2. • Phases of Clinical Trial
– Phase 0
– Phase I
– Phase II
– Phase III
– Phase IV
Agenda
3. • Phase 0
• Phase I
• Phase II
• Phase III
• Phase IV
Phases of Clinical Trial
4. • Also known as Human Microdosing studies, Pre-phase 1 trial or a "proof-of-concept"
trial.
• This are done to speed up the drug development process
• Aim to gather preliminary PK and PD parameters of the drug (what the drug does to
the body and what the body does to the drug).
• A small sub-therapeutic dose (1/100th of therapeutic dose) is administered to a small
numbers of the subjects (i.e. 10-15 healthy volunteers)for minimal durations of less
than seven days.
• Phase 0 study gives no data on safety or efficacy of the drug, since the dose is too low
to cause any therapeutic effect.
• These are not mandatory
Phase 0
5. • Also known as Human Pharmacology or Clinical Pharmacology studies.
• This is 1st in Human studies.
• The objective of studies in this phase is the estimation of safety and tolerability
with the initial administration of an investigational new drug into humans.
• Conducted in 20-80 healthy volunteers
• There are some circumstances when clinical patients are used, such as patients
who have cancer or HIV and the treatment is likely to make healthy individuals
ill.
• Drugs with significant potential toxicity e.g. cytotoxic drugs are usually studied
in patients.
Phase I
6. • Phase I trial should preferably be carried out by investigators trained in clinical pharmacology with access to
the necessary facilities to closely observe and monitor the subjects.
• These studies are usually conducted in tightly controlled clinics called CPUs (Central Pharmacological
Units), where participants receive 24-hour medical attention and oversight.
• Objectives of Phase I trial
(a) Maximum tolerated dose: To determine the tolerability of the dose range expected to be needed for later
clinical studies and to determine the nature of adverse reactions that can be expected. These studies include
both single and multiple dose administration.
(b) Pharmacokinetics, i.e., characterisation of a drug's absorption, distribution, metabolism and excretion:
Although these studies continue throughout the development plan, they should be performed to support
formulation development and determine pharmacokinetic parameters in different age groups to support dosing
recommendations (What body does to the drug.)
• ADME –Absorption, Distribution, Metabolism and Excretion
• Cmax – Peak concentration of drug in blood
7. • Tmax – Time to achieve peak concentration.
• Elimination half life – Time taken to eliminate half of the drug from the body
(c) Pharmacodynamics: Depending on the drug and the endpoints studied, pharmacodynamic studies and studies
relating to drug blood levels (pharmacokinetic or pharmacodynamic studies) may be conducted in healthy
volunteer subjects or in patients with the target disease. If there are appropriate validated indicators of activity
and potential efficacy, pharmacodynamic data obtained from patients may guide the dosage and dose regimen to
be applied in later studies (What drug does to the body)
(d) Safety evaluation of the drug : The drug’s side effects are documented through physical exams, blood tests
and other medical tests.
(e) Route of administration
8. Single Ascending Dose (SAD):
Single ascending dose studies are usually conducted in a small number of healthy volunteers . The aim is
to find out the safe dose range, and to look for any side effects. The initial dose given will be very small
and increased gradually (in a new group of volunteers) if no or only mild side effects are seen.
Researchers will also take measurements to determine how the medicine is processed in the body.
Multiple Ascending Dose (MAD):
A group of subjects receives multiple low doses of the drug, while blood (and other fluids) are
collected at various time points and analyzed to understand how the drug is processed within the
body. Multiple Ascending Dose studies are intended to fully characterize the pharmacokinetics of a
drug and its metabolites at steady state, investigate a drug’s accumulation potential, explore its dose
proportionality, and determine the Maximum Tolerated Dose (MTD).
Types of Phase I study
9. • Subjects in a MAD study receive multiple doses of the study drug, whereas subjects in a SAD study
receive only one dose of the study drug.
• Phase I clinical trials each last several months to a year.
10. • Also known as Therapeutic Exploratory Study.
• Conducted in 100-300 patients.
• Main objective is to determine
(i) The primary objective of Phase II trials is to evaluate the effectiveness of a drug for a
particular indication or indications in patients with the condition under study and to
determine the common short-term side-effects and risks associated with the drug.
(ii)An important goal for this phase is to determine the dose and regimen for Phase III
trials.
Doses used in Phase II are usually (but not always) less than the highest doses used in
Phase I.
Phase II
11. • (ii) Additional objectives of Phase II studies can include evaluation of potential study endpoints, therapeutic
regimens (including concomitant medications) and target populations (e.g. mild versus severe disease) for
further studies in Phase II or III.
Endpoint - an event or outcome that can be measured objectively to determine whether the intervention
being studied is beneficial. The endpoints of a clinical trial are usually included in the study objectives.
12. Phase II a study:
Phase 2a is focused specifically on dosing requirements. A group of patients is
administered the drug in various quanitites to investigate dosage and optimal
frequency of doses.
Phase II b study:
Phase 2b trials are designed specifically to rigorously test the efficacy of the drug
in terms of how successful it is in treating, preventing or diagnosing a disease.
• Duration of Phase II study – Several months to 2 years
Types of Phase II study
13. • Also known as Therapeutic Confirmatory Trials
• Conducted in large number of patients (300 –3000)
• Most expensive and time consuming.
• Objectives:
(a) Phase III studies have primary objective of demonstration or confirmation of therapeutic
benefits. Studies in Phase III are designed to confirm the preliminary evidence accumulated in
Phase II that a drug is safe and effective for use in the intended indication and recipient
population.
(b)To check how effective the drug is in comparison to the gold standard treatment.
The gold standard is the term used in medicine for the test (imaging, blood test, biopsy,
etc.) that is felt to be the current best for diagnosis of a particular condition.
Phase III
14. (c) These studies should be intended to provide an adequate basis for marketing approval.
(d) Studies in Phase III may also further explore the dose-response relationships (relationships among
dose, drug concentration in blood and clinical response), use of the drug in wider populations, in
different stages of disease, or the safety and efficacy of the drug in combination with other drugs.
• Due to the larger number of participants and longer duration or phase III, rare and long-term side
effects are more likely to show up during this phase.
• Duration of study : 1-4 years
15. Phase III a study:
Testing safety & efficacy of the drug in comparison to the gold standard treatment.
Phase III b study:
Phase 3b Clinical Trial means a human clinical trial of a product that is
initiated after the NDA is filed, but before such product obtains Regulatory
Approval, the goal of which trial is to provide additional data for marketing
support and the launch of such product.
Types of Phase III study
16. • Also known as Post Marketing surveillance.
• Conducted after marketing of the drug
• Conducted in large number of patients (1000-3000)
• In a phase 4 trial, any rare or long-term effects of the drug can be observed in a
much larger population of patients and over a much longer period of time.
• If safety surveillance does indeed reveal concerns about the drug, it may be
withdrawn from the market and no longer made available on prescription.
Phase IV
