36 Annual Meeting Preconference Workshop P4 Handout

36th Annual Meeting

Preconference Workshop

P4

Handout

5/13/2015

1

Clinical Trial Management in Multicenter Trials: Collaborating for Success

Meet Our Team

Dixie Ecklund, RN, MSN, MBA Associate Director, University of Iowa Clinical Trials Statistical & Data Management Center

Marianne Kearney Chase, BA Director of Research Operations, Neurological Clinical Research Institute, Massachusetts General Hospital

Leigh Ann Chamberlin, RD, MEd Supervisor of Clinical Research, Cincinnati Children's Medical Center

Our Team’s Goals

Provide you with tools and tips to achieve better harmonization of efforts to successfully implement and conduct from start to finish multicenter clinical trials from all partner perspectives.

5/13/2015

2

Taking those first steps towards teamwork

Creating Your Team

• Identify the right team members

– Experience, Strengths, Passion

• Regulatory

• Financial

• Study Material Development

• Data Entry

• Data Analysis

– Use central resources

• Define and refine roles

Get to Know Your Players

• Build rapport, trust and confidence – Begins immediately

– Frequent interactions • Face to face and phone

• Regularly scheduled meetings

• Maximize time with collaborators

• Create a vision

• Budget time wisely – It will take more time than you ever thought!

5/13/2015

3

All I Really Need to Know I Learned in Kindergarten (A Guide to Leadership) - Robert Fulghum

“When you go out into the world, watch out for traffic, hold hands, and stick together.”

“Imagination” What Is Needed to Succeed?

• Brand your trial with a logo or acronym • Separate Trainings for PI and Coordinator • Pocket References

– Who to Contact – Study Visit Schedule – Inclusion/Exclusion Criteria – Key Handouts

“I believe that imagination is stronger than knowledge.”

-Robert Fulgham

“Share Everything” -Robert Fulgham

5/13/2015

4

“It doesn’t matter what you say you believe - it only matters what you do.”

-Robert Fulgham

• Go Above and Beyond

– Educate yourself

– Appreciate the work of others

• Celebrate Successes

• Embrace Failures

• Be Prepared for the Unknown

– “Who would have known?”

When Challenges Arise

Freedom to challenge practices that are out of alignment or ineffective

– Listen even if passionate about your perspective

– Honest, open communication

– Conflict management

• “It’s business, not personal”

Four Stages of a Clinical Trial

Protocol Synopsis finalized

Schedule of Activities finalized

Enroll subjects

Distribution of study drug

and supplies Ongoing training for sites Answer protocol

questions

Monitor site compliance

Data management

Manage Key Study Events Financial Sponsor and DSMB Communications Newsletters Payments

•Data query process •Clean/Close

database •Transfer database

to Biostatistics •Primary/

secondary analysis

Submit manuscript

Submit Clinical trial report

Post-hoc analysis Orientation or

Initiation Meeting

Database Lock

Data Analysis

PROJECT

CONCEPT

STUDY START

UP

FIRST ENROLLED TO

LAST VISIT

STUDY

COMPLETION

Grant Award and/or Parent

contract established

Protocol and ICF finalized

Sites selected

Operations Manual/MOP completed

CRFs finalized

IRB approvals obtained

Site contracts

Vendor contracts

Build database

Finalize study drug packaging/labeling

5/13/2015

5

The Marathon Begins




Protocol and ICF finalized

Sites selected


CRFs finalized


Site contracts

Vendor contracts

Build database


PROJECT

CONCEPT

STUDY START

UP

FIRST ENROLLED TO

LAST VISIT

STUDY

COMPLETION



Orientation / Investigator

Meeting

Project Team PI, PM, DM, SM, GM, OT,

Biostatisticians

Funding

Source

Steering

Committee

Consultants

Others

Vendors

Sites

DSMB

Medical

Monitor

5/13/2015

6

Create Core Project Team

PPI/ Co-PI Project Manager(s) Data Manager(s) Systems Manager/ Analyst Grants and Contracts Manager Study Monitors Outcome Measures Trainers Administrative Assistance

Create Steering Committee: Advisory to Study Team

Study design

Scientific integrity of study

Ethical and overall conduct of the study

Safety of study subjects

Review and approval of amendments

Publication policy

Trouble shooting

Site issues

Safety Monitoring

Independent Medical Monitor/ Safety Monitor Data and Safety Monitoring Board

Periodically review accumulated data for safety, study conduct and when appropriate, efficacy

Make recommendations concerning continuation, modification, or termination of trial

Responsibility to: Participants, Institutional Review Board (IRB)/ Ethics Committee (EC), Principal Investigator (PI), Financial Sponsor, Regulatory Agencies (FDA/Health Canada/EMA/other)

5/13/2015

7

Site Selection

How many sites will be needed to meet enrollment target within budgeted timeline?

Site feasibility: Patient population

Equipment

Interest/ Excitement

Experience and staff availability

Protocol and Consent Form Development

Ensure protocol contains all required elements

Read protocol with a focus of collecting data required for analysis of study endpoints

Is the protocol “patient-friendly”? Frequency of visits

Time commitment per visit

Prepare a “model” Informed Consent Form (ICF) with standard language to describe study rationale, procedures and potential risks/ benefits

Data Capture System

Determine what data needs to be entered into the database

Use standardized terms for collecting data Common Data Elements (CDEs)

Create CORE forms Demographics,

Medical history,

Standard outcome measures

Create tools to assist sites with collection of study data (source document templates)

5/13/2015

8

Vendor Selection

Who will be manufacturing your Drug/ Device/ placebo?

Do you need to contract with a central pharmacy to distribute your drug/placebo?

Will your laboratory samples be processed locally or centrally?

If ECGs are included in your study, will they be read locally or centrally?

Vendor management can be challenging!

Regulatory and Contracts

Does your study require oversight by a regulatory agency (FDA/EMA/ Health Canada)?

Will your study be reviewed by local IRB/ EC at each site or will there be central IRB/EC review?

What type of a clinical trial agreement needs to be executed with each site?

Request site specific regulatory documents from all sites and review for accuracy/completeness

Track study metrics (time to execute contract, time to IRB approval, etc.)

NINDS funded NeuroNEXT Network

“Expand the NINDS capability to test promising new therapies, increase efficiency of clinical trials before embarking on larger studies, and respond quickly as

new opportunities arise to test promising therapies for people with neurological disorders”

Initiatives to improve efficiency during study start up: Master Clinical Trial Agreement

Central IRB review of protocol

5/13/2015

9

Develop Study Management Tools

Data Management Plan How will data be reviewed throughout the study?

Statistical Analysis Plan Will there be an interim analysis?

Randomization Plan Will you need an Interactive Web-based Response

System (IWRS)?

Study Monitoring Plan Remote data review vs. on-site visits?

Risk-based monitoring

Develop Manuals/ Workflows

Site Manual of Procedures (MOP)

Site supply/re-supply

Adverse Events/ Serious Adverse Events

Protocol Deviations

Independent Medical Monitor and/or DSMB

Vendors

More Hurdles Ahead!

5/13/2015

10

Plan/Execute Investigator Meeting

Good Clinical Practice (GCP)

Scientific Rationale

Overview of protocol and study procedures

Statistical considerations

Potential risks of study, investigational product

Investigational product storage, dispensing and accountability

Study monitoring and Safety monitoring

Outcome measures training/ certification**

Recruitment and Retention plan for the study**

Contracts and payment

Data Capture system

Laboratory/Pharmacy and/or other vendor related items

Provide Sites with Study Materials

Distribute to Sites

Manual of Procedures

Regulatory binders

Pharmacy binders

Investigator’s brochure

Study tools (source document templates, recruitment materials, etc)

Upload documents to study portal

Post study on clinicaltrials.gov and other websites, as appropriate

Training/Lab Kits/Supplies/Drug

Plan and execute training:

Site Initiation Visit

EDC training

Pharmacy training

Outcome measures training

Ship study supplies to site

Ship study drug to site

Trigger Central Laboratory to ship lab kits to sites

5/13/2015

11

Site Activation

Track site readiness to begin recruiting subjects:

Site Staff regulatory documents complete

Staff training complete

Site IRB/ EC approval

Fully executed contract

Study supplies received by site

Drug received by site

Send confirmation letter to confirm site can begin recruiting subjects

Study Start Up is Exhausting, but…

5/13/2015

12




Protocol finalized

Model ICF finalized

Sites selected


CRFs finalized


Site subcontracts/ payment schedule in place

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

Build database


PROJECT

CONCEPT

STUDY START

UP

FIRST ENROLLED TO

LAST VISIT

STUDY

COMPLETION



Enroll subjects

Distribution of study drug and supplies Ongoing training for sites Answer protocol questions


Data management


Orientation or Initiation Meeting

Ready to Enroll?

Investigators – Educate your clinic team

– Introduce key players

– Consider clinical flow and space needs

– Develop talking points

Coordinators – Print materials

– Practice consenting process

– Communicate with your sponsor

“It doesn’t matter what you say you believe - it only matters what you do.”

-Robert Fulgham

Be available when sites need help

• Go above and beyond

• Respond immediately

• Consider time zone differences

• Provide cell phone numbers after hours

• Monthly coordinator teleconferences

5/13/2015

13

Enrolling the first subject

• Avoid waiting too long

• Understand recruitment flow

• Weekly interaction between site investigator and coordinator

• Pace yourself

• Follow Up with your team

Site Retraining Visit

Site Visits as Opportunities

Personalized attention

– Clinic flow(every site functions differently)

– Staffing needs

– Data entry

– Study documents

– Questions and answers

– Study drug storage

5/13/2015

14

Staff Turnover

Monitoring Site Performance

Enrollment Metrics • Define in site contract “Site will enroll and complete all the aspects of the trial for 17 subjects and their families (not to exceed a maximum enrollment of 675 subjects across all sites). Sites are expected to enroll subjects at a rate of 1 subject every two months.”

• Track through Weekly Reports/Enrollment Graphs • Site Probation and Termination Policy

Monitoring Site Data

Remote monitoring

– Promote data quality

– Prevent data entry errors

• Mandatory fields

• Data entry ranges

• Drop down boxes

• Radio buttons

• Skip patterns

5/13/2015

15


On Site Monitoring Visits – Initial Visit Parameters

• After 3 subjects randomized or annually

– Subsequent Visits • Additional 6 subjects randomized

• Center issues – Adverse Events

– Missing Data

– Out of Window Visits

– Protocol Deviations

– Drug Accountability

– Enrollment Issues


Data Queries/Monthly Reports

• User friendly

• Training

• Point of contact

• Follow up to ensure data changes are made

Managing Key Study Events

5/13/2015

16


Protocol Deviations

– Present safety concern

– Demonstrative impact on study integrity

– Others assess through quality improvement

– Clearly defined reporting criteria and time frame


Adverse Events

• Common Terminology Criteria for Adverse Events (CTCAE codes)

• Training

• Frequently used codes

• Role of Independent Medical Monitor – Prompt Review of Serious Adverse Event

• AE relatedness determination

– Blinded monthly AE tabulation reports

Sponsor Communications

• Emails

• Newsletters

• Monthly Coordinator Calls

• Investigator Calls

• In Person Meetings in conjunction with Scientific Meetings

• Annual Updates/Mailings

• DSMB Interim Analyses

5/13/2015

17

Celebrate milestones

Site Payments

• Start Up Funds

– Incremental Release based on deliverables

• Quarterly Site Payment based on visits conducted and data entry

• Decrease site costs (FedEx, study supplies)

Avoiding burnout

5/13/2015

18




Protocol finalized

Model ICF finalized

Sites selected


CRFs finalized


Site subcontracts/ payment schedule in place

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

Build database


PROJECT

CONCEPT

STUDY START

UP

FIRST ENROLLED TO

LAST VISIT

STUDY

COMPLETION



Enroll subjects

Distribution of study drug and supplies Ongoing training for sites Answer protocol questions


Data management


Orientation or Initiation Meeting

•Data query process •Clean/Close

database •Transfer database

to Biostatistics •Primary/

secondary analysis

Submit manuscript

Submit Clinical trial report

Post-hoc analysis

Database Lock

Data Analysis

Study Close-Out Activities

Text

5/13/2015

19


Planning for Close-Out Activities • Communication between all collaborators

on close-out procedures and timeline for data lock

• Work with sites to complete data entry and resolve all outstanding data queries

• Resolve all data queries and data issues • Data freeze/Data lock



5/13/2015

20


Planning for Close-Out Activities • How to handle missing data? • Analysis programs are developed and

debugged • Final analysis done per Statistical Analysis

Plan specified apriori


• Planned closed out? OR

• Close-out as a result of an

interim analysis and DSMB decision?


Close-outs due to interim analysis • Closed for safety, futility, or efficacy? • Early drug withdrawal visits • Safety assessments • Unblinding • Endpoint data

5/13/2015

21


Planned Close-Outs • Query missing data until completed • AE follow-up and resolution period • Resolution of all AEs (with or without

sequalae) • All deviations reported and CAPAs identified


Site Close-Out Visits

• Final on-site monitoring visit

• Reconciliation of files

• Final drug and supply accountability

• Sites must retain all original study records until receive notification from Sponsor

• Close-out letter

• When to close IRB?


Reports

• Steering Committee

• DSMB

• IRB

• Sponsor

• FDA

How are subjects informed of results?

5/13/2015

22


Publications

• Lead authors determined through Publication Policy

• In order to be published, phase II and III studies must have been registered on clinicaltrials.gov

• CONSORT requirements



Publication plan (pre-close out)

• Methodology paper published in start-up phase (referenced in results paper)

• Baseline paper published after all subjects enrolled and randomized (referenced in results paper)

5/13/2015

23


Publication plan (post-close out) • Primary results manuscript

• Authorship • Timelines

• Secondary analyses • Data access • Authorship • Timelines

• Post-hoc analyses • Data access • Authorship • Timelines


FDA submissions

• If conducted under an IND, a final Clinical Study Report (CSR) must be submitted to FDA


5/13/2015

24


Data Sharing (Results) • Requirement for NIH-funded studies • Need to consider sharing with

Participants, Sponsor, Community • Media releases • Conflicts of Interest

• Submit results to clinicaltrials.gov within 12 months of LPLV (fines!)


Data Sharing (Data Sets) • Requirement for NIH-funded studies • Need to consider sharing with

Participants, Sponsor, Community • Prepare data sets for sharing

• Linked • De-identified • Anonymized


Data Sharing with De-Identification

• Must be consistent with ICF

• Remove all HIPAA identifiers

• Replace original ID numbers with new ID numbers

• Remove geography data

• Recode dates to time intervals (reference point)

• Remove sensitive data not integral to study

• Recode or group other potential identifiers

• Low frequency medical conditions or procedures

5/13/2015

25


Preparing Data Sets for Sharing

• CDISC, CDASH or CDEs

• SAS data sets

• Data Dictionary

• Annotated CRFs


Data Sharing Partners

• Scientific Community

• Sponsor

• Repository

• NLM


5/13/2015

26

Different Perspectives in Clinical Trials

Text

Scenario #1

Suzie, the Site Coordinator, is preparing to enroll the first subject in a multicenter clinical trial at her site.

• What preparations has the Coordinating Center made to prepare for this day?

• What considerations should Suzie and her PI be thinking about prior to enrolling the subject?

• What concerns does the Sponsor have about enrolling the first Subject?

5/13/2015

27

Scenario #2

Tom, the Study Coordinator called a subject for a phone follow-up and learned that the subject had been hospitalized for pneumonia. • How does the site know whether it was a Serious

Adverse Event and how to report it? • What does the Independent Medical Monitor

need to review? • What and when will the IRB need to review? • What and when does the DSMB need to review? • What are the Sponsors concerns and what will

they need to review/report?

Scenario #3

Sarah, the Study Coordinator, gets a letter from the Coordinating Center stating that they are sending a monitor to visit the clinical site next week!

• What preparations should the Site PI/coordinator be making?

• What is the Coordinating Center preparing for the visit?

• What are the Sponsors concerns?

Scenario #4

A study on prevention of pediatric migraine has a planned interim analysis due to the DSMB in four weeks.

• What does the Site PI and coordinator have to worry about?

• What will the Coordinating Centers be doing to prepare the report?

• What will the DSMB be expecting to see?

• What are the Sponsor concerns?

Documents

36 Annual Meeting Preconference Workshop P4 Handout