Clinical Trial Timelines

Cornelia Kamp, MBA Executive Director Strategic InitiativesClinical Materials Services Unit (CMSU)

Clinical Trials Coordination Center (CTCC)University of Rochesterwww.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

Drug Development Timeline Overview

Drug Development Process/Overall Timeline

Drug Development Process

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

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

Protocol Synopsis finalized

Schedule of Activities finalized

Protocol finalized

Model ICF finalized

Sites selected

Operations Manual/MOP completed

CRFs finalized

IRB approvals obtained

Site subcontracts/ payment schedule in place

Finalize Contracts with third party vendors (labs, ECGs etc.)

DSMB established

Build database

Finalize Study drug packaging/labeling*

Enroll subjects*Distribution of study drug to sitesAnswer Protocol/CRF questions

Take incident callsSAEsDosage AdjustmentsPremature WithdrawalsDrug Disclosure

Data query processClean/Close databaseTransfer database to

Biostatistics

Perform primary/ secondary analysis

Submit abstract

Submit manuscript

Submit CTR

Post results on www.clinicaltrials.gov

Post-hoc analysis

Orientation or Initiation Meeting

Database Locked

Analysis

CONCEPTUAL

PHASE

PLANNING PHASE

IMPLEMENTATION PHASE

ANALYSIS/ PUBLICATION

PHASE

Grant Award and/or Parent

contract established

The Process of Conducting Clinical Trials:

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

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

To Ensure Adherence to the Timeline HIRE a GOOD Project Manager

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 Steering Committee Sponsor Operational Team

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

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

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) 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)

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

Site Activation Drives Enrollment

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

Site Subcontract Responsiveness-NIH contract July 1997

49%

23%

14%

14%

30 days

60 days

90 days

90+

Ref: Data from A. Shinaman, Clinical Trials Coordination Center. Unpublished data

Subcontract Response Rate-Industry Sponsored contract 2000

25%

32%18%

25%30 days

60 days

90 days

90+days

Ref: Data from A. Shinaman, Clinical Trials Coordination Center. Unpublished data

Data Management

Creation of Case Report Forms (CRFs)/eCRFs 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

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

Operations Manual/Manual of Procedures (MOP) Includes detailed operational instructions for the site on:

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 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:

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

Items for consideration: 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

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 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

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": 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).

Orientation Meeting or Site Initiation Meeting 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

At the Starting Line (6-9 months later)

Implementation Phase Timeline Milestones

Key Implementation Milestones 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. 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

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 Convene the Data Safety Monitoring Board (DSMB)

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

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)

Analysis Timeline Milestones

Analysis Key Timeline Milestones

Top-line results Industry standard is 48 hours post DB lockAcademic 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 1-7 years later.

Driven mostly by: Enrollment Duration Duration of subject

participation Adequate Drug

Supply

Conclusion

Key Points to Remember

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 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

Metrics Champion Consortiumwww.metricschampion.org

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

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.