CLINICAL REVIEW

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

         
Pre clinical study

         
Clinical research à IND

         
Marketing à NDA 

Drug discovery process

Process for successful molecule

1. Phase 1 – 5-10,000 Molecule

2. Phase 2 – 250 Molecule

3. Phase 3 – 5 Molecule

4. NDA

5. 1 Molecule

6. Marketing 

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

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.

         
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

         
Dose Ranging

 

         
Safety

         
Efficacy

         
Dose

         
Route

         
Efficacy vs. standard

         
Defined endpoints

 

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.

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.

S.No

Phases

No of
People

Population
Group

Safety/Efficacy

Goal

1

Phase I

20-100

Healthy Individuals

Safety

  • 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

  • ,Safety
    Studies

2

Phase II

100-500

Diseased
Individuals

Safety
and efficacy

  • 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 strength and schedules for using the drug.

3

Phase III

1000-5000

Diseased
Individuals

Safety
and efficacy and benefit-risk relationship

  • This
    phase of research is key in determining whether the drug is safe and
    effective.                                                                

  • It
    also provides the basis for labeling instructions to help ensure proper
    use of the drug (e.g., information on potential interactions with other
    medicines).

4

Phase IV

>5000

Real Life
Population

Ongoing monitoring
of safety of drug

  • These
    trials can be set up to evaluate long-term safety or how the new
    medicine affects a specific subgroup of patients.

 

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