Clinical trials follow a phased process to evaluate new treatments. Phase I trials test safety in small groups. Phase II trials assess efficacy in larger groups. Phase III trials compare new treatments head-to-head with standard treatments in large randomized controlled trials. Higher levels of evidence come from systematic reviews and meta-analyses of multiple randomized controlled trials, while lower levels of evidence derive from expert opinions and single descriptive studies.

1. Clinical trials and levels of evidence
Dr. pratik patil
Medical oncology resident

2. CLINICAL TRIAL
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

3. Comparative studies and
Open Label studies are the two groups of clinical
trials

4. Comparative, also known as controlled, clinical trials involve
one group of patients who receive the new drug and a control
group who receives a placebo or gold standard treatment.
 A placebo is an injection, infusion or pill that seems identical
to the new treatment, but is actually inactive.
Comparative studies are typically conducted as double-blind
trials, where neither the physician nor the patient knows which
group is receiving the new drug.
Double-blind trials help to eliminate any biased results

5. Open Label clinical trials do not attempt to disguise the new
drug or treatment, meaning that no standard treatment or
placebo is utilized.
This leans towards bias, as both the patient and the physician
are aware of which groups are receiving what type of treatment

6. Phases of trials –
The four phases of clinical trials are Phase I, Phase II, Phase III
and Phase IV.
These phases are all separate and individual clinical studies.
The entire process from Phase I to Phase IV can take anywhere
from eight to 10 years to complete.
But some trials have an earlier stage called phase 0, and there
are some phase 4 trials done after a drug has been licensed.

7. Phase 0 Trail
Phase 0 trials are the first clinical trials done among
people. They aim to learn how a drug is processed
in the body and how it affects the body.
In these trials, a very small dose of a drug is given
to about 10 to 15 people.

8. Phase 1
Patients with advanced disease that is resistant to standard therapy but
who have normal organ function are usually included in such trials.
Initiated at a low dose that is not expected to produce serious toxicity.
A starting dose of one-tenth the lethal dose, dose is increased for
subsequent patients according to a series of preplanned steps.
 Dose escalation for subsequent patients occurs only after sufficient
time has passed to observe acute toxic effects for patients treated at
lower doses.
Cohorts of three to six patients are treated at each dose level.

9. Usually, if no dose-limiting toxicity (DLT) is seen at a given
dose level, the dose is escalated for the next cohort.
If the incidence of DLT is 33%, then three more patients are
treated at the same level. If no further cases of DLT are seen in
the additional patients, then the dose level is escalated for the
next cohort. Otherwise, dose escalation stops.
If the incidence of DLT is >33% at a given level, then dose
escalation also stops. The phase 2 recommended dose often is
taken as the highest dose for which the incidence of DLT is is
<33%.

10. Limitations -
1. They sometimes expose too many patients to
subtherapeutic doses of the new drug.
2. The trials may take a long time to complete.
 3. They provide very limited information about interpatient
variability and cumulative toxicity.

11. Phase II
 Safety and efficacy of a fixed dose of a new anti-cancer drug in
a much larger number of patients than a Phase I trial.
It usually tests the experimental drug on patients with one
specific cancer type .
This is in contrast to a Phase I trial, where patients with different
solid tumor types such as breast, lung, pancreatic, ovarian cancer
etc. may be enrolled.
The decision to treat that specific cancer type in Phase II is based
on evidence from pre-clinical and Phase I data.
Participants in a Phase II trial may or may not have had previous
anti-cancer therapy, depending on the eligibility criteria of the
specific trial.

12. 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

13. 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

14. Single-Arm Phase 2 Trials
The objective is simply to determine whether the drug has activity against the
tumor type in question.
For this objective, response rate based on the response evaluation criteria in
solid tumors guidelines may provide a satisfactory approach.

A variety of statistical accrual plans and sample size methods have been
developed for single-arm phase 2 trials.
One of the most popular approaches is the optimal two-stage design.
n1 evaluable patients are entered into study in the first stage of the trial. If no
more than r1 responses are obtained among these n1 patients, then accrual
terminates and the drug is rejected as being of little interest. Otherwise, accrual
continues to a total of n evaluable patients. At the end of the second stage, the
drug is rejected if the observed response rate is less than or equal to r/n, where r
and n are determined by the design used.

15. Combination Regimens
Determination whether a new drug adds anticancer activity to an
active regimen is inherently comparative
For comparative trials of response rates using specific historic
controls, the sample size should be planned using the formulas
appropriate for randomized clinical trials. By inserting the
number of historic controls to be used, one can compute the
number of patients needed to treat on the new regimen in the
single arm phase 2 trial.

16. Randomized Phase 2 Trials
Time to tumor progression or disease-free survival has been
recommended for evaluation of single-agent phase 2 trials of
drugs that may be cytostatic and for trials adding a new drug to an
active regimen.
Even single-agent phase 2 trials of cytotoxics have been criticized
on the basis that they do not provide much evidence that the drug
will be able to prolong survival when incorporated into a regimen
with other active drugs.
Demonstrating that the regimen incorporating the new drug
prolongs progression-free survival compared to the control
regimen may provide a stronger basis for conducting a phase 3
trial of the new regimen.

17. Phase III
 trial Phase III oncology treatment trials test the safety and
effi- cacy of a new anti-cancer drug that has shown promising
safety and efficacy trends in Phase II trials.
 In a Phase III trial, the study drug is tested in a large number
of patients with statistical rigor.
 Each Phase III trial has strict and well-defined eligibility
criteria (i.e. inclusion and exclusion criteria), and those
monitoring trial enrollment must ensure that the patients
enrolled in the trial meet these criteria.

18. Phase III oncology trials are typically double-blinded and
randomized trials.
 Stratification techniques may be used to ensure a balanced
distribution of specific important patient baseline characteristics .
In the two arm parallel arm design, patients are randomized to
either the study drug or the standard of care.
Patients on trial are allowed for ethical reasons to take
subsequent anti-cancer therapies after progressive disease on trial
therapy.

19. Phase III oncology trials are commonly superiority trials
(i.e. to test if the study drug is superior to the standard of
care in terms of the primary efficacy endpoint and not worse
in terms of safety).
However, Phase III oncology trials may also be designed as
equivalence trials to test if the study drug and the standard of
care are the same within an equivalence margin, or non-
inferiority trials to test if the study drug is not worse than the
standard of care within a margin

20. The efficacy endpoints
Overall survival (OS) is defined as the time from randomization until
death from any cause, and is an endpoint that is most commonly used in
Phase III oncology trials.
Progression free survival (PFS) is defined as the time from
randomization until PD or death.
PFS is commonly used as a surrogate for OS and OS is generally
considered the gold standard for approval.
 Disease-free survival is defined as the time from randomization until
recurrence of tumor or death from any cause, and is an endpoint that is
usually used in the adjuvant setting, where the patients have no tumor
after surgery or radiotherapy.
Time to progression (TTP) is defined as the time from randomization
until PD (death is excluded per FDA guidelines).

21. 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

22. PURPOSE OF CONTRIOL
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

23. 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

24. Historical control group
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

25. Randomized control clinical trial
Patients assigned at random to either treatment(s) or control
Considered to be “Gold Standard”

26. Comparing treatment
 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

27. 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

28. Levels of evidence (sometimes called hierarchy of
evidence) are assigned to studies based on the
methodological quality of their design, validity, and
applicability to patient care. These decisions gives
the "grade (or strength) of recommendation."

29. Level I
Evidence from a systematic review or meta-analysis of all relevant RCTs
(randomized controlled trial) or evidence-based clinical practice
guidelines based on systematic reviews of RCTs or three or more RCTs
of good quality that have similar results.
Level II
Evidence obtained from at least one well-designed RCT (e.g. large multi-
site RCT).

30. Level III
Evidence obtained from well-designed controlled trials without
randomization (i.e. quasi-experimental).
Level IV
Evidence from well-designed case-control or cohort studies.
Level V
Evidence from systematic reviews of descriptive and qualitative
studies (meta-synthesis).

31. Level VI
Evidence from a single descriptive or qualitative study.
Level VII
Evidence from the opinion of authorities and/or reports of expert
committees.