1. Drug Development : Basic Overview of Clinical Trials: Phase I-III
Patricia Mucci LoRusso, D.O.
Associate Center Director – Innovative Medicine
Yale Cancer Center

3. <3% of all Cancer Patients Enroll in Clinical Trials
~1.3% of African Americans Enroll in Clinical Trials
Women are Underrepresented

4. Aggregate Patient Recruitment Success Rates
How do patients learn about trials? – CISCRP
Tufts CSDD; N=3,534 Phase II-IV protocols

6. *Cutting Edge Information, “Clinical Operations Benchmarking Per-Patient Costs, Staffing and Adaptive Design” 2011

10. Non-performing Sites By Therapeutic Area
“Addressing Ever-Rising Cost in Conducting Clinical Trials”
Covance Inc. 2015

12. One Large Scale Oncology Trial
“Addressing Ever-Rising Cost in Conducting Clinical Trials”
Covance Inc. 2015

13. Non-Performing Sites Average $50k start-up cost
Result in budget overrun
Many never enroll a single patient or very few
Selection of sites often carried out in a non-scientific, non-systematic way
Causes delay, impacting trial schedule
$ million wasted on non-performing oncology sites from
“Addressing Ever-Rising Cost in Conducting Clinical Trials”
Covance Inc. 2015

14. Potential Accrual Barriers – Patient Level
Awareness of trials as an option
Understanding of what trial participation involves
Concerns around side effects
Education about particular trial phase
Education about particular treatment
Fear of distrust (guinea pig) instead of trust in physician recommendations
History of discrimination in medical research
Inconvenience of trial logistics: travel, times, number of visits
Financial burden

15. How do patients learn about trials? – CISCRP

16. Barriers to Enrollment – Physician Factors
Concerns about potential toxicity from study treatment
Concerns about comorbid conditions of patients
Lack of awareness of accessible clinical trials
Lack of access to clinical trials
Physicians’ own perceptions about the relevance of the questions being addressed in the available trials
Lack of time in busy practices to discuss trial options

17. Potential Accrual Barriers – Provider Level
Payment metrics at respective practice
Time & resources required to discussing trials
Fear of “losing” patients if refer to clinical trials
Concerns around trial suitability for patient (eg tolerability, benefit)
Belief patient should not be offered trial (not adherent, competent)
Comfort with, and style of, communicating trial to patients

18. Barriers to Enrollment
Lack of encouragement or support from the attending physician
Unaware of appropriate open trials
Lack time to discuss options at length
Concerned about lack of control over their patient
Unrealistic, inconvenient protocol requirements
Unrealistically restrictive inclusion/exclusion criteria
The most motivated patients are most likely to be excluded
Rejected patients often don’t try again

19. Barriers to Enrollment (cont.)
Politics
Rivalry between physicians and/or hospital administrators
Bad publicity
Trials conducted unethically garner the most press
Physician or hospital concerns about potential liability
Insurance or HMO policies that may preclude reimbursement for care or make it difficult
HIPAA restrictions
Standardized order sets for “quality”

20. Logistics Factors
Physicians – lack of support and infrastructure (trial nurses, study coordinators, pharmacy capability, etc) to enable enrollment of patients into trials
Reimbursement of costs incurred by patients during participation in clinical trials (e.g. parking)
Patient – lack of social support to attend doctor visits (e.g. for study treatment, management of treatment-related adverse events)
Language barrier

21. Trial Factors
Dissemination of up-to-date knowledge of available and ongoing trials and how to access them
Paucity of trials for specific patient populations e.g. hepatic/renal dysfunction, elderly
Changing landscape in clinical trial designs e.g. histologic and/or molecular selection including rare subsets
Need for innovative and attractive clinical trials that efficiently evaluate novel agents
Burden of research investigations and visits in clinical trials

22. Potential Accrual Barriers – Site Level
Staffing (research nursing & support staff)
Redundant review processes
Slow trial activation
CRO relationships & issues
Lack of standard processes for patient screening
Lack of effective clinical trials tools

23. Potential Accrual Barriers – Systems Levels
Overly optimistic accrual goals and/or limited accrual feasibility assessment prior to activation
Inadequate recruitment planning during trial development process
Limited funding & incentives for site & provider involvement (to conduct & offer trials)
Trial availability & eligibility for incident patients (eg exclusion for comorbidities, prior # treatments)
Massett, et al., Clin Can Res, November 2016

24. Clinical Trials
Clinical trial: a prospectively planned experiment for the purpose of evaluating potentially beneficial therapies or treatments
In general, these studies are conducted under as many controlled conditions as possible so that they provide definitive answers to pre-determined, well-defined questions

25. Primary vs. Secondary Questions
most important (i.e., central question)
ideally, only one
stated in advance
basis for design / sample size calculations
Secondary
related to primary
also stated in advance
limited number but usually more than one

26. Why Clinical Trials?
Most definitive method to ultimately determine treatment effectiveness
Other designs more potential biases
One cannot determine in uncontrolled setting whether intervention has made a difference in outcome
Correlation versus causation

27. Why Clinical Trials?
Help determine incidence of side effects and complications
Theory not always best path
May not actually prove itself in reality
May not be tolerable/ feasible solution

28. Elements of Clinical Protocols
Objectives – Primary and Secondary
Biostatistics
Patient selection criteria – Inclusion/Exclusion
Therapeutic Intervention
Dose and Schedule and Mechanism/Route of Delivery
Clinical Work-up and Follow-up Assessment
Toxicity
Toxicity criteria
Dose modifications
Efficacy
Clinical, pharmacodynamic (PD) and QOL
Analysis and interpretation
Primary & secondary endpoints
Correlative studies

29. Questions to be Answered in Clinical Trials
Why?
Who?
What?
Which?
Where?
When?
How (bad)?
So what?

30. Why: Define Trial Objectives
Why are you doing this study?
“The primary objective of this trial is …”
Limit number of objectives
Too many will limit trial success
Well planned & thought out objectives
Biostatistics important here
Critical outcome for study a “go/no go” decisions?
Define and use secondary endpoints to generate hypotheses to be explored in future research
Remember laboratory correlative objectives
“translational research”
Make sure assay and tissue available
Confirm reproducibility and relevance
Design must take this into account when answering this question!

31. Who: Patient Selection
Who should enter the trial?
One of the most critical factors affecting study outcome
Each selection criterion should be based on a sound scientific, medical, ethical rationale
Do not copy/paste from other trials!
Inclusion/exclusion should be study directed
Disease type
Prior treatment
Age, sex, organ function and other variables
Measurability and disease status
Proper patient selection is key for successful completion and scientific impact of your study!

32. What: Trial Intervention
What treatment?
What dose and schedule?
Which dose or schedule variations are planned?
How long may the treatment last?
What are specific steps in drug administration?
What should be done to prepare, treat, and monitor the patient prior/during/after treatment?
Will the same treatment be given to all patients?
If not, what are the differing procedures?
What are the methods to assess compliance with the procedures defined in your protocol?

33. Which: Assessment of Critical Endpoints
Methodology is used to select patients (Performance status? Pain score? NYHA?...)
Standard will be used to assess response?
Instrument for evaluation of safety and toxicity
Methodology to be applied for the statistical, correlative and translational endpoints?

34. Where: Tumor and Response Assessment
Where are primary tumor lesions to be measured?
What happened to it during treatment?
Location, size, density
Criteria for response: RECIST vs. WHO
Define deviations from standard methodology
Pre-baseline assessment of progression required?
Target vs. non-target lesions
Other clinical or correlative parameters of effect being studied adequately?
TTP, TTF, OS, duration of response, etc.
Growth modulatory rate
Immune response
Target modulation in tumor tissue or surrogate
Functional imaging

35. When: Timing of Assessment
When will assessments of primary, secondary and translational endpoints be performed?
Is the timing of assessments compatible with the chosen endpoints?
Will dose delays or modifications affect the schedule of reassessment?
Will there be a sufficient number of patients remaining on study to obtain adequate information?
Is the chosen timing compatible with the routines of physicians, nursing staff, hospital and patient?

36. How (bad): Safety and Toxicity
To what degree does treatment interfere with patient well-being?
How assessed (CTC? QoL? Self-made instrument?)
What modifications are incorporated to avoid or minimize the risk or severity of toxicity?
Dose reduction
Dose delay
Dose omission
Supportive care (prophylaxis, intervention, secondary prevention)
Discontinuation of individual treatment?
Termination from the study (specify criteria!)

37. So What: Analysis and Interpretation
Has study design been followed, is the trial “mature”?
Evaluate the compliance of all involved parties
So what do the results and observations mean?
Primary endpoint reflects the hypothesis tested
Secondary endpoints reflect hypotheses generated
Have the appropriate statistical tools been used?
Beware of sporadic “significant” results that result from multiple, unplanned comparisons
Beware of retrospective subgroup analyses
Given the results, how should we move forward (go/no go; generate confirmatory evidence in laboratory models; additional clinical trials…)?

38. Definitions

39. Definitions
Single Blind Study: A clinical trial where the participant does not know the identity of the treatment received
Double Blind Study: A clinical trial in which neither the patient nor the treating investigators know the identity of the treatment being administered.

40. Definitions Placebo: Used as a control treatment
1. An inert substance made up to physically resemble a treatment being investigated
2. Best standard of care if “placebo” unethical
3. “Sham control”
4. Used in Randomized trials

41. Definitions Adverse event:
An incident in which harm resulted to a person receiving health care.
Examples: Death, irreversible damage to liver, nausea, drop in white cells or platelets
Not always easy to specify in advance because many variables will be measured
May be known adverse effects from earlier trials or preclinical toxicology studies
Animals and man different – can’t always predefine
Not necessarily linked to assigned treatment
Important to decipher if drug effect

42. Adverse Events (Aes) Challenges Example – COX II inhibitors
Long term follow-up versus early benefit
Rare AEs may be seen only with very large numbers of exposed patients and/or long term follow-up
Example – COX II inhibitors
Vioxx & Celebrex
Immediate pain reduction versus longer term increase in cardiovascular risk

44. Characterization of Trials
Phase
Single Center
Multi Center
Randomized
Non-Rand. I
Never
Yes
Sometimes II
Rare
III
Use of Historical Controls
Carrying out a multi-center randomized clinical trial is the most difficult way to generate scientific information.

45. Phase I Trial
Primary Objective : Determine an acceptable range of dose(s) & schedule(s) for a new drug
Determine toxicities (dose-limiting and others)
Secondary Objectives: Pharmacokinetics, Pharmacodynamics and Anti-tumor Activity
Usually seeking maximum tolerated dose or target dose based on pre-clinical exposure
Maximum biological dose
Participants have often failed other treatments
Important to have adequate performance status & “normal” organ function (except organ dysfxn trials)
Not an alternative to Hospice

46. Definitions of Key Concepts in Phase 1 Trials
Pharmacokinetics (PK):
“what the body does to the drug”
ADME: absorption, distribution, metabolism and excretion
PK parameters: Cmax, AUC (drug exposure), t1/2, Clearance, etc.
Pharmacodynamics (PD):
“what the drug does to the body”
e.g. nadir counts, non-hematologic toxicity, molecular correlates, imaging endpoints

47. Phase I Design Strategy
Designs often based on tradition
Typically do some sort of dose escalation to reach targeted endpoint (MTD, OBD, MFD)
Has been shown to be safe and reasonably effective
Dose escalation based on mathematical model: Fibonacci, 2-fold escalation, Continuous Reassessment Method, etc.

48. Examples of Study Schemes
Fibonacci
“Standard”
“1 Up, 1 Down”
D. “2 Up, 1 Down”
“Extended Standard”
Baysian
Continuous Reassessment Method
Currently, significant alteration of previous trial designs – Fit for Purpose

49. Typical Scheme 1. Enter 3 patients at a given dose
2. If no toxicity, go to next dosage and repeat Step 1
3. a. If 1 patient has serious toxicity, add 3 more patients at that does (go to Step 4)
b. If 1/6 have serious toxicity, consider MTD
4. a. If 2 or more of 6 patients have toxicity,
drop down 1 dose to confirm safety
b. If 1 of 6 has toxicity, increase dose and go back to step 1

50. Types of Phase 1 Trials Multiple types of Phase 1 Trials Dose finding
Food effect study
QTc prolongation study
Bioequivalence study
Approved or investigational agent with pharmacokinetic focus (adding of CYP inhibitor)
Typically considered drug-drug interaction study
Investigational agent + investigational agent
Investigational agent + approved agent(s)
Approved agent + approved agent(s)
Approved or investigational agent with pharmacodynamic focus (e.g. evaluation using functional imaging)
Approved or investigational agent with radiotherapy

51. Phase II Trials
Objective: To determine if new drug has any beneficial activity and thus worthy of further testing / investment of resources.
Doses and schedules may not be optimum
Begin to focus on population for whom this drug will likely show favorable effect

52. Phase II Trials
Goal
Screen for therapeutic activity
Further evaluate toxicity
Test using MTD or defined Dose(s) & Schedule(s) from Phase I (RP2D)
Make go/no-go decisions for Phase III trials
Perform translational work
Might also randomize patients into multiple arms each with a different dose and/or schedule
can then get a dose response curve

53. Phase II Design Design(s) No control (is this wise?)
Two-stage (double sampling)
Goal is to reject ineffective drugs ASAP
Decision I:Drug unlikely to be effective in  x% of patients
Decision II: Drug could be effective in  x% of patients
Other two-stage designs based on determining p1-p0 > x% where p0 is the standard care combination

54. Phase III Trial
Objective : To compare experimental or new therapies with standard therapy or competitive therapies
Often large & expensive studies
Typically required by FDA for drug approval
If drug approved, often followed by Phase IV trials to follow-up on long-range adverse events – concern is safety

55. Phase III Trial Designs
The foundation for the design of controlled experiments established for agricultural experiments
The need for control groups in clinical studies recognized, but not widely accepted until 1950s
No comparison groups needed when results dramatic:
Vismodegib in Advanced Basal Cell Carcinoma
Use of proper control group necessary due to:
Natural history of most diseases
Variability of a patient's response to intervention

56. Phase III Design Comparative Studies
Experimental Group vs. Control Group
Establishing a Control
1. Historical
2. Concurrent
3. Randomized
Randomized Control Trial is gold standard
Eliminates several sources of bias

57. Purpose of Control Group
To allow discrimination of patient outcomes caused by test treatment vs those caused by other factors
Natural progression of disease
Observer/patient expectations
Other treatment
Fair comparisons
Necessary to be informative

58. Significance of Control Group
Inference drawn from the trial
Ethical acceptability of the trial
Degree to which bias is minimized
Type of subjects
Kind of endpoints that can be studied
Credibility of the results
Acceptability of the results by regulatory authorities
Other features of the trial, its conduct, and interpretation

59. Use of Placebo Control The “placebo effect” is well documented
Could be
No treatment + placebo
Standard care + placebo
Matched placebos necessary so patients & investigators cannot decode the treatment assignment
eg. Vitamin C trial for common cold
Placebo was used, but was distinguishable
Many on placebo dropped out of study – not blinded
Those who knew they were on vitamin C reported fewer cold symptoms and duration than those on vitamin who didn't know

60. Historical Control Study
A new treatment used in a series of subjects
Outcome compared with previous series of comparable subjects
Non-randomized
Rapid, inexpensive, good for initial testing of new
treatments
Vulnerable to biases
Different underlying populations
Criteria for selecting patients
Patient care
Diagnostic or evaluating criteria

61. Randomized Control Clinical Trial
Patients assigned at random to either treatment(s) or control
Considered to be “Gold Standard”

62. Disadvantages of Randomized Control Clinical Trial
1. Generalizable Results?
Subjects may not represent general patient population – volunteer effect
2. Recruitment
Twice as many new patients
3. Acceptability of Randomization Process
Some physicians will refuse
Some patients will refuse
4. Administrative Complexity

63. Comparing Treatments Fundamental principle
Groups must be alike in all important aspects and only differ in the treatment each group receives
In practical terms, “comparable treatment groups” means “alike on the average”
Randomization
Each patient has the same chance of receiving any of the treatments under study
Allocation of treatments to participants is carried out using a chance mechanism so that neither the patient nor the physician know in advance which therapy will be assigned
Blinding
Avoidance of psychological influence
Fair evaluation of outcomes

64. Randomized Phase III Experimental Designs
Assume:
Patients enrolled in trial have satisfied eligibility criteria and have given consent
Balanced randomization: each treatment group will be assigned an equal number of patients
Issue
Different experimental designs can be used to answer different therapeutic questions

65. Commonly Used Phase III Designs
Parallel
Withdrawal
Group/Cluster
Randomized Consent
Cross Over
Factorial
Large Simple
Equivalence/Non-inferiority
Sequential

66. Clinical Trials are a necessary component of cancer drug development
Conclusions
Clinical Trials are a necessary component of cancer drug development
There are discrete developmental phases of clinical drug development, often with some endpoint overlap (1o or 2o):
Phase I Trials, although many different types, are typically answering questions for one of the first times in man
Phase II Trials are focused on efficacy
Phase III Trials help determine benefit over Stand of Care treatment

67. We must work together in the fight against Cancer – please encourage patients and caregivers to consider treatment on a clinical trial

68. THANK YOU!!!