Phase-IV Clinical trialsPhase-IV Clinical trials

Dr.Pratibha Nadig.M.D.

Assoc.Professor

ICRI,Bangalore

Phase IV Clinical trialsPhase IV Clinical trials

• Studies performed after marketing of the pharmaceutical product.

• Other than the routine surveillance studies

Phase IV Clinical trialsPhase IV Clinical trials

• Carried out on the basis of product characteristics on which marketing authorization was granted.

• Required by the licencing authorities for optimising the drug use

Phase-IV trialsPhase-IV trials

• Objectives of the trial

• The pre-requisites

• Ethical guidelines

• Regulatory requirements • Conduct of the trial

Phase-IV trialsPhase-IV trials

• Clinical trial design

• Types of studies

• Outcome

• Limitations

ObjectivesObjectives

Conform the efficacy and safety Conform the efficacy and safety profile in large populations during profile in large populations during practice practice

Detect the unknown adverse drug Detect the unknown adverse drug reaction/sreaction/s

Evaluation of over-dosage and Evaluation of over-dosage and

treatmentstreatments

Identifications of new indicationsIdentifications of new indications

ObjectivesObjectives

Evaluation of new formulations, Evaluation of new formulations, dosages, durations of treatmentdosages, durations of treatment

Evaluation of different age groups Evaluation of different age groups and other types of patientsand other types of patients

Cost effectiveness Cost effectiveness

PharmacoeconomicsPharmacoeconomics

Prerequisites Prerequisites

• NDA approval NDA approval

• Ethical approval for Ethical approval for

selected studiesselected studies

Ethical considerationsEthical considerations

IRB approval & IC are required • if the study requires follow ups and investigations which are not

routinely carried out• in case of drugs which could lead to

potential inconvenience or harm• in cases of new formulations,new

dosage forms, newer indications and fixed dose combinations

Drivers of Phase IV studiesDrivers of Phase IV studies

• Commercial

• Academic • Regulatory PMC,

• Efficacy

• Safety

Regulatory requirementsRegulatory requirements

• SAFETY

e.g: yellow card system in UK

• NEW INDICATIONS

Change of licence

• OTC from POM

Registrations for change in the class

Conduct of the trialConduct of the trial

• Post authorisation studies,post marketing studies,post licencing studies.

• Site: Clinics and hospitals

• Players Principal investigators-General practitioners

and Specialists Participants patients-2000-10000+

Clinical trial designClinical trial design

• OBSERVATIONAL STUDIES

• Cohort studies- Prospective uncontrolled or controlled studies

• Case- control studies- Retrospective

Types Phase-IVTypes Phase-IV

• Pharmacovigilance

• Pharmacoeconomics

• Pharmacoepidemiology-Seeding studies

• Comparative studies

• Studies for new indications,dosage and formulations

PhamacovigilancePhamacovigilance

• Monitoring medicines to determine unrecognised adverse effects or changes in the patterns of their adverse effects– yellow cards, signals from clinical trials

• Continuously assessing the risks and benefits of medicines, taking action if necessary to improve their safe use– restricting use of a drug, withdrawing a drug

PharmacovigilancePharmacovigilance

Techniques • Voluntary reporting

• Prescription event monitoring

• Medical record linkage:

• Population statistics

Quality of life studiesQuality of life studies

Conducted for :• Physical

• Social

• Psychological parameters

Eg: Captopril,Methyldopa, Propranolol in hypertension

Pharmacoeconomic studiesPharmacoeconomic studies

• Application of economic theory to drug usage

• Comparison of cost- effectiveness of two drug therapies

Eg: ondansetron and metaclopramide in the prevention of acute emesis

Seeding studiesSeeding studies

• Uncontrolled cohort studies

• Questionnaire based study conducted by the marketing department

• Large number of doctors required

• Aim –to change the prescribing pattern of the physician

Comparative studiesComparative studies

• Comparisons in the same therapeutic area but different chemical class,e.g.Enalapril and Propranolol

• Same class Nifedipine and Amlodipine

• Added beneficial end points over the existing e.g: enalapril - left ventricular hypertrophy

• Different patient population Nitrendipine in elderly patients for stroke

New IndicationsNew Indications

• Aspirin as anti-platelet agent

• Metformin in polycystic ovarian disease

• Propranolol in migraine

New dosage formsNew dosage forms

• E.g.Sustained release forms of Diclofenac

New formulationsNew formulations

• Change in fluorocarbons as propellants in metered dose inhalers

Change of status PMOs to Change of status PMOs to OTCsOTCs

• E.g.Paracetamol

• Extensive safety data to be generated

Outcome of Phase-IVOutcome of Phase-IV

• Safety profile; Signals of adverse reaction

• Confirm the efficacy and comparisons in overall tolerability and QOL

• Efficacy in larger population for a longer time

• Generalisation

Outcome of Phase-IVOutcome of Phase-IV

• Newer indications for existing drugs

• Newer formulations

• New dosage forms

• Arrival at the best treatment for the patient population

Thank youThank you