Potential of phase II clinical trials in drug development
1. POTENTIAL OF PHASE II
TRIALS IN DRUG
DEVELOPMENT
Dr. Bhaswat S. Chakraborty
Senior Vice President and Chairman,
R&D Core Committee
Cadila Pharmaceuticals Ltd.
5th Annual Clinical Trials Summit,
Virtue Insight, Mumbai, June 11, 2014
2. CONTENTS
Disease severity & Unmet medical needs:
when a well designed Phase II study is adequate for
approval
Design and control issues in PoC Phase II studies:
Best Phase II designs : Randomized or Single arm
End point selection
Decision to proceed to Phase III or terminate based
on Phase II results
Concluding remarks
3. PATIENT FOCUSED DRUG
DEVELOPMENT
Severity of Condition
Unmet Medical Need
These two provide regulators with the clinical context for
weighing benefits and risks and the associated uncertainties
Benefit
Risk
Benefit and Risk incorporate expert judgments based on
evaluation of the efficacy and safety data
Risk Management
To reduce and further characterize risks
Source: USFDA
Often disease severity & unmet need prompt fast tracking a
submission with a Phase II trial only (e.g., Oncology)
4. DISEASE SEVERITY & UNMET
MEDICAL NEED
Serious or Life threatening diseases
Cancer, Autoimmune & other serious diseases
Diseases with high unmet medical need
Sometimes a large market
Epratuzumab for lupus (SLE)
Billion dollar market opportunity
But often not a large market (orphan)
Some development so far, needs further work
Clivatuzumab for pancreatic cancer
Encouraging survival benefit data from Phase I/IIb study
5. SUCCESS OF A [PHASE II] CLINICAL
TRIAL
Right
Scientific
Questions
Generalizable
Results
Right conduct of the trial
Adequate scope, time &
budget
Proceed to higher phases
PoC of Efficacy, Safety,
Dose & Frequency
Does this drug increase
survivability in …cancer?
6. PHASE II TRIALS
Ideally, a Phase II trial should
Establish the PoC
Have a high benefit to risk ratio
Can be generalized to a maximum number of sub-groups and
Be either adequate for approval or need just one confirmatory
Phase III trial.
However, in reality the current Phase II trials rarely show
this potential
> 60% oncology Phase II trials fail; other categories of Phase II
also have a high failure rate
Do not represent a true screen for either success or futility
Combination therapy Phase II trials are difficult to interpret
(unquantifiable effect size)
Often data is not rich enough to suggest a clear “go” for Phase III
7. Brown S et al: (2014) A Practical Guide
to Designing Phase II Trials in
Oncology, Wiley
Statistical Considerations
8. DESIGN & CONTROL ISSUES IN PHASE II
CANCER TRIALS
One of the major issues is the use of controls
One study* finds that only ~20% Phase II Cancer Trials use active
or historical control or placebo (notwithstanding a higher reporting
of Onco trials)
Remember the primary objective of a phase II cancer clinical trials is
to determine whether to proceed for a further Phase II or a Phase III
study
This requires basically a demonstration of substantial efficacy of a
new regimen
However, oncology Phase II has been limited by high rates of
failure (lack of efficacy) in subsequent phase III testing
This is in part because Phase II studies which can easily discard a
study with an apparent low efficacy that due to factors other than the
drug itself
*Michaelis et al. (2007). Clin Cancer Res,13, 2400–5
9. DESIGN & CONTROL ISSUES IN PHASE II
CANCER TRIALS..
Herceptin, Erbitux, and Avastin may have only modest activity as
single agents and produce few clinical responses
Their effect requires more subtle trial designs
e.g., delay time to progression or recurrence or enhance response rates
to standard cytotoxic agents.
single arm phase II trial, with response as the end point, may lead to the
abandonment of a valuable drug
Larger trials, and more complex phase II designs with TTP end
points, may be required to show effectiveness of the new agent
here, concurrent controls, treated with standard agents or or other
strategies might show valuable aspects of the toxicity and effectiveness
of the new agent
e.g sorafenib, [U of Chicago Researchers] randomized stable patients to
continued therapy vs. drug discontinuation, with positive for patients
continuing with experimental drug
Chabner B. (2007). Clin Cancer Res,13, 2307
10. RANDOMIZED PHASE –II (RP-II)
TRIALS
At least in theory, RP-II trials are likely to give more valid
and comprehensive data.
By reducing selection biases
By providing comparability across study arms
Inclusion of both arms in the same protocol assures similar
assessment methods and supportive care measures
Valid comparison of primary and secondary end points
Able to use the bio specimens from the trial to develop
predictive bio markers for therapy
Without the randomized control group one cannot determine
if a bio marker is prognostic and predictive
Sargent DJ et al: (2005). J Clin Oncol 23:2020-2027
Fleming TR et al: (2004). J Infect Dis 190:666-674
O’Shaughnessy J et al: (2009). J Clin Oncol 27:6s
11. FURTHER BENEFITS OF RP-II
TRIALS
Able to generate robust and rich data to allow for full drug
approval
A highly significant and meaningful (statistically and clinically)
endpoint in a RP-II trial would preclude a phase –III study
A definitive RP-II trial is the one where a strong biological
effect of a novel therapy is observed
For such studies would make phase-III trials with random
assignment to a control arm ethically questionable
e.g. efficacy of VEGF inhibitors in the treatment of clear cell renal
carcinoma, the activity of imatinib in GI stromal cell tumors……..
A definitive RP-II trial may be particularly useful for a rare
malignancy in which a phase-III trial would be difficult to
conduct
A strong biological effect: hazard ratio <0.60 and p < 0.0005
with quality standards similar to phase-III trials.
Sargent DJ et al: (2005). J Clin Oncol 23:2020-2027
Fleming TR et al: (2004). J Infect Dis 190:666-674
O’Shaughnessy J et al: (2009). J Clin Oncol 27:6s
12. SINGLE ARM PHASE-II (SA-II)
TRIALS
SA-II trials are well suited to screening drugs for further
development
Simple in design and easily executed; N is usually <50
Conservatively restrict their false-positive (α) and false-
negative (β) rates to ≤0.05 and ≤0.12, respectively (found in
a review of 146 SA studies)
Almost all SA-II trials can completed without any problems
During 1998-2008, on eight occasions the US FDA based
their initial approval for an oncology drug solely on SA-II
trials
Zia MI et al. (2005), J Clin Oncol 23:6982-6991
Thezenas S et al. (2004). Eur J Cancer 40:1244-1249
Gan HK et al. (2010). J Clin Oncol 28:2641-2647
13. Gan HK et al. (2010). J Clin Oncol 28:2641-2647
†Capecitabine in patients with advanced breast cancer;
ixabepilone monotherapy in advanced/metastatic breast cancer resistant/refractory to
anthracycline, taxanes, and capecitabine; paclitaxel in AIDS-related Kaposi’s sarcoma;
temozolomide in relapsed anaplastic astrocytoma.
‡Cetuximab in recurrent/metastatic squamous cell carcinoma of the head and neck;
imatinib in the treatment of multiple malignancies;
sunitinib in the treatment of advanced renal cell carcinoma;
trastuzumab in chemotherapy-pretreated metastatic Erb2-positive breast cancer.
14. ONE POSSIBLE DESIGN
Endpoint RECIST objective response (PR/CR)
Simon Two-stage minimax
<30% no interest, ≥ 50% interest
If 8 or more patients show responses in the first 28, 11
additional patients are treated for a total of 39. If ≤15 show
responses, the regimen will not be recommended for further
study. If ≥16 patients show responses in the 39, the regimen
will be studied further.
15. RANDOMIZED SELECTION SA-II
STUDIES
A randomized phase II selection design allows conducting
multiple single-arm studies in the same time frame & with
same entry criteria
Advantages:
Decreases the effects of patient selection bias, population drift
and stage migration, and the ability to ensure uniform
evaluation
Designed to separately evaluate each arm
A predetermined plan for selection of arms for future study
can be made
Disadvantages
Not adequate power for formal tests if arms are compared
Gray R et al.(2006). Clin Cancer Res;12:1966-1969
17. ENDPOINTS IN ONCOLOGY TRIALS
Must show either direct evidence of clinical benefit or
improvement in an established surrogate for clinical benefit
Clinical benefit: survival improvement
Overall survival (OS)
Progress-free survival (PFS) (usually Ph III)
Improvement in a patient’s quality of life (QOL) (usually Ph III)
Other endpoints on which approval has been given are:
Objective response rate (ORR)
by RECIST or any radiological tests or physical examinations
Improvement in survival, improvement in a QOL, improved
physical functioning, or improved tumor-related symptoms do not
always be predicted by, or correlate with, ORR
Source: US FDA Guidance
18. OVERALL SURVIVAL (OS)
OS: The time from randomization until death from any cause
Measured usually in the intent-to-treat (ITT) population
Most reliable cancer endpoint, and when studies can be conducted to
adequately assess survival, it is usually the preferred endpoint
Precise and easy to measure – no influence of technicality of measurement
Bias is not a factor in endpoint measurement
Survival improvement should be analyzed as a risk-benefit analysis to
assess clinical benefit
OS should be evaluated in RCTs
Historical trials are seldom reliable for time-dependent endpoints (e.g.,
OS, PFS).
The OS in control arm has to be compatible
19. Rosell et al. (2008), Annals of Oncology, 19, 362–369
20. ENDPOINTS BASED ON TUMOR
ASSESSMENTS
Disease-free survival (DFS)
Objective response rate (ORR)
Time to tumor progression (TTP)
Progress-free survival (PFS)
Time-to-treatment failure (TTF)
They are all time-dependent endpoints
Collection and analysis of these endpoints are based on indirect
assessments, calculations, and estimates (e.g., tumor measurements)
Two critical judgments:
1. whether the endpoint will support either accelerated approval or regular
approval
2. endpoint should be evaluated for the potential of bias or uncertainty in tumor
endpoint assessments
Drug applications using studies that rely on tumor measurement-based
endpoints as sole evidence of efficacy may need confirmatory
evidence from a second trial
21. Rosell et al. (2008), Annals of Oncology, 19, 362–369
CONTROL
EXPERIMENTAL
22. CAUTIONS IN TUMOR
ASSESSMENTS
Accuracy in measuring tumors can differ among tumor settings
Imprecision can happen in locations where there is a lack of
demarcated margins (e.g., malignant mesothelioma, pancreatic
cancer, brain tumors).
When the primary study endpoint is based on tumor
measurements (e.g., PFS or ORR), tumor endpoint assessments
generally should be verified by central reviewers blinded
to study treatments
This measure is especially important when the study is not blinded
It may be appropriate for the FDA to audit a sample of the scans to
verify the central review process
23. DECISION TO PROCEED TO PHASE
III
The “go or no go” decision at the end of phase II is perhaps the most
difficult one to make in the drug development cycle
data are limited
future investment required for a phase III trial is vast
success of the company may depend on the drug in question
an informative phase II trial is crucial
after phase II, the decision makers need to understand toxicity and
pharmacokinetics, should have strong indications of activity in a
specific kind of cancer, and should have a clear sense of an approval
strategy
There are often gaps in this knowledge, and the decision is guided by
both fact and intuition
The decision becomes easier when the case is unmet medical needs
Chabner B. (2007). Clin Cancer Res,13, 2307
24. DECISION TO PROCEED TO PHASE III
OR TERMINATE BASED ON SA-II
Single arm studies
If properly designed and powered can be the basis for approval in S&E
Sometimes, futility is better predicted than success
However, when success/failure response is used
Summarize success as the proportion of number of totally included patients
To proceed for Phase III, it is important to know the norm (activity of current
standard) and that the new treatment is expected to exceed this
Example
The standard treatment for AML is fludarabine + ara-C (50% success)
Addition of GCSF would be beneficial if Phase II shows ~70% success
In most cases, irrespective of the design of Phase II studies, a
definitive Phase III would be required
Well designed, controlled, adequate study
Thall & Simon (1994). Biometrics, 50, 337-349
Gan HK et al. (2010). J Clin Oncol 28:2641-2647
25. CONCLUDING REMARKS
Phase II [cancer] clinical data can very complex (low N, mismatched
action and outcome data, censored, skewed, often fraught with missing
data point), therefore, proper clinical and statistical considerations
treatment of data are required
Phase II single arm (SA-II) trials can even be definitive and sometimes a
basis of approval
Well designed and powered
There are ways to reduce bias (randomized selection)
SA-II trials are often exploratory studies
Efficient to exclude inactive therapies
Results must be interpreted cautiously, in the context of the availability of
other therapies
Phase II two- or multi-arm randomized trials (RP-II) have all features of
well designed studies but haven’t always been proven superior to SA-II
26. CONCLUDING REMARKS..
Both RP-II ans SA-II estimate clinical activity and provide further safety
information – important in the “go/no go” to Phase III decision
There are many endpoints that are scientifically valid but OS as primary
end point is often preferred by regulatory agencies
PFS & Tumor assessment trials may need another confirmatory CT
Endpoints must be demonstrative (directly or indirectly) of clinical
benefit
Missing data, infrequent treatment, increased type I error and other
confounding factors must be addressed
Consistent ITT & PP facilitate approval
Well designed SA-II or RP II have 10-15% chance of being the basis of
approval – not a bad potential!
The best of these drugs, such as Herceptin (Trastizumab, anti-HER2/neu receptors), Erbitux (Cetixumab, anti-EGFR), and Avastin (Bevacizumab, anti-VEGF-A), may have only modest activity as single agents and produce few clinical responses. Their value may only be obvious in more subtle trial designs, in which they delay time to progression or recurrence or enhance response rates to standard cytotoxic agents (5, 6). The traditional single-agent phase II trial, with response as the end point, may lead to the abandonment of a valuable drug. Larger trials, and more complex phase II designs with time-to-progression end points, may be required to show effectiveness of the new agent. In this sort of trial, concurrent controls, treated with standard agents or randomized either to discontinue the experimental drug or perhaps to begin the drug after a period of placebo treatment, might show valuable aspects of the toxicity and effectiveness of the new agent. Such is the case with sorafenib, in which the University of Chicago group randomized stable patients to continued therapy versus drug discontinuation, with strikingly positive findings for patients who continued to receive the experimental drug (2). In other settings, in which a standard cytotoxic is an alternative to a new targeted drug, the choice of appropriate end points may be complicated. Although time to progression might be most appropriate for the cytostatic agent, partial or complete remission might be a clearer end point for the cytotoxic drug.
Sorafenib (co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar),[1] is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma).
The different approaches to phase II trial design which are described in this section will be illustrated by the design
of a single-arm phase II trial described by Thall & Simon [2]. The purpose of the trial was to assess treatment with
¯udarabine +ara-C+ granulocyte colony stimulating factor (GCSF) for poor prognosis acute myelogenous
leukaemia patients. All patients in the trial receive the new treatment. The clinical endpoint is complete remission
(CR) of the leukaemia. For patients achieving such a state,
the treatment will be termed successful. The standard
treatment is ¯udarabine+ara-C, for which the success rate
is 50%. The use of GCSF would be considered bene®cial
if it increased the success rate to 70%.