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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