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Clinical trials phase-i-ii-trials
- 1. Conducting Phase I& II Studies 1
- 2. 2 Phase IVPhase IIIPhaseIIbPhase IIa Clinical Trials Phase 1 Pre- clinical Phase Candidate Profiling Phase Discovery Phase Drug Development Frame Life Cycle Management Full Development Early Development Research Candidate SelectionPoint CSP sPoC DDP FDP 3CP SDP Selectedfor ProofofConcept Development DecisionPoint Full DevelopmentPoint PhaseIII Checkpoint Submission DecisionPoint IND – Investigational New Drug NDA – New Drug Application
- 3. Clinical Trial Fourphases: ◦ Phase I ◦ Phase II ◦ Phase III ◦ PMS /Phase IV 3
- 4. Pre-clinical to clinicalstudies - the transition On completion of pre-clinical studies, number of lead compounds whittled down to many fewer useful candidate drugs. Some then advanced to clinical development stage, involving testing in humans. Data on Pre-clinical studies must be submitted to regulatory authorities for registration of compound as an investigational drug. Permission from regulatory authorities then obtained for undertaking studies in humans 4
- 5. Objectives for First-In-Man studies 5 Oneof the most exciting times in drug development process Pharmacodynamic Activity Pharmacokinetic Characterization General Pharmacology Toxicologic Profile Favorable pharmacodynamics Toxicity Ratio Toxicity –Not serious Measurable, Reversible NO Develop for all patient classes Acceptable to administration to normal volunteers or patients YES Develop only for patient with life-threatening diseases
- 6. Phase I Clinicaltrials Tests take about a year. Involve about 20 to 80 normal healthy volunteers aged 18 to 45 years May also be conducted in severely ill patients (e.g. cancer patients) or in patients in whom the illness is stabilized (e.g. to evaluate metabolism of a new drug in Stable epileptic patients in whom liver enzymes have been induced by other anti-epileptic drugs) Not included: ◦ Children ◦ Women of child –bearing age – unless nature of IND necessitates their inclusion e.g. oral contraceptive study ◦ Elderly 6
- 7. Phase I Clinicaltrials Criteria for selection of volunteers needs to be carefully laid down in protocol & strictly adhered to. To document : ◦ Dose level at which signs of toxicity first appear in humans ◦ Determine a safe tolerated dose ◦ Attempt made to establish dose range tolerated by volunteers for single and multiple doses Pharmacokinetic trials – regardless of when they are conducted during the development of the drug 7
- 8. Phase I ClinicalTrials Single or multiple doses. Dose range and route of administration established. Pharmacokinetic data. Pharmacodynamic data. Maximum tolerated dose. Other parameters as necessary. 8
- 9. Phase I Clinicaltrials End point of these studies is toxicity ◦ Informed consent, a prerequisite ◦ Participants need to be closely supervised by medical personnel and have access to emergency facilities Protocol that describes the conditions and personnel involved in the clinical study needs to be submitted to regulatory authorities before initiation of Phase I study. 9
- 10. Start withlow 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 for oncology drugs Patient monitored for adverse drug reactions 10 Phase I Clinical trials
- 11. Use of PK/PDin Phase I studies In Phase I studies: PK/PD is important in : ◦ Understanding dose–concentration–effect (pharmacological and toxicological)- relationship - ◦ Characterization of PK & PD in special populations ◦ Probing effect of Drug-drug and drug– disease interaction ◦ Initial determination of dosing regimens to be used in Phase II studies 11
- 12. Phase I Studies Four major types of subjects enrolled: ◦ Normal, male volunteers ◦ Patients who are severely ill with disease –when it is unethical to expose normal volunteer to test drug ◦ Patients with target disease who are stable and generally healthy – to evaluate PKs or safety ◦ Surrogate patients who are severely ill, but do not have targeted disease may be evaluated e.g. patients with AIDS who do not have P carinii pneumonia may be enrolled to test a new anti-PCP drug in Phase I 12
- 13. Phase I Studies Four major reasons for enrolling patients rather than volunteers in Phase I Studies: ◦ Ethical- when test drug is too toxic ◦ Regulatory- some authorities e.g. Germany prohibit enrollment of volunteers in Phase I studies ◦ Pharmacokinetics- when patients are known or suspected to have altered metabolism or absorption ◦ Scientific or Medical interest 13
- 14. Phase I Clinicaltrials Types of clinical trials conducted: ◦ Single-dose tolerance trial in volunteers /patients who are exposed to a single dose of the drug ◦ Multiple –dose trial in volunteers or patients- lasts for 3 to 28 days –subjects receive a fixed –dose of drug although dose-titration is sometimes permitted ◦ Evaluation of the PK parameters after multiple doses 14
- 15. Phase I Clinicaltrials Types of clinical trials conducted: ◦ Increasing dose range of a IND to define the upper limit of safety or to ensure safety when lower dose have failed to demonstrate activity ◦ Interaction of the drugs with food or other investigations in normal volunteers. 15
- 16. Phase I ClinicalTrials Types of clinical trials conducted: ◦ Concentrations followed after a single intravenous dose to measure PK parameters. ◦ Evaluation of the distribution, metabolism & elimination in normal volunteers using radioactive or other methods ◦ Bioequivalence trials to compare two or more formulations 16
- 17. Phase II ClinicalTrial Begin after satisfactory preliminary evidence of safety has been obtained. Involve supervised administration of the drug to about 80 to 100 patients for Rx or prophylaxis against the disorder for which the drug is intended. Usually randomized study comparing new drug with proto-type drug for the intended disorder. Provide first opportunity to observe the effect of long-term administration of the drug to humans. Ideally participants should have no health problems other than the intended disorder. 17
- 18. Phase II Clinicaltrial Purpose ◦ To determine an optimal dose – response range for the new drug ◦ To verify its efficacy for the intended disorders Participants also monitored for adverse effects ◦ Population is large; hence greater chances of detecting additional adverse effects Phase crucial ◦ Data used to determine whether to proceed with extensive studies in large populations 18
- 19. Phase II- Clinicaltrial Types: ◦ Phase IIa ◦ Phase IIb 19
- 20. Phase IIa ClinicalTrials Types of clinical trials conducted: ◦ Pilot trial (or trials) of test drug in patients; may be either an open-label or single-or double-blind manner ◦ Pilot trial (or trials) of test drug in normal volunteers challenged to determine the efficacy of drug (e.g. citric acid may be used to produce cough) 20
- 21. Phase IIa ClinicalTrials Types of clinical trials conducted ◦ Dose-response trial in patients to identify the range of active doses ◦ Trials evaluating variations in dose level or dosing schedule 21
- 22. Phase IIa ClinicalTrials Types of clinical trials conducted: ◦ Duration of dosing required to achieve a sufficient magnitude of efficacy ◦ Dose-interval trial evaluating the time between doses 22
- 23. Phase I &II Studies –An Overview 23 First in Man Safety and tolerability of drug, including safe dose range Pharmacokinetics and duration of action PHASE I PHASE II Proof of concept Dose Ranging Safety / PKs in special populations and Risk factors
- 24. Phase Test groupPurpose Duration Phase I 10 - 100 healthy volunteers To establish basic safety and blood levels achieved with different doses of the drug 1.5 years Phase IIa & IIb 50 to 500 people who have the disorder being studied To establish the drug’s effectiveness and dosage range, to determine drug kinetics, and to identify side effects 2 years 24 Overview of Phase I and Phase II trials
- 25.