The document discusses the different phases of clinical research trials for new drugs. It provides details on: - Phase 0 (microdosing) trials which involve limited human exposure to gather pharmacokinetic data early in development. - Phase I trials which are the first stage of testing in humans to determine safety, tolerability and pharmacokinetics through single and multiple ascending dose studies. - Phase II trials which are larger therapeutic exploratory studies to further test safety, pharmacokinetics and determine optimal doses and endpoints. - Phase III trials which involve randomized and blinded testing in hundreds to thousands of patients to gather extensive data on effectiveness and adverse reactions compared to standard treatments. - Phase IV post

1. CLINICAL RESEARCH
Venugopal N

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4. Phase O
Microdosing

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Micro-dosing history
• The concept of Micro Dosing existed from past 10-15 years but
its application was enforced only after the Paraxel Tragedy at
London in 2006, where a life threatening multi organ failure
occurred during the first-in-human (Phase 1) trail of TGN1412,
an experimental monoclonal antibody, in 6 healthy male
volunteers.
• The diagnosis was Cytokine Release syndrome due to the
dosage of the drug administered after a series of calculations
and dose extrapolation from preclinical studies.
• This amounted to be the maximal immune stimulatory dosage
for humans, thereby causing the reaction and residual
complications.

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• Hence leading to the realisation that species specificity of
action may not reproduce intended effect or predict “on
target” toxicity in humans and can provide misleading PK and
PD results.
• Hence, recommendation for an alternative initial dose-setting
assessment for certain novel agents was put forward leading to
Micro Dosing studies, in very few human volunteers to analyze
absorption, distribution, metabolism, excretion of drugs and to
calculate dose related parameters from the pharmacokinetic
values obtained in vivo.

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• These are Exploratory IND (investigational new drug) studies
conducted early in Phase I (hence, the term Phase 0) involving
limited human exposure and have no therapeutic or diagnostic
intent.
• Micro dosing is defined as the ‘use of 100 µg of candidate drug
or less than 1/100th of the pharmacological dose determined
from animal models and in-vitro systems using the test
substance” (a dose of drug that is 1 % of the
pharmacologically active dose, up to a maximum of 100 µg).
• Minute quantity of the drug, neither intending to produce
pharmacological response nor any toxicity, when administered
to humans provide useful pharmacokinetic data early in drug
development.

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Phase-0
• Because exploratory IND studies refer to clinical trials that are
conducted early in Phase I, such studies have been
subsequently dubbed “pre-Phase I studies” or “Phase 0 trials.”
• Phase 0 trials bridge the gap between traditional preclinical
testing and clinical studies and are intended to provide a better
understanding of a new compound’s PKs, PDs, and target
localization before initiation of Phase I trials.

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• While eligibility and profile of participants in Phase 0 and Phase
I may not necessarily be different, ethical concerns regarding
informed consent are certainly not the same due to the lack of
therapeutic intent in Phase 0 studies.
• Because Phase 0 studies use either a sub-pharmacologic dose
or a dose that produces a pharmacologic but not a toxic effect,
the risk to human subjects is far less than in Phase I to establish
maximum tolerated dose.

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PHASE 0 PHASE 1
PRIMARY GOAL:
To evaluate mechanism of action/target
modulation; asses PK?PD relationships;
optimize target assay.
PRIMARY GOAL:
To determine maximum tolerated dose
(MTD)
Involves 10-15 patients Involves 20-80 patients
No therapeutic intent No therapeutic benefit expected, but may
enable continued evaluation if there is
evidence of clinical response
Limited dosing, only to achieve target
modulation, thus less risk of toxicity
Multiple dosing and dose escalation
aimed at establishing safety and toxicity
Requires incorporation of biomarker
assays/imaging studies
Biomarkers/imaging studies not
required since less focus on PD markers

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Utility
Determination of drug pharmacokinetics
Determination of drug pharmacodynamics
Determination of pharmacologically significant
doses of drug
Accelerating new drug development
Emerging use

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Merits
• Earlier selection and evaluation of a potential new test substance
in humans reduces the time periods to Phase 1 studies
• Reduces the unnecessary exposure of the participants
• Non-potential molecules can be rejected earlier, hence saving costs
• Decreases human toxicity due to minute dose of the test substance
and shorter duration of administration/ exposure to the drug
(since they mostly involve a single dose administration as
compared to a dose escalation study in the traditional Phase 1
trials)
• Less number of human/animals are used
• Small quantity of the test drug is essential

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Demerits
• Absence of any therapeutic and/or diagnostic intent
• Motivating volunteers to become a part of the trial is difficult as
there is no therapeutic intent
• Predicting the absorption characteristics at the MD levels is
challenging since certain drugs dissolve easily at low-doses;
however, display limited solubility at higher doses,
• Unnecessarily extends the process and increases the
expenditure as Phase 1 still needs to be carried out

14. Phase I and subtype studies

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Phase I
• First stage of testing in humans.
• The primary aims of Phase 1 clinical trials are to determine the safety,
tolerability and pharmacokinetics (PK) of a compound.
• Because the FDA emphasizes “safety first,” it is logical that the first of
4 stages (known as “phases”) of a clinical trial is designed to test the
safety and maximum tolerated dose (MTD) of a drug, human
pharmacokinetics and pharmacodynamics, and drug–drug
interactions.
• These phase I trials (synonymous with “dose-escalation” or “human
pharmacology” studies) are the first instance in which the new
investigational agent is studied in humans, and are usually performed
in a small number of “healthy” volunteers.

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Phase I
The Phase I trials are generally conducted in the following
sequence:
A. Single ascending dose (SAD),
B. Multiple ascending dose (MAD),
C. Examination of preliminary effect of food on exposure, and
D. Any potential drug-drug interaction,
with assessments to determine the effect of gender, age,
bioavailability and bioequivalence performed as required.

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A. SAD
• A small group of subjects/healthy volunteers receive a single
dose of study drug while being observed and tested for a period
of time to confirm safety and characterize the PK of the study
drug, where safety and PK assessments are done for a
predefined time.

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B. MAD
• Multiple ascending dose studies investigate the
pharmacokinetics and pharmacodynamics (PK and PD) of
multiple doses of the drug, looking at safety and tolerability.

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Phase I
• The MTD, or the drug dose before a dose-limiting toxicity, can
be determined using various statistical designs.
• Dose escalation is based on very strict criteria, and subjects are
closely followed for evidence of drug toxicity over a sufficient
period.
• Single ascending dose (SAD) & multiple ascending dose (MAD)
are integral part of the Phase I trials.
• SAD and MAD help in determining how the drug is processed
within the body and how well it is tolerated by the body.

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C. Food effect
• Studies are conducted to allow a preliminary assessment of
how absorption of the compound is affected when administered
after a specifically designed and standardized test meal, usually
a high fat breakfast in the first instance.
• Such studies are usually conducted following a crossover design
such that the same subjects receive doses of the study drug on
different occasions under fasted and fed conditions.
• These studies are important as the results are likely to
contribute to the wording on the label as to when drugs should
be administered relative to food in order to increase, or indeed
decrease, exposure.

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D. Drug-drug interaction
• Clearly, the selection of drugs for drug-drug interaction studies
is based upon those for which co administration is likely for the
particular indication and target population of the compound.
• There should be a particular emphasis on monitoring for
adverse events (AEs) that occur at a greater frequency or
severity during combination treatment than during treatment
with either drug alone.

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Phase II/Exploration studies
• Phase II trials, also referred to as “therapeutic exploratory” trials,
are usually larger than phase I studies, and are conducted in a small
number of volunteers who have the disease of interest.
• They are designed to test safety, pharmacokinetics, and pharmaco-
dynamics, but may also be designed to answer questions essential to
the planning of phase III trials, including determination of optimal
doses, dose frequencies, administration routes, and endpoints.
• However, the small number of participants and primary safety
concerns within a phase II trial usually LIMIT its power to establish
efficacy, and thereby supports the necessity of a subsequent phase III
trial.

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Characteristics of Phase II trials
Participants
• Phase II trials are performed on large groups of participants
(usually around 100-500 participants). There are often more
than 30 participants per treatment group. Participants are
usually selected using strict inclusion criteria, meaning that
the study population is relatively homogenous. A
homogenous study population helps the interpretation of study
results.
Duration
• Phase II trials are typically quite short, lasting just several
weeks or months.

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Types of Phase II
• Phase II studies are sometimes divided into Phase IIA and Phase IIB.
There is no formal definition for these 2 sub-categories.
• Phase IIA studies are usually pilot studies designed to demonstrate
clinical efficacy or biological activity ('proof of concept' studies);
• Phase IIB studies look to find the optimum dose at which the drug
shows biological activity with minimal side-effects (‘definite dose-
finding’ studies).
Phase IIa
• EARLY PHASE
• Pilot (additional) clinical trials
• 20-200 PATIENTS
• Not multicentric
• SINGLE BLIND comparison with a
standard drug
Phase IIb
LATE PHASE
Pivotal (Evidence) clinical trials
50-300 PATIENTS
Multicentric
DOUBLE BLIND compared with a
placebo or standard drug

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POC studies
Exploring therapeutic efficacy: Proof of Concept
(POC) studies
• Phase II trials must show that the investigational medicinal
product treats the intended indication in a particular
patient population. This is called ‘Proof of Concept (PoC)’.
• Proof of Concept studies must clearly show clinical
improvement so that the existence of activity or ‘response’ can
be determined. The outcomes and results of these trials are
considered when making the ‘go/no-go’ decision to progress
to Phase III development of the medicine.

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Estimating dosage levels and schedules: Dose-
response studies
• Phase II trials must also gather information about the
best dosage levels and schedules. Proof of Concept is usually
tested at the maximum tolerated dose (MTD) in order to
minimize false-negative results, provide the best test
of hypothesis, and maximize the pharmacodynamic (PD) effect.

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Dose-response studies seek to:
• Discover a minimum effective dose
– The smallest dose at which an effect is observed
• Discover an optimal dose
– The dose at which the optimum (desired) effect is observed
– Mitigate the risk of the MTD not being tolerated
Typically, dose-response studies use randomized parallel group
studies looking at three or more dosage levels, one of which may
be zero (placebo).
Dose-response data are important, and must be gathered not only
from formal dose-response studies, but from all other possible
sources during previous studies of the investigational medicinal
product.

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Phase III
• Studies involve randomized and blind testing in several 100 to several 1000
patients.
• last for several years,
• Provides more thorough understand of the effectiveness of the drug or device,
the benefits and the range of possible adverse reactions.
• 70% to 90% of drugs complete this phase of testing.
• These trials compare new treatments with the best currently available treatment
(the standard treatment).
• These trials may compare :
-A completely new treatment with the standard treatment
-Different doses or ways of giving a standard treatment
-A new way of giving radiotherapy with the standard way
• Phase 3 trials usually involve many more patients than phase 1 or 2. This is
because differences in success rates may be small. So, the trial needs many
patients to be able to show the difference.

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• Phase III studies are randomized controlled multi-center trials
on large patient groups (300–3,000)
• Aim: assessment of how effective the drug is, in comparison
with current 'gold standard' treatment.
• Because of their size and comparatively long duration Phase III
trials are the most expensive, time-consuming and difficult
trials to design and run, especially in therapies for chronic
medical conditions.
• Phase III trials of chronic conditions or diseases often have a
short follow-up period for evaluation, relative to the period of
time the intervention might be used in practice called the "pre-
marketing phase“ because it actually measures consumer
response to the drug.

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Phase III studies
Subtypes
• Phase IIIA: to get sufficient and significant data.
• Phase IIIB: allows patients to continue the treatment, Label
expansion, additional safety data.
Phase III B studies are known as "label expansion” to show the
drug works for additional types of patients/diseases beyond
the original use for which the drug was approved for marketing

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New Drug Application (NDA)
• Formal proposal for the FDA/DCGI to approve a new drug for sale
• Sufficient evidences provided to FDA/DCGI to establish:
– Drug is safe and effective.
– Benefits outweigh the risks.
– Proposed labeling is appropriate.
• For decades, the regulation and control of new drugs in the United States has
been based on the New Drug Application (NDA).
• The NDA application is the vehicle through which drug sponsors formally
propose that the FDA approve a new pharmaceutical for sale and marketing
in the USA
• The data gathered during the animal studies and human clinical trials of an
Investigational New Drug (IND) become part of the NDA.

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New Drug Application (NDA)
• The goals of the NDA are to provide enough information to permit FDA reviewer
to reach the following key decisions:
– Whether the drug is safe and effective in its proposed use(s), and whether the benefits of
the drug outweigh the risks.
– Whether the drug's proposed labeling (package insert) is appropriate, and what it should
contain.
– Whether 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
(Stability studies).
• The documentation required in an NDA is supposed to tell the drug's whole
story, including
– what happened during the clinical tests,
– what the ingredients of the drug are, the results of the animal studies,
– how the drug behaves in the body, and
– how it is manufactured, processed and packaged.

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NDA Contents

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Phase IV
• A Phase IV Clinical trial is also known as Post Marketing
Surveillance Trial.
• Phase IV trials involve the safety surveillance
(Pharmacovigilance) and ongoing technical support of a drug
after it receives permission to be sold.
• Phase IV studies may be required by regulatory authorities or
by the sponsoring company for various reasons (for example,
the drug may not have been tested for interactions with other
drugs, or on certain population groups such as pregnant
women, who are unlikely to subject themselves to trials).

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• Phase IV begins after drug approval and these studies are also known
as Therapeutic use studies. Therapeutic use studies go beyond the
prior demonstration of the drug’s safety, efficacy and dose definition.
They are studies that were not considered necessary for approval but
are often important for optimising the drug's use.
• The main rationale/reason behind conducting Phase IV trials is :
– In prior clinical trials, up to Phase 3, patients are selected and
limited in number
– Conditions of use in trials differ from those in clinical practice
– Duration of trials is limited
– Information about rare but serious adverse reactions, chronic
toxicity, use in special groups (such as children, the elderly or
pregnant women) or drug interactions is often not available.

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