CLINICAL TRIAL S

CLINICAL TRIALS
(synonyms: clinical studies, research protocols, medical research is the application of scientific method to human health). Observational studies are those in which individuals are observed and their outcomes are measured by the investigators (e.g., natural experiment). Clinical trials are only a small part of the research that goes into developing a new treatment. Conducted to allow safety and efficacy data to be collected for new drugs or devices. These trials can only take place once satisfactory information has been gathered on the quality of the product and its nonclinical safety, and Health Authority/Ethics Committee approval is granted in the country where the trial is taking place.

Overview
In planning a clinical trial, the sponsor or investigator

first identifies the medication or device to be tested.

Usually, one or more pilot experiments are conducted

to gain insights for design of the clinical trial to follow.
In coordination with a panel of expert investigators the sponsor
decides what to compare the new agent with and what kind of patients might benefit from the medication/device In coordination with a panel of expert investigators the sponsor decides what to compare the new agent with and what kind of patients might benefit from the medication.

Types The U.S. National Institutes of Health (NIH) organizes trials into five (5) different types:
Prevention trials: look for better ways to prevent disease in people

who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vitamins, vaccines, minerals, or lifestyle changes. Screening trials: test the best way to detect certain diseases or health conditions. Diagnostic trials: conducted to find better tests or procedures for diagnosing a particular disease or condition. Treatment trials: test experimental treatments, new combinations of drugs, or new approaches to surgery or radiation therapy. Quality of life trials: explore ways to improve comfort and the quality of life for individuals with a chronic illness. Compassionate use trials: provide experimental therapeutics prior to final FDA approval to patients whose options with other remedies have been unsuccessful. Usually, case by case approval must be granted by the FDA for such exceptions.

Design
A fundamental distinction in evidence-based medicine is

between observational studies and randomize controlled trials.

Types of observational studies in epidemiology such as the

cohort study and the case-control study provide less compelling evidence than the randomized controlled trial. In observational studies, the investigators only observe associations (correlations) between the treatments experienced by participants and their health status or diseases.
provide the most compelling evidence that the study treatment causes the expected effect on human health.

A randomized controlled trial is the study design that can

Currently, some Phase II and most Phase III drug trials are

designed as randomized, double blind, and placebo-controlled.

Clinical trial protocol

clinical trial protocol is a document used to gain confirmation

of the trial design by a panel of experts and adherence by all study investigators, even if conducted in various countries. The protocol describes the scientific rationale, objective(s), design, methodology, statistical considerations, and organization of the planned trial. The protocol contains a precise study plan for executing the clinical trial, not only to assure safety and health of the trial subjects, but also to provide an exact template for trial conduct by investigators at multiple locations (in a "multicenter" trial) to perform the study in exactly the same way. This harmonization allows data to be combined collectively as though all investigators were working closely together.

Phases
Clinical trials involving new drugs are commonly classified into four

phases.- Phase I,II,III and IV

Each phase of the drug approval process is treated as a separate

clinical trial.
The drug-development process will normally proceed through all

four phases over many years

. If the drug successfully passes through Phases I, II, and III, it will

usually be approved by the national regulatory authority for use in the general population.
Phase IV are 'post-approval' studies. Before pharmaceutical companies start clinical trials on a drug, they

conduct extensive pre-clinical studies.

Pre-clinical studies
Pre-clinical studies involve in vitro (test tube) and in

vivo (animal) experiments using wide-ranging doses of the study drug to obtain preliminary efficacy, toxicity and pharmacokinetic information
Such

tests assist pharmaceutical companies to

decide whether a drug candidate has scientific merit

for further development as an investigational new

drug.

Pre-Clinical Research
Animal pharmacology/toxicology testing Is it safe

to proceed to human trials? (The Nuremberg Code)

Approximately 2-3 yrs development 20-30 substances Minimum FDA requirements: pharmacological profile Determine acute toxicity in at least 2 species of animals Conduct short-term toxicity studies (2 wks 3 mos)

Investigational New Drug Application (IND)

Documentation that allows investigational clinical testing of a new medicine Must be filed with FDA before drug administered to humans Studies may begin within 30 days of application..if no response from the FDA An IND contains the following sections

Table of contents - Protocols for each planned study Introduction - Investigator Investigators Brochure - Facilities and IRB General investigational plan - Manufacturing and control Previous human experience - Additional information Pharmacology & toxicology

Clinical Trials
IND filed first

3-5 years
Process:
Clinical Trials - Phase I Phase III On-going Biological tests (safety) On-going formulation work

Phase 0
Phase 0 is a recent designation for exploratory, first-in-human trials

conducted in accordance with the U.S. Food and Drug Administrations (FDA) 2006 Guidance on Exploratory Investigational New Drug (IND) Studies.
Phase 0 trials are also known as human microdosing studies and are

designed to speed up the development of promising drugs or imaging agents by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies.

Phase

trials

include

the

administration

of

single

subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacokinetics (how the body processes the drug) and pharmacodynamics (how the drug works in the body).

Phases of Clinical Trials

What are Clinical Trials

Systematic study of new drug therapy or medical

intervention Performed in humans To discover or verify:

Pharmacodynamics (how it works) Pharmacokinetics (what happens to it) Therapeutic effects (efficacy) Adverse reactions (safety)

Form the basis of changing current medical practice

Pre-clinical to human studies - the transition

On completion of pre-clinical

studies, fewer useful candidate drugs. Advance to involving testing in humans. Registration of compound as an investigational drug. Permission obtained for undertaking studies in humans

DRUG DISCOVERY & DEVELOPMENT

Can be divided into two broad classes having subclasses of their own
1.

Drug Discovery
a. b. c.

Target based design Compound based design Lead optimization

Preclinical Phase

2.

Drug Development
a.

Pharmacokinetics in animals Pharmacodynamics in animals (Animal models of diseases) GLP Toxicology and Safety studies, Calculation of 1st Human dose

b.

Clinical Phase

Phase I Clinical Trials Phase II Clinical Trials Phase III Clinical Trials Phase IV Studies/Trials

SEQUENCE OF PHASES OF DRUG DISCOVERY & DEVELOPMENT

Drug discovery
Phase Target-based / Compound-based Lead optimization

Drug development
Preclinical development Phase I Phase II Phase III

Discovery Chemistry Discovery Biology Target identific ation Assay development and screening In vitro metabolism Screening Animal disease models of

ADME

Pharmacokinetics (animal) Preclinical GLP toxicology

(human)

Metabolism Drug-drug interactions

Toxicology

Effect on Reproduction and Embryo-fetal Development, carcinogenesis

Development chemistry

Medical

Safety exposure

Efficacy dose selection

Registration trials

IND

NDA

LIFE CYCLE OF DRUG DISCOVERY, DEVELOPMENT & APPROVAL

Drug discovery (2-5 years) Chem & Biol Toxicol ogy Clinical Drug development (5-9 years) Postapproval regulation

End of Phase II meeting

Toxicology studies IND filed Ph. I trials Ph. II trials

Ph. III trials Manufacturing begins

NDA filed: Regulatory Aprvl for Marketing ANDA filed

Ph. IV

Compound Biological identification & characterization optimization

Ph. IV

Manufa cturing Legal Patent application

Develop manufacturing Develop QA/QC program, GMP practices Patent granted

Pharmacovigilance activity/ Patent expires/ Generics available

Phases of Clinical Trials

Clinical trials divided into four phases:
Phase I Safety & Early Clinical Pharmacology Phase II Initial Efficacy & Safety Phase III Comprehensive Efficacy & Safety Phase IV Post-marketing Studies

Each phase:
Cumulatively exposes greater numbers of human

subjects to the drug Collects increasing amounts of safety and efficacy data

Clinical Trials - Phases

Phase Purpose
Safety, ADME, bioactivity, drug-drug interaction

Length Scope

Subjects
Healthy volunteers or subj. w/ indications Subjects with indications Subjects with indications

(per phas e)
6-12 mos

20-80

II III

Short-term side effects & efficacy

Safety & efficacy Basis for labeling, new formulations

Several hundred Hundredsthousands

1-2 yrs

2-3 yrs

IV

New indications, QoL, surveillance

Subjects with indications

Hundredsthousands
21 CFR 312.21

1-5 yrs

Human Pharmacology or Phase I Clinical trials

Tests take about a year.

Involve about 20 to 80 normal healthy

volunteers Not included:

Children
Women of child bearing age unless nature of

IND necessitates their inclusion e.g. oral contraceptive study Elderly

Phase I Clinical trials

Place Special testing facilities Monitored closely Physician Trained investigator Criteria for selection of volunteers needs to be carefully laid down in protocol & strictly adhered to. To document : Determine a safe tolerated dose Dose level at which signs of toxicity first

appear in humans

Phase I Clinical Trials

Single or multiple doses. Dose range and route of administration

established.
Pharmacokinetic data.
Pharmacodynamic data.

Maximum tolerated dose.

Other parameters as necessary.

Determination of Maximum Recommended Starting Dose (MRSD)

NOEL No Observed Effect Level

NOAEL No Observed Adverse Effect

Level o Preferred by FDA HED - Human equivalent Dose

HED (mg/Kg) = animal NOAEL x

(weight animal/ weight human)1-b

b=0.67

Maximum Recommended Starting Dose (MRSD)

Margin of safety = HED x safety factor

(=10)
Differences in toxicity in animals Unexpected toxicities Interspecies difference in ADME

Differences in receptor densities or affinities

MRSD

Phase I Clinical trials

Start with low dose Fraction of the clean or no-effect

dose observed in toxicologic studies Unwritten rule is dose should be 1/25 to 1/100 of the no effect dose in mg/kg. or (1/3 to 1/5 that which is lethal to 10% of the animals(LD10) expressed as mg/m2 for oncology drugs Patient monitored for adverse drug reactions

Use of PK/PD in early Clinical Development

In Phase I studies: PK/PD is important in :
Understanding doseconcentrationeffect

(pharmacological and toxicological)-relationship Initial determination of dosing regimens to be used in Phase II studies

Phase I - Clinical trial

types of subjects enrolled:
Normal, male volunteers Patients who are severely ill with disease when

it is unethical to expose normal volunteer to test drug Patients with target disease who are stable and generally healthy to evaluate PKs or safety

Data needed to Start efficacy Study

Determination

of

primary

efficacy

parameter

Clinical endpoint

Surrogate

Clinical and Surrogate Endpoints

Indication Hypertension Clinical Endpoint Strokes Renal damage Mortality Surrogate Decrease blood pressure

Diabetes type II Neuropathies Nephropathies Retinopathies

Osteoporosis Fractures

Decreased glucose Decreased HbA1c

Increased bone density

Therapeutic exploratory trial or Phase II Clinical Trial

Pre requisite pre clinical data and phase 1 safety

report Supervised administration Randomized study comparing new drug with prototype drug for the intended disorder.

Therapeutic exploratory trial or Phase II Clinical Trial

First opportunity to observe the effect of long-term

administration of the drug to humans.

Participants should have no health problems other

than the intended disorder.

Phase II Clinical trial

Purpose To determine an optimal dose response range for

the new drug To verify its efficacy for the intended disorders Participants also monitored for adverse effects Phase crucial
Data used to determine whether to proceed with extensive

studies in large populations

Phase II- Clinical trial

A. Phase II a
Pilot clinical trial

B. Phase II b
Pivotal clinical trial

PHASE II a PILOT CLINICAL TRIAL

Feasibility trial

Small scale
Often un-blind and open label Intended to provide experience to investigator

PILOT CLINICAL TRIAL OBJECTIVES

To confirm that trial medicine, procedure are safe, suitable, and operational. Dose range of new drug Initial efficacy evaluation of a new drug, or for new indication Determine the duration required

PILOT CLINICAL TRIAL OBJECTIVES

Evaluation of variables related to clinical pharmacology Estimation of required sample size For evaluation of methodology Determination of availability of patient Exploration of ethical questions

PHASE II b PIVOTAL CLINICAL TRIAL

Well planned, well controlled trial, Rigorous demonstration of drug efficacy Conducted in units with specialist investigators

with experience of particular indication Adequate investigational facilities to monitor safety and efficacy Doses are usually less than the highest doses used in phase I

PHASE II b
Usually, only 3-4 centers are

included Normally, 10-12 patients should be studied at each dose-level May or may not randomized Open or double blinded trial Placebo or comparator controlled Further evaluation of safety, pharmacokinetic data

Therapeutic confirmatory trial or Phase III trials

Confirmatory phase

Trials are done to obtain sufficient

evidence about efficacy and safety Conducted in larger number of patients In comparison with standard drug/placebo

Phase III
After Phase II studies are completed

Decision of the sponsor to go ahead

Drug

evaluted in much larger group of patients (1000 3000) Randomized, Double blind studies Comparing new drugs with alternatives Extremely costly Difficult to organize Time consuming (several years)

Phase III
Using data of phase I and II, phase III trials

are designed to minimize errors in placebo effects, variable disease course, etc. Double blind, cross over design commonly used Settings are similar to that associated with the ultimate use of the drug Investigators usually clinical specialists Some toxic effects (immunological) may first become apparent in Phase III

Phase III
Phase

III may also be pharmacoeconomic analysis

used

to

do

GCP guidelines need to be followed :

- patient group - data collection methods - recording information - statistical analysis - documentation

Phase IIIdetails
All documents (IB, protocol, CRF, etc.) need to be

approved by regulator/Ethics Committee

Clinical trial site and clinical investigator selected,

and trained on procedures

Confidentiality statement and financial agreement

worked out and finalized

Phase III
At the end of Phase III, or if results meet

expectations, drug submitted to regulatory authority for licencing The dossier needed is a massive . Detailed compilationof all preclinical and clinical data obtained Evaluation by the regulatory authority may take a year or more Aspects of submission may have to be clarified 66 % of submissions gain marketing approval

Phase III
New Drug Application (NDA)

Runs in several volumes

All precilinical and clinical data on drug Priority given to drugs that represent significant

improvements over standard available drugs In case of urgency (eg. Anti-cancer drug) the process may be accelerated

Phase III : objectives

To test the comparative safety, efficacy and

special properties (if any) of new drug with reference to the old drug/placebo To determine dosage schedule ( it should as close as possible to the clinical use) Interests of regulator and sponsor Data obtained very component of NDA application

Phase III studies

Clinical Trial Co-ordinator From Clinical Research Unit of Sponsor Authorized for all clinical trial related activities,

viz : - Organization - Management - Financial aspects - Study report

Phase III ..requirements

Randomized, Controlled trials (RCT)

Gold Standard in clinical research

Parallel or Crossover design Investigators meeting : to decide and

ensure

uniformity As multicentric study and data has to be pooled, designing of CRF and other related documents must be similar

Phase III
Large sample size : 1000 3000 Adult males (preferably) Both outpatients and inpatients Disease criteria to be unifiom

Inclusion / Exclusion criteria very clearly defined

at the outset

Phase III : Statistics

Inputs from biostatistician
Expected difference in efficacy Availability of patients Inclusion/Exclusion Criteria Expected ; Drop out rate, Withdrawal, Placebo

responders
Interim Analysis: if required Statistical Analysis

Phase III.Controls
Placebo or standard drug

Placebo : as per regulatory guidelines

Standard drug :

- Registration status - Current therapeutic status - PK PD information - General marketing inputs (prescriptions..)

Phase IIIEfficacy
Changes in subjective and objective parameters End points :

- Dynamic (primary and surrogate) - Kinetic - Biochemical - Histological

To determine which endpoints are important with

reference to the objective of the study

Phase IIIADRs
Assessment of untoward effects

Common ADRs from symptoms, lab reports, ECG

etc. Sometimes eliciting information required Observe : Type, Severity, Duration, Causality Report ADR to : Sponsor, Ethics Committee, Regulator

Phase III..Monitoring
Important component of Phase III trials To Monitor the following:

- clinical trial supplies - data entry in the CRF - collection of completed CRF - collection of unused rug - drug supplies inventory check Regular visits to each of the clinical trial centres

Phase IIItermination
Rescheduling of treatment of trial patients Collection of CRFs, randomization codes, unused

rug
Storing of CRFs, hospital records, raw data sheets Responsibility of clinical trial monitor

Phase III.Audit
Clinical trial audit Both internal and external Regulatory authorities (archiving) Verification of CRFs with raw data sheets /case

records

Phase IV
Begins after approval to market the drug has

been obtained Monitoring of safety of new drug under actual condition of use in large numbers Careful and complete reporting of toxicity Detect ADR incidences of 1 : 10,000 Also after chronic dosing Many drugs withdrawn from market during this phase

Phase IV
Obligatory post-marketing surveillance May result in limiting drug use or even with

drawal Phase IV has no fixed duration Unsupervised use of the drug in the community Wider spectrum of use : viz. beyond inclusion /exclusion criteria, co-morbidities /drugs, etc.

Phase IV Objectives
Comparative Benefit-Risk assessment

Drug usage in the community

Quality Of Life assessment Dose-refinement Rare ADRs and long term safety Benefit-Cost assessment (Pharmaco-economics) Improvement in Primary End-points of disease

Phase IVWho ?
Pharmaceutical Industry Specialty Medical Associations Government organizations International Agencies

Phase IVcharacterstics
Very large sample size No or little supervision: Physician shopping

Fewer data collected from each patient

Fewer Exclusions (Contraindications only)

Phase IVcharactersrtics
Longer drug administrations Expensive

Comorbidities and co-medications

Non adherence to treatment: Common Self-medication common

Types of Phase IV studies

Prospective studies : - Extension of Phase III (Longer drug treatment )

- Comparative Benefit-Risk evaluation

- Comparative Benefit-Cost evaluation

Prospective Phase IV
Outcome Studies: Primary Endpoints used
Promotional Trials Special Population Groups

Phase IV studiesTypes
Observational studies 1. Monitoring Log-term Safety
Prospective and Retrospective

2. Drug Utilization Studies - Prescribed and Consumption trends - Impact of National Drug Regulatory Practices or Treatment - Guidelines on drug usage

Phase IVtypes (contd.)

Observational studies:
3. QOL Assessment Studies

4. Pharmacoeconomic Studies
5. Meta analysis (Statistical inputs basedRetrospective)

Phase IVQOL assessment

Impact of the disease or drug on the quality of life

of patients, specially the elderly Patients asked about problems, expectations, improvement Components of well being assessed : emotional, social, physical Questionnaire used to elicit response (comprehensive method)

Phase IV.Meta analyses

Popular in Phase IV syudies When

results of published clinical trials are conflicting Results of similarly conducted clinical trials are pooled and analysed Expressed as Odds ration and Confidence Intervals

Phase IV : ADR reporting

Spontaneous Voluntary Reporting Case Control Studies Intensive Hospital Monitoring Prescription Event Monitoring Literature Surveys

Prospective population based studies for rare

ADRs Automated patient Data Banks

Pharmacovigilance
The science and activities related to ADR

monitoring National Pharmacovigilance Programme National, Zonal, Regional and Peripheral PVig Centres in India UMC is the international regulatory body Well structured PVig programme essential for rational drug use

Summary
Clinical trials are a must for new drug

development Phase III and IV studies are very crucial Phase III : focus of sponsor is speedy delivery to the market Phase IV : focus is to assess result of widespread, unsupervised use in the population