1. Role of Clinical Trials in Drug
Discovery & Development
Presented at Gupta College of Technological Sciences on 24th September 2011
Dr. Bhaswat S. Chakraborty
Senior Vice President and Chairman
R&D Core Committee, Cadila Pharmaceuticals

2. Blockbuster Drugs
Drug Trade name Company Sales (billion $) year
Atorvastatin Lipitor Pfizer 12.5 (2009)
Bristol-Myers Squibb
Clopidogrel Plavix 9.5 (2009)
and Sanofi-Aventis
Fluticasone
Advair Glaxo-Smith-Kline 7.7(2009)
and salmeterol
Enbrel Etanercept Amgen 6.2 (2009)
Valsartan Diovan Novartis 6.0 (2009)
Infliximab Remicade Johnson & Johnson 5.9 (2009)
Bevacizumab Avastin Roche and Genentech 5.7 (2009)
Rituximab Rituxan Roche and Genentech 5.6 (2009)
Adalimumab Humira Abbott 5.5 (2009))
Quetiapine Seroquel AstraZeneca 5.1 (2009)

3. Drug Discovery and IT
• Using HTS robotics, data processing and control software, liquid handling
devices, and sensitive detectors, a researcher can now conduct millions of
chemical, genetic or pharmacological tests in few days.
• High impact of in silico molecular modelling, resulting in acceleration of
the drug discovery process.
– For example, using traditional drug development techniques it took
nearly 40 years to capitalize on a basic understanding of the
cholesterol biosynthesis pathway to develop statin drugs – those that
inhibit the enzyme HMG-CoA reductase, the rate limiting step in
cholesterol biosynthesis.
– Whereas, a molecular-level understanding of the role of the HER-2
receptor in breast cancer led to the development of the
chemotherapeutic agent Herceptin® within only three years.

4. Drug Discovery Initial Steps
Disease Characterization

5. Drug Discovery Middle Steps
Target Selection and Validation

6. Use of Combinatorial Chemistry and HTS
• Pharmaceutical companies often use combinatorial chemistry
and HTS to predict these target-lead interactions.
• Recently the in silico techniques for predicting these
molecular events have advanced to the point where biotech
companies are beginning to skip much of the bench work
involved in combinatorial chemistry and synthesize only the
most promising compounds based on a structural
understanding of the receptor and associated ligands.
• Having identified the most relevant targets and selected the
most promising lead compounds, the focus shifts to clinical
trials.
Augen J. 2002. DDT, 7, 315-323

7. Drug Discovery Final Steps
ADME & Clinical Studies

8. Rounds of Drug Discovery Process
• Results from clinical trials are fed back to enhance the next
round of target selection and lead identification and
optimization.
• Although each step in the process involves specific
information tools, the tools are related and in some cases
overlap.
– e.g., Much of today’s animal model work involves comparative
genomics including tools for multiple sequence homology and pattern
matching.
– Many of these tools are also used to help find genes that code for
target proteins.
– similarly, both target validation and lead optimization are enhanced
by the use of programs that facilitate predicting 3D structures of
proteins and protein–ligand complexes. Augen J. 2002. DDT, 7, 315-323

9. Superordinate Goals of New Drug Discovery
• To evidence that the drug is safe and effective in its proposed
use(s), and whether the benefits of the drug outweigh the
risks.
• To evidence that the the methods used in manufacturing the
drug and the controls used to maintain the drug's quality are
adequate to preserve the drug's identity, strength, quality,
and purity.
• To evidence that the drug's proposed labeling (package
insert) is appropriate, and what it should contain.
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10. Drug Discovery Final Steps
ADME & Clinical Studies

11. Investigational New Drug
• The pharmaceutical industry sometimes informs the FDA
prior to submission of an IND
• Sponsors, research institutions, and other organizations that
take responsibility for developing a drug must show the FDA
results of preclinical testing they've done in laboratory
animals and what they propose to do for human testing
• At this stage, the FDA decides whether it is reasonably safe
for the company to move forward with testing the drug in
humans
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12. Phase 1
• Phase 1 studies are usually conducted in healthy
volunteers
• The goal here is to determine what the drug's most
frequent side effects are and, often, how the drug is
metabolized and excreted
• Dose escalation-response data
• What is maximum tolerated dose and what dose
limited toxicities are
• The number of subjects typically ranges from 20 to
100
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13. Early Phase Clinical Trials
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14. Phase 2
• Phase 2 studies begin if Phase 1 studies don't reveal
unacceptable toxicity
• While the emphasis in Phase 1 is on safety, the emphasis in
Phase 2 is on effectiveness
• This phase aims to obtain preliminary data on whether the
drug works in people who have a certain disease or condition
at selected doses
• For controlled trials, patients receiving the drug are compared
with similar patients receiving a different treatment--usually
an inactive substance (placebo), or a different drug
• Safety continues to be evaluated, and short-term side effects
are studied. Typically, the number of subjects in Phase 2
studies ranges from a few dozen to about 300
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15. Phase 3
• At the end of Phase 2, the FDA and sponsors try to come
to an agreement on how the large-scale studies in Phase 3
should be done
• How often the FDA meets with a sponsor varies, but this is
one of two most common meeting points prior to
submission of a new drug application
• The other most common time is pre-NDA, right before a
new drug application is submitted
• Phase 3 studies begin if evidence of effectiveness is shown
in Phase 2
• These studies gather more information about safety and
effectiveness, studying different populations and different
dosages and using the drug in combination with other
drugs
• The number of subjects usually ranges from several
hundred to about 3,000 people
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16. Phase 4
• Postmarketing study commitments are called Phase
4 commitments
– studies required of or agreed to by a sponsor that are
conducted after the FDA has approved a product for
marketing
• The FDA uses postmarketing study commitments to
gather additional information about a product's
safety, efficacy, or optimal use
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17. 17

18. Institutional Review
• IRBs approve the clinical trial protocols
– the type of people who may participate in the clinical
trial
– the schedule of tests and procedures
– the medications and dosages to be studied
– the length of the study
– the study's objectives
– other details
• IRBs make sure the study is
– acceptable
– participants have given consent
– Participants are fully informed of their risks
– researchers take appropriate steps to protect patients
from harm 18

19. Design Concepts
Non-Inferiority
Difference in Clinical Efficacy (Є)
Superiority
+δ
0
Equivalence
-δ
Inferiority
Non-Superiority
Equality δ = Meaningful Difference
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20. Adequate and Well-Controlled
Studies..
• Minimization of Bias: a unidirectional tilt favoring one group,
i.e., a non-random difference in how test and control group
are selected, treated, observed, and analyzed
– These are the 4 main places bias can enter
• Remedies:
– Blinding (patient and observer bias)
– Randomization (treatment and control start out equal)
– Careful specification of procedures and analyzes in a
protocol to avoid
• Choosing the most favorable analysis out of many (bias)
• Having so many analyses that one is favorable by chance
(multiplicity)
Source: RJ Temple, US FDA, Unapproved Drugs Workshop January 20
2007

21. Clinical Trials: Testing Medical Products in Humans
• Clinical studies test potential treatments in human volunteers
to see whether they should be approved for wider use in the
general population
– A treatment could be a drug, medical device, or biologic,
such as a vaccine, blood product, or gene therapy
– A new treatment may or may not be “better”
– Complete and accurate research
– Protection and well being of participants
• Ethics, consent, audit
– Documentation
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22. Randomized Clinical Trials
• Gold standard is Phase III RCTs = Evidence based medicine
• Single centre CT
– Primary and secondary indications
– Safety profile in patients
– Pharmacological / toxicological characteristics
• Multi-centre CT
– Confirmation of the above
– Effect size
– Site, care and demographic differences
– Epidemiological determination
– Complexity
– Far superior to meta-analyzed determination of effect
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23. 23

24. Study Design: Approaches
• Randomised Controlled Trials (RCT) most preferred approach
– Demonstrating superiority of the new therapy
• Other approaches
– Single arm studies (e.g., Phase II)
• e.g., when many complete responses were observed or
when toxicity was minimal or modest
– Non-inferiority & Equivalence Trials
– No Treatment or Placebo Control Studies
– Isolating Drug Effect in Combinations
– Dose escalation
– ….
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25. Adequate & Well-Controlled Studies
• Because the course of most diseases is variable, you need a control group,
a group treated just like the test group, except that they don’t get the
drug, to distinguish the effect of the drug from spontaneous change,
placebo effect, observer expectations
• 21 CFR 314.126 describes the following controls
– Placebo
– No treatment
– Dose response
– Active control
• Superiority of non-inferiority
– Historical
• Placebo, dose response or superiority are usually convincing studies
• Adequate means – adequate sample size, power, design and analysis plan
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26. Placebo Control Trials
• Only when it is ethical
• Sometimes acceptable otherwise
– e.g., in early stage cancer when standard practice is to give
no treatment
– Add-on design (also for adjuvants)
• all patients receive standard treatment plus either no
additional treatment or the experimental drug
– Placebos preferred to no-treatment controls because they
permit blinding
– Measures “effect size” accurately
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27. Active Control Trials
• The purpose of an active control trial could be to
demonstrate that a new experimental treatment is
either
– superior to the control
– equivalent to the control, or
– non-inferior to the control
– superior to a virtual placebo
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28. Non-Inferiority Trials
• New drug not less effective by a predefined
amount, the noninferiority (NI) margin
– NI margin cannot be larger than the effect of the
control drug in the new study
– If the new drug is inferior by more than the NI
margin, it would have no effect at all
– NI margin is some fraction of (e.g., 50 percent) of
the control drug effect
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29. What to Measure?
• Primary outcome measure: The health parameter measured
in all study participants to detect a response to treatment.
Conclusions about the effectiveness of treatment should
focus on this measurement.
• Secondary outcomes measure: Other parameters that are
measured in all study participants to help describe the effect
of treatment.
• Baseline variables: The characteristics of each participant
measured at the time of random allocation.
– This information is documented to allow the trial results to
be generalised to the appropriate population/s
– Specific characteristics associated with the patient’s
response to treatment (such as age and sex) are known as
prognostic factors
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30. Data
• There are legal and ethical reasons for reporting all
relevant data collected during the drug development
process
• Some reporting strategies already exist in the 1988
Guidelines, ICH E3 and E9
• Electronic Submissions and desktop review capabilities
will help all of us make better use of clinical data in NDA’s
• There may be better strategies and these should be
considered
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31. Intent-to-Treat Principle
• All randomized patients
• Exclusions on pre-specified baseline criteria permissible
– also known as Modified Intent-to-Treat
• Confusion regarding intent-to-treat population: define and agree upon in
advance based upon desired indication
• Advantages:
– Comparison protected by randomization
• Guards against bias when dropping out is related to outcome
– Can be interpreted as comparison of two strategies
– Failure to take drug is informative
– Reflects the way treatments will perform in population
• Concerns:
– “Difference detecting ability”
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32. Per Protocol Analyses
• Focuses on the outcome data
• Addresses what happens to patients who remain on therapy
• Typically excludes patients with missing or problematic data
• Statistical concerns:
– Selection bias
– Bias – difficult to assess
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33. From the Results of Clinical Trials,
What does FDA Conclude?
• If CMC is OK, FDA approves a drug
application based mainly on RCT results
– Substantial evidence of efficacy & safety from
“adequate and well-controlled investigations”
– A valid comparison to a control
– Quantitative assessment of the drug’s effect
• The design of clinical trials intended to
support drug approval is very important
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34. Conclusions
• Randomized Clinical Trials are very sophisticated and
complex
• Principal Investigators’, Trial Monitors’ and Biostatisticians’
roles are invaluable
• Higher Phase (Phases 2, 3) Clinical Trials provide for the
main evidence of efficacy and safety
• Clinical data is very complex (confounded, censored,
skewed, often fraught with missing data point), therefore,
proper hypothesization and statistical treatment of data are
required
• Prospective RCTs are usually the preferred approach for
evaluation of new therapies
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35. Conclusions..
• Clinically meaningful margins must be well defined in
Control trials prospectively
– Superiority and non-inferiority margins must not be
confused
• All trials must be medically and statistically well designed
and adequate
• Both ITT and PP data analyses are important for approval
• If CMC is OK, FDA approves a drug application based mainly
on RCT results
• …
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36. Thank You Very Much