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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
Key Timeline Milestones in the various phase of the lifecycle Keys to staying on Time
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.
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 Protocol finalized Orientation or and/or Parent Model ICF finalized Initiation contract Meeting established Sites selected
Operations Manual/MOP completed CRFs finalized
Perform primary/ secondary analysis Submit abstract Submit manuscript Submit CTR Post results on www.clinicaltrials.gov Post-hoc analysis
finalized
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
Finalize Study drug packaging/labeling*
CONCEPTUAL PHASE
PLANNING PHASE
IMPLEMENTATION 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)
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
Both documents will provide the roadmap for the overall project Tools for timeline development:
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
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
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
Submission to other Regulatory authorities as applicable (e.g. Health Canada, European Union etc.)
Select Sites
Based on:
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
Site Activation
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
25%
18%
Ref: Data from A. Shinaman, Clinical Trials Coordination Center. Unpublished data
Data Management
Database creation/validation
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
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
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
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:
ACTIVELY MANAGE ALL ASPECTS OF THE STUDY DRUG AS EARLY AS THE CONCEPTUAL PHASE (INITIAL GRANT SUBMISSION)
Drug Supply
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
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":
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).
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
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
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
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)
Continuous management of drug supply from FPFV to LPLV Develop Statistical Analysis Plan (SAP):
Created within ~4 weeks of a complete Data Management Plan (DMP) being finalized Must be finalized BEFORE database lock and unblinding of study results
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
Conclusion
Create a REALISTIC TIMELINE from day 1 There are many road blocks along the way that impact timelines Dont 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
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
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
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)
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.