Clincal Trial Phases Final

8/8/2019 Clincal Trial Phases Final

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Phases of Clinical Trials

Dr Hemant Mittal


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What are Clinical TrialsWhat are Clinical Trials

Systematic study of new drug therapy or medicalintervention

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


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On completion of pre-clinical studies,fewer useful candidate drugs.

Advance to involving testing inhumans.

Registrationof compound as aninvestigational drug.

Permission obtained for undertakingstudies in humans

Pre-clinical to human studies - the

transition


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DRUG DISCOVERY & DEVELOPMENT

Can be divided into two broad classes having

subclasses of their own1. Drug Discovery

a. Target based design

b. Compound based design

c. Lead optimization

2. Drug Developmenta. Preclinical Phase

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

dose

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


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Drug discovery Drug developmentPhase Target-based /

Compound-based

Lead

optimization

Pre-clinical

develop-ment

Phase I Phase II Phase III

DiscoveryChemistry

DiscoveryBiology

Targetidentificati

on

Assaydevelop-

ment andscreening

Animal models of disease

ADME In vitro meta-bolism

Pharmaco-kinetics(animal)

(human)

Metabolism

Drug-drug interactions

Toxicology Screening Preclinical GLPtoxico-logy

Effect on Reproduction and Embryo-fetalDevelopment,

carcinogenesis

Developmentchemistry

Medical Safetyexposure

Efficacy doseselection

Registration trials

IND NDA

SEQUENCE OF PHASES OF DRUG DISCOVERY &

DEVELOPMENT


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LIFE CYCLE OF DRUG DISCOVERY,

DEVELOPMENT & APPROVALDrug discovery(2-5 years)

Drug development

(5-9 years)

Post-approvalregulation

Chem &Biol

Compoundidentification &optimization

Biologicalcharacterization

Toxicolog

y

Toxicology

studies

Clinical INDfiled

Ph. Itrials

Ph. IItrials

Ph. III

trials

Ph. IV Ph. IV

Manufacturing

Develop manufacturing

Develop QA/QC program,GMP practices

Manufac-turingbegins

Pharmaco-vigilanceactivity/Patentexpires/Genericsavailable

Legal Patentapplication

Patent granted

E

n

dofPhas

eI

Ime

eting

ANDAfiled

NDA

file

d:Regu l

atory

Aprvlfo r

Ma

rketing


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Phases of Clinical TrialsPhases of Clinical Trials

Clinical trials divided into four phases:Phase I Safety & Early Clinical Pharmacology

Phase II Initial Efficacy & Safety

Phase IIIComprehensive Efficacy & Safety

Phase IVPost-marketing Studies

Each phase:Cumulatively exposes greater numbers of

human subjects to the drugCollects increasing amounts of safety and

efficacy data


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Human Pharmacology or Phase I

Clinical trials

Tests take about a year.

Involve about 20 to 80 normal healthy volunteers

Not included:

ChildrenWomen of child bearing age unless nature of

IND necessitates their inclusion e.g. oral

contraceptive study

Elderly


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Phase I Clinical trials

Place Special testing facilities

Monitored closely

Physician

Trained investigatorCriteria 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 appearin humans


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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.


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Determination of Maximum

Recommended Starting Dose (MRSD)

NOEL No Observed Effect Level

NOAEL No Observed Adverse EffectLevel

Preferred by FDA

HED - Human equivalent Dose

HED (mg/Kg) = animal NOAEL x

(weight animal/ weight human)1-b

b=0.67


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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


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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

foroncology drugs

Patient monitored for adverse drug reactions

Phase I Clinical trials


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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 beused in Phase II studies


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Phase I - Clinical trial

types of subjects enrolled:Normal, male volunteersPatients who are severely ill with disease

when it is unethical to expose normal volunteerto test drug

Patients with target disease who are stable andgenerally healthy to evaluate PKs or safety


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Data needed to Start efficacy

Study

Determination of primary

efficacy parameter

Clinical endpoint

Surrogate


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Clinical and Surrogate Endpoints

Indication ClinicalEndpoint

Surrogate

Hypertension Strokes

Renal damageMortality

Decrease blood

pressure

Diabetes type II Neuropathies

Nephropathies

Retinopathies

Decreased glucose

Decreased HbA1c

Osteoporosis Fractures Increased bone density


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Therapeutic exploratory trial or

Phase II Clinical TrialPre requisite pre clinical data and

phase 1 safety report

Supervised administrationRandomized study comparing new drug

with proto-type drug for the intended

disorder.


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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 healthproblems other than the intended disorder.


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Phase II Clinical trial

PurposeTo 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 crucialData used to determine whether to proceed with extensive

studies in large populations


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Phase II- Clinical trial

A. Phase II a

Pilot clinical trial

B. Phase II b

Pivotal clinical trial


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Feasibility trial

Small scale

Often un-blind and open label

Intended to provide experience to

investigator

PHASE II a

PILOT CLINICAL TRIAL


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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


OBJECTIVES


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OBJECTIVES 2

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


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Well planned, well controlled trial,

Rigorous demonstration of drug efficacy

Conducted in units with specialistinvestigators with experience of particularindication

Adequate investigational facilities to

monitor safety and efficacyDoses are usually less than the highest

doses used in phase I

PHASE II b

PIVOTAL CLINICAL TRIAL


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PHASE II b 2

Usually, only 3-4 centers are includedNormally, 10-12 patients should be

studied at each dose-level

May or may not randomizedOpen or double blinded trialPlacebo or comparator controlled

Further evaluation of safety,pharmacokinetic data


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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


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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 organizeTime consuming (several years)


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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 usedSettings are similar to that associated with the

ultimate use of the drug

Investigators usually clinical specialistsSome toxic effects (immunological) may first

become apparent in Phase III


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Phase III

Phase III may also be used to dopharmacoeconomic analysis

GCP guidelines need to be followed :

- patient group

- data collection methods

- recording information

- statistical analysis- documentation


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Phase IIIdetails

All documents (IB, protocol, CRF, etc.) needto be approved by regulator/EthicsCommittee

Clinical trial site and clinical investigatorselected, and trained on procedures

Confidentiality statement and financialagreement worked out and finalized


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Phase III

New Drug Application (NDA)

Runs in several volumes

All precilinical and clinical data on drugPriority given to drugs that represent

significant improvements over standard

available drugsIn case of urgency (eg. Anti-cancer drug)

the process may be accelerated


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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


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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


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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 bepooled, designing of CRF and other

related documents must be similar


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Phase III

Large sample size : 1000 3000

Adult males (preferably)

Both outpatients and inpatients

Disease criteria to be unifiom

Inclusion / Exclusion criteria very clearly definedat the outset


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Phase III : Statistics

Inputs from biostatisticianExpected difference in efficacy

Availability of patients

Inclusion/Exclusion Criteria

Expected ; Drop out rate, Withdrawal, Placebo

responders

Interim Analysis: if requiredStatistical Analysis


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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..)


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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


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Phase III..Monitoring

Important component of Phase III trialsTo Monitor the following:

- clinical trial supplies

- data entry in the CRF- collection of completed CRF

- collection of unused rug

- drug supplies inventory checkRegular visits to each of the clinical trial

centres


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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


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Phase III.Audit

Clinical trial audit

Both internal and external

Regulatory authorities (archiving)

Verification of CRFs with raw datasheets /case records


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Phase IV

Begins after approval to market the drug has beenobtained

Monitoring of safety of new drug under actualcondition 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


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Phase IV

Obligatory post-marketing surveillance

May result in limiting drug use or even with drawal

Phase IV has no fixed durationUnsupervised use of the drug in the community

Wider spectrum of use : viz. beyondinclusion /exclusion criteria, co-morbidities

/drugs, etc.


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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


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Phase IVWho ?

Pharmaceutical Industry

Specialty Medical Associations

Government organizations

International Agencies


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Phase IVcharacterstics

Very large sample size

No or little supervision: Physician shopping

Fewer data collected from each patient

Fewer Exclusions (Contraindications only)


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Phase IVcharactersrtics

Longer drug administrations

Expensive

Comorbidities and co-medications

Non adherence to treatment: Common

Self-medication common


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Types of Phase IV studies

Prospective studies :

- Extension of Phase III

(Longer drug treatment )

- Comparative Benefit-Risk evaluation

- Comparative Benefit-Cost evaluation


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Prospective Phase IV

- Outcome Studies: Primary End-

points used

- Promotional Trials

- Special Population Groups


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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


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Phase IVtypes (contd.)

Observational studies:

3. QOL Assessment Studies

4. Pharmacoeconomic Studies

5. Meta analysis (Statistical inputs based-Retrospective)


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Phase IVQOL assessment

Impact of the disease or drug on thequality of life of patients, specially theelderly

Patients asked about problems,expectations, improvement

Components of well being assessed :emotional, social, physical

Questionnaire used to elicit response(comprehensive method)


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Phase IV.Meta analyses

Popular in Phase IV syudies

When results of published clinical trials

are conflictingResults of similarly conducted clinical

trials are pooled and analysed

Expressed as Odds ration andConfidence Intervals


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Phase IV : ADR reporting

Spontaneous Voluntary Reporting

Case Control Studies

Intensive Hospital Monitoring

Prescription Event MonitoringLiterature Surveys

Prospective population based studies for

rare ADRsAutomated patient Data Banks


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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


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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

Documents

Clincal Trial Phases Final