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Setting Up Clinical Trials. Cynthia M. Otto, DVM, PhD DACVECC Associate Professor of Critical Care. What is a clinical trial?. A prospective evaluation in which the factor of interest is controlled by the investigator RANDOMIZATION Provides evidence of causality

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setting up clinical trials

Setting Up Clinical Trials

Cynthia M. Otto, DVM, PhD DACVECC

Associate Professor of Critical Care

what is a clinical trial
What is a clinical trial?
  • A prospective evaluation in which the factor of interest is controlled by the investigator
    • RANDOMIZATION
  • Provides evidence of causality
  • Gold standard for clinical decisions about treatment efficacy
clinical trial subjects
Clinical Trial Subjects
  • Classically understood to be studies in humans
  • Veterinary Clinical Trials are studies in Client-owned animals
veterinary clinical trials
Veterinary Clinical Trials
  • Test Drugs or Devices
  • Initiated by
    • Company
      • Human Pharma
      • Veterinary Pharma
    • Investigator

Why Human Pharma?

clinical trials in spontaneous disease of companion animals
Clinical Trials in Spontaneous Disease of Companion Animals
  • Highly clinically relevant models
    • Heterogeneity, diversity
    • Spontaneous disease treated after clinical signs present
    • Directed and supportive care provided
    • Outcome = Survival
  • Takes advantage of advanced critical care facilities
  • Cost effective
  • Success may be more likely to

predict positive human clinical trials

regulatory requirements for veterinary clinical trials
Regulatory Requirements for Veterinary Clinical Trials

Uncharted waters

  • Currently no government oversight of:
    • Investigator-initiated Veterinary Clinical Trials
    • Human Pharma conducting clinical trials in pet animals with drugs for human use.
  • Regulatory Agencies for Industry Sponsored Trials
    • FDA
      • Reviews safety data and approves clinical trial design
      • Approval required for animal drugs tested in animals
        • Center for Veterinary Medicine (CVM)
    • USDA (governs testing of biologicals)
requirements for veterinary clinical trials
Requirements for Veterinary Clinical Trials
  • Patient Safety is Paramount!
  • Regardless of who initiates
    • informed client (owner) consent
  • Safeguards
    • Good Clinical Practice (GCP) compliance
      • Guidance document for the design and conduct of all clinical studies
    • Institutional approval (IACUC, IRB)
      • Independent board to review protocols and ensure patient safety
phases of clinical trials
Phases of Clinical Trials
  • Phase I
    • Safety – must be performed prior to any clinical trial in humans or client owned animals
    • Pharmacokinetics
    • Pharmacodynamics
phases of clinical trials1
Phases of Clinical Trials
  • Phase II
    • Efficacy
    • Limited enrollment
    • may or may not be controlled
phases of clinical trials2
Phases of Clinical Trials
  • Phase III
    • Large scale
    • Comparison of Drug/device
    • Randomized with controls
  • Phase IV
    • Large scale field trials
    • Post marketing
scenario 1
Scenario 1
  • Your department is approached by a Pharmaceutical Company, CatsRUS to test a new drug CR348 for the treatment of feline asthma
can you participate
Can You Participate?
  • How many asthma cats do you see in month?
    • Primary cases
    • Referral cases
    • Emergency cases
  • Do you have the staff to conduct a clinical trial . . . And are they interested?
  • Do you have experience with clinical trials?
can you participate1
Can You Participate?
  • Do you have the space?
    • Drugs
    • Binders
    • Mailers
    • Samples collected
    • Office space for monitors/FDA inspections*
  • Do you have the time?
what do you do
What do you do?
  • Confidentiality agreement
    • A document clearly stating your obligations regarding the information shared with you
    • Defines what is confidential
    • Who can you share information with
    • How long you are obliged to maintain confidentiality
    • Do you have legal

counsel to review this?

the protocol
The Protocol
  • Review the protocol carefully
  • Based on the specifics of what is expected
    • Do you have the necessary caseload
    • Do you still have the interest
    • Do you still have the time
    • Do you still have the staff
    • Do you have still the space
    • Are you comfortable with the protocol

Cost/benefit?

the protocol1
The Protocol
  • Protocol Deviations
    • Errors in data collection
    • Alteration in treatment
    • Missed timepoints
    • All lead to loss of $, time

and potentially case data

It makes FDA unhappy!

what do you do1
What do you do?
  • Contract or sponsored research agreement
  • Defines Scope of Work (Protocol)
    • approved by the CVM at the FDA
  • Principal Investigator
    • The person RESPONSIBLE
  • Performance Period
  • Record Keeping and Access
what do you do2
What do you do?
  • Contract or sponsored research agreement (cont.)
  • Cost and Payment
  • Confidential Information
  • Publications
  • Patents and Inventions
  • Use of the Institution or Sponsor’s Name
expectations
Expectations
  • You will
    • Enroll a specified number of cases
    • In a specified period of time
    • You will be GCP compliant
      • Provide complete and accurate data
      • Report protocol deviations or adverse events
      • You will handle the test material appropriately
    • You will work with the study monitor
    • Provide a final report
expectations1
Expectations
  • They will provide
    • GCP training
    • The protocol
    • Client consent and regulatory assurances
    • Test agent
    • Data capture forms
    • Study monitor
    • Incentives/payment
scenario 2
Scenario 2
  • A faculty member would like to test the efficacy of the new human asthma drug “BreatheEZ” in cats with asthma
investigator initiated trial
Investigator Initiated Trial
  • Determine the safety of the material
  • Obtain the test material*
  • Design the trial
  • Provide Informed Client Consent
  • Regulatory approval*
  • Secure funding
  • Recruit and enroll cases
  • Collect and Analyze data
  • Write the paper!
designing a trial
Designing a Trial
  • What is your question?
    • Standard of care
    • Placebo
  • What is your population?
    • Inclusion
    • Exclusion
  • What is your clinical outcome?
designing a trial1
Designing a Trial
  • Sample size – power
    • Outcome
  • Tracking subjects
    • Eligible
    • Randomized
    • Enrolled
    • Completed Study
  • Intent to treat

population

excluded

eligible

randomized

control

treatment

Withdrawn

LTF

analyzed

limiting bias
Limiting Bias
  • Randomization
    • Equal chance of being in treatment vs control group
    • Baseline data
  • Blinding or masking
    • Prevents differences in interpretation of outcomes or data collection between groups
  • Placebo controlled
regulations
Regulations
  • Institutional Animal Care and Use Committees?
  • Institutional Review Board?
    • Privately owned animal protocols
  • Center for Veterinary Medicine?
    • Regulates manufacture and distribution of additives and drugs for animals
informed consent
Informed Consent
  • Why participate?
    • Participation is voluntary
  • Purpose of the study
    • In clear lay language
    • A Clarification that the drug/device is investigational
  • The duration of the study
  • The expectations of the owner and pet
    • Clarify experimental components vs standard of care
    • number of visits required, additional procedures required
    • requirement for a necropsy if the animal dies
informed consent1
Informed Consent
  • The possible risks or discomfort to the pet
    • If there is no safety data in the population under study, this should be clearly stated.
    • Include a statement that the research may involve risks that are currently unforeseeable.
  • The possible benefits
    • “Your pet may not benefit from participation in this study. However, we may learn additional information about your pet’s disease which may affect how your pet is treated.”
informed consent2
Informed Consent
  • The alternatives to participation
    • Treatment alternatives for the condition being investigated (eg supportive, palliative care)
  • A description of any compensation
    • Financial incentives or treatments costs covered
    • “Complications may happen during the study treatment because of your pet’s disease, as a result of treatment for the disease, or for unrelated reasons. You are responsible for all costs of tests and treatments except those specifically mentioned as being included in the study.
informed consent3
Informed Consent
  • Detailed explanation of the owner’s financial responsibility
  • Impact of early termination of participation or of the study
    • Define when the overall study is to end.
    • Explain what events could lead to early study closure.
    • Note that the owner can elect to withdraw his pet from the study at any time.
    • If early withdrawal could expose the pet to medical risks, describe and how those risks will be minimized or prevented.
other considerations
Other considerations
  • Hospital Impact
    • Affect on caseload
      • Outside recruitment?
    • Affect on other services
      • Anesthesia, radiology etc
    • Nonmedical resources?
      • Faxing, copying etc
    • Cost recovery?
      • Overhead – cost of doing business
  • Public impact?
why participate in clinical trials
Why Participate in Clinical Trials?
  • Advance animal health
  • Opportunity for clients
  • Intellectually stimulating
  • Challenging
  • Income source
    • Pharmaceutical funding
    • Grant funding
    • Recruit new cases
why trials fail
Why Trials Fail
  • Inadequate recruitment
  • Poor data collection
    • Quality
    • Quantity
  • Poor design
  • Inadequate budget
  • Insufficient investigator benefit
study design
Study Design
  • What is your question?
    • Standard of care
    • Placebo
  • What is your population?
    • Dogs with parvovirus
  • What is your clinical outcome?
    • Survival
sample size
Sample Size
  • How many cases needed to show an effect (or confirm NO EFFECT)
  • Power – 80% chance that the lack of effect is real
  • Survival rate:
    • 92%
    • 324 cases needed
slide37

Wrong date format

Need units, not #

Errors!

Inconsistent with each other

Missing date

data collection
Data Collection

Time for the next study sample!!

data quality
Data Quality

Oh . . . you are supposed to add the calcium to the sample before you run it?

funding
Funding
  • I didn’t think it would cost so much
  • I didn’t think to include nursing time
  • I need to recruit cases? Advertising?
  • I was turned down because of no track record
successful trials
Successful Trials
  • Patient Recruitment
  • Incentives for Participation
  • Cost recovery
    • TIME!!
    • Resources
  • High quality data
    • Good Clinical Practice (GCP)
    • Dedicated staff

$

structuring for success
Structuring for Success
  • Trained personnel
    • Study Coordinators
    • Data collectors
    • PI’s role limited to expert clinical advice
  • Culture of Clinical Investigation
  • Appropriate Budget
  • Establishing a Reputation
vcic structure
VCIC Structure

Director

Industry CTs

NIH CTs

Investigator CTs

Clinical trial

coordinator

Clinical trial

coordinator

Clinical trial

coordinator

Study

coordinator

Study

coordinator

Study

coordinator

PI

PI

PI

PI

PI

PI

Data

collector

Data

collector

Data

collector

Data

collector

Data

collector

Data

collector

Data

collector

Data

collector

Data

collector

vcic structure1
VCIC Structure

Director(s)

Who: Standing Faculty up to 50% time

Role: Identification of PIs for potential compounds

Reconciles issues regarding trials

Identification of faculty generated protocols (discovery/PII)

Facilitates trial management within hospital/University

Protocol development related to hospital impact

Clinical Trials Coordinator

Who: Veterinarian (CVT) with clinical trials training

Role: Working knowledge of all trials, can stand in for PI if needed

Protocol development with PI

Study coordinator and data collector management

(recruiting, training etc, 1 vet for up to 5 coordinators)

Quality control on data management and input

Animal Use Protocol development

Placebo/drug compounding protocols

Quarterly reports on each trial

slide50

Study coordinator

Who: Nurse (vet/human) with CT training

Role: Manage trial recruitment

Manage Trial inquiries

Initial screening/appts

Data management

Compliance management

Coordinate trial supplies

PI

Role: Provide clinical expertise

Protocol

Initial patient assessment

Data collector

Who: AHT

Role: Animal and

client contact

Data collector

Who: AHT

Role: Animal and

client contact

Data collector

Who: AHT

Role: Animal and

client contact

roles for vcic study design
Roles for VCIC: Study Design
  • Refining the question
  • Determining the target population
  • Determining the outcome
  • Determining the sample size necessary to answer the question
budgeting
Budgeting
  • Hospital services
  • VCIC nursing support
  • Recruitment
  • Indirect costs – 26%
clinical trial nursing support
Clinical Trial Nursing Support
  • Study binders
    • Development
    • Maintenance
  • Tracking databases
    • Development
    • Maintenance
  • Client communication
nursing support
Nursing Support
  • Paperwork
    • IACUC
    • Consent Form
    • Data collection forms
  • Data Collection
    • All animal and owner contact
    • Scheduling protocol appointments
    • Owner follow-up
    • Referring veterinarian follow-up
recruitment
Recruitment
  • Clinical Trials Nurses
  • Current Patients or Employee-owned
    • Flyers and emails
  • Direct to Owner
    • Print, Postcards, Radio
  • Referring Veterinarians
end result
End Result

‘Clean’ data – GCP standards

Minimal missing data

Minimal losses-to-follow-up

THE ANSWER TO THE QUESTION!

the answer to the question
THE ANSWER TO THE QUESTION!

Benefits Global Animal Health

+ Benefits to Human Health

enrollee benefits
Enrollee Benefits
  • Individual animal benefit
    • Direct benefit from an intervention
    • Access to care
  • Owner benefit
    • Easy & immediate access to advice
    • Relief of financial constraints
    • Knowledge of larger benefit to global animal and human health
investigator benefits
Investigator Benefits

Academic success

with

Minimized effort

academic success
Investigator initiated study

Publish study results

Present study results

Sponsor

initiated study

Publish study results

Present study results

and/or

Publish ancillary study results

Present ancillary study results

and/or

Compensate PI research fund

Academic Success
hospital success
Hospital Success
  • 456 patients screened
  • 14 trials

62% were NEW clients!

potential benefits from veterinary clinical trials
Potential Benefits from Veterinary Clinical Trials
  • Intellectually stimulating
  • Disease is not being created in animals
  • Animals with disease receive treatment in your hospital
    • that might not otherwise be available
  • New reagents, therapeutics available to companion animals
  • Pets win, clients win, science wins
slide67

10th Anniversary Tribute to the Canine Search and Rescue (SAR) Community of 9/11

Working Dog Conference

September 7-9, 2011

www.findingoneanother.org