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 IIAis specifically designed to assess dosing requirements (how much drug should be given).

•          Phase IIBis 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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