1. Phases in Clinical Trial

2. CLINICAL RESEARCH Drug Discovery Drug Development
Preclinical/ Non Clinical/Animal Studies
Clinical Trials
Phase I
Phase II
Phase III
Phase IV

3. Dr Deepti Sanghavi

4. PHASES IN CLINICAL RESEARCH
PHASE II
III A
III B IV
Pre-
marketing
Post –Marketing
NDA
IND
Marketing

5. CLINICAL TRIALS
Any investigation in human subjects intended to discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy

6. PHASES OF CLINICAL TRIALS
PHASE-I HUMAN PHARMACOLOGY
PHASE-II THERAPEUTIC EXPLORATORY
PHASE-III THERAPEUTIC CONFIRMATORY
PHASE-IV POST-MARKETING STUDIES

7. PHASE I STUDIES HUMAN / CLINICAL PHARMACOLOGY STUDIES

8. TRANSITION
Animal studies
Human studies
Single most important event

9. WHAT IS A PHASE I TRIAL? “First in human” study
Show promise in animal studies
Find the ‘best dose’ in humans
Small number of subjects (20-80)

10. PHASE-I PREREQUISITES
PRE-CLINICAL STUDIES COMPLETED
SINGLE DOSE TOXICITY STUDIES
REPEATED DOSE TOXICITY STUDIES
LOCAL TOLERANCE STUDIES
MUTAGENICITY STUDIES(INVITRO)
CARCINOGENICITY STUDIES
SELECTION OF DOSE

11. PHASE-I OBJECTIVES SAFETY & TOLERABILITY PHARMACOKINETICS
MAXIMUM TOLERATED DOSE
SAFE DOSE
NATURE OF EXPECTED A.D.R
PHARMACOKINETICS
T ½, ADME
PHARMACODYNAMICS- MOA
MEASUREMENT OF DRUG ACTIVITY- Dose Response

12. CLINICAL TRIAL PROCESS
SUBJECTS
INVESTIGATOR
SITE
ETHICS COMMITTEE
PROTOCOL
INFORMED CONSENT

13. WHO CONDUCTS ?
Usually a clinical pharmacologist Medical specialist Should have thorough knowledge of: -Medical conditions -Regulatory requirements

14. Where are Phase I studies carried out?
Clinical pharmacology unit- well equipped with facilities
Inpatient stay
To monitor all physiological functions and signs
To take care of any eventualities, A.D.R
Have facilities for processing blood/plasma
( Lab Inv)
Have facilities for estimation of drug levels in biological fluids

15. STUDY DESIGN
Depends on – Objectives Time frame Available resources Usually not blind, open study Number of volunteers < 100 Conducted in 1 or 2 centers simultaneously

16. SUBJECTS Consenting healthy subjects (not for anticancer drugs)
Subjects of either sex (unless for gender specific agents)
Females? – Occasionally, but in non child bearing age groups
Adults subjects only (unless the drug is for pediatric population only)
Less number

17. Subjects enrolled: ‘Normal subjects’
W.H.O. defines normal subject as
‘ A person who is free from any abnormality that would complicate interpretation of data or increase the sensitivity of the subject to toxic potential of a drug.’

18. Patients – Special circumstances:
Drug is too toxic Toxicity is known Unethical to expose a volunteer Stable patients otherwise healthy Antiepileptics- Kinetics Antiarrythmics- Safety Severely ill patients with disease to be treated – Cancer, HIV

19. PROCEDURE Subject recruitment Informed consent Screening
Recording baseline parameters
Drug administration
Blood sampling
Recording post treatment parameters

20. PROCEDURE Analysis of biological samples (blood) for drug levels
Data Collection
Data Analysis
Statistical analysis
Report Generation

21. MONITORING Volunteer admitted:
Continuous Monitoring- to decide dose adjustment and discontinuation of study due to A.D.R.
Symptoms
Physical examination and Vital signs
Laboratory & clinical investigations
Blood sampling / urine collection for pharmacokinetic data

22. INITIAL DOSE
A million dollar question!!

23. INTUTION AND EXPERIENCE
INITIAL DOSE
ED50 of most sensitive animal species
LD50 /MTD50
1/10 to 1/5 of maximum tolerated dose
1/10 of projected human dose
1/25 to 1/100 of NOAEL
1/3 to 1/10 of LD10
Available PK data in animals
INTUTION AND EXPERIENCE

24. Phase I Trial Designs
Single rising doses, dose-escalating studies, Single ascending dose (SAD)
Multiple Ascending dose (MAD) Repeated administration
Doses of the drug are given for tested time. If they don’t exhibit any adverse effects, the dose is escalated and groups are given a higher dose. This is continued until intolerable side effects start showing up ( at which point the drug is said to have reached MTD- Maximum Tolerated Dose)

25. Maximum Tolerable Dose [MTD]
MTD determination is many a times a objective of phase I trials
The MTD is that dose which exhibits acceptable and predictable toxicity
The MTD will be recommended as the starting dose for subsequent phase II trials

26. Phase I Trial Designs
Food Effect- A short trial is designed to investigate any differences in absorption caused by eating and its effect in PK profile.
These studies are usually cross over study, with volunteers given two identical doses of the drug on different occasions; one while fasted and one after being fed.

27. Adverse effects
Serious adverse event is a major challenge Investigational drug responsible–prevent subsequent adm. Other causes to be ruled out Significant A.E. – subject withdrawn from the study Decide role of drug and whether study to be contd.

28. Design issues in Phase I
? Can the drug be given to humans
? Volunteers or patients
? The starting dose
? Dose escalation procedure
? The maximum dose
? Number of subjects
? Study design

29. Phase- I studies: Outcome
Around 30% of NMEs fail in Phase I clinical testing despite extensive pre-clinical screening of potential candidates
Safety, inappropriate ADME properties, unsuitable PK
The best model for Man, is Man.

30. Regulatory aspects
Phase I trials of drugs discovered elsewhere cannot be done in India
Drug should have cleared Phase I elsewhere before the trial is undertaken in India.
Simultaneous Phase I trials are not yet permitted, but following Phase I abroad the study may be repeated in India.

31. Ethical issues in phase I studies
Phase I studies: examine potential toxicities and define safe dosing ranges (maximum tolerated dose)
Subject selection fair (where inclusion criteria stipulate that only health volunteers will be recruited)
Appropriate compensation for participation
Risks appropriate given potential “benefits”
Expectations of subject harm/discomfort near study completion

32. Suggestions for phase I studies
Patient-subjects need to understand that the purpose of a phase I study is to define drug toxicities and establish maximum tolerated dosages.
Patient-subjects need to be told that the probability of positive response is very low and significant improvement is unlikely.
Patient-subjects need to be told about plans to escalate doses until toxicities are observed.
Patient-subjects should be made aware of therapeutic options that may be available to them, including palliative care for patients with life-threatening conditions.

33. Phase II Trials

34. PHASE II TRIALS Therapeutic exploratory trials
First trials in patients with the diseases to be treated.
To evaluate drug in a particular indication
Common short term side effects and risks with I.N.D.
To determine dosage regimen for phase III trials

35. PLAYERS IN PHASE-II PARTICIPANTS(50-300) PLACE PHYSICIAN PATIENTS
SPECIALISED HOSPITAL UNITS
CLOSELY MONITORED
PHYSICIAN
TRAINED INVESTIGATORS

36. PHASE-II COMPONENTS PHASE-II A PHASE-II B OPEN UNCONTROLLED TRIAL
SMALL NUMBER OF PATIENTS
DETERMINES DOSE RANGES
PHASE-II B
PLACEBO CONTROLLED, DOUBLE BLIND.
DETERMINES CLINICAL DOSAGE SCHEDULE
ESTABLISH INCIDENCE OF BENEFICIAL AND UNDESIRABLE EFFECTS

37. Phase III Trials

38. PHASE III TRIALS Confirmatory Multi-centric trials
For preventive or therapeutic effects
In large number of patients
The Pharma Company should be seeking to assess real outcome in a variety of patients approximating to “real life” population of patients who will receive the drug once it will be launched.

39. CLINICAL TRIAL DESIGN PROSPECTIVE RANDOMISED MULTICENTRIC
CONTROLLED OR UNCONTROLLED TRIALS
IIIa Trials carried out on a large number-or in a special category e.g. patients with renal failure
IIIb Extended trials of IIIa after applying for approval but before launch

40. Randomized Clinical Trials (RCTs)
Placebo Control
  Compares one or more active treatments to a dosage form not containing an active treatment
e.g. Ibuprofen and lactose
Active Treatment 
Compares two or more treatments each with different ingredients
e.g. Ibuprofen and Diclofenac
Historical Control
Compares observations in a current study with a previously conducted, similar study

41. Randomized Clinical Trials (RCTs)
No Treatment Control
Compares two groups, only one of which receives treatment
e.g. For pain one receives No drug and one receives Ibuprofen
Dose -Comparison Concurrent Control
Compares different dose regimens of same treatment
E.g. 200 mg or 400 mg of Ibuprofen for pain

42. Outcome Confirmation of efficacy in a more realistic population
Efficacy in special population
Tolerability and safety
Advantages/disadvantages over standard treatment

43. Ethical issues in phase III studies
Phase III: more definitive studies of both safety and efficacy done in a controlled manner
Subject understandings of “randomization” and “placebo”
Choice of controls (e.g., placebo vs. active control; psychiatry)
Existence of clinical equipoise (would most physicians have a preference for one treatment arm over the others?)
Subject monitoring (e.g., for SAEs across multiple sites)
Data monitoring (for early assessments of study viability, possibility of early termination, loss of clinical equipoise, etc.)
Inclusion of women, children, and underrepresented minorities (benefits of research distributed equitably)

44. Phase IV TRIALS AND PMS

45. PHASE IV TRIALS: WHY?
Studies required as a condition of approval by FDA.
Additional efficacy / safety profile
New comparisons
New dosage schedules, treatment duration,drug /food interaction
New formulations
Different age groups, races, patient subgroups
New Indications (become Phase II / III) 45

46. Categories of Phase IV Clinical Trials
Pharmacovigilance, Post marketing surveillance study (PMS)
Comparative studies
Studies for new indications, dosage and formulations
Marketing oriented including seeding trials

47. PHASE IV CLINICAL TRIALS
Pharmacoepidemiology and Pharmacoeconomics
VI. Quality of Life studies
VII. Investigating interaction with other
drugs

48. POST MARKETING SURVEILLANCE (PMS)
Adverse effects detected by Phase IV trials may result in the withdrawal of a drug
Thalidomide- used in Morning sickness but withdrawn as a result of Phocomelia.
Cerivastatin was used to reduce cholestrol but withdrawn from market as it caused rhabdomylosis
Troglitazone used as antidiabetic drug but caused drug induced hepatitis
Rofecoxib (Vioxx) used to treat Osteoarthritis and acute pain was withdrawn as it caused adverse cardiovascular events
PMS is a phase IV study
Primarily observational or non-experimental in nature

49. Difference between Phase I-III and Phase IV – Marketing oriented studies
Item Ph I-III study Ph-IV-Mk. Oriented
Medical Environment Clinic or Hospital Medical practice
Patient Population Restricted Un-restricted
No. of patients Few Many
Investigator Research Oriented Practice Oriented
Protocol Fixed Flexible
Concomitant therapy Uncommon Common
Patient evaluation as objective as less detailed fewer
possible objective tests
Design of trial Formal structure Less formal
often double blind Usually open
Sponsor’s goal Evaluation of Obtaining data for
efficacy & safety promotional purposes

50. PMS : WHAT DOES IT ACHIEVE?
Expose larger number of patients to confirm the efficacy and safety of the drug.
Evaluate the drug in different patient population, children, pregnant women, nursing mother, elderly patients, immuno suppressed patients.
Elicits rare but potentially serious reactions.
Elicits long-term safety.
Elicits drug interactions. 50

51. Post marketing study designs
Cross- sectional studies
Eg - Survey or prevalence studies
Case controlled studies / Retrospective
Eg - To investigate whether there is an association between a drug
Cohort studies / Prospective
Eg - to know the incidence rates

52. Ethical issues in phase IV studies
Phase IV: post-approval studies (marketing studies, safety, efficacy, comparative efficacy, etc.)
Shifting epistemic standards prior to drug approval
Post-approval “commitment studies”
Little incentive to follow through
Reimbursement for research procedures
Payment for research or treatment
Blurring of research and therapy
Marketing masquerading as research

53. Clinical Trials - Phases
Ongoing
Hundreds-thousands
Subjects with indications
New indications,
QoL, surveillance IV
2-3 yrs
Safety & efficacy
Basis for labeling,
new formulations
III
1-2 yrs
Several hundred
Short-term side
effects & efficacy II
6-12 mos
20-80
Healthy volunteers or subj. w/ indications
Safety, ADME, bioactivity,
drug-drug interaction I
Length
(per phase)
Scope
Subjects
Purpose
Phase
Define ADME
21 CFR

54. Phases

55. THANK YOU -PHARMA STREET