1. Clinical Trials - PHASE 1

2. 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.

3. 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.

4. 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.

5. PRE-CLINICAL DATA Pre-clinical evaluation gives us information on:  The approximate starting dose for Phase I human trials.  Parameters for potential adverse effects.

6. 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

7. INITIAL HUMAN DOSE A starting dose can be selected low enough to avoid unnecessary risk. Generally, first dose can be related to ED50 in pre clinical studies.

8. 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.

9. 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.

10. 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

11. 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.

12. EXPERIMENTAL DESIGN  Phase I studies are carried out in 2 stages Single rising dose Repeat administration

13. 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.

14. 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 discharge 4-10 hrs after dose.  Only after results of 1 st group analyzed, drug administered to the next group.

15. 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 days Anticonvulsants tested for 4 weeks or more  Interval between doses is usually one half life.

16. STAGE 2 REPEATED ADMINISTRATION (contd.)  Study design - Typically dose escalating studies  Kinetic data obtained from blood and urine sample collected after 1 st and last dose  ‘Trough samples’ – blood sample taken immediately prior drug administration give information about accumulation and attainment of steady state blood concentration

17. 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

18. 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.

19. Study Subjects  Healthy adult volunteers or patients  Moderately ill patients likely to benefit from the drug, can volunteer  Small number - 20 to 80

20. 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.

21. 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.

22. 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.

23. 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.