1. business and industrial
2. business operations
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4. project management

Clinical Trial Timelines
Cornelia Kamp, MBA
Executive Director Strategic Initiatives
Clinical Materials Services Unit (CMSU)
Clinical Trials Coordination Center (CTCC)
University of Rochester
www.clinicalmaterial.com
Agenda
Drug Development Timeline Overview
 Lifecycle of a Clinical Trial

 Sample
Timeline Handout
Key Timeline Milestones in the various
phase of the lifecycle
 Keys to staying on Time
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Drug Development
Timeline Overview
Drug Development Process/Overall Timeline
Drug Development Process
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It costs about $802
million* (in year 2000
dollars) over 12 years
to bring one medicine
from discovery in a
laboratory to the
patient.
For everyone one
medicine that reaches
the marketable stage,
between 10,000-30,000
compounds must be
screened.
*Ref: DiMasi JA, Hansen RW, Grabowski HG. The price of innovation; new
estimates of drug development costs. J Health Econ2003;22:151-85.
A Median Phase III study
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Includes ~800 subjects
50 investigator sites
~700 days (2 years) from First Subject First Visit (FSFV)
to Last Subject Last Visit (LSLV)
Costs ~$25 million (including per subject fees, drug
supply, laboratory, Project and Data management fees)
or ~$36,000/day
Ref: Li, Gen: Site Activation, The Key to more Efficient Clinical
Trials; 2008 Advanstar Communications Inc.
Gen Li: former head of R&D Operations for Pharmacia & Pfizer
Lifecycle of a
Clinical Trial
Life Cycle of a Clinical Trial
Grant Award  Protocol finalized Orientation or
and/or Parent
 Model ICF finalized Initiation
contract
Meeting

Sites
selected
established
 Operations
Manual/MOP
completed
 Protocol
Synopsis
finalized
 CRFs finalized
 IRB approvals
obtained
Database Locked
 Enroll subjects*
 Distribution of study drug
to sites
 Answer Protocol/CRF
questions
 Site subcontracts/
 Schedule of payment schedule in
place
Activities
finalized
Analysis
 Take incident calls
 SAEs
 Dosage Adjustments
 Finalize Contracts with
 Premature Withdrawals
third party vendors
 Drug Disclosure
(labs, ECGs etc.)
 Data query process
 Clean/Close database
 DSMB established
 Transfer database to
 Build database
Biostatistics
 Perform primary/
secondary analysis
 Submit abstract
 Submit manuscript
 Submit CTR
 Post results on
www.clinicaltrials.gov
 Post-hoc analysis
 Finalize Study drug
packaging/labeling*
CONCEPTUAL
PHASE
PLANNING
PHASE
IMPLEMENTATION
PHASE
ANALYSIS/
PUBLICATION
PHASE
The Process of Conducting Clinical
Trials:

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Fully understand the full lifecycle of
any clinical trial, regardless of the
phase (I-IV) or indication
The process stays the same
Love the process, not the compound
under study
 Compounds
are a “dime a dozen” and
come and go. (Quote from: Michael
Poole, MD Vice President, Wyeth)

The process is here to stay
Keys to Staying on Schedule
Are developed in the conceptual and
planning phase.
 Develop a REALISTIC timeline and
workscope in the planning phase of a
study
 Keep It Simple Stupid! whenever possible

Timeline and Work Scope

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Create a scope of work document clearly delineating
who is responsible for what: sponsor, SC, Project Team,
External Vendors, Sites, Monitors
Create a detailed timeline of all activities that need to
complete in each phase of the Project Lifecycle

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Both documents will provide the roadmap for the overall project
Tools for timeline development:
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Excel
Microsoft Project
SmartDraw
Liquid Planner
http://www.eriban.com/ Pharmaceutical Development Project
Management Tools (Erbian Research Inc.)
Copyright © 2009 Clinical Trials Coordination Center/University of Rochester: All Rights Reserved
To Ensure Adherence to the Timeline

HIRE a GOOD Project Manager
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Is highly organized
Is remarkably flexible
Has planned and executed a large birthday party (Ira Shoulson,
MD), Bar-mitzah/Bat-mitzah or a large wedding
Has Anal Retentive tendencies (OCD)..a good thing in this
industry
Can still see the forest through the trees
Has excellent oral and written communication skills
Can build strong relationships with all kinds of staff both internal
and external to the institution
Can influence people without a direct reporting relationship
Is not afraid to raise issues early on and work on finding
solutions
Willing to put in long hours
Is always planning at least 6 months ahead
It Takes a Small Army to Run a Study:
with Excellent Communication

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Steering Committee
Sponsor
Operational Team
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Project Manager
Database Manager
Information Analyst
Administrative Support
Biostatistican
Programmer
Meeting Planner
Monitors
Enrolling Site Team
Data Safety Monitoring Board
Vendor Teams
Conceptual Phase
Timeline Milestones
Formalize the idea/obtain funding
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Develop a Protocol Synopsis and Schedule of Activities
(2-3 months)
Develop full research plan following requirement for
potential funding source (e.g. NIH, FDA, DOD,
Pharmaceutical unrestricted educational grant,
Foundation, or approval of internal pharmaceutical
company budget etc.)
Submit for funding and go through the review process
(typically max of 2 submissions of the same idea)

Can take anywhere from ~6-9 month to 4-5 years or longer

In some cases funding does not materialize….
Planning Phase
Timeline Milestones
Key Planning Milestones
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Protocol Synopsis and Schedule of Activities
Procurement of Drug Supply
Set-up and maintain Trial Master File (TMF)
Final Protocol
Model Informed Consent Form (ICF)
Develop patient recruitment materials: patient
brochure; website; newspaper, TV and radio
ads; 1-800 call center scripts etc.
Regulatory Submissions

IND submission(~2-4 wks after final protocol available)
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FDA approval/complete or partial hold status – (must wait 30
days before starting the study for FDA to respond)
Most IRBs require proof of IND status via written documentation
(email/formal letter) from the FDA that the trial may proceed
Pros/Cons of submitting Final protocol/model consent to sites
prior to IND/protocol approval from FDA
Submission to other Regulatory authorities as applicable
(e.g. Health Canada, European Union etc.)
Initiate Site Selection Process
Send Confidential Disclosure Agreement
(CDA) to possible sites (must be returned
before site selection materials can be
sent) (~2 weeks to send and receive)
 Site selection questionnaire sent to sites
with fully executed CDAs (completed ~1
week after final protocol synopsis is
available)
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Select Sites
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Based on:
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Access to patient population/geographic distribution
Past performance of investigator/coordinator team
Projected number of subjects/anticipated enrollment rate
Receipt of FDA 483s
Lack of competing studies
Ability to attend orientation mtg
Availability of required equipment or specialized staff
Notify selected and back-up sites of status
Notify sites not selected
Site Activation Drives Enrollment
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Budget/Contract negotiation
Gain Institutional Review Board (IRB) approval
in the US or ethics Board approvals in
Europe/Canada
Collect other regulatory documents (e.g. FDA
form 1572, CVs, financial disclosure etc.)
Provide sites with clinical supplies (e.g. lab kits,
drug supply)
Patient Recruitment
 Begins
once above elements are completed
Site Activation
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Enrollment cycle time varies by disease state
and sponsor, but across disease states site
activation accounts for 70% of enrollment cycle
time
Activation of a single center on average takes
100 days (3.3 months)
20-50% of studies have rescue missions where
new sites are brought in late in the game to
enhance enrollment
Ref: Li, Gen. Site Activation the Key to More Efficient Clinical Trials. Pharmaceutical
Executive, 12/12/2008. www.PharmaExec.com
Site Subcontract
Responsiveness-NIH contract
July 1997
14%
14%
49%
23%
30 days
60 days
90 days
90+
Ref: Data from A. Shinaman, Clinical Trials Coordination Center. Unpublished data
Subcontract Response RateIndustry Sponsored contract 2000
25%
18%
25%
32%
30 days
60 days
90 days
90+days
Ref: Data from A. Shinaman, Clinical Trials Coordination Center. Unpublished data
Data Management
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Creation of Case Report Forms (CRFs)/eCRFs
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Database creation/validation
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First draft of full set of forms within ~4 weeks of final protocol,
final version available ~4 weeks after first draft
Obtain appropriate permissions to use forms, often including
purchase of such forms (e.g., Beck Depression Scale, SF-36)
Include appropriate references on published forms (e.g. UPDRS,
UHDRS, MMSE, PDQ39 etc.)
Cannot begin until final CRFs/eCRFs are available
Takes ~6-8 weeks to complete
Timeframe varies base on whether a CRF library is already
available for most of the CRFs or if all is being created from
scratch
Create/Finalize Data Management Plan (DMP)
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First draft ~4 weeks after final CRFs available, with final DMP
~2-3 weeks after first draft
Operations Manual/Manual of
Procedures (MOP)
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Includes detailed operational instructions for the site on:
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SAE reporting
Drug packaging, distribution and storage requirements
Full complement of CRFs and instructions for completion
Monitoring expectations
Project Team contact list
Laboratory procedures
Contents of Regulatory binder
Proper procedures for conducting various assessments
First draft available within 4-6 weeks after final protocol
Final MOP available for the Orientation mtg/Site initiation mtg
Typically updated throughout the study via Study Newsletters or
complete replacement of certain sections
Select and Contract with External
Vendors
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Central laboratory for safety labs
PK analysis
Central ECGs
Electronic diaries
Holter monitoring
Manufacturer of study drug
Primary and secondary drug packager and distributor
Monitoring
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Obtain bids from ~2-3 vendors to compare prices/services early
in planning
All vendor contracts should be completed prior to Orientation
mtg
The number one rate limiting step in any
clinical trial is:
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Study Drug!!!
Study Drug!!!
Study Drug!!
ACTIVELY MANAGE ALL ASPECTS OF
THE STUDY DRUG AS EARLY AS THE
CONCEPTUAL PHASE (INITIAL GRANT
SUBMISSION)
Drug Supply
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Items for consideration:
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Purchase active and matching placebo or have donated?
How will drug be delivered (e.g. Bulk shipment in drums, unit
packaged, all at once, quarterly shipments)
Secondary packaging/labeling and distribution requirements?
Blindedness testing: Are active and placebo identical in: color,
taste, smell, appearance, shape, size?
Stability testing: ambient and accelerated: how many lots of each
or is it even required?
Expiry/retest issues?
Storage requirements: ambient, refrigerated, light sensitive,
moisture sensitive?
Drug Accountability centrally and at site level
Site SOPs to address all aspects of study drug receipt,
dispensing, return etc. (overall accountability)
Sources for Drug Supply Delays
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Lack of sufficient animal toxicology data
Held up in manufacturing: impurities found, long
queue, API not available, stability issues
Problems matching active with placebo supplies
Failure to place order with enough lead time
Custom delays (e.g. shipment exported/imported
from other countries)
Cosmetic Bottling (paneling) Problem
Paneling caused a 4 month delay in study start due to inspection time,
Corrective Action Plan, and requirement for resupply
Establish Data Safety Monitoring
Board (DSMB) and Charter
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Select DSMB members
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Create/Finalize DSMB charter
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Typically 3-5 independent scientists with no conflicts-of-interest
and no other role in the study (should include: a biostatistican,
disease expert, expert on drug under study, expert in body
system with AE profile of greatest concern , ideally most have
prior clinical trials experience)
Specifies exactly what the DSMB is charged to monitor, stopping
rules for efficacy/safety, major areas of concern (e.g. renal,
hepatic etc.)
DMSB members and final charter should be in-place
prior to FPFV
Register Trial with
www.clinicaltrials.gov Before FPFV

Food and Drug Administration Amendments Act of 2007 or FDAAA),
Title VIII, Section 801 mandates that a "responsible party" (i.e., the
sponsor or designated principal investigator) register and report
results of certain "applicable clinical trials":
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Trials of Drugs and Biologics: Controlled, clinical investigations, other
than Phase I investigations, of a product subject to FDA regulation;
 Trials of Devices: Controlled trials with health outcomes of a product
subject to FDA regulation (other than small feasibility studies) and
pediatric postmarket surveillance studies.
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"Applicable clinical trials" generally include interventional studies
(with one or more arms) of drugs, biological products, or devices
that are subject to FDA regulation, meaning that the trial has one or
more sites in the U.S, involves a drug, biologic, or device that is
manufactured in the US (or its territories), or is conducted under an
investigational new drug application (IND).
Orientation Meeting or Site
Initiation Meeting
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Depending on size of the study “training” of
investigators, coordinators and other site staff
can be accomplished via either mechanism
Materials to be created include:
 Agenda
 Presentations
to include: Study overview, review of
inclusion/exclusion criteria, drug/device under study,
GCPs, adverse event reporting, eCRF/CRF
completion, use of eDC system, laboratory
requirements, unique safety assessments, primary
outcome measure, diaries etc.
Orientation Mtg
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Secure meeting space and lodging ~3-6 months
prior to the planned mtg
Timing of the mtg should be such that at least
half of the sites have IRB approval and
subcontracts in place
Meetings held too soon are wasteful given staff
turn-over, people forget etc. Typically requires
additional training mtgs when sites are actually
ready to go
Initiation Meeting
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Directly at the participating site; conducted by the lead
monitor, project manager, and the PI or their designee
Not conducted until individual site has IRB approval,
subcontract in place and has received drug supply
Allows for complete training of ALL staff at the site that
have been delegated responsibilities per the “Delegation
of Authority Log”
Sites should be ready to start screening/enrolling
subjects immediately following this training
Format usually used for smaller studies (1-7 sites);
phase I-II
Most phase III studies use the Orientation mtg format
where all investigators/coordinators attend the mtg and
hear the same information
Some pharmaceutical sponsor may have both a
Orientation Mtg and a Site Initiation Meeting
At the Starting Line (6-9 months
later)
Implementation Phase
Timeline Milestones
Key Implementation Milestones
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Drug Supply available at the site – (within days of the
orientation mtg or at the initiation visit)
FPFV = First Patient First Visit (typically a screening
visit; within days of the orientation mtg)
FPI = First Patient In (randomized) - (within days of the
orientation mtg)
Submit Press Release announcing study start
FPLV = First Patient Last Visit - (determined by duration
of treatment)
LPI = Last Patient In (randomized) – [based on planned
enrollment period. (# Subjects Enrolled/Site/Month)]
LPLV = Last Patient, Last Visit
Database Lock – (eDC: ~1-2 weeks following LPLV;
paper: ~6- 8 weeks following LPLV)
Implementation Timeline Killer
ENROLLMENT DELAYS
 86%: Percentage of studies in which enrollment is
delayed 1 to 8 months
 14%: Percentage of studies in which enrollment is
completed on time
 Significant effort should be spent on identifying
appropriate sites and setting up realistic enrollment
expectations.
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Always have a back-up plan
Be sure to train any back-up sites brought on board after study
start and any new site staff at existing sites
Ref:http://www.ciscrp.org/information/documents/101FactsaboutClinicalResearch.pdf
Other Implementation Milestones
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Continuous management of drug supply from FPFV to
LPLV
Develop Statistical Analysis Plan (SAP):
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Created within ~4 weeks of a complete Data Management Plan
(DMP) being finalized
Must be finalized BEFORE database lock and unblinding of
study results
Convene the Data Safety Monitoring Board (DSMB)
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Regularly during the conduct of the trial per the DSMB charter
developed/finalized in planning
Submit DSMB letters indicating findings following each meeting
to the sites for submission to their IRBs
Other Implementation Milestones
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Submit unexpected SAEs to the IND as they occur
Submit Annual IND reports (per 21 CFR part 312.23)
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Must be submitted annually within 60 days of the IND
submission
Submit required regulatory reports to other Regulatory
authorities as required
Submit Annual Progress Reports to Funding Agency

Depends on the funding institute what information the report
requires and timeline for submission (e.g., NIH requires annual
reports that coincide with each contract year)
Analysis Timeline
Milestones
Analysis Key Timeline Milestones

Top-line results
 Industry
standard is 48 hours post DB lock
 Academic Institutions depends on Biostatistics
group

Full Analysis
 Typically
4-8 weeks post DB lock
Publication/
Regulatory Timeline
Milestones
Full Abstract
 Develop and submit press release with
findings
 Complete Manuscript
 Post Results on www.clinicaltrials.gov
 Share Results with Subjects
 Submit Final Clinical Technical Report
(CTR) to the IND
 Submit Reports to other Regulatory
Authorities as applicable

The Finish Line: Anywhere from 17 years later.
Driven mostly by:
 Enrollment Duration
 Duration of subject
participation
 Adequate Drug
Supply
Conclusion
Key Points to Remember
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Create a REALISTIC
TIMELINE from day 1
There are many road blocks
along the way that impact
timelines
Don’t be discouraged, just
figure out how to go around,
over, under or through the road
block and you will eventually
get there!!!
Re-evaluate timelines along
the way based on
nature/timing of “roadblocks”
Failure to adhere to realistic
timelines
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Increases study budget
Planned resources downstream may not be
available (e.g. enrollment goes longer than
planned, DM staff may not be able to lock the
DB based on competing priorities)
Reduces time for market exclusivity: every day
of delay in getting to market = $ 2-3 million/day
in lost revenue
on annual sales of a good drug $500M/year –
blockbuster sales of $1B/year
 based
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Delay in getting needed drugs to patients
Metrics Champion Consortium
www.metricschampion.org

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The MCC is an open, multidisciplinary, non-profit
organization comprised of biotechnology,
pharmaceutical, research institutions and service
provider organizations
The mission of the MCC is to develop, Performance
Metrics within biotechnology and Pharmaceutical
industry with the intent to jointly encourage performance
improvement, effectiveness, efficiency and appropriate
levels of controls for both Sponsors and Service
Providers in support of the drug development process
Metrics for: central laboratories, ECG , CRO and
imaging; including standard timeline metrics
Backup Slides
Post results on
www.clinicaltrials.gov

Report results on www.clinicaltrials.gov (Sept
2008)
 Basic
Results: Baseline characteristics, Primary and
secondary analysis, statistical analysis

Generally submission within 12 months of the earlier of
estimated or actual trial completion date (of primary outcome)
 Adverse
Event Reporting (Sept 2009)
 Expansion of results by rulemaking (Sept 2010)
Sharing Results with Subjects
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In conjunction with Press Release, coordinate
webnairs/teleconferences with subjects/families to
discuss results and particularly impact on treatments*
Notify subjects of study results via copy of the abstract
and/or full manuscript
Notify subjects of their individual treatment assignment

This typically takes place 12-18 months following subject
completion in the study. Ensuring sites maintain accurate contact
information for this follow-up is important.
*Reference: Dorsey E. R., Beck C., Adams M., Chadwick G., de Blieck E.A., Mcallum C., Briner L.,
Deuel L., Clarke A., Stewart R., Shoulson I., and the Huntington Study Group TREND-HD Investigators.
Communicating Clinical Trial Results to Research Participants. Arch Neurol. 2008; 65(12):1590-1595.