Assignment on Experimental Study- RCT and Non RCT, Observation Study: Cohort, Case Control, Cross sectional, Roles and responsibilities of Clinical Trial Personnel: Investigator, Study Coordinator, Sponsor, Contract Research Organization and its management Guidelines to the preparation of documents, Preparation of protocol, Investigator Brochure, Case Report Forms, Clinical Study Report Clinical Trial Monitoring-Safety Monitoring in CT

1. HISTORY
 The first proper clinical trial was conducted by the
physician James Lind. He concluded a dietary
supplement of an acidic quality in the experiment after
two months, sea when the sheep was already afflicated
with scurvy.
 Frederick Akbar Mahomad who worked at Guy’s
Hospital in London, made substantial contributions to
the process of clinical trials, where he separated
chronic nephritis with secondary hypertension from
what we now term secondary hypertension.

2. Continue…
 The first randomised curative trial was carried out at the
MRC Tuberculosis Research Unit by Sir Geoffrey Marshall .
The trial carried out between 1946-1947, aimed to test the
efficacy of the chemical streptomycin for curing pulmonary
tuberculosis. The trial was both double blind and placebo-
controlled.
 The British Medical Research Council officially recognised
the importance of clinical trials from the 1930. The council
established the Therapeutic Trials Committee to advise
and assist in the arrangement of properly controlled
clinical trials on a new products that have value in disease
treatment on experimental ground.

3. INTRODUCTION
 Clinical trials is a systematic investigation in human
subjects for evaluating the safety and efficacy of any
new drug.
 Clinical trials are a set of test in medical research and
drug development that generate safety and efficacy
data for health interventions in human beings.

4. INTRODUCTION
• Clinical trials are conducted only when satisfactory
information has been gathered on the quality of the
nonclinical safety
• Health authority/ethics committee approval is granted in
the country where approval of the drug is sought
• Clinical trial is the main stay for bringing out new drugs to
the market

5. INTRODUCTION
 EXPERIMENTAL UNIT : An experimental unit is usually
referred to as a subject from a targeted population under
study. Therefore the experimental unit is usually used to
specify the intended study population to which the results
of the study are inferred, for example the intended
population could be patients with certain diseases at
certain stages or healthy human subjects.
 TREATMENT: In clinical trials a treatment can be a
placebo or any combinations of a new pharmaceutical
identity e.g., a compound or drug, a new diet, a surgical
procedure, a diagnostic test, a medical device, a healthy
education program, no treatment.

6. Continue…
 TREATMENT: Other examples include sugical excision,
radiotherapy and chemotherapy as a combination of
surgical procedure and drug therapy for breast cancer;
magnetic resonance imaging (MRI) with a contrast
imaging agent as a combination of diagnostic test and a
drug for enhancement of the efficacy of a diagnostic test.
• EVALUATION: It is recommended that clinical trials
should not only evaluate the effectiveness and safety of the
treatment but also assess quality of life, impact on genetic
factors, pharmaco-economics and outcomes research
associated with treatment.

7. TYPES OF CLINICAL TRIALS
 TREATMENT TRIALS: Test experimental treatments,
new combinations of drugs, or new approaches to
surgery or radiation therapy.
 PREVENTION TRIALS: Look for better ways to
prevent disease in people who have never had the
disease or to prevent a disease from returning. These
approaches may include medicines, vaccines,
vitamins, minerals, or lifestyle changes.

8. Continue…
 DIAGNOSTIC TRIALS : Are conducted to find better
tests or procedures for diagnosing a particular disease
or condition. Diagnostic trials usually include people
who have signs or symptoms of the disease or
condition being studies.
 SCREENING (EARLY DETECTION) TRIALS: test
the best way to detect certain diseases or health
conditions.
 QUALITY OF LIFE TRIALS( or supportive care
trials): explore ways to improve comfort and the
quality of life for individuals with a chronic illness.

9. PHAES OF CLINICAL TRIALS
 Clinical trials involving new drugs are commonly
classified into four phases (I, II, III, & IV) each phase
of the drug approval process is treated as a separate
clinical trial. If the drug successfully passes through
phase I, II and III, it will usually be approved by the
national regulatory authority for use in the general
population .
 Phase 4 are post-approval studies. Before
pharmaceutical companies start clinical trials on a
drug, they conduct expensive pre-clinical studies.

10. PHASES OF CLINICAL TRIAL

13. DRUG DEVELOPMENT PROCESS

14. PHASE 0 STUDY/MICRODOSING
 Study of new drug in microdose to derive PK
information in human before undertaking phase 1
studies is called PHASE 0
 Microdose: Less than 1/100 of the dose of a test
substance calculated to produce pharmacological
effect with a max dose<100 micrograms
 Objective: To obtain preliminary efficacy, toxicity
and pharmacokinetic data
 Preclinical Data: Substance toxicity study in one
species by two routes of administration

15. PHASE 0 STUDY
 These are very early studies of the pharmacodynamic
and pharmacokinetic properties of a potential drug in
humans.
 Microdosing approach could accelerate drug
development without compromising clinical safety.
 Microdosing helps researchers select better drug
candidates for clinical trials by providing early human
PK and bioavilability data.

16. STEPS INVOLVED IN DESIGNING A
PRE-CLINICAL STUDY
 Identifying a Drug Target: All drugs target specific
points in biochemical pathways. Almost all illness
except infectious diseases are caused by problems
associated with specific biochemical pathways,
identifying the appropriate target step in the
biochemical pathway is critical and can determine the
chances of success of the prospective drug molecule.

17. Continue…
 Developing a Bioassay: A bioassay is a live system
that is devised to measure the effects of a drug. It
varies from a cell or tissue culture system to organs or
even a whole living being, for example a zebra fish
embryo can be used to observe the effects of drugs on
bone density, blood vessel growth, among other
systems.
 Screening the Drug in Bioassay: This is a screening
test done with the bioassay to determine the safety and
effectiveness of the molecule. The drug must clear this
step.

18. Continue…
 Establishing Effective and Toxic Doses: This step
involves establishing the safe and toxic dose ranges.
Future studies takes ideas from here about the dose
ranges to be tested in humans.
 Filling for an Approval as an IND (investigation
new drug ): After all these steps are cleared the drug is
fit for an application to the FDA as an IND.

19. PHASE 0 STUDY
 Advantages:
1. Less chances of adverse effects
2. Short duration
3. Less number of volunteers
4. Reduced cost of development
5. Reduced drug development time

20. PHASE 0 STUDY
 Limitations:
1. Study mainly based on PK parameters- not efficacy
and safety based
2. Agents having different kinetic characterstics
between microdose and full dose are not evaluated
by phase 0 trials
3. Of limited use for agents having Non linear PKs
4. The laboratory parameters are very limited and
expensive researchers have to depend on labs

21. PHASE 1
INTRODUCTION
 First stage of testing in human subjects
 Designed to asses the safety ,tolerability,PK and PD of
drug
 20-25 healthy volunteers
 Patients: Anticancer drugs, AIDS therapy
 Duration:6-12 months
 No blinding/ open labelled

23. PHASE 1 BASIC PRE-REQUISITES
 Preclinical data
 IND application
 Approval by the regulatory authority
 Protocol approval by the Ethics Committee
 informed consent
 Adherence to declaration of ICH-GCP guidelines, at
start as well as from time to time, during the study

24. PHASE 1 STUDY
 The aim of a phase 1 trial is to determine the maximum
tolerated dose (MTD) of the new treatment
 The MTD is found by escalating the treatment dose
until the dose-limiting toxicity (DLT) is reached.
 Kinds of phase 1
 SAD : single ascending dose studies
 MAD: multiple ascending dose studies
 Food effect: investigates differences in caused by food
absorption

25. Phase 1 CT’s are Designed to
obtain following information:
 Safety: Determine the most significant adverse events
in human subjects.
 Tolerability: the safe dose range is determined by
dose escalations and corresponding serial lab tests.
 Pharmacokinetics: How the drug molecule is
absorbed in the body and its metabolites are
distributed and eliminated from the body.
 Pharmacodynamics: The effects of the drug on the
body i.e. how the effects of the the drug vary with the
plasma concentration.

26. SINGLE ASCENDING DOSE
STUDIES(SAD)
 Small groups of subjects are given a single dose of the
drug while they are observed and tested for a period of
time
 If no adverse effects – dose is escalated with 3 new
healthy subjects
 If toxicity is observed then – 3 more subjects are given
the same dose
 If found toxicity – the dose is considered as max.
tolerated dose (MTD)

27. MULTIPLE ASCENDING DOSE
STUDIES (MAD)
 Conducted to understand the pharmacokinetics and
pharmacodynamics of multiple doses of the drug
 A group of patients receives multiple low doses of the
drug
 Samples of blood and other fluids are collected at
various time points
 Analyzed : how the drug is processed within the body

28. PHASE 1 STUDIES OBJECTIVES
 Primary - tolerability and safety
- pharmacokinetics
• Secondary - pharmacodynamic

29. LIMITATIONS OF PHASE 1 STUDIES
 Trial restricted to homogenous subjects
 Performance extrapolated to heterogeneous market
place

30. PHASE 2
 Therapeutic extrapolatory trial
 20-300 subjects
 To confirm effectiveness, monitor side effects ,futher
evaluate safety
 First in patients ( who have the disease that the drugs
is expected to treat )
 Duration : 6 months to several years

31. PHASE 2 OBJECTIVES
 Efficacy in patients ( primary objective)
 Safety issues (secondary objectives)
 Optimum dose finding-
 dose efficacy relationship
 Therapeutic dose regimen
 Duration of therapy
 Frequency of administration
 Therapeutic window

32. PHASE 2 STUDIES PRE-REQUISITES
 Review of phase 1 data
 Innovator/experts
 IRB
 DCGI
 Prior approval by IRB and DCGI is mandatory
 For new actions of a marketed drug, start with phase 2
(phase 1 exemption obtained )

33. PHASE 2 STUDY
 Phase 2 types:
 Phase 2A : designed to assess dosing requirements
(how much drug should be given )
 Phase2B : designed to study efficacy ( how well the
drug works at the precribed doses)

34. PHASE 2 CLINICAL TRIAL
PHASE 2A PHASE 2B
 Early phase
 Pilot clinical trials
 20-200 patients
 Not multicentric
 Single blind comparison
with a standard drug
 Late phase
 Pivotal clinical trials
 50-300 patients
 Multicentric
 Double blind comparison
with placebo or standard
drug

35. PHASE 3
 Therapeutic confirmatory trials
 Large scale, multicentre, randomised controlled trials
 Target population: several 100 to 3000 patients
 Takes a long time : up to 5 years
 To establish efficacy of the drug against existing
therapy in larger number of patients , methods of
usage,to collect safety data etc.

36. PHASE 3 OBJECTIVES
 To assess overall and relative therapeutic value of the
new drug efficacy, safety and special properties
 To determine optimal dosage schedule for use in
general
 The dosage schedule in CT’s should be as close as
possible to its anticipated clinical use

37. PHASE 3 : PRE-REQUISITES
 Efficacy and dose schedule defined in Phase 2 studies
 No gross ADR’s
 Long term preclinical safety studies completed –
chronic toxicity, reproductive toxicity and
carcinogenicity
 Marketing inputs favorable
 IRB and DCGI approval obtained

38. PHASE 3 STUDIES
 Phase 3 studies types:
 Phase 3A: to get sufficient and significant data.
 Phase 3B: allows patients to continue the treatment,
label expansion, additional safety data.
 Phase 3B studies are known as “label expansion” to
show the drug works for additional types of
patients/diseases beyond the original use for which
the drug was approved for marketing.

39. PHASE 3
Phase 3A Phase 3B
 Prior to NDA
 Generates data on safety
and efficacy
• After the NDA but prior to
the approval and launch
These may supplement or
complete the earlier trials
or may be directed to
Phase 4 trials

40. PHASE 3: End of Clinical Trial
Activities
 Sponsor: Expert committee review of efficacy, safety
and potential sales (profit)
 Go-No Go decision to file new drug application with
DCGI
 Expert review by DCGI’s committee
 DCGI approval
 NCE marketed – phase 4 begins

41. PHASE 4
 Done after drug has been marketed
 Post marketing Surveillance (PMS)
 No fixed durarion/patient population
 Studies continue to collect data about effects in various
populations and side effects from long term use
 These are primarily observational or non-experimental
in nature

42. PHASE 4 : OBJECTIVES
 Confirm the efficacy and safety profile in large
populations during practice
 Detect the unknown/rare adverse drug reactions
 Evaluations of over-dosage
 Identifications of new indications
 Dose refinement : evaluation of new formulations,
dosages, durations of treatment

43. PHASE 4 STUDY
 Helps to detect rare ADRs, drug interactions
 Also to explore new uses for drugs (sometimes called
Phase 5)
 Periodic Safety Update Reports
 To be submitted by the manufacturer every 6 months
for 2 years and then annually for next 2 years after
marketing approval
 Harmful effects discovered may result in a drug being
no longer sold, or restricted to certain uses

44. Continue…
 Evaluation in different age groups /types of
patients
 Comparative benefit-risk assessment
 Benefit-cost assessment (pharmacoeconomics)
 Drug usage in the community
 Quality of life assessment

45. REPORTING TIMELINES IN INDIA
Clinical trials Post marketing
 Site to sponsor: 24 hrs
 Site to EC: 7 working days
 Sponsor to DCGI: 14
calendar days
 Sponsor to other
investigators: 14 calendar
days
 Site to sponsor: 24 hrs
 Sponsor to DCGI : 15
calendar days

46. REPORTING OF ADR
 If health care personal suspects that a particular
medication is associated with an adverse event
observed during the course of caring for a patient , he
can report the ADR to a formal reporting system
 Various reporting systems are :
 WHO International System
 USFDA –Medwatch
 INDIA-National Pharmacovigilance Programme

47. CLINICAL TRIALS DESIGN
 The basic considerations that needs to be kept in mind
while designing a trial are as follows:
 Objective of the Trial: The medical questions that
need to be answered should be clearly formulated so
that necessary resources such as the number of
subjects, study duration, study endpoints for
evaluation of the study drug , facility/equipment, and
clinical inference for addressing these questions, the
objective may be more than one and may be
segregated into primary and secondary as
demonstrated by the example of lung cancer.

48. Continue…
 Primary Objectives: This is a randomised, parallel
group trial to demonstrate that the one- year survival
of patients with pre-treated advanced(stage 3B/4)
non-small cell lung cancer (NSCLC) receiving the oral
investigational drug is not inferior to those receiving
intravenous(4) docetaxel.
 Secondary Objectives: These are to evaluate overall
survival , time to progression, response rate, time to
response, improvement in quality of life and
qualitative and quantitative toxicities.

49. Continue…
 Target Population and Patient Selection: In clinical
trials a set of eligibility criteria is usually developed to
define the target patient population from which
qualified patients can be recruited to enrol the studies.
Typically a set of eligibility criteria is used to roughly
outline the target patient population, while the set of
exclusion criteria is used to fine tune the target patient
population by removing the expected sources of
variability. To be eligible for the intended study,
patients must meet all the inclusion criteria .

50. Continue…
 Selection of Controls: In clinical trials, bias and
variability can occur in many ways depending on the
experimental conditions . These have impact on the
accuracy and reliability of statistical and clinical
inference of the trials, since definitive efficacy data
are unobtainable and data on adverse events can be
difficult to interpret.
 FDA requires that adequate well controlled clinical
trials be conducted to provide an unbiased and valid
evaluation of the effectiveness and safety of study
medicine.

51. Continue…
 Statistical Considerations: At the planning stage some
statistical considerations regarding the manner in which
the data will be tabulated and analysed at the end of the
study should be carefully considered. These considerations
include the primary and secondary response variables, the
criteria for efficacy and safety assessment, sample size
estimation, possible interim analysis and data monitoring,
statistical and clinical inference.
 Other Considerations: In addition to these
considerations, some other issues are dependent on
individual trials e.g. treatment duration, patient
compliance, missing value and drop outs.

52. NON-RANDOMISED CONTROLLED
CT’S DESIGNS
 In non-randomised controlled trials, participants are
allocated into treatment and control arms by the
investigator. In these trials, control groups can be
concurrent controls or historical controls. When using
a historical control, all subjects in the trial receive the
study medicine: the results are either compared to the
patient’s history for example a patient living with a
chronic illness or a previous study control group.

53. RANDOMISED CONTROLLED CT
DESIGNS
 In randomised controlled trials, trial paticipants are
randomly assigned to either treatment or control arms.
The process of randomly assigning a trial participant
to treatment or control arms is called randomisation.
Different tools can be used to randomise (closed
envelops, computer generated sequences, random
numbers). There are two components to
randomisation: the generation of a random sequence
and the implementation of that random sequence,
ideally in a way that keeps participants unware of the
sequence. Randomisation removes potential for bias.

54. Different Types of Randomised
Trial Designs
 Parallel group trial design
 Cross-over trial design
 Matched pair trial design
 Stratification
 Cluster sampling
 Withdrawal trial
 Factorial design

55. DIFFERENT DESIGNS OF TRIALS
 Parallel Group Design: A parallel group design is a
complete randomised design in which each patient
receives one and only one treatment in a random
fashion. Basically there are twotypes of parallel group
design for comparative clinical trials, namely, group
comparison (or parallel-group) designs and matched
pairs parallel designs. The simplest group comparison
parallel group design is two group parallel design
which compares two treatments (e.g. a treatment
group vs. a control group). Each treatment group
usually, but not necessarily, contains approximately
the same number of patients.

56. Continue…
 Run in Periods : before patients enter in clinical trial,
a run in or lead in period of placebo, no active
treatment, dietary control, or active maintenance
therapy e.g. diuretic and digoxin in heart failure is
usually employed prior to randomisation. The
inclusion of a run in period prior to the active
treatment has the following advantages:
 It act as a washout period to remove effects of previous
therapy
 It helps in identifying placebo responders

57. Continue…
 It can be used to obtain baseline data and to evaluate if
patients fulfils study entry criteria
 It can be used as a training period for patients,
investigators and their staff
 It provides useful information regarding patient
compliance
 It can be used to estimate and compare the magnitude
of possible placebo effects between groups

58. Cross Over Design
 In the crossover design each subject is randomized to a
sequence of two or more treatments and hence act as his
own control for treatment comparisons. This simple
manoeuvre is attractive primarily because it reduces the
number of subjects and usually the number of assesments
needed to achieve a specific power, sometimes to a marked
extent. In the simplest 2*2 crossover design each subject
receives each of two treatments in randomised order in two
sucessive treatment periods, often separated by a washout
period. Numerous variations exit, such as designs in which
each subject receives a subset of n>2 treatments or ones in
which treatments are repeated with a subject.

59. Titration Designs
 For phase 1 safety and tolerance studies, Rodda et al.
(1988) classify traditional designs as follows:
 Rising single dose design
 Rising single dose cross over design
 Alternative panel rising single dose design
 Alternative panel rising single dose cross over design
 Parallel panel rising multiple dose design
 Alternative panel rising multiple dose design

60. Factorial Designs
 In a factorial design two or more treatments are evaluated
simultaneously through the use of varying combinations of
the treatments. The simplest example is 2*2 factorial
design in which subjects are randomly allocated to one of
the four possible combinations of two treatments , A and B
say. These are A alone, B alone, both A and B and neither A
nor B. The statistical test of interaction may lack power to
detect an interaction if the simple size was calculated
based on the test for main effects. This consideration is
important when this design is used for examining the joint
effects A and B in particular, if the treatments are likely to
be used together.

61. Matched Pair Trial Design
 In the matched pair design, participants are first
matched in pairs according to certain characteristics.
Then, each member of a pair is randomly assigned to
one of the two different study subgroups. This allows
comparison between similar study participants who
undergo different study procedures.
 After screening, participants are matched into pairs.
Within each pair one participant is randomised into
treatment A while the other is randomised onto
treartment B.

62. Stratification
 Stratification also allows for comparison between
similar study participants who undergo different study
procedures. All study participants are grouped
according to one or more factors for example age,
gender, lifestyle factors, concomitant medication
before being randomised. This ensures balanced
allocation within each combination.

63. Cluster Sampling
 Randomised trials can also use cluster sampling. In
cluster sampling, suitable geographical areas are found
for instance, city, region etc. A number of these
geographical areas are then randomly chosen. For each
of these chosen geoghraphical areas, a proportionate
subsample from the members of the study sample in
that area are chosen and these subsamples are then
combined into a sample group.

64. Withdrawal Trials
 In a withdrawal trial, the participant receives a test
treatment for a specified time and are then
randomised to continue either with the test treatment
or a placebo (withdrawal of active tharapy).
 During a withdrawal trial, after the first specified
period of time has elapsed, participants are
randomised into two groups, one of which receive the
active treatment.

65. Cohort Studies
 A cohort study is a particular form of longitudinal
study (panel study) that sample a cohort ( a group of
people who share a defining characteristic, typically
who experienced a common event in a selected
period,such as birth) performing a cross-section at
intervals through time. A cohort study is a panel study,
but a panel study is not always a cohort study as
individuals in a panel study do not always share a
common characteristic.
 A cohort study is a quasi-experiment used in medicine,
nursing, psychology, social science and ecology.

66. Continue…
 For instance , in medicine , it is an analysis of risk
factor and follows a group of people who typically do
not have a given disease and uses correlations to
determine the absolute risk of subject contraction. It is
one type of clinical study design and should be
compared with a cross-sectional study. Cohort studies
are largely about the life histories of segments of
populations and the individual people who constitute
these segments.

67. Continue…
 Indicators of cohort study:
 When there is a strong association between cause and
effect , established by any observational study
 When the exposure is rare, but incidence of disease
among exposed is high
 When people’s attrition can be minimised
 When resources are sample
 Cohort studies can be retrospective(looking back in
time) or prospective(requiring the collection of new
data).

68. Continue…
 Advantage of prospective cohort study data is that it
can help determine risk factors for contracting a new
disease because it is a longitudinal observation of the
individual through time and the collection of data at
regular intervals so recall error is reduced.
 In a cohort study the population under investigation
consists of individuals who are at risk of developing a
specific or health outcome.

69. ROLES AND RESPONSIBILITIES OF
THE CLINICAL RESEARCH TEAM
The Research Team
 Need sufficient study staff to perform clinical research
efficiently and effectively:
 Appropriate skill set and training
 GCP ( Good Clinical Practice ) standards
 Follow protocol requirements

70. RESEARCH TEAM
 Principal Investigator (PI)
 Sub Investigator (Sub I)
 Clinical Research Nurse Coordinator (CRNC)
 Clinical Research Coordinator (CRC)
 Regulatory Coordinator
 Key Personnel

71. Principal Investigator
 An individual who conducts a clinical investigation or
in the event of an investigation conducted by a team of
individuals is the responsible leader of the team.
 Principal Investigators responsibilities can be found in
the following sections of the regulations:
 IND trials
 IDE trials
 ICH E6 Guidelines
 The investigator must also be aware of any local rules
or regulation in addition to those outlined in the CFR

72. INVESTIGATOR STATEMENT
 A contract between the sponsor and the investigator in
which the investigator agrees to comply with the protocol
and all regulations pertaining to clinical research
 Signed before a clinical trial involving an investigational
drug or biologic can begin
 Not a regulatory requirement, used frequently in IND
(Investigational New Drug) studies
 Investigators participating in IDE (Investigational Device
Exemption) studies do not complete a form FDA , but
similar information is collected by the sponsor sometimes
called an investigator agreement

73. Continued...
 Investigators must understand and adhere to federal
regulations.....it’s the law
 The regulations are in place to protect the rights, safety
and welfare of study subjects

74. Clinical Research Coordinator
 Manages and conducts the day to day study activities
in accordance with the protocol, applicable regulations
and GCP requirements
 Vital to the success of a trial
 Come from a variety of backgrounds
 The responsibilities of CRC have expanded to beyond
the clinical management of subjects to much more
sophisticated expertise in compliance, research
administration, marketing, fiscal and legal activities

75. Continued...
 CRC qualities:
 Attention to detail
 Excellent communication skills
 Flexibility
 Ability to work independently
 Organizational skills
 Grit / can do attitude

76. DATA MANAGER
 Manage the collection of data throughout the course
of a clinical trial. This person –
 Enters the data
 Works with the principal investigator and research
nurse to identify what data will be tracked
 Provides data to monitoring agencies
 Prepares summaries for final data analysis

77. STAFF PHYSICIAN OR NURSE
 Helps take care of the patients during a clinical trial.
This person-
 Treats patients according to the clinical trial protocol
 Assesses and records how each patient responds to the
treatment and the side effects they may have
 Works with the principal investigator and research
nurse to report trends of how patients are doing on the
treatment
 Manage each patient’s care

78. Additional Research Personnel
 Sub-investigator : A member of the research team
designated and supervised by the PI to perform critical
study related procedures and to make important study
related decisions
 The FDA regards sub investigators as those individuals
authorized to make medical judgements and decisions
regarding study subjects
 CRNC Clinical Research Nurse Coordinator
 Certain protocol related activities may require a license
or certificate of training (ex. Administration of
medications or Glasgow Coma Scale)

79. Additional Research Personnel
 Regulatory Coordinator/ specialist
 Prepares and maintains IRB submissions and
regulatory documents
 Tracks study progress in clinical trial management
systems
 Key Personnel
 Personnel considered to be of primary importance to
the successful conduct of a research project

80. Continued...
 DCGI under CDSCO has the Prime responsibility for
regulating CTs in India
 Declaration of Helsinki by WMA provides Ethical
Guidelines & Principles to the Physicians, other
participants & Human subjects
 ICMR code includes statement of general & specific
principles on research using human subjects in
biomedical research.

81. Continued...
 ICH-GCP Guidelines unified standard for EU, Japan &
USA to facilitate the mutual acceptance of Clinical
Data by the Regulatory Authorities in these
jurisdiction
 Indian GCP Guidelines are in line with WHO, ICH,
USFDA and European GCP Guidelines as well as ICMR
code
 Drugs and Cosmetics Act 1940 & schedule Y tells the
requirement and guidelines on Clinical Trials for
import & manufacture of new drug in India

82. Continued...
 Clinical trials are different than routine Medical care
 India became a member of WTO in 1995 and agreed to
adhere to product & process patent regime from 2006
 India provides excellent environment for CT: in terms
of less cost, speed, quality parameters of global clinical
trials leading to significant growth in clinical trial
outsourcing to India
 Study team at trial site include investigator, co-
investigator, study coordinator, nurse, pharmacist.

83. Continued...
 Unblinded personnel
(coordination/nurse/pharmacist) are required in
blinded trials for dispensing the trial medications to
the study subjects
 Clear delegation of duties to the study team members
is essential for the smooth execution of a clinical trial

84. Continued...
 Individual Member of the study team can be delegated
specific trial duties such as :
 Administration of ICF
 Recruitment of Subjects
 Correspondence with EC/CRO/Sponsors
 Storage, dispensing & Accountability of Drugs
 Completion of source documents
 Completion of CRF
 Medical Management of the trial subject

85. Continued...
 Reporting of SAE (Adverse Events)
 Escalations, resolutions, management of deviations
 Logistics management
 Resolution of data enquiries
 Patients visit scheduling, protocol compliance & follow
up
 Maintenance of site master file
 Compliance with GCP & regulatory guidelines
 Tracking of payments/ study grants

86. INFRASTRUCTRUAL REQUIREMENTS
 Space for storing trial documents & materials
 Communication facility
 Local laboratory facility
 USG/ Biopsy / CT-Scan /MRI Scan facility
 Wards /ICU/ Operation theatre facility
 Archival facility
 SOP
 Lockable trial rooms/ storage cabinets
 National or internationally accredited laboratories
 Well defined quality control standards

87.  Well defined rules & requaltions of the site
 SOP for trials & subject recruitment
 Recruit study coordinator, research staff
 Ensure storage & archival facility
 Tripartite/ bipartite agreement

88.  Sponsor/CRO forwards the following documents to
the clinical investigator for review & completion:
 Study protocol
 Patient information sheet & PIC
 Investigator brochure
 Case record form
 Insurance/ indemnity certificate
 Patient diaries/ questionnaire
 Format of understanding by investigator

89.  Draft of CTA between investigator & sponsor/ CRO
 Regulatory clearance ( DCGI ) NOC
 No. Of copies of above documents for EC application

90.  Site is selected for CT after sucessful evaluation of the
site by the sponsor/ CRO
 Careful CTA drafting& suggestions can avoid issues
like, payment delays, frequent amendments, retain
dedicated study personnel.
 Investigators training meeting is conducted to provide
a uniform understanding of protocol & process to all
the paricipants

96. RESEARCH STUDY DOCUMENTATION
 STUDY AND SUBJECT REQUIREMENT:
 Study specific should be able to recreate the study
form the study documentation. All study from the
study documentation. All study documents related to
the study are generally found in the regulatory
file/binder.
 Subject specific: should tell the story of the subjects
participation in the study and the conduct of the
study. Use case report forms and source records to
document.

97. PROTOCOL LEVEL DOCUMENTATION
REQUIREMENT
 ICH-E6 GCP
 Investigator : ensure the accuracy, completeness,
legibility and timelines of CRF data and in all required
reports
 CRF data is consistent with the source documents or
the discrepancies should be explained
 Maintain study documents as specified in Essential
documents or regulatory requirements take measures
to prevent accidental or premature destruction of
these documents.

98. STUDY DOCUMENTATION
 To verify that subject rights and welfare were protected
 To ensure the integrity and credibility of the collected data
 To ensure the study was conducted in compliance with the
protocol, regulations, institutional requirements
 All documentation by study staff, including investigators,
coordinators, assistants and anyone who has study related
contact with the participant
 Study related documents/data study staff initiate, receive
or send
 Documentation by other clinical provider
 Documentation by other entities involved in the study

99. REGULATORY DOCUMENTATION
 Regulatory files are the repository for a study’s
essential documents.
 Before any trial can begin, federal and sponsor
required regulatory documents will be collected
 Usually the originals are kept at the site and copies are
provided to the sponsor.

100. Regulatory file
 Keep one regulatory file for each study:
 Binder
 Filling cabinet drawer
 Electronic
 Documents are filled in order under each main tab and are
organised in reverse chronological order (the most recently
dated item is filled at the front of the section)
 As the contents exceed the capacity of one binder or file
box, additional binders/boxes are added. The table of
contents should list the binder or box number in which
each section is located

101.  Files will have varying documents depending on
regulations being followed
 Subject files are kept separately
 Keep file audit ready

102. Required documents
 Signed, IRB approved protocol and amendments and
any SOPs if not spelled out in protocol
 IRB approved consent forms
 IRB approved letters
 IRB member roster
 Delegation of authority log
 Form 1572, if applicable
 Financial disclosure forms
 Training records of staff

103. Subject specific documentations
 Attributable: it should be obvious who wrote or did what
 contemporaneous: the notation, signature and date need
to be completed at the same time and as close to event as
possible
 Legible: capable of being read
In a human readable format
Print name if signature is illegible
 Original: for recording of the information (paper,
electronic)
 Accurate: errors have been identified and corrected

104. Source data
 All information in original records and certified copies
of original records of clinical findings, observations or
other activities in a clinical trial necessary for the
reconstruction and evaluation of the study
 Confirmation of subject existence and observations
 Substantiation of study data integrity

105. Source documents
 All information in original records and certified copies
of original records ...
 Includes clinical findings, observations and other
study activities
 The first time data is captured : napkin, report, log,
database

106. Data collection tools
 Record of the protocol required data for the study
 Forms the basis for analysis of the study data
 Standardizes the collection of data to help ensure that
the medical, statistical, regulatory and data
management needs of the study are met
 CRF and databases

107. CRF
 Can be paper or electronic
 Information is complete, accurate and legible
 All fields are completed : use ND or NA ( follow SOP)
 DIRECT ELECTRONIC DATA CAPTURE
 Diaries: participants are asked to enter data into a
device provided by sponsor on regular basis
 Collection of direct responses from participants to
questionnaries
 Directly enter source information in a database

108. Importance of documentation
 Over the past 5 years, 25-30% of all warning letters
from the FDA to investigators were related to
inadequate/inaccurate records
 This is the 2nd most sited deficiency in the country

109. RESEARCH DOCUMENTATION
 Source documents: are original records and certified
copies of original clinical findings and observations, or
other activities in a clinical trial necessary for the
reconstruction and evaluation of the trial.
 Case report form(CRF) : a printed, optical or
electronic document designed to record all of the
protocol required information to be reported to the
sponsor for each trial subject to capture essential
source data about the subject for analysis to answer the
hypothesis of a study.

110.  Data management : is the responsibility of the research
staff and a host of other IT professionals related to
collecting, entering, securing and preserving data as a
valuable and reproducible resources for the outcome of the
study
 Data integrity: includes the development of policies and
ethical practices for consistent procedures that properly
manage the full data lifecycle needs for the outcome of the
clinical trial. The principal investigator (PI) is the person
responsible for data integrity, but must reply on the team of
research professional in IT and the research coordinator to
uphold the policies.

111. REFRENCE
 http://www.google.com
 http://www.slideshare.net
 Wikipedia
 “Publishing and Presenting clinical Research”,third
edition by S. Warren
 “Practical Guide to Clinical Data Management”, third
edition by P.S.
 “Fundamentals of Clinical Trials”, 4th edition by F.M.
Lawrence

112. THANK
YOU