Cornelia Kamp, MBA
Executive Director Strategic Initiatives
Clinical Materials Services Unit (CMSU)
Clinical Trials Coordination Center (CTCC)
University of Rochester www.clinicalmaterial.com

 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

Drug Development Process/Overall Timeline

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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.

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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

Grant Award and/or Parent contract established
 Protocol finalized Orientation or
Database Locked
 Model ICF finalized
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Sites selected
 Build database
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Finalize Study drug packaging/labeling*
Initiation
Meeting
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Operations
Manual/MOP completed
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Protocol
Synopsis finalized
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CRFs finalized
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IRB approvals obtained
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Schedule of
Activities finalized
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Site subcontracts/ payment schedule in place
 Finalize Contracts with third party vendors
(labs, ECGs etc.)
 DSMB established
Analysis
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Enroll subjects*
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Distribution of study drug to sites
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Answer Protocol/CRF questions
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Take incident calls
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SAEs
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Dosage Adjustments
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Premature Withdrawals
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Drug Disclosure
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Data query process
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Clean/Close database
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Transfer database to
Biostatistics
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Perform primary/ secondary analysis
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Submit abstract
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Submit manuscript
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Submit CTR
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Post results on www.clinicaltrials.gov
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Post-hoc analysis
CONCEPTUAL
PHASE
PLANNING
PHASE
IMPLEMENTATION
PHASE
ANALYSIS/
PUBLICATION
PHASE

 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

 Are developed in the conceptual and planning phase.
 Develop a REALISTIC timeline and workscope in the planning phase of a study
 K eep I t S imple S tupid! whenever possible

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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
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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

 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

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Steering Committee
Sponsor
Operational Team
 Project Manager
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Database Manager
Information Analyst
Administrative Support
Biostatistican
Programmer
Meeting Planner
Monitors
Enrolling Site Team
Data Safety Monitoring Board
Vendor Teams

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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
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In some cases funding does not materialize….

 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.

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IND submission(~2-4 wks after final protocol available)
 FDA approval/complete or partial hold status – (must wait 30 days before starting the study for FDA to respond)
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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.)

 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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 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

 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

 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

14%
14%
49%
30 days
60 days
90 days
90+
23%
Ref: Data from A. Shinaman, Clinical Trials Coordination Center. Unpublished data

25% 25%
18%
32%
Ref: Data from A. Shinaman, Clinical Trials Coordination Center. Unpublished data
30 days
60 days
90 days
90+days

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Creation of Case Report Forms (CRFs)/eCRFs
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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.)
Database creation/validation
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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)
 First draft ~4 weeks after final CRFs available, with final DMP
~2-3 weeks after first draft

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 Includes detailed operational instructions for the site on:
 SAE reporting
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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

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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)

 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)

 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)

Paneling caused a 4 month delay in study start due to inspection time,
Corrective Action Plan, and requirement for resupply

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Select DSMB members
 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)
Create/Finalize DSMB charter
 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

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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.
"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).

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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.

 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

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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

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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)

ENROLLMENT DELAYS
 86%: Percentage of studies in which enrollment is delayed 1 to 8 months
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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

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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

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Submit unexpected SAEs to the IND as they occur
Submit Annual IND reports (per 21 CFR part 312.23)
 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)

 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

 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

Driven mostly by:
 Enrollment Duration
 Duration of subject participation
 Adequate Drug
Supply

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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”

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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
 based on annual sales of a good drug $500M/year – blockbuster sales of $1B/year
Delay in getting needed drugs to patients

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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

 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)

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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.