Setting Up Clinical TrialsCynthia 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• Gold standard for clinical decisions

about treatment efficacy

Clinical Trial Subjects• Classically understood to be

studies in humans• Veterinary Clinical Trials are

studies in Client-owned animals

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

• 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 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)

•Currently no government oversight of:–Investigator-initiated Veterinary Clinical Trials

–Human Pharma conducting clinical trials in pet animals with drugs for human use.

Uncharted waters

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• Phase I

–Safety – must be performed prior to any clinical trial in humans or client owned animals

–Pharmacokinetics–Pharmacodynamics

Phases of Clinical Trials• Phase II

–Efficacy –Limited

enrollment– may or may

not be controlled

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• Your department is approached by a

Pharmaceutical Company, CatsRUS to test a new drug CR348 for the treatment of feline asthma

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 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?• 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–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

The Protocol• Protocol Deviations

– Errors in data collection– Alteration in treatment– Missed timepoints– All lead to loss of $, time and potentially case dataIt makes FDA unhappy!

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 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• 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

Expectations• They will provide

– GCP training– The protocol– Client consent and regulatory assurances– Test agent– Data capture forms– Study monitor– Incentives/payment

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• 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• What is your question?

– Standard of care– Placebo

• What is your population?– Inclusion– Exclusion

• What is your clinical outcome?

Designing a Trial• Sample size – power

–Outcome • Tracking subjects

– Eligible– Randomized– Enrolled– Completed Study

• Intent to treat

population

eligibleexcluded

randomized

control treatment

analyzedWithdrawn

LTF

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• 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• 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 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 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 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• 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?• Advance animal health• Opportunity for clients• Intellectually stimulating• Challenging• Income source

– Pharmaceutical funding– Grant funding– Recruit new cases

Why Trials Fail• Inadequate recruitment• Poor data collection

– Quality– Quantity

• Poor design• Inadequate budget• Insufficient investigator benefit

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• 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

That’s a lot of puppies!!

Need units, not #

Wrong date format

Missing date

Inconsistent with each otherErrors!

Missing DataCase #VHUP # dog name WBC Temp

13 699495 Champ Day 1 0.71 1043 mos mixb Day 2 0.73

Day 3 1.19 101Day 4 5.82 101

18 699721 Killer Day 1 0.17 103Day 2 1.46 103Day 3 5.75 103Day 4 17.1 101

9 699286 Sheba Day 0 0.24 1072 mos? rotw Day 1 0.25 103

Day 2 101Day 3 0.12 euthanized

Where did all the trauma go???

Too busy to enroll cases

No Benefit to Enroll?

Data Collection

Time for the next study sample!!

Data Quality

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

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• Patient Recruitment• Incentives for Participation• Cost recovery

– TIME!!– Resources

• High quality data– Good Clinical Practice (GCP)– Dedicated staff

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 Director

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 Structure

Director(s)Who: Standing Faculty up to 50% timeRole: Identification of PIs for potential compounds

Reconciles issues regarding trialsIdentification of faculty generated protocols (discovery/PII)Facilitates trial management within hospital/UniversityProtocol development related to hospital impact

Clinical Trials Coordinator Who: Veterinarian (CVT) with clinical trials trainingRole: Working knowledge of all trials, can stand in for PI if needed

Protocol development with PIStudy coordinator and data collector management

(recruiting, training etc, 1 vet for up to 5 coordinators)Quality control on data management and inputAnimal Use Protocol developmentPlacebo/drug compounding protocolsQuarterly reports on each trial

Study coordinatorWho: Nurse (vet/human) with CT trainingRole: Manage trial recruitment

Manage Trial inquiriesInitial screening/apptsData managementCompliance managementCoordinate trial supplies

PIRole: Provide clinical expertise

Protocol Initial patient assessment

Data collectorWho: AHT

Role: Animal and client contact

Data collectorWho: AHT

Role: Animal and client contact

Data collectorWho: AHT

Role: Animal and client contact

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

• Hospital services

• VCIC nursing support

• Recruitment

• Indirect costs – 26%

Clinical Trial Nursing Support

• Study binders– Development

– Maintenance

• Tracking databases– Development

– Maintenance

• Client communication

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• Clinical Trials Nurses• Current Patients or Employee-owned

–Flyers and emails• Direct to Owner

–Print, Postcards, Radio• Referring Veterinarians

End Result

‘Clean’ data – GCP standardsMinimal missing data

Minimal losses-to-follow-up

THE ANSWER TO THE QUESTION!

THE ANSWER TO THE QUESTION!

Benefits Global Animal Health

+ Benefits to Human Health

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

Academic success

with

Minimized effort

Academic SuccessInvestigator initiated study

Publish study results

Present study results

Sponsor initiated study

Publish study resultsPresent study results

and/orPublish ancillary study resultsPresent ancillary study results

and/orCompensate PI research fund

Hospital Success• 456 patients screened• 14 trials

62% were NEW clients!

Hospital SuccessDemographic Information for Clinical Trial Patients

80%76%

37%

87%

79%

10%

79% 79%75%

55%

25%

81%

90%

11%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

OSA(

03)

OSA(

05)

OA(1

1)

LSA(

19)

FIV(2

0)

LSA(

23)

OSA(

01)

BPH(

02)

SCC(

18)

Card

io(17

)

Ceph

alex

in(1

3)

HSA(

12)

SM(0

9)

Diab

etes

(7/8

)

Disease Process Being Studied

% o

f Clie

nts

New

to V

HUP

Series1NEWClients

Hospital SuccessVHUP Returning Client Status

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

OSA(03

)

OSA(05

)OA(11

)

LSA(19

)

FIV(20

)

LSA(23

)

OSA(01

)

BPH(02

)

SCC(18

)

Cardi

o(17)

Cepha

lexin(

13)

HSA(12

)SM

(09)

Diabete

s(7/8)

Disease Process Being Studied

% o

f Cl

ient

s Re

turn

ing

to V

HU

P af

ter

Tria

l Pa

rtic

ipat

ion

Series1

Hospital Success

Hospital Success

Visits by Clinical Service

1%2%3%3%

3%3%

4%

4%

5%

6%

6%

10% 12%

38%

Emergency

Medicine

Oncology

Orthopedic

Dermatology

Soft Tissue

Clinical Investigations

Ophthalmology

Dental

Radiation Therapy

Cardiology

Exotics

Neurology

Genetics

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

10th Anniversary Tribute to the Canine Search and Rescue (SAR) Community

of 9/11

Working Dog ConferenceSeptember 7-9, 2011

www.findingoneanother.org