My presentation gives an overview of salient features of fundamentals of clinical trials Phases 0 to 3 before NDA for marketing approval.

1. Clinical TrialPhase 0-3
Dr. Shakeeb Dhorajiwala,
JR II,
TNMC, Mumbai.
10-09-
2020
1

2. Historical Aspects
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850 BC –The First Clinical Trial? The Book of Daniel in Bible
Surgeon Ambroise Par´ e - boiled oil vs. mixture of egg yolks, oil
of roses & turpentine - over soldiers’ wounds
1753- James Lind: citrus fruits cure scurvy

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1863 – Gull & Sutton - used placebo
treatment in rheumatic fever patients
1865 – Claude Bernard – used the word
‘control’
1923 – 1st use of randomization –
Fisher & Mac Kenzie (agricultural field
experiments)
1924 – randomization 1st used in trial
by Dr. Amberson - sanocrysin in
treatment of pulmonary tuberculosis
1927- Fergusson- Blinding

4. General Aspects Of A
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5. Clinical Trial
Def: Prospective study comparing the effect and value of
intervention(s) against a control in human beings.
The ideal clinical trial is one that is randomized and
double-blind
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6. Drug Development Process
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7. Where does it fit?
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8. Phase 0
Micro dosing
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9. Phase 0 (Micro dosing)
• “A microdose is defined as < 1/100th of the dose of a test
substance calculated (based on animal data) to yield a
pharmacologic effect with a max. dose of < 100 micrograms
(for imaging agents, the latter criterion applies).” (FDA)
• First-in-human trial
• Administration - single sub therapeutic dose.
• Small no. of healthy human subjects (10 to 15)
• Preliminary data of pharmacokinetics (PKs) in humans
obviating the need for such study in animals and carried out
before conducting toxicity studies in animal.
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10. • Based on the principle of:
‘The best models for humans are humans’
• Fundamental concept of Micro-dosing :-
Under conditions of PK dose proportionality,
- PK data obtained at lower doses can be used to predict PK
at higher doses.
- Small dose, pharmacological effect - not intended , so
adverse reaction - unlikely
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11. Bioanalytical Methods
Methods Used:
• Accelerator Mass Spectrometry (AMS)
• Nuclear Magnetic Resonance (NMR) Spectroscopy
• Positron Emission Tomography (PET)
• Liquid Chromatography-Tandem-Mass
• Spectrometry (LC/MS)
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12. Application Of Micro-dosing
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13. Advantages of Micro dosing
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• Micro dose so low - risk of AE too small, Hence
animal testing substantially reduced. .
• Gives an estimation of therapeutic dose in human.
• Preclinical animal data less predictive due to : species
difference, unavailability of suitable animal models,
metabolic differences
• no prediction of racial or individual diff. in PK.
• Conventional phase I - US $1.5- 5 million.
• Microdosing - US $ 0.3-0.5million
Impact on financial aspect:

14. COMPARISON OF MICRODOSING
& PHASE I APPROACH
Features Microdosing strategy Phase I -Conventional
Approach
Time from preclinical to
first in man studies
6-8 months 12-18 months
Cost of early phase of
drug development
US $ 0.3-0.5 million US $ 1.5-5.0 million
Amount of drug required < 100 micrograms About 100 mg
Special requirements 14C labelled Compound,
if using AMS
None required
Regulatory requirements Very few and limited
GLP to be followed for
synthesis
Established firmly GMP
to be followed for
synthesis
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15. Phase I
Human Pharmacology
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16. Phase I: Human pharmacology
Initial introduction of IND into man
• Main objectives :-
• Safety & tolerability
• Dose finding
• Design:-
• Single ascending dose (SAD)
• Multiple ascending dose (MAD)
• Unblinded, Uncontrolled
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Duration :- 12 – 18 months
Population :-
• Mostly healthy volunteers
• Pts in Oncology & anti-HIV trials
Special populations
• children
• pregnant &
• breastfeeding females
• not included unless drug specific for the population
Informed consent form is mandatory
Sample size :- 20 – 100
Location :-
• Single well equipped center.
• Emergency care available.

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Advantages of tolerability studies in healthy
• Rapid enrollment & completion of study
• Greater physiological reserve
• If AE occurs, more likely to recover
• Freq. measurements
• Complete picture of drug obtained as observed. Not
confounded by underlying disease or concomitant
treatment.
Advantages of including patients
• PD effects measurable only in patients.
• Tolerability differs in healthy subjects & patients

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Inclusion criteria
• healthy Volunteers (History + examn + lab)
• age range (18-50)
• body wt. (+ 15% of ideal)
• not participated in any drug study in previous 3-4 months
Exclusion criteria
• h/o alcohol or drug abuse
• regular medication
• smokers
• blood donation within 3 months
Patients- depending on disease
• age, gender
• severity of disease
• duration

20. Objective
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• Route of administration
• Drug in fed or fasted state
• Extrapolation from animal to human dose
• Dose ranging
• Measurements
• Pharmacokinetics
• Pharmacodynamics
• Safety parameters
• Any predictable toxicity - AE

21. Routes Of Administration
Intended route for patients
IV route used even if systemic exposure in pts
achieved by other route for PK studies
Benefits of IV route
• control of administration
• If AE, drug can be halted
• 100% exposure
• overcomes problems related to bioavailability
• less tissue & plasma conc. variability: less intersubject
variability
• easier assessment of PK/PD relationships 10-09-2020 27

22. Drug in Food or Fasted State
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• Commonly – fasted state
• Food – retardation & variable absorption
• Fasted state – easier quantification of PKs.
• Animal data - ↑ absorption in fasted state
- initial dosing in fasted state
• Fat soluble drugs – with food
• Food-drug interaction study- not usually indicated in phase I

23. Initial Dose
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• Start with low dose
- Fraction of “clean "or “no-effect” dose – observed in
toxicology
- Rule - dose1/25 to 1/100 of no effect dose in mg/kg.
- 1/3 to 1/5 of which is lethal to 10% of animals(LD10)
- expressed as mg/m2 for oncology drugs
• Samples from a group of subjects. should be assayed
first,
- before enrollment of next group.
- If non linearity of PKs, - then ↑ dose cautious

24. Dose Escalation
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• 3 main schemes to obtain MTD (Max. tolerated dose)
- ↑ dose in logarithmic manner
- Doubling the dose
- Fibonacci sequence
• Other
- Modified Fibonacci escalation scheme
- Pharmacokinetically guided dose escalation
- Accelerated titration designs
- Modified continual reassessment methods
- Intra-patient dose escalation

25. Fibonacci Sequence
Step
Ideal Percent Dose
Increment
1 D
2 2 × D 100
3 3× D 67
4 5× D 50
5 8× D 40
6 13× D 29
7 21× D 33
8 34× D 33
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Dose escalation to reach maximum tolerated dose (MTD)
Dose escalation based on Fibonacci Series
1 2 3 5 8 13 . . . .

26. Measurements
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Predetermined in protocol
Plasma concentration of drug
Deriving PK parameters like t1/2, bioavailability,
clearance
Helps in establishing dosing, frequency & duration
of drug
Also includes blood study, imaging, body fluid study
etc

27. Absorption & Bioavailability
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• Absorption:-
- solubility, lipophilicity, pKa
- molecular size & animal data
• Quantitative data of absorption & bioavailability
- by comparison of areas under plasma conc-time curves
- following IV & oral dosing
• Other methods used
- urinary estimation of drug & metabolites

28. Plasma Drug Concentration
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• Phase I & II
• Guide to systemic drug exposure
• Reason – lack of effect or exaggerated response
• Early warning of nonlinearity
• Provides plasma conc - time relationship
• Enables development of sensitive assay method

29. Metabolism
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• Methods used for universal detection of drug &
metabolites
1) Incorporating 1 or more radioactive atoms in molecule
- 14C commonly used
- radiation hazard
2) Stable isotope labeled drug
- requires mass spectroscopy
- expensive
3) Using unmodified drug
- by magnetic resonance spectroscopy
- ↓ sensitivity

30. Safety Parameters
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• 2 categories of safety issues:-
1) Result of extension of therapeutic effects
- predictable & should be carefully monitored
- should be related to exposure or plasma conc
- so rational dosage schemes for further phases & eventual clinical
use can be established.
- effect seen in pts but not healthy subjects
2) Toxicological profile of drug
Toxicity 2 types :-
a) parallel with preclinical obs.
b) unexpected

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• In trial design
- Always consider human as most sensitive species compared
to animal species
- consider occurrence of unexpected & unpredictable effects
Monitor
- for early signs of severe toxicity
- imp organ systems along with the critical & target organs
identified in preclinical studies.
- Broad effects initially and specific later.

32. Phase II
Therapeutic Exploration
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33. Phase II: Therapeutic Exploratory
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Objectives
• Primary
• evaluate efficacy
• determine short term SE
• Identify common risks
• Secondary
• evaluation of study endpoints
• therapeutic regimen
• target population for phase III

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• Primary focus:-
- Dose response & effects
- Efficacy
- Adverse effects
• Design:-
- Randomized, blinded
- Placebo controlled
• Duration :- 1-3 years
• Population:- Individuals with target disease
• Sample size :- 200-300 usually calculated from endpoints
• Location :- Multiple centres, well equipped

35. Selection Of Subjects
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Patients with target disease
• Inclusion criteria depending on the disease
• age
• gender
• severity of disease
• duration
• not participated in trials - previous 3 months
• Exclusion criteria (narrowly defined)
• h/o alcohol or drug abuse
• regular medication
• smokers

36. Factors To Be Studied
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Therapeutic effectiveness
Efficacy at various doses
Pharmacodynamics Pharmacokinetics
Patient safety
Bioavailability
Drug-food interactions
Drug-drug interactions

37. Phase IIa
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Proof of Concept (POC)
• Establish dose range for more definitive therapeutic trials
• beneficial efficacy of drug
• to be undertaken in late phase.
• usually single blind
• Small no. of patients (20-200)
• Conducted on homogenous population
• Use of surrogate biomarkers
• POC realized if drug improves disease condition & alters
surrogate biomarkers
• Goal: To guide decisions on further development

38. Trial Types in Phase IIa
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Pilot trial to test drug in patients
Dose response trial in patients
Trials evaluating doses & dosing schedule
Evaluation of duration of dosing

39. Phase IIb
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• Mainly to study efficacy in target population
• Multicentric but few centers
• In heterogeneous population
• Mostly double blind
• Estimation of clinical benefit versus placebo
• Endpoint based detailed PD & safety evaluation
• Observe safe dose range
• Regular monitoring visits

40. Phase II b : Pivotal Trial
Placebo / active drug controlled double blind trial
At single or multiple sites
Trials to focus on one or more aspects of II A
Rigorous demonstration of efficacy
Well controlled ‘Pivotal trials’
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41. Intervention Vs Standard
Treatment/Placebo In Phase II
Usually std therapy as comparator & use of placebo
only in self-limiting conditions if rescue available
Declaration of Helsinki Statement on Placebo
Use:
• New intervention must be tested against best current
proven intervention, except:
• when no current proven intervention exists;
• where use of placebo necessary to determine efficacy or
safety
• pts receiving placebo or no treatment
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42. Dose Ranging in Phase II
Initial dose
• no effect dose & max. effective dose
Main aim → optimum dose for phase III
• titrate dose upwards or downwards depending upon clinical/
surrogate endpoint
Escalation
• highest dose if large gap between desirable & SE
- max. pts likely to benefit
- ↑ cost & SE
• Lowest dose – safe & tolerable
Ideally –dose benefiting majority + min. SE 10-09-2020 48

43. Dose Response and Time course
Of PD effects
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• Dose – plasma conc range is studied
• C0 C50 & Cmax are found.
• Conc- effect relationship studied
• Time course considerations:
- providing a clue to regulatory authorities
- for dosing intervals selected
- speed of onset &duration of action
↓
(whether consistent with desired clinical response)

44. Demonstration Of Clinical Benefit
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Methods used:
• Clinical benefit compared to std therapy
• Clinical benefit compared to placebo
• Statistical benefit compared to very low dose
• Statistically significant dose response relationship
• Regression of tumor size (oncology)

45. Efficacy Study
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1) Determination of primary efficacy parameter
• Surrogate &
• Clinical endpoint
2) Dose or plasma conc. a/w range
• Lowest PD effects
• Max. dose or conc.
• Max. tolerated dose
• Max dynamic effect over dosing interval
3) Dosing interval
• Based on PKs
• Based on PDs

46. Endpoints to determine clinical efficacy
Endpoints - quantify the potential effect of
treatment or therapy under study.
Essential points
• should predict outcome
• measurement :- precise , accurate & reproducible
• justification & rationale for selection
• correlation with benefit
• limitations should be known & substituted
Clinical endpoint should be:
• Relevant & easy to interpret;
• Clinically apparent & easy to identify; &
• Sensitive to treatment differences. 10-09-2020 52

47. Surrogate endpoint
• physiological or biological
markers that correlate
with the clinical
endpoints for which they
are substituting.
• used instead of clinical
outcomes.
• substitute for undesirable
or rare primary endpoint.
• track clinical course of
disease
• evident in short period
Essential Criteria
• should be validated for
disease studied
• should predict outcome
of disease
• correlation with outcome
should be demonstrated
• validated with a drug of
known MOA
• not appropriate for drug
with other MOA
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48. Interaction Study
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Drug interaction
• Does Exp. Drug affect PKs
of std drug ?
• Does concomitant drug
affect PKs of Exp. drug ?
• study only drugs with
narrow TI
• PKs of Exp. Drug +
metabolic studies predicts
interactions
• e.g. in vitro enzyme study
• renal clearance
• protein binding
Food interactions
• imp to study as affects
bioavailability
• food → no effect, ↑ or ↓
absorption ?
• determined by studying
• small no. of pts ingesting
drug
• with a standard meal
• postprandial changes in
hepatic blood flow
• Formal & adequately
powered study required
• for registration purpose

49. Comparison between Phase I &
Phase II
Phase I Phase II
First in man study First in patient- POC
20-80 subjects 100-300 subjects
12-18 mnths 1-3 yrs
To establish basic safety &
blood levels with diff. doses
To establish drugs efficacy &
dose range
Study PK & duration of
action
Study safety & PK in special
population & risk factors
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50. Phase III
Therapeutic confirmation
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51. Pre Requisites For Phase III Trial
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Preclinical safety data
• Toxicological
• Teratological
• Fertility studies
Completed Phase 1 & 2
data; Decision to proceed
taken by the sponsor
Approval by the DCGI
before commencing a trial at
any site
Review and Approval by the
IEC/ IRB

52. 10-09-2020 59
Points In Ethical Consideration*
Seven
criteria
essential
for the
ethical
conduct
of
clinical
research:
• Value,
• Scientific validity,
• Fair selection of
participants,
• Favorable benefit/risk
balance,
• Independent review,
• Informed consent,
• Respect for participants

53. 10-09-2020 60
Institutional Review Board
• Institutional Review Board/Research
Ethics/Committees/ethics Committees/Ethics Review
Committees.
• Investigators and sponsors of clinical trials have ethical
obligations to trial participants and to science and medicine

54. 10-09-2020 61
Informed Consent
• Communication between researcher and participant
• Nuremberg Code [4], the Declaration of Helsinki [5], the
Belmont Report [3], and the International Ethical
Guidelines for Biomedical Research Involving Human
Subjects.
• Surrogate consent i/c/o emotionally/ mentally impaired and
pediatric population.

55. 10-09-2020 62
Privacy And Confidentiality
• Electronic medical records have simplified the tasks of
finding potentially eligible participants for trials, conducting
international multicenter studies, following up on
participants during and after the studies, and sharing data
with other researchers. They have also led to laws restricting
what kinds of medical records can be shared and with
whom, in the absence of clear permission from the patients
• It is probably not possible to share data and specimens that
are useful to the recipient investigator while also maintaining
perfect deidentifiability

56. Phase III
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• Primary objective : Demonstration or confirmation of
therapeutic benefits
• Designed to confirm that a drug is safe & effective for use
in intended indication & recipient population
• Provide an adequate basis for marketing approval
• dose- response relationships,
• use of drug in wider populations,
• in different stages of disease ,
• in combination with other drugs

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• Drugs intended to be administered for long periods – trials
involving extended exposure to drug conducted in Phase
III, although they may be initiated in Phase II
• Complete information needed to support adequate
instructions for use of the drug
• New drugs approved outside India – phase III studies
carried out to generate evidence of efficacy & safety of
drug in Indian patients

58. 10-09-2020 65
Large scale, multi-
centered
Randomised,
double blind
controlled
1000 – 5000
patients
Duration : 3 - 5
years
Most rigorous &
extensive type
Most expensive,
time consuming,
difficult trials to
design & run

59. Phase IIIA
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• Conducted after efficacy is
demonstrated in Phase II and
before submission of NDA
(new drug application)
• Provide confirmatory &
additional safety and
efficacy data in large no. of
populations
• Compare with previously
established or placebo
therapy
• Information for package
insert & labelling of drug
• Determine the Risk –
Benefit ratio of the
treatment
• Studies conducted after or
during regulatory filing i.e.
submission of NDA (New
Drug Application) but
before its approval
• Supplement earlier trials ,
complete earlier trials
• Effectiveness of drug in
special patient subgroups-
pregnant women, the
elderly, children, or
patients with other health-
related problems
• Long term studies
Phase IIIB

60. Outline Of Phase III Trials
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Randomized controlled trial
Type of control – standard or placebo
Objectives - endpoints
Patient selection
Bias
Randomisation
Trial design
Types of trials

61. RANDOMISED
CONTROLLED TRIALS
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• Most reliable form of scientific evidence in hierarchy of
evidence
• Gold standard
• Comparative studies with an intervention group and a
control group; the assignment of the subject to a group is
determined by randomization
• Randomization: process by which all participants are equally
likely to be assigned to either the intervention group or the
control group.

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• Removes the potential of bias in the allocation of
participants to the intervention group or to the
control group.
• Produce comparable groups (measured as well as
unknown or unmeasured prognostic factors and
other characteristics of the participants at the time
of randomization will be evenly balanced between
the intervention and control groups)
• Validity of statistical tests of significance is
guaranteed
Advantages of RCTs

63. Pros and Cons of an RCT
Pros
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Limitations of external
validity
• Where RCT are performed
• Characteristics of patients
• Study procedures
Cost
Time
Difficulty in studying rare events
Cons
•Controls selection bias
•Balances confounding
factors
•Permit the use of
probability theory to
express the likelihood that
any difference in outcome
between treatment groups
merely indicates chance

64. Study Objectives
Study objectives are often stated as primary and secondary
endpoints (variables)
Endpoints are measures believed to quantify the potential
effect of a treatment or therapy under study
Types of endpoints:
• Primary or Secondary endpoints
• Hard or Soft endpoints
• Definitive or Surrogate endpoints
• Composite endpoints
• Health economic endpoints 10-09-2020 72

65. End Points: Primary vs Secondary
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Primary vs Secondary
Primary endpoint measure outcomes that will answer the
primary (or most important) question being asked by a trial
Secondary endpoints ask other relevant questions about the
same study
E.g. Objective : survival ( anti – cancer drugs)
Primary endpoint: no of deaths
Secondary endpoint : non fatal events, hospitalizations

66. Endpoints: Hard vs Soft
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Hard endpoints are definitive, quantifiable, no subjectivity
required
Soft endpoints either do not relate strongly to the disease or
are subjective.
E.g. Objective : efficacy of antihypertensive drug
Hard endpoint : BP measurement
Soft endpoint: patient’s self assessment of QOL

67. Endpoints: Definitive vs
Surrogative
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 Definitive endpoint relates to symptoms and/or course of
disease
 Surrogate endpoint - measured in place of biologically
definitive or clinically most meaningful endpoint; easy to
measure, show an effect sooner
E.g. Objective: efficacy of a lipid lowering agent
 Definitive endpoint : cardiovascular mortality
 Surrogate endpoint : serum cholesterol measurement

68. Composite Endpoints
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Composite endpoints : An endpoint that combines several
endpoints into one
Mortality & morbidity due to cardiovascular diseases
E. g : UK PDS

69. Health Economic Endpoint
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Quality of life:
QALY : measurement of duration of individual’s life taking
into account the well being that they experience during that
time
SF- 36, DASI ( Duke Activity Status Index),
FACT – G ( Functional assessment of Cancer
Therapy – Genaral)
Cost : direct & indirect costs

70. Patient Selection
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Number
• large population , 1000 - 5000
Inclusion/ Exclusion criteria
• Medical or social standards determining whether a person may
or may not be allowed to enter a clinical trial
• Based on:
• Age
• Gender
• Type & stage of disease
• Other medical conditions
• Previous treatment history

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General requirements:
• Represent clinical practice scenario to the possible extent
• Support a reasonable recruitment rate
• Must have potential to provide scientifically valid data
• Produce widely acceptable & extendable results
• Special populations – children, pregnant & breastfeeding
females- not included unless drug specific for the population
• Informed consent form is mandatory

72. Bias
Type of bias Method of bias control
Selection bias
Randomized assignment
Concealment of assignment
Bias in study management
Standardized study procedure
Standard equipment
Training and certification of
research personnel
Observer ascertainment bias Blinding or masking
Biased introduced by inclusion
after randomization
Intention to treat analysis
Worst case scenario analysis
Publication bias
Prospective registration of
clinical trials
Publication of negative trials
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73. Randomization
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• Randomization is the unpredictable allocation of a patient to
a particular treatment strategy in a clinical trial
• To ensure that intervention & control groups are similar in
all respects with exception of the therapeutic measure being
tested
• Maximizes the chance that a difference between 2 groups is
due to true effect of the drug being evaluated

74. Method Of Randomization
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Common types of randomization:
• Simple
• Block
• Stratified
• Minimization or adaptive

75. Allocation Concealment
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• Procedure for protecting randomization process so that
treatment to be allocated is not known before the patient is
entered into study
• Methods:
• Sequentially numbered opaque sealed envelopes (SNOSE)
• Sequentially numbered containers
• Pharmacy controlled randomization
• Central randomization

76. Blinding
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• Experimental methology in which groups of
individuals involved in a trial are made unaware
of which treatment the participants are assigned
to
• Open label: All parties are aware of treatment
being received after randomisation
• Single blind: Either the patient or clinician
(usually the patient) remains unaware of the
treatment assignment
• Double blind: Both the patient & investigator
are unaware of the allocated treatment

77. Trial Design
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• Parallel design
• Crossover design
• Factorial design
• Withdrawal design
• Cluster randomized design
• Sequential design

78. Parallel vs Cross-over
PARALLEL CROSS OVER
Groups assigned different
treatments
Each patient receives different
treatment
Shorter duration Longer duration
Larger sample size Smaller sample size
No carryover effect Carryover effect
Between group comparison Within patient comparison
Robust to problems like missing
data, missed visits
Less variability, greater sensitivity
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79. Latin2 Design
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Essential feature is that every treatment appears only once in
every row (each subject) and once in every column (each time
period)

80. Factorial Design
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• E.g. : Aim of the Canadian Trial in Threatened Stroke was to
investigate the use of aspirin and sulfinpyrazone for
preventing strokes and deaths

81. Withdrawal Design
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DARWIN STUDY: A Prospective, d/b, Placebo Controlled, Multicenter,
Randomized/Withdrawal Efficacy and Safety Study of Dexloxiglumide for the Relief of
Symptoms in Patients With Constipation-Predominant Irritable Bowel Syndrome

82. Cluster Randomized Design
• Trials that randomize groups of subjects, not individuals
E.g. : villages, schools
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83. RCT vs LST
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84. Interim Analysis
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• Performed at any time before the final data analysis, usually
to evaluate treatment differences, efficacy, and significant
safety issues
• REASONS:
• Ethical & scientific reasons
• Financial
• Practical
• Purpose and timing of planned interim analyses must be
stated in the protocol
• One or more analyses may be specified at designated
timepoints during the course of a study

85. Data Safety And Monitoring Board
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• Independent committee of clinicians, statisticians, ethicists,
and other specialists who are knowledgeable in the area of
study
• To assess the progress of a trial, its safety, and/or its efficacy
at intervals specified in the protocol
• Committee may recommend that a study may continued,
modified or stopped based on the data provided at the time
of interim analysis

86. New Drug Application
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• NDA – vehicle through which drug sponsors formally
propose that US FDA approve a new drug for sale &
marketing
• NDA includes:
• Full reports of animal & clinical studies carried out to
determine whether drug is safe & effective
• Statement of drug’s composition
• Description of methods, facilities & controls used in drug’s
manufacturing, processing & packaging.
• Samples of drug & its components as required
• Copy of proposed labelling

87. 10-09-2020 97
Goals of NDA are to provide enough information to permit
an FDA reviewer to reach the following key decisions:
• Whether drug is safe & effective in its proposed use
&whether benefits of drug outweigh its uses
• Whether drug’s proposed labelling (package insert) is
appropriate & what it should contain
• Whether methods used in manufacturing the drug &
controls used to maintain drug’s quality are adequate to
preserve the drug’s identity, strength, quality & purity

88. 10-09-2020 98
• Under Food & Drug Administration Modernization Act
(FDAMA), reviews for NDA are designated either as
Standard or Priority:
• Standard designation sets target date for completing FDA
review at 10 months after the date it was filed
• Priority designation sets target date for FDA action at 6
months

89. 10-09-2020 101
Selection biases led historical control studies to favor
inappropriately the new interventions
Not all clinical studies can use randomized controls for e.g. in
case when the disease prevalence is too low that a large enough
population cannot be readily obtained. In such an instance, only
case–control studies might be possible.
Another major criticism of this controversial design centers
around the ethical concern of not informing participants that
they are enrolled in a trial.
efficiency of the design has also been evaluated. It depends on
the proportion of participants consenting to comply with the
assigned intervention. To compensate for this possible
inefficiency, one needs to increase the sample size
Limitations of Clinical Trials

90. Conclusion
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• Phase I & II yield important results that affect further
Phases.
• Only 30 % drugs clear phase I & II.
• Must ensure well-being of participant
• Microdosing can reduce the time & cost required for drug
development
• After the successful completion of Phase III the road is
further paved for Phase IV after marketing approval to
assess its clinical usefulness in actual population.
• Clinical trials are only ethical if there are adequate resources
to conduct them and see them to completion
• To fail to complete the study is a serious breach of ethics

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