year project, budget and spending detail should be further broken down into greater detail as the project progresses.

6. We chose to use pivot tables with a single data table so that making adjustments would be easy and changes universal.

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Underlying Cost Model and Estimation

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Annual Hourly Fully Burdened (* 2)

Environmental Health and Safety Manager = $79,404 79 37.98 75.96

Executive Director = $70,705 71 34.13 68.27

Clinical Manager = $63,958 64 30.77 61.54

Clinical PM = $84,291 84 40.38 80.77

Senior CRA = $91,931 92 44.23 88.46

Finance Manager = $85,855 86 41.35 82.69

HR Manager = $59,151 59 28.37 56.73

Legal Manager = $74,577 75 36.06 72.12

Manufacturing Manager = $83,162 83 39.90 79.81

Marketing Manager = $60,981 61 29.33 58.65

Regulatory Affairs Manager = $91,063 91 43.75 87.50

Regulatory Compliance Manager = $74,986 75 36.06 72.12

Biotech PM = $98,278 98 47.12 94.23

QA Manager = $70,808 71 34.13 68.27

R&D Manager, Pharmaceuticals = $108,209 108 51.92 103.85

Regulatory Affairs Director = $144,385 144 69.23 138.46

Salary Calculations

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12. Change Management Plan

Change Requests may be initiated by any stakeholder; however, all project changes must go through the Change Management Process.

Begin the Change Management Process by filling out a change request form and submitting it to the Project Manager. The Project Manager will review the request and decide the best course of action, which can include denial of change request, continuation of the approval process, or approval.

All Change Requests will be logged in the Change Request Log. Approvals will be sent to initiator and pertinent Department Managers.

Please fill out Section 1 of the Change Management Form completely and turn in to the Project Manager. Incomplete forms will be returned to requestor. Attach additional pages as needed.

The PM will review the request for accuracy and clarity. In the case of minor changes that do not impact scope, quality, timeline or cost of the project, the PM can approve the change. Copies of approved IRB and IACUC protocols will be kept with project documentation during the project, but not archived. Original IRB/IACUC approvals will be held by the IRB/IACUC, and are retained by the appropriate department as per the retention policy for those records. At final archiving, the change requests and log will be entered into the Project Archive - the log serving as an index for the actual request forms.

Please note:

All requests for changes to animal protocols must be accompanied by a completed IACUC Change Form. No changes may be implemented without both Institutional and IACUC approval. Please download necessary forms from the IACUC section of the Team 3 Inc. Intranet.

All requests for changes to human protocols must be accompanied by an IRB change form. No changes may be implemented without both Institutional and IRB approval. For downloadable forms, please go to:

http://www.wirb.com/Pages/DownloadForms.aspx

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Change Request Form

Part 1 – Requestor

Project Number Requestor Date

Department Extension

WBS number Predecessor Successor

Reason for change request:

Description of change:

Departments involved:

Submit to IACUC? Yes☐ No☐ Submit to IRB? Yes☐ No☐

Benefit:

Part 2 – Change Controller

Change Number Date Received

Implementation Date If denied, reason for denial:

Part 3 – Review

Change Control Committee

Disposition (cancel of continue) Date

Business PM Business Manager Technical PM

Part 4 - Investigation Team

Assigned to: Date:

Part 5 – Approval Committee

Disposition (cancel or continue) Date

IACUC Approval? (if required) Date

IRB Approval? (if required) Date

Senior Manager Project Manager

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CHANGE MANAGEMENT LOG page 1 of 2Project Name: Bioprojimab

Company/Division: Team 3, Inc/Biosimilars

Project Manager: Marie Beltran, Jim Hancock, Todd Lester, Elizabeth Oseid, Matthew Skallet

Project Description: Preclinical and clinical testing of Bioprojimab, a biosimilar intended to compete with Herceptin

CurrentStatus Priority Change Request

Description Assigned ToExpected

ResolutionDate

EscalationRequired

(Y/N)?

ActionSteps

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CHANGE MANAGEMENT LOG page 2 of 2Project Name: BioprojimabCompany/Division: Team 3, Inc/BiosimilarsProject Manager: Marie Beltran, Jim Hancock, Todd Lester, Elizabeth Oseid, Matthew SkalletProject Description: Preclinical and clinical testing of Bioprojimab, a biosimilar intended to compete with Herceptin

ImpactSummary

ChangeRequest

Type

DateIdentified Change # Entered By

ActualResolution

Date

Final Resolution& Rationale

By signing this log, I acknowledge that I have reviewed this document for accuracy and completeness.

Change Controller Name:Signature of Change Controller: Date

Project Manager Name:Signature of Project Manager: Date

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13. Visibility and Control Plan

Objectives for a Project Visbility and Control Plan

Initiating, launching, and managing a major project time line takes meticulous planning, yet allows room for adjustment. An ideal comprehensive system would identify sequential phases, deliverables, and key milestones that are tracked for progress or any variances in real time. A snap shot in time can also be assessed as predecessor and successor tasks are taken into account to measure performance. Projects are always susceptible to time (project ahead or behind schedule), resource (availability of personnel), and budget constraints (project over or under budget, monitor cash flow). This plan should also be able to trigger an alert/action or red flag system to mitigate any potential risk factors. Issues or excursions that are identified can be addressed in a timely fashion via a corrective action preventative action (CAPA) system. Accessibility to this plan also enhances cross-functional group decision making and facilitates project transparency. When used in tandem with MS Project 2010, Gantt charts, Excel spreadsheets or other tracking programs, the project visibility and control plan is a useful project management tool.

Project Update Report

Individuals responsible for work packages will report on a bi-weekly basis to project management via a password protected spreadsheet. The validated spreadsheet has a header bar or dashboard can be created across the top to include the some of the following (see below). Additional points of reference can be added as discussed and later approved by project management. Likewise if the overall budget allows for it, a project management program can be purchased, tailored to project metric requirements, and also validated. A program should be commonly used in the industry and deemed acceptable by the FDA and other regulatory agencies.

Milestone by Phase

Triggers any Overdue Task or Deliverable

Triggers Trend Excursion of Task

or Deliverable

Identify underutilized or underperforming resources to streamline or

eliminate

Reference Point for Project

Budget

(ND11 data)

Other Desired Metrics to Monitor

Example:Clinical Phase

1

Assay Transfer to

Quality

Delay in equipment installation

qualification (IQ)

GMP plate reader

Schedule to be readjusted due to 1-2 week delay in software upgrade

Projected 8/27/14 to 12/2/14

Review materials inventory needed to

complete IQ, OQ, and PQ validation

studies

Direct CostE14: QA$75,097

Indirect CostE18 Equipment

$101,294

Timeline to draft, review, approve final IQ/OQ/PQ

validation reports

Identify affected teams: QC, QA,

IT/Validation

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Information from this spreadsheet can be condensed to provide a Project Update Report (PUR), a virtual real-time snapshot format from each cross-functional team leader (if applicable, based on timeline or Gantt chart). This information is assembled in a pre-approved, pre-formatted template. Assorted pre-approved, pre-formatted templates are available in a folder accessible online by all cross-functional members. The report is then submitted electronically to project management with bi-weekly frequency. This is overridden if a project team meeting is convened where the meeting agenda with action item status supersedes the bi-weekly report.

The Project Update Report (PUR) would identify the cross-functional team leader and affected team members, note the specific task/project deliverable based on the master schedule/project timeline, status circled (on schedule, off schedule, or not applicable), reason for any schedule variance, identify other affected departments due to the variance, identify any additional issues or excursions (which can be cross-referenced by QA), summarized corrective action and projected time for completion. This report would be reviewed for content and then signed/dated electronically by project management before being forwarded to QA Document Control.

Project Management Update Report

PURs will be used to prepare the Project Management Update Report (PMUR). This specific report will be prepared on a monthly basis by project management and provided to executive management (director level upward) and other designated milestone stakeholders. The streamlined content would have team project status highlighted by bullet points from the Project Update Report (PUR) or cross-functional team meeting minutes. Again, these documents are also controlled and filed electronically.

Metrics – Determination of Variances in the Project Plan

How are variances, such as cost and schedule, to the Master Plan or Work Breakdown Schedule and Project Budget detected? The password protected, validated spreadsheet program briefly described above will have specific criteria that are tailored to the project objectives and milestones. This will trigger any minute variance in the project and how much drift there is from the desired time point or designated value. Project management will need a system to identify and flag any alert/action excursions to be able to react appropriately based on the variance. This allows for proactive risk mitigation, cost and task factors addressed and adjusted, and timely oversight from project management’s standpoint.

Earned Value Management will be employed to assess project performance and progress. Three key measures for each work package will be monitored and reported in the PMUR:

1) Planned value (PV) - the authorized budget assigned to the work package ($ amount)2) Earned value (EV) - value of work performed (% complete)3) Actual cost (AC) - total cost incurred for work performed ($ amount)

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Cumulative EV and AC will be charted on the following Progress Chart and compared against baseline PV.

Progress Chart

Time (months)

Cum

ulati

ve V

alue

s Planned value (PV)

Actual costs (AC)

Earned Value (EV)

Variances from approved baselines will be monitored as follows and reported in the PMUR:

Schedule Variance (SV): Difference between EV and PV (i.e. SV = EV – PV).

Cost Variance (CV): Difference between EV and AC (i.e. CV = EV – AC).

Project status will be further monitored with schedule and performance indices calculated as follows:

Schedule Performance Index (SPI): Ratio of EV/PV. If SPI is one, then the project is perfectly on schedule. If SPI is less than 1 then the project is behind schedule. If SPI is greater than one then the project is ahead of schedule.

Cost Performance Index (CPI): Ratio of EV/AC. If CPI is one, then the project is perfectly on budget. If CPI is less than 1 then the project is over budget. If CPI is greater than one then the project is under budget.

Deviation from Baseline

For any month where SPI or CPI falls below 0.9, an investigation will be triggered to determine the root cause and take corrective action if necessary.

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14. Bioprojimab Closeout PlanThe closeout plan will be followed at the end of each phase of the project, as phase I and phase III trials will be closed out at different times during the lifecycle of the project:

1. Since this project is performed in house for phase I clinical trials, all team members will be aware of the end of their contribution period, therefore there will be no need for a termination manager.

2. Sponsor and core team hold meeting in which all core team members bring all deliverables that are still in progress.

a. The control plan is discussed and updated if necessaryb. Lessons learned template is brought by PM and core team members are

assigned action items to address lessons learnedc. Status of deliverables is discussed and deadlines are set for any

outstanding actions

3. For phase III clinical trials, the CRO contract will be reviewed upon submission of 351(k) to regulatory agencies:

a. Contract will be reviewed with CRO and all debts and obligations will have a timeline put in place for final payments.

b. Conduct and complete a post-implementation audit and final report. Submit the report to the CRO.

c. A voice of the customer will be sent to the CRO for feedback to the core team.

4. Post-Implementation Review for internal team. Recommendations will be asked of all team members for improvements and paths forward.

5. Meeting with marketed drug production team. This is to coordinate information transfer once FDA approves drug license so product can be immediately released to market.

6. Assessment meeting: Once feedback has been collected and evaluated, an assessment meeting will be conducted to derive best practices and formulate lessons learned as an effort to inform future projects.

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7. Prepare end of project or close out reports: Project objectives and scope Archival of data process Approval from FDA Potential for Bioprojimab to apply to other indications Implementation to market Study documentation and data documentation files complete and in order

8. Sponsor close out meeting. Sponsor will provide details of celebratory company party for all employees with recognition provided to core team members. Letter of approval from FDA will be introduced as well.

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A. Appendix A – Bioprojimab Product Development Plan

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B. Appendix B – Total Costs (Pivot Source)

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Team 3 UW Biotechnology Project Management Capstone

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Transcript of Team 3 UW Biotechnology Project Management Capstone