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CLINICAL REVIEW
Content
• Fundamentals of clinical research

• Different phases of clinical trials

Objective
After completion of this lecture, student will be able to:

• To know about the fundamentals of clinical research

• To know the different phases of clinical trials

• To study each phase of clinical trial in detail

Drug Discovery and Development

Drug discovery process

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Process for successful molecule

Pre-clinical studies
Once the drug is designed it have to be tested

In vitro [in laboratory conditions-glass wares

• Generates Pharmacodynamic data

• Gives an understanding on pharmacological action of drug, mechanism of action of drug,Mutagenicity

In vivo [in animals (rodents and non-rodents, lab models)]

• Generates Pharmacokinetic, Pharmacodynamic and toxicokinetic data

• Gives an understanding of dose, dose range, side effects, drug receptor binding capabilities,

Importance of pharmacokinetic studies

• Research and selection of a promising molecules

• Formulation

• Dosage

• Toxicology and safety assessment

• Dosing recommendation for age groups and subgroup population

• Effect of meals and dosing

Investigational new drug application (INDA)

• Sponsors

• IND

• FDA

• To initiate the conduct of clinical trials

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Contents of INDA
• Table of content

• Cover Letter

• Introductory Statement and General Investigational Plan

• Investigator’s Brochure

• Clinical Protocol

• Chemistry Manufacturing and Controls Information

• Pharmacology and Toxicology Information

• Previous Human Experience

• Additional Information

Clinical Trials
• Phase I:- Studies in normal healthy volunteers to understand pharmacokinetics

• Phase II: Dose ranging efficacy safety studies to determine the optimal dose for a particular indication

• Phase III: Large scale multicentre comparative studies to assess efficacy safety of the study drug v/s currently
accepted treatment.

• Phase IV: Post Marketing Studies.

Clinical Trial – Phase I

• Done in 20-100 subjects.

• Usually healthy volunteers

• To understand the metabolic and pharmacological action of drug

• Maximum Test Dose determination,etc

• Provide information of pharmacology effects of drug.

• Safety is the major aspect of study.

Types of phase I trial:

SAD (Single Ascending Dose) studies

• Small l group of people receives single dose.

• Adverse Event –Nil, Escalation of dose

• Continued till intolerable side effects start showing

MAD (Multiple Ascending Dose) studies

• In these studies, a group of patients receives multiple low doses of the drug

• The dose is subsequently escalated for further groups, up to a predetermined level.

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• Continued till intolerable side effects start showing.

Clinical Trial – Phase II

• Rigid and well-controlled

• Small population between 100 - 300.

• Double blind studies using placebo or standard treatment are done.

• Efficacy and safety are evaluated.

• Pharmacokinetic and other pharmacological studies are done.

Types of phase II studies

• Phase IIA is specifically designed to assess dosing requirements (how much drug should be given).

• Phase IIB is specifically designed to study efficacy (how well the drug works at the prescribed dose(s)).

Clinical Trial – Phase III

• Done in a large population- above 300

• Evaluation of efficacy and safety profile (initial risk benefit assessment)

• Identification of the disease sub types for which drug is effective.

• Comparison with other standard drugs.

• Pharmacokinetics with others drugs and Quality of life (depends) are evaluated.

Types of phase III

• Done while the New Drug Application (NDA) is submitted to FDA

• Studies which start pre-launch but which are not intended to form part of Regulatory dossier are referred to as
Phase III-b

• The data of this study also submitted to FDA

Difference between phase I, II and III trials

phase I phase II phase III
• Safety • Safety • Efficacy vs. standard
• Dose Ranging • Efficacy • Defined endpoints
• Dose
• Route

New Drug Application (NDA)

The formal request to be allowed to market a drug.

Sponsor submit NDA to FDA after phase III trials are competed.

Have to submit everything that is known about the drug to date, all protocols, and case report forms.

Regulation for NDA are found in 21 CFR 314.

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Clinical Trial – Phase IV

• Done after the approval of FDA.

• To gather the additional information of safety and efficacy drug.

• Studies conducted to look at the compound in comparison with other marketed products.

• To familiarize physicians with the compound.

No of
S.No Phases People Population Group Safety/Efficacy Goal

• The main goal of a Phase 1 trial is to

discover if the drug is safe in humans.
Researchers look at the
pharmacokinetics
of a drug. How is it absorbed? How is it
metabolized and eliminated
from the body?

• They also study the drug’s

Pharmacodynamic: Does it
cause side effects? Does it produce
desired effects?

• Dose ranging studies

1 Phase I 20-100 Healthy Individuals Safety • ,Safety Studies

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• In Phase 2 trials researchers evaluate

the candidate drug’s effectiveness
Examine the possible short-term side
effects (adverse events) and risks
associated with the drug.

• Researchers also analyze optimal dose

Phase Safety and strength and schedules for using the
2 II 100-500 Diseased Individuals efficacy drug.

• This phase of research is key in

determining whether the drug is safe
and effective.

• It also provides the basis for labeling

Safety and instructions to help ensure proper use
efficacy and of the drug (e.g., information on
Phase 1000- benefit-risk potential interactions with other
3 III 5000 Diseased Individuals relationship medicines).

• These trials can be set up to evaluate

Ongoing long-term safety or how the new
Phase monitoring of medicine affects a specific subgroup of
4 IV >5000 Real Life Population safety of drug patients.

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