This document discusses key aspects of Phase 3 clinical trials including objectives, sample sizes, endpoints, and review processes. Phase 3 trials involve 400-4000 patients across multiple centers to confirm efficacy, monitor safety, and compare effectiveness to existing therapies. They have two parts - Phase 3A requires regulatory approval for NDA while Phase 3B extends trials after approval. Objectives are to confirm efficacy, monitor adverse events, compare effectiveness in different patient types, and describe benefit-risk. Sample sizes are typically at least 500 patients over 10-15 centers for new substances or 100 patients over 4-5 centers for substances already approved elsewhere. Primary endpoints are most clinically relevant for the objective and determine sample size. Secondary endpoints

1. PHASE 3
Dr.Himali D Rajgadhi
NHL Muncipal Medical college ,Ahmedabad
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Is the treatment safe?

3. 3Does the treatment work?

4. Is it better than what’s already available?
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5. Objective
■ Population & Sample Size
■ Types of trials
■ Ethics committee approval
■ Endpoints
■ CTRI Registration
■ NDA
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Phase
3
Patients
Most
expensive
Therapeutic
confirmatory
trials
400-4000
Multicenter
trials
Time-
consuming

7. PHASE 3 CONSIST OF TWO PARTS
PHASE 3A
■ Trials carried out on a large number-or in a
special category – Regulatory requirement for
NDA
PHASE 3B
■ Extended trials of IIIa after applying for
approval but before launch.
■ Phase 3b studies are known as "label expansion".
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8. Objectives of a Phase III study
■ Confirm the efficacy of the therapy
■ Monitor adverse events and side effects
■ Compare effectiveness relative to current therapies
■ Describe the benefit/risk ratio across different types
of patients
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At least 500
patients
over 10-15
centers.
Not
marketed in
any other
country
New drug
substance
discovered
in India

10. At least 100
patients
over 4-5
centers
First time
in India
Already
approved/
marketed
in other
countries
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11. New Drugs – developed in India as an IND
and not marketed anywhere in world.
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Form 44
Treasury Challan of INR 50,000
Source of bulk drugs /raw materials

12. 12
Form 44

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15. New Chemical Entity approved &
marketed in other countries not approved
in India• indicated for serious/life threatening conditions.
• is indicated for a disease of special relevance to the Indian health scenario
• indicated for a disease for which there is no or limited satisfactory therapeutic
options.
• Existence of significant unmet medical needs or significant public health issue
• indicated for a rare disease or a disease in which patient population is scanty
• offering added significant advantage over the existing treatment modalities
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16.  A drug already approved by the
Licensing Authority which is now
proposed to be marketed
modified or new claims,
indications,
dosage, dosage form (including
sustained release dosage form)
route of administration.
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17. Who Regulates the phase 3Trials?
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18. Data and Safety Monitoring Board
■ A group of individual experts that reviews the
ongoing conduct of a CTs to ensure safety,
validity and scientific merit of a trial
■ Clinical experts
■ Methodological experts
■ Ethical experts
■ 3-7 members
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20. Population?
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21. • Drug–disease interactions
• Drug–drug interactions
• Dosage intervals
• Risk–benefit information
• Efficacy and safety for
subgroups
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22. ClinicalTrials in Pediatrics
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23. In 1963, Dr. Harry Shirkey coined the term
“therapeutic orphans”
to
describe children
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24. THE ETHICS OF CLINICAL RESEARCH
IN CHILDREN
Jany is an 8-year-old, prepubescent healthy girl. Her best friend
suffers from precocious puberty, which is embarrassing to her, and
she regularly visits an endocrinologist.Jany is fascinated by biology
and joins her friend on a clinic visit.There she notices a person
recruiting healthy volunteers for a study to help characterize puberty
onset. Her scientific interest piqued, and trying to be supportive of
her friend’s plight, she excitedly volunteers.The study requires
12 blood samples over a 6-week period.
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25. ■ The US Department of Health and Human
Services, under the Children’s Health Act of
2000
■ defines four categories of research in which
children are allowed to participate
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27. 27
Jany receives praise from her family about her actions in support
of her friend and her scientific interest. Silently, by the third
lab draw, she is terrified of returning to the clinic. She develops
a fear of needles, hates the smell of the latex tourniquet, and
quickly comes to despise the kind nurse who repeatedly offers
her the same sticker after each visit. In her 8 years, she has not
yet developed the poise to gracefully terminate her participation.
She quietly, dutifully completes her part in
the study.Years later, she has repeatedly “forgotten” to schedule
her own annual health maintenance exams with her internist,
secretly fearing he may want routine labs.

28. age-specific
adverse reactions
Ineffective dosing
Therapeutic failure
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29. ClinicalTrials In Pregnant and NursingWomen
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30.  After successfully completed Phases I and II in men and
nonpregnant women
 Late Phase II or Phase III trials once the investigational
product had passed safely through Phase I and at least
early Phase II in men and nonpregnant women
 Preclinical toxicology and teratogenicity data and animal
models are useful and required by regulatory authorities
 if vaccines are to be used during pregnancy, they must be
tested during pregnancy
 the research is irrelevant to pregnant women or the trial
involves a known or probable teratogen
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31. ClinicalTrials In PregnantWomen
Nontreatment
Undertreatment
Mistreatment
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32. INFORMED CONSENT
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33. In all clinical trials freely given, informed
written consent is required to be obtained
from each study subject
■ Verbal information of the study using a
patient information sheet
■ Language that is nontechnical and
understandable by the study subject.
■ Where a subject is not able to give informed
consent, the same may be obtained from a
legally acceptable representative.

34. Age for Informed Consent
■ Adults >/= 18 years of age
■ Parental permission for Minors
■ For 7-17 years – Assent to participate
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35. How many Patients in each Clinical trial?
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36. Sample Size
■ Provide an estimate of the needed size of a study
■ Ensure sufficient statistical power to detect clinical
meaningful difference between groups
■ Provide adequate levels of significance
■ Parameters for sample size estimation shall be as
conservative as possible while still being realistic
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37. ■ The sample size in Phase III trials almost always
provides >80% power to detect a clinically relevant
treatment effect
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38. Parameters for Sample Size Calculations
■ –Type I error α (or Significant level)
How big a risk can be taken if the drug is concluded
effective when in fact it is NOT?
■ –Type II error β (or Power)
What is the smallest difference between treatments
that is important to detect ,and with what degree of
certainty?
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40. Statistical Power
■ The power of a statistical test is the probability that the test
will reject the null hypothesis when the null hypothesis is false
■ As the power increases, the chances of making aType II error
decrease
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43. Types of trial
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44. Types OfTrial
• Randomized ClinicalTrials
■ Cross‐over design
■ Factorial design
■ Stratified Block Randomization
■ Superiority trial
■ Non‐inferiority trial
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46. ■ • Example: NCIC CTG MA.27
■ – Original design (2003): 2 by 2 factorial
Amendment (2006)
■ • Remove Celecoxib arm
Exemestane Anastrozole
Celecoxib C & E C & A
Placebo P & E P & A
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47. MA.27 Design (2003)
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48. MA.27 Amendment (2006)
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49. Stratified Block Randomization
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50. ■ Example: stratify with age and gender,
■ • Cell 1 (6 pts):Age > 60, Male:ABAB BA BA
■ • Cell 2 (6 pts):Age > 60, Female: AABB AB AB
■ • Cell 3 (4 pts):Age < 60, Male:ABBA
■ • Cell 4 (4 pts): Age < 60, Female: BAAB
Arm A Arm B Total
<60 4 (50%) 4 (50%) 8
>60 6 (50%) 6 (50%) 12
Female 5 (50%) 5 (50%) 10
Male 5 (50%) 5 (50%) 10
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51. Dynamic Randomization /
Minimization
■ – Large number of cells
■ • Age (3 levels), Gender (2 levels), smoking history (3
■ levels), centre (5 levels), node status (3 levels): 270 cells
■ – For a new subject in a give cell, total number of
■ patients allocated in each treatment group is counted.The subject will be
allocated to group with smallest number (coin tossing if tied)
■ – Guarantee balance but treatment allocation may be predictable
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52. Non‐inferiorityTrials
■ Show Effect of new drug on a certain endpoints
is no worse than existing drug
Why approve drugs that are not superior to what
already in the market??
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53. Better safety
Ease Of
Administration
Cost effective
Provide more
treatment
Option
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54. Superiority trial
■ Effect of one treatment is superior than other treatment
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55. ■Where should I end my clinical trial?
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56. Endpoints
■ Primary Endpoints
■ Most clinically relevant and direct related to primary objective
of the trial
■ Base for sample size calculation
■ Analysis to be adjusted forType I error if there are multiple
primary endpoints
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57. • Secondary Endpoints
■ Supportive measurements of effects related to the
secondary objective
■ Hypothesis generation
■ No need to adjust trial results for secondary
endpoints
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58. Surrogate endpoint
■ An outcome measure that substitutes for a clinical event of true importance
■ “surrogate markers” “Quick & Dirty”
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Smaller Sample size Shorter follow up Period

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Fluorides in Osteoporosis
Surrogate End
point
Bone Mineral Density
Trial End Results Increased Fracture

60. 60
Heart Disease in PostmenopausalWomen
Oestrogen And Medroxyprogesterone acetate
Serum CholesteroleSurrogate Endpoint
Increased MortalityTrial End Result

61. Examples of Endpoints
Time to event endpoints
 Overall survival
Event free survival
 Progression free survival
 Recurrent free survival
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62. Continuous endpoints
Quality of life scores
Incremental cost‐effectiveness ratios
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63. Example:Time to Event Endpoint
Progression free survival (PFS), the primary
endpoint of this study, is defined as the time from
randomization to the time when a protocol
defined failure is observed.
If a patient has not developed a failure at the
time of final analysis, PFS will be censored on the
date of the last disease assessment.
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65. Intension to treat
Perprotocol Analysis
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66. intention to treat
■ Subjects allocated should be followed up,assessed and
analyzed irrespective of their compliance to the planned
course of treatment
■ Patients often fail to start, complete or continue
■ Considered who has taken at least one dose of treatment
■ Admits non compliance and protocol deviation, thus
reflecting a real clinical situation
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67. Per Protocol
■ Who complete the treatment originally
allocated Per protocol set
■ Valid cases
■ adherent to medication
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68. New Drug Application (NDA)
■ NDA filing process is applying for marketing approval to
regulatory body.
■ Aplication contains often in hundreds of volumes, full reports
of all preclinical and clinical data.
■ Review and decision of approval may take 3 years or longer.
■ Controlled marketing allowed for life threatening diseases
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69. ■Why India is a Hub of clinicalTrials?
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70. ■ India hosts nearly a fifth of all global clinical trials with
a huge potential for financial and scientific gains
■ large pool of patients, highly skilled medical
investigators, lower drug development costs and
timely completion of clinical trials in India
■ Clinical trials are more than 50 per cent cheaper in
India compared to developed countries
■ India is home to more than 17 per cent of world
population and around one‐fifth of the global burden
of disease
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71. Currently running phase 3 trials
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72. ■India 615 sites
Ahmedabad 26 sites
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73. Novartis Investigative Site
■ A Phase III, Randomized, Double-blind, Placebo
Controlled Multi-center Study of Subcutaneous
Secukinumab (150 mg and 300 mg) in Prefilled
Syringe to Demonstrate Efficacy (Including Inhibition
of Structural Damage), Safety, andTolerability up to 2
Years in SubjectsWith Active Psoriatic Arthritis
(FUTURE 5)
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74. Novartis Investigative Site
■A Multicenter Study to Evaluate Safety
andTolerability in PatientsWith
Chronic Heart Failure and Reduced
Ejection Fraction From PARADIGM-HF
Receiving Open Label LCZ696
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75. Care Institute Medical Sciences
■ A clinical trial to evaluate treatments using
UT-15C (treprostinil diethanolamine) for
patients with Pulmonary Arterial
Hypertension
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76. Department of Medical Oncology, Navneet
Memorial Hospital, "Sushrusha“
HCG Multi Specialty Hospitals
■ A Multicenter Open-label Randomized Study of BCD-020
(Rituximab, CJSC BIOCAD, Russia) Efficacy and Safety in
ComparisonWith MabThera (F. Hoffmann-La Roche Ltd.,
Switzerland) in Monotherapy of CD20-positive Indolent
Non-Hodgkin's Lymphoma
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77. Review Process
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78. FastTrack
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To facilitate the
development, and
expedite the
review
Treat serious
conditions and fill
an unmet medical
need
To get important
new drugs to the
patient earlier
Avoiding serious
side effects of an
available therapy
Ability to address
emerging or
anticipated public
health need

80. Rolling Review
■ which means that a drug company can submit
completed sections of its Biologic LicenseApplication
(BLA) or New Drug Application (NDA) for review by
FDA, rather than waiting until every section of the
NDA is completed before the entire application can
be reviewed. BLA or NDA review usually does not
begin until the drug company has submitted the
entire application to the FDA
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81. BreakthroughTherapy
■ BreakthroughTherapy designation is a process designed to
expedite the development and review of drugs .
■ In general, the preliminary clinical evidence should show a
clear advantage over available therapy.
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82. ■ BreakthroughTherapy designation is requested by the drug
company.
■ If a sponsor has not requested breakthrough therapy
designation, FDA may suggest that the sponsor consider
submitting a request if:
■ (1) after reviewing submitted data and information
(including preliminary clinical evidence), the Agency thinks
the drug development program may meet the criteria for
BreakthroughTherapy designation and
■ (2) the remaining drug development program can benefit
from the designation.
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83. ■ Ideally, a BreakthroughTherapy designation
request should be received by FDA no later than
the end-of-phase-2 meetings.
■ FDA will respond to BreakthroughTherapy
designation requests within sixty days of receipt
of the request.
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84. Accelerated Approval
■ When studying a new drug, it can sometimes take many years to learn
whether a drug actually provides a real effect on how a patient survives,
feels, or functions.
■ in 1992 FDA instituted the Accelerated Approval regulations.These
regulations allowed drugs for serious conditions that filled an unmet
medical need to be approved based on a surrogate endpoint. Using a
surrogate endpoint enabled the FDA to approve these drugs faster
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85. Priority Review
■ Prior to approval, each drug marketed in the United States must go
through a detailed FDA review process. In 1992, under the Prescription
Drug User Act (PDUFA), FDA agreed to specific goals for improving the
drug review time and created a two-tiered system of review times –
Standard Review and Priority Review.
■ A Priority Review designation means FDA’s goal is to take action on an
application within 6 months (compared to 10 months under standard
review).
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86. ■ FDA grants FastTrack designation for the
Phase III clinical investigation of arimoclomol
as a treatment of Niemann-Pick disease type
C
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91. References
Baylis F, KaposyC.Wanted: inclusive guidelines for research involving pregnant women. J.
Ob. Gyn. Can. 32(5) 473–476 (2010).
Draft guidance on approval of clinical trials & new drugs,cdsco
Growth and Structure of the Services Sector in India, Jesim Pais, January 2014
Note for guidance on general considerations for clinical trial
ICHTopic E 8 General Considerations for ClinicalTrials
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