Clinical Trials - PHASE 1

WHAT ARE PHASE I TRIALS ?

Phase I trials refer to the first introduction of an experimental drug into the human population.

Subjects are usually healthy male adult volunteers.

WHY PHASE I TRIALS?

The primary concern - assessment of the drug’s safety and safe effective dose for further phase studies

To determine what happens to the drugs in the human body.

To determine the dosage level of the drug.

To evaluate how a new drug should be administered.

Side effects of the drug.

Problems Most problems associated with this

phase are related to the direct pharmacodynamic effect, i.e inter species differences.

E.g. Penicillin oral produces toxic GI bleed in Guinea pigs but it is well tolerated in man.

There are certain types of drug activities which are seen only in man.

E.g. changes in mood, arousal, sleep etc.

PRE-CLINICAL DATA

Pre-clinical evaluation gives us information on:

The approximate starting dose for Phase I human trials.

Parameters for potential adverse effects.

DOSE IN PHASE I

NOEL No Observed Effect Level NOAEL No Observed Adverse Effect

Level MRSD Maximum Recommended Starting

Dose MRDD Maximum Recommended Daily

Dose

INITIAL HUMAN DOSEA starting dose can be selected low enough to avoid unnecessary risk.

Generally, first dose can be related to ED50 in pre clinical studies.

STUDY SITE

Should have a well equipped Clinical Pharmacology Unit.

Be able to conduct tests such as that of blood/plasma etc.

Medical experts should be around. Should be well equipped to handle

emergencies or any such eventualities.

REGULATORY ASPECTS

Under the directives of the Drugs and Cosmetics Rules, phase I trials are not normally permitted for foreign companies and is usually reserved for the new drug substance discover in India.

The 2005 amendment of the Schedule-Y of the Drugs and Cosmetics Rules made parallel trials possible in India.

DRUGS UNDERGOING PHASE I TRIALS AT PRESENT ARE: Praneem, a neem based poly-herbal

microbicide being developed by Pune based NARI is in the phase I stage.

HIV Vaccine (tgAAC09) is now undergoing phase I trials for safety and immunogenicity assessment in healthy HIV uninfected volunteers at NARI, Pune.

Gropep is presently carrying out a phase I trial of its infertility drug- PV903

STUDY TEAM DESIGN

The team designing a clinical study must possess a comprehensive understanding of

Medical consideration Regulatory requirements

Therefore, involvement of regulatory affairs group is important and fundamental to the principles of good clinical project management.

EXPERIMENTAL DESIGN

Phase I studies are carried out in 2 stages

Single rising doseRepeat

administration

STAGE 1–SINGLE RISING DOSE

Each volunteer given a single dose of drug/placebo.

Dose-escalating study design. Initial dose and route of administration

decided from existing pre-clinical data. 8 -12 volunteers admitted after

meticulous screening. 2-4 volunteers receive placebo and 6-8

volunteers receive drug under study.

STAGE 1-SINGLE RISING DOSE Study subjects admitted in an inpatient

clinic, observed by full time medical staff.

Test and examination done:Prior to start of drug administration At interval during the study (e.g. 2h, 4h,

8h, 16h )Before discharge4-10 hrs after dose.

Only after results of 1st group analyzed, drug administered to the next group.

STAGE 2 REPEATED ADMINISTRATION

Start after single dose administration results assessed.

Drug / placebo given repeatedly for 1 or more weeks

E. g. Antibiotics given for 5-7 daysAnticonvulsants tested for 4 weeks or

more Interval between doses is usually one

half life.

STAGE 2 REPEATED ADMINISTRATION (contd.)

Study design - Typically dose escalating studies

Kinetic data obtained from blood and urine sample collected after 1st and last dose

‘Trough samples’ – blood sample taken immediately prior drug administration give information about accumulation and attainment of steady state blood concentration

Requirements

All documents of pre-clinical data Plans, protocols and CRF ’s for phase I

studies. Name, address and bio-data of investigator. Agreement from the sponsors to inform the

drug controller of any AR’s occurring during ongoing animal/human studies.

Nature of ‘informed consent’ Agreement to submit annual progress report

FEES

Regulatory fees payable to the DCGI’ s office for reviewing submitted documents.

Rs. 50,000/- for phase I studies. Application to be submitted to the

Drugs Controller General (India) office at Nirman Bhavan.

Fees to be paid in a Nationalized bank in government account.

Study Subjects

Healthy adult volunteers or patients

Moderately ill patients likely to benefit from the drug, can volunteer

Small number - 20 to 80

DOSE INCREMENT

First 3-4 patients based on on-going experience in tolerability.

Increase can be 1.5 or 2 times the previous dose depending on -

Pharmacodynamic effects of the previous dose.

Margin between projected therapeutic dose.

Theoretical max human tolerated dose.

ADVERSE EFFECTS

Appearance of a SAE major challenge in new drug testing.

If investigational drug responsible for AE, subsequent administration to be prevented.

Significant AE-subject withdrawn from further dosing.

Assessment of data and expert consultation done to decide-role of drug in AE and study continuation.

ADVERSE DRUG REACTIONS

Serious toxicity is rare and needs judgment for proceeding

Interpretation of clinical and lab deviations from normal range.

Within- subject comparison of data is mandatory.

DATA RECORDING AND STORAGE

Accurate record of each experiment mandatory for scientific purpose, statutory and other review requirements.

Mode and time of entries should be standardized for future interpretation.

Data should be available in duplicate/triplicate and store at 2/3 different places to avoid accidental loss.