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
PILOT CLINICAL TRIAL
OBJECTIVES
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PILOT CLINICAL TRIAL
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