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CLINICAL TRIALS OVERVIEW

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Title: CLINICAL TRIALS OVERVIEW


1
CLINICAL TRIALS OVERVIEW
John Janik, M.D.
2
What is a Clinical Trial?
  • The Way We Make Progress Against Disease
  • Research studies to find better ways to
    prevent, detect, or treat disease
  • Help health care providers find ways to improve
    patient care

3
Why Conduct a Trial if We Know the Answer?
4
Types of Clinical Trials
  • Treatment Trials
  • Prevention Trials
  • Screening Trials
  • Diagnostic Trials
  • Genetics Trials
  • Quality of Life Trials

5
Treatment Trials
6
Prevention Trials
7
Screening Trials
8
The Drug Development and Approval Process
  • 1. Early research and preclinical testing
  • 2. IND application filed with FDA
  • 3. Clinical trials (phases 1, 2, and 3)
  • 4. NDA filed with FDA
  • 5. FDA validates claim and approves drug

9
Challenges in the development of new agents
  • Only 10 of new molecular entities that enter
    late stage clinical trials are approved by the
    FDA for human use
  • For new agents tested in patients with cancer the
    figures are lower approaching only 5 of agents
    for which an Investigational New Drug (IND) is
    filed

10
History of the Development of Gleevec for the
Treatment of Chronic Myelogenous Leukemia
11
Imatinib (Gleevec)
12
Kaplan-Meier Estimates of the Rates of Event-free
Survival and Progression to the Accelerated Phase
or Blast Crisis of CML for Patients Receiving
Imatinib
13
Why Do a Clinical Trial?
  • Evaluate New Drugs
  • Phase I - Safety
  • Phase II - Effectiveness
  • Phase III - Role in Treatment

14
Drug Development100,000 drugs have anti-tumor
activity.In preclinical studies, animal studies
are done on 1,000 drugs and 100 drugs have
chemistry formulation. In clinical studies, 10,
5 and 1 are tested in phase I, Phase II and Phase
III clinical trials respectively.
15
Why Do a Clinical Trial?
  • Optimize Therapy
  • Explore New Drug Combinations
  • Minimize Treatment Toxicity
  • Which Types/Stages of Lymphoma
  • When in Disease Natural History

16
Why Do a Clinical Trial?
  • Other Benefits
  • Expert Care
  • State of the Art Treatment
  • Patient Education
  • Reduce Treatment Costs

17
Why Do a Clinical Trial?
  • Disadvantages
  • Randomization to lesser arm
  • Unknown or Increased Toxicity
  • Increased Cost and Time

18
Phases of Clinical Trials
  • Phase I
  • Determine the relation
  • between toxicity and dose schedule of treatment
  • Phase II
  • Phase III
  • Phase IV

19
Phase I
  • Determine the Safe Dose
  • Increase Dose in Patient Groups
  • Stop Escalating if too Toxic
  • Carefully Monitor all Toxicity
  • Pharmacokinetics
  • Effectiveness
  • Experimental Endpoints

20
Phase I dose escalation scheme
21
Hazards of Alternative Phase I Designs
22
Limitation of standard Phase I design
  • Ethical Many patients treated with
    subtherapeutic dose of agent
  • Efficiency Modified Fibonacci scheme results in
    lengthy trials

23
Alternative strategies for Phase I clinical
trials
  • Higher initial starting doses
  • Accelerated dose escalation
  • Recruitment of only one patient per dose level
    until mild toxicity is observed
  • Accrual then reverts to standard phase I design
    with accrual of three patients per dose level

24
Starting dose levels for phase I studies
  • Preclinical experiments define dose at which 10
    of mice die (LD10)
  • Additional animal testing performed in another
    species to confirm toxicity (dog, monkey)
  • Phase I trials in general are started with a dose
    that is one tenth that of the LD10 in mice (or
    most sensitive species)

25
Safety and Number of Dose Levels in 21 Trials (14
Agents) With Varying Starting Doses
Expressed as a fraction of MELD10 Unsafe as
defined as requiring less than 4 dose escalations
to reach MTD
Eisenhauer, J Clin Oncol 18684, 2000
26
Accelerated Dose Escalation Modified Fibonacci
escalation
27
Accelerated Titration Design
Design reverts to 40 dose increments with 3-6
patients per dose level with the occurrence of
DLT or two occurrences of grade 2 toxicity
Eisenhauer, J Clin Oncol 18684, 2000
28
Phases of Clinical Trials
  • Phase I
  • Phase II
  • Identify diseases in which the treatment is
    effective
  • Phase III
  • Phase IV

29
Phase II
  • Determine Effectiveness
  • Single or Limited Disease Types
  • Pharmacokinetics
  • Experimental Endpoints

30
Criteria for Measuring Response to Treatment
  • Lymphoma Cheson non-Hodgkin's Lymphomas
    International Working Group
  • Solid tumor patients RECIST (Response Evaluation
    Criteria in Solid Tumors)

31
RECIST
  • CR (complete response) disappearance of all
    target lesions
  • PR (partial response) 30 decrease in the sum
    of the longest diameter of target lesions
  • PD (progressive disease) 20 increase in the
    sum of the longest diameter of target lesions
  • SD (stable disease) small changes that do not
    meet above criteria

32
Mantle cell lymphoma post idiotype vaccine
Before treatment
After treatment
MDX-CTLA4 3 mg/kg 6 weeks post treatment
33
Proposed European Organization for Research and
Treatment of Cancer criteria for assessment of
response by FDG-PET
  • Progressive metabolic disease    
  • Increase of SUV gt25    
  • Visible increase of FDG uptake (gt20 of longest
    dimension)    
  • Appearance of new focus
  • Stable metabolic disease   
  •  Increase of SUV lt25 or decrease lt15 
  •  No visible increase of the extent of FDG uptake
  • Partial metabolic response    
  • Reduction of a minimum of 15-25 of SUV after
    one treatment cycle
  • gt25 after more than one treatment cycle
  • Complete metabolic response    
  • Complete resolution of FDG uptake

34
F-18 FDG -PET
35
FDG-PET predicts response to chemotherapy in lung
cancer
36
FDG-PET predicts response to imatinib
37
Patient Number Required for Phase II TrialSample
size (N) of a preliminary trial (Phase IIA)
required to rule out given levels of therapeutic
effectiveness and Type II errorTherapeutic
effectiveness ()
38
Phases of Clinical Trials
  • Phase I
  • Phase II
  • Phase III
  • Determine if a new treatment is superior to
    standard treatment. Determine the effects of
    treatment relative to the natural history of the
    disease.
  • Phase IV

39
Phase III
  • Compare New and Standard Treatments
  • Randomized
  • New Treatment Well Studied

40
Randomization
41
Stratification
42
Phases of Clinical Trials
  • Phase I
  • Phase II
  • Phase III
  • Phase IV
  • Post-FDA approval studies to further assess
    efficacy and toxicity. Evaluates long-term
    effects, including under represented populations.

43
Phase IV
  • Post-Marketing Studies
  • Expanded Treatment Groups
  • Under studied groups (racial/gender)
  • Long term benefit
  • Long term risk
  • Low frequency toxicity

44
Phase 0 validation
45
Pharmacodynamics
46
Compressing drug development
47
Differences Between Phase 0 Phase 1 Trials
48
Differences Between Phase 0 Phase 1 Trials
49
Differences Between Phase 0 Phase 1 Trials
50
Protocol Components
  • A written guide to the treatment and research
    studies.
  • Major Sections
  • Study Objectives
  • Background and Rationale
  • Eligibility Criteria
  • Study Design
  • Research Tests
  • Statistical Section
  • Toxicity Reporting
  • Pharmacy Information

51
Protocol DevelopmentIt takes 1-6 months for a
protocol concept to be appoved by
Investigator/IND Holder Cooperative Group. It
takes 2-3 months for protocol development by the
Department Review, Institutional Scientific
Review . It takes 2-3 months for the protocol
approval by the IND holder, institutional review
board and FDA.It takes 2-6 years for clinical
trials monitored by the Investigator,Institutiona
l Review Board,Data Safety and Monitoring Board,
IND Holder, andFood and Drug Administration
52
NCI Protocol Review
  • Scientific review - Branch Review
  • IRB - Institutional Review Board Ethical review
  • RSC - Radiation Safety Committee Research
    related radiation review
  • RAC - Recombinant DNA Advisory Committee Gene
    therapy review
  • CTEP Sponsor for NCI supported studies of
    investigational agents
  • FDA For investigator held INDs

53
Institutional Review Board
  • Protection of Human Subjects from
    Research Risks
  • Risks are minimized and reasonable in relation to
    anticipated benefits
  • Assess risks in relation to accepted practices
  • Minimize risks sound research design
  • Assess benefits to subjects
  • Assess importance of knowledge that might
  • reasonably be obtained

54
Institutional Review Board
  • Monitor data to ensure safety
  • Monitors Adverse Events
  • Data, Safety and Monitoring Boards
  • (DSMB)

55
Unanticipated Problems
56
Other Safety Reviews
  • Gene Therapy
  • RAC Recombinant DNA Advisory Committee
  • OBA Office of Biotechnology Activities
  • Research-related Radiation
  • Radiation Safety Committee
  • Data Safety and Monitoring Board (DSMB)

57
Food and Drug Administration
  • To promote the public health by promptly and
    efficiently reviewing clinical research and
    taking appropriate action on the marketing of
    regulated products in a timely manner
  • To ensure that human drugs are safe and effective

58
Logistics of Clinical Trials
  • Clinical Trial Venues
  • Single v Multi-Institutional
  • Phase I and II
  • Cooperative Groups
  • Phase III and IV
  • Pharmaceutical
  • Phase I-IV

59
Barriers to Clinical Trials
  • Annual Accrual
  • Pediatrics 50
  • Adults 3
  • Barriers
  • Physician Bias
  • Time and cost
  • Patient Bias
  • Lack of education
  • Guinea Pig syndrome
  • Cost and time
  • Insurance Denial

60
Frequently Asked Questions
  • Could I Receive Less Effective Treatment?
  • Phase I- Usually restricted to patients who
  • have received standard therapy
  • Phase II- May be less or more effective
  • Phase III- Compares a new but well studied
    regimen
  • to standard care. Treatment could be more
    effective.

61
Frequently Asked Questions
  • Will the Research Be Placed Above my
  • Well Being?
  • No this should not happen. Investigators are
  • obligated to put patient care above the
    study.
  • However, confidence in your treating
    physician
  • is essential.
  • Conflict of interest should be addressed in the
    protocol and with the patients
  • Studies are closely monitored PI, IRB, DSMB,
    FDA

62
Frequently Asked Questions
  • Will I receive a placebo?
  • Most oncology trials do not give placebos. If
    you
  • randomize to a less treatment arm, you will
    be told.
  • A less treatment arm is only included when we
    do
  • not know if more treatment is necessary.
  • More treatment may be more toxic and no more
    effective
  • Data Safety and Monitoring Boards closely monitor
    randomized studies

63
Frequently Asked Questions
  • How can I find Out About Clinical Trials?
  • Ask your physician
  • Resources
  • Lymphoma Research Foundation
  • National Cancer Institute
  • Physicians Data Query (PDQ)
  • Internet
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