Clinical Trials

CLINICAL TRIALS
LATHA ELANGOVAN
OVERVIEW
• Introduction: Clinical research
• Drug development phases
• Pre-phases 1 activities
• Phases of Clinical trials
• Regulatory approvals: IND & NDA
• Summary of Clinical trial phases
INTRODUCTION
• Clinical trials is a systematic investigation in
human subjects for evaluating the safety &
efficacy of any new drug.
• Clinical trials are a set of tests in medical
research and drug development that generate
safety and efficacy data for the health
interventions in human beings.
INTRODUCTION
• Clinical trials are conducted only when
Satisfactory information has been gathered on the quality
of the non clinical safety. Health authority/ethical committee
approval is granted in the country where approval of the drug
is sought.
• Clinical Trial is the mainstay for bringing out
New Drugs to the Market.
DRUG REVIEW STEPS
1. Preclinical (animal) testing
2. An investigational new drug application(IND)
3. Phase 1 studies
4. Phase 2 studies
5. Phase 3 studies
6. Submission of New drug application NDA is the formal step
asking the FDA to consider a drug for marketing approval.
7. FDA reviewers will approve the application or find it either
“approvable” or “not approvable”.
8. Phase 4 studies
DRUG REVIEW
• Before one can initiate testing in human beings, extensive pre-
clinical or laboratory research is required.
• Research usually involves years of experiments in animal and
human cells.
• If this stage of testing is successful, the sponser then provides
thus data to the FDA requesting approval to begin testing in
humans. This is called an INVESTIGATIONAL NEW DRUG (IND)
APPLICATION.
• If approved by the FDA, testing in human beings. This is done
through a formally written and approved protocol.
PHASE (ANIMAL STUDIES)
Major areas are:
• Pharmacodynamics studies In vivo in animals,
In vitro preparation
• Absorption, distribution, elimination studies
(Pharmacokinetics)
• Acute, sub acute, chronic toxicity
studies(toxicity profiles)
• Therapeutic index (safety &efficacy
evaluation)
IND APPLICATION FILLING
• Once preclinical studies have indicated the safety and efficacy
of a drug an IND application has to be filed with the
regulatory authorities.
• For obtaining regulatory Approval for Phase I, Phase II and
Phase III clinical evaluation.
• Contents of IND application:
Preclinical Data (All data from animal studies)
Information on composition and source of drug
Chemical and manufacturing information
Proposed clinical plans and protocol
Ethical committee clearance
PHASE 0 STUDY/MICRODOSING
• Study of new drug doses to derive PK information in human
before undertaking phase 1 studies is called PHASE 0.
• MICRO DOSE: Less than 1/100of the dose of a test substance

calculated to produce pharmacological effect with a max dose
less than 100 micrograms.
• OBJECTIVE: To obtain preliminary pharmacokinetic data.
• PRECLINICAL DATA: Sub acute toxicity study in one species by

two routes of administration.
PHASE 0 STUDY/MICRODOSING
ADVANTAGES:
 Less chances of adverse events
 Short duration
 Less No. of volunteers
 Reduced drug development time
LIMITATIONS:
 Study based on PK parameters-not efficacy and safety based
 The laboratory parameters are limited and expensive
 Agents having different kinetic characteristics b/w micro dose
and full dose are not evaluated by phase 0 trials
PHASE 1
• First stage of testing in human subjects.
• Designed to assess the safety, tolerability, PK and PD of drug.
• Patients: Anticancer drugs, AIDS therapy.
• 20-25 healthy volunteers; Duration 6-12 months.
• The aim of the phase 1 trial is to determine the maximum
tolerated dose MTD of the new treatment.
• Kind of phase 1:
SAD: Single ascending dose studies
MAD: Multiple ascending dose studies
FOOD EFFECT: Investigates differences in absorption
caused by food.
PHASE 1
SUBJECTS:
• Healthy human volunteers: commonly used
• Patient volunteers: Cytotoxic drugs, AIDS therapy
LIMITATIONS:
• Trail restricted to homogenous subjects
• Performance extrapolated to heterogeneous market place
PHASE 2
• It is a Therapeutic exploratory trail consists of 20-300 subjects.

• To confirm effectiveness, monitor side effects, & further
evaluate safety.
• First in patients (who have the disease that the drug is
expected to treat).
• Duration: 6 months to several years.
• Optimum dose finding:
Dose efficacy relationship
Therapeutic dose regimen
Duration of therapy
Frequency of administration
Thearpeutic window
PHASE 2
• For new actions of a marketed drug, start with
Phase 2 (phase 1 exemption obtained).
• Phase 2 study types:
• Phase 2 a: Designed to assess dosing
requirements.
• Phase2 b: Designed to study efficacy.
PHASE 3
• It is a THERAPEUTIC CONFIRMATORY TRIAL.
• Target population: several 100’s to 3000 patients.
• Duration: Takes a long time, up to 5 years.
• To establish efficacy of the drug against existing
therapy in larger number of patients, method of
usage, & to collect safety data etc.
• To assess overall and relative therapeutic value
of the new drug efficacy, safety and special
properties.
PHASE 3
• SUBTYPES:
Phase 3 A: To get sufficient and significant data.
Phase 3B: allows patients to continue the
treatment, label expansion, additional safety
data.
Phase 3B studies are known as “label expansion”
to show the drug works for additional types of
patients/diseases beyond the original use for
which the drug was approved for marketing.
PHASE 3:END OF CLINICAL TRIAL ACTIVITIES
• Sponsor: Expert committee review of Efficacy,
Safety and potential sales(profit).
• Go-No-Go decision to file new drug
application with DCGI.
• Expert review by DCGI’s committee
• DCGI approval.
• NCE marketed – phase 4 begins.
NDA: New Drug Application
• NDA refers to New Drug Application.
• Formal proposal for the FDA/DCGI to approve a new
drug for sale.
• Sufficient evidences provided to FDA/DCGI to
establish.
Drug is safe and effective.
Benefits outweigh the risks.
Proposed labeling is appropriate.
PHASE 4
• Post marketing surveillance (PMS)
• No fixed duration/ patient population
• Helps to delete rare ADR’s, Drug interactions and also to
explore new uses for drugs (sometimes called phase 5).
PERIODIC SAFETY UPDATE REPORTS:
To be submitted by the manufacturing every 6 months for 2
years and then usually for next 2 years after marketing approval.
• Harmful effects discovered may result in a drug being no
longer sold, or restricted to certain uses.
OBJECTIVES OF PHASE 4:
• Confirm the efficacy and safety profile in large populations
during practice.
• Detect the unknown/rare adverse drug reactions.
• Evaluation of over-dosage.
• Dose refinement: Evaluation of new formulations, dosages,
durations of treatment.
REPORTING OF ADR:
The ADR can be reported to a formal reporting system such as
WHO International system
USFDA –Medwatch
UK- Yellow card system
INDIA- National Pharmacovigilance Programme (CDSCO)
CONCLUSION
• Clinical trial is a human experiment designed to study the
efficacy and safety of a new drug/intervention.
• Involves phase 1-4 with specific objectives and end results.
• Application to Regulatory authority:
IND- Permission to conduct CT
NDA- Permission to Market new drug
• Well designed and effectively executed clinical trials form the
base of therapeutic decisions.
• CT must follow guidelines & protocol to ensure well being of
participants.

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CLINICAL TRIALS

• MICRO DOSE: Less than 1/100of the dose of a test substance

• OBJECTIVE: To obtain preliminary pharmacokinetic data.

• PRECLINICAL DATA: Sub acute toxicity study in one species by

• It is a Therapeutic exploratory trail consists of 20-300 subjects.

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