Clinical research

Introduction
 Clinical Research is a branch of healthcare science
that determines the safety and effectiveness of
medications, devices, diagnostic products and
treatment regimens intended for human use.
 Research is a laborious and time consuming task that
can take several years. Drug development research in
particular is long and arduous and bringing a single
new drug costs on an average USD 1.7 billion and takes
approximately 13.5 years from discovery to the market.

Introduction
 Clinical trial is any research study that prospectively
assigns human participants or groups of humans to
one or more health related interventions to evaluate
the effects on health outcome.
 Clinical trials are conducted to collect the data
regarding the safety and efficacy of new drug and
device development.
 Father of clinical trials---James Lind.

Importance of clinical trials
 Clinical trials are important for discovering new
treatments for diseases as well as new ways to detect,
diagnose and reduce the chance of developing the
disease.
 Clinical trials can show researchers what does and
doesn’t work in humans that cannot be learned in the
laboratory or in animals.
 Clinical trials also help doctors decide if the side
effects of a new treatment are acceptable when
weighed against the potential benefits

 Preclinical trials: Investigational drug must be tested
on animals to determine the safety to administer
humans. This phase lasts from 1 to 5 years.
 This test provides information about the
pharmaceutical composition of the drug, safety and
how the drug will be formulated, manufactured and
how it will be administered to the human subjects.

Types of Clinical Trails
 There are two main types of clinical trials----
observational and interventional
 Observational Clinical trials: these trials does not
involve treatments or drugs. Researchers observe
participants by monitoring their health over a period
of time. These studies provide researchers with data
that advances our understanding of Parkinson’s and
how to treat the disease.

Types of Clinical Trials
 Interventional Clinical trials: These trials test the
safety and effectiveness of a candidate drug, therapy or
experimental treatment.
Within these broad categories, trials also can be
classified as follows.
 Treatment trials: Generally involves an intervention
such as medication, psychotherapy, new devices or
new approaches to surgery or radiation therapy

 Prevention trials: looks for better ways to prevent
disorders from developing or returning. Different
kinds of prevention research may study medicines,
vitamins, vaccines, minerals or lifestyle changes.
 Diagnostic trials: refers to the practice of looking for
better ways to identify a particular disorder or
condition.
 Screening trials: aims to find the best ways to detect
certain disorders or health conditions

 Quality of life trials: explores ways to improve
comfort and the quality of life for individuals with a
chronic illness.
 Genetic studies: aims to improve the prediction of
disorders by identifying and understanding how genes
and illness may be related. Research in this area may
explore ways in which a person’s genes make him or
her more or less likely to develop a disorder. This may
lead to development of tailor made treatments based
on a patient’s genetic make up.

Who conducts the clinical trial?
 The clinical trials are conducted by the Principle
Investigator in Academic center, Clinical Research
Organizations and Hospitals etc called as sites.

Sponsors for clinical trial
 Sponsor is an individual, institution, company or
organization that takes the responsibility to initiate,
manage or finance the clinical trial.
 Pharma and Biotechnology companies
 National Institute of Health
 National Cancer Institute
 Department of Defence
 Medical Institutions and foundations.

Regulatory Bodies
 The Central Drug Standard Control Organization is
the National Regulatory Authority in India. Other
regulatory bodies are USFDA, Health Canada,
European Medicines Agency.
 CDSCO is an arm of the Ministry of Health and Family
Welfare, Government of India. Its mission is to
safeguard and enhance public health by assuring the
safety, efficacy and quality of drugs, cosmetics and
medical devices.

Regulatory Bodies
 The Drugs Controller General of India (DCGI) is an
official of the CDSCO who is final regulatory authority
for the approval of clinical trials in the country.
 Indian Council of Medical Research (ICMR) is the
apex body that is responsible for the formulation,
coordination and promotion of biomedical research. It
provides the ethical guidelines for conducting the
clinical trials.

Trial Master File
TMF is a collection of essential documents which are
necessary for conducting a clinical trial. TMF is usually
maintained by the sponsor or sponsor representative
(CRO). The following essential documents are
1) Protocol: It is a document that describes the
background, rationale, objectives, design,
methodology, statistical considerations and
organization of clinical research project.

Trial Master File
2) Informed Consent Form: According to ICH-GCP
Informed consent is a process by which a subject
voluntarily confirms his or her willingness to
participate in a particular trial, after having been
informed of all aspects of the trial that are relevant to
the subject’s decision to participate. Informed consent
is documented by means of a written, signed and
dated informed consent form. If the subject is minor
or older, an Assent form is obtained and is also signed
by the guardians.

Trial Master File
3) Investigator Brochure: It is a compilation of the
clinical and non clinical data on the investigational
products that are relevant to the study of the products
in human subjects.
4) Financial aspects of the trial: It is essential to
document the financial agreement between the
investigator/ institution and the sponsor for the trial.
5) Insurance statement: It is essential to document
that compensation to subjects for trial related injury
will be available.

Trial Master File
6) Signed agreement between the involved parties:
It is essential to document the agreements between
the Investigator/Institution and sponsor,
Investigator/Institution and CRO, Sponsor and CRO,
Investigator/Institution and authority.
7) IRB/IEC Composition: It is essential to document
that the IRB/IEC is constituted in agreement with
GCP.

Trial Master File
8) Regulatory authority approval document: To
document appropriate authorization/ approval
/notification by the regulatory authority has been
obtained prior to initiation of the trial in compliance
with the applicable regulatory requirements.
9) Curriculum Vitae of Investigator, sub
investigator: To document qualifications and
eligibility to conduct trial and provide medical
supervision of subjects.

Trial Master File
10) Normal value ranges for medical laboratory/
technical procedures /tests included in the
protocol: To document normal values and ranges of
the tests.
11) Medical laboratory technical procedures tests: To
document competence of facility to perform required
tests and support reliability of results.

Trial Master File
12) Samples of labels attached to the investigation
product containers: To document compliance with
applicable labeling regulations and appropriateness of
instructions provided to the subjects.
13) Instructions for handling of investigational
product and trial related materials: To document
instructions needed to ensure proper storage,
packaging, dispensing and disposition of
investigational product and trial related materials.

Trial Master File
14) Shipping records for investigational products
and trial related materials: To document shipment
dates, batch numbers and method of shipment of
investigational product and trial related materials.
15) Certificate of analysis of investigational
products shipped: To document identity, purity
and strength of the investigational product to be
used in the trail.

Trial Master File
16) Decoding procedure for the blinded trials: To
document how incase of emergency identity of
blinded investigational product can be revealed
without breaking the blind for the remaining subjects
treatment.
17) Master randomization list: To document method
for randomization of trial population.
18) Pre trial monitoring report: To document that the
site is suitable for the trial.

Trial Master File
19) Trial Initiation monitoring report: To document
that trail procedures were reviewed with the
investigator and the investigator’s trial staff.

Eligibility Criteria
 Each study protocol has guidelines for who can or
cannot participate in the study. These guidelines called
eligibility criteria. It describe characteristics that must
be shared by all participants. This criteria differ from
study to study. They may include age, gender,
medical history and current health status.
Eligibility criteria for treatment studies often require
that patients have a particular type and stage of cancer.

Randomization
 Randomization is the process of assigning patients by
chance to groups that receive different treatments. In the
simplest trial design, the investigational group receives the
new treatment and the control group receives standard
therapy. Randomization is of 4 types.
1) Simple randomization
2) Randomized block design
3) Stratified randomization
4) Adaptive randomization

Randomization
Simple Randomization: The most common and
basic method of simple randomization is flipping a
coin. Computer generated random numbers can also
be used for simple randomization of subjects.
Randomized Block design: The subjects are divided
into 2 blocks based on gender such as male and
female. Then within each block, subjects are randomly
assigned to treatment group and control group. Then
samples are collected analyzed and compare the
results.

Randomization
Stratified Randomization: Stratified randomization
refers to the situation in which strata are constructed
based on values of prognostic variables and a
randomization scheme is performed separately within
each stratum. For example, suppose that there are two
prognostic variables, age and gender, such that four
strata are constructed.

Randomization
Adaptive Randomization: It refers to any scheme in
which the probability of treatment assignment
changes according to assigned treatments of patients
already in the trial.
 Parallel study: One group receives only A treatment
and other group receives only B treatment.
 Cross over study: One group receives A and followed
by B and other group receives B and followed by A.

Bias
Bias is the intentional or unintentional adjustment in
the design or conduct of clinical trial and analysis and
the evaluation of the data may affect the result. Bias
can occur during the trial design, data collection, data
analysis and publication.

Blinding
 Blinding is a procedure in which one or more parties
in a trial are kept unaware of which treatment arms
participants have been assigned to that is which
treatment was received in order to avoid bias.

Types of Blinding
 Un blinded or Open labeled study: In which both
the participant and investigator knows about
medication details.
 Single blinded study: The participant don’t know
about the medication but the investigator knows
about medication.
 Double blinded study: The participant and
investigator both don’t know about the medication.
 Triple blinded study: The participant, investigator
and statician also don’t know about the medication

Phase 0
Phase 0 (Micro dosing studies):
 Duration—1 week
 Participants—10 to 15
 Dose of drug---≤100 µg
 Use---Determination of preliminary PK parameters.
If the medication acts differently than expected, the
investigators will likely to do some additional
preclinical research before deciding whether to
continue the trial.

Phase I
Phase 1 (Human Pharmacology studies):
 Duration---one month to several months
 Participants---20 to 80 Healthy volunteers
 Use---Determination of safety, tolerability,
Pharmacokinetics and pharmacodynamics.
 The main aim of this phase is to determination of
highest dose that human can take without serious side
effects.

Phase I
 Finding best ways to administer the drug such as
orally, intravenously and topically etc.
 Investigators monitor participants very closely to see
how their bodies react to the medication during this
phase. While preclinical research usually provides
some general information about dosing, the effects of
medication on the human body can be un predicatble.
 According to FDA approximately 70% of medications
move on to phase 2.

Phase I
 There are 3 methods to conduct phase 1 studies:
 Single ascending dose(SAD) or phase I A: A single
dose of the drug is given to small group (3 members)
of people. If they are safe then we will increase the
dose to another 3 members.
 Multiple ascending dose (MAD) or Phase IIA:
Multiple doses of the drug is given at different time
points. Samples are collected and analyzed.

Phase I
 Food effect: Designed to investigate any differences in
absorption of the drug by the body caused by eating
before the drug is given. These studies are run as cross
over studies.
 Reasons to select healthy volunteers:
 Large number of people available and greater
compliance
 Risks are considerably reduced
 More homogenous group and rapid recruitment rate.
 Incase of ADR’s chances of speedy and complete
recovery will be more.

Phase II
 Phase II (Therapeutic Exploratory studies):
 Duration---several months to 2 years.
 Participants---20 to 300 patients.
 Use ---Determination of efficacy of drug.
 Dose ---there’s is usually given the same dose that was
found to be safe in the previous phase.
 According FDA approximately 33% medications move
on to phase 3.

Phase II
 Phase II trials are of 2 types
Phase II A:
 These studies are also called as early phase, pilot
clinical trails.
 Require 20 to 200 patients.
 Single blinded and single center trials
 To assess safe dose of the drug
 Test drug compares with the placebo.

Phase II
Phase II B:
 These studies are also called as late phase, pivotal
clinical trials
 Require 50 to 300 patients.
 Double blinded and multicentric trials.
 We should know about therapeutic dosage regimen,
frequency of administration and duration of therapy.
 Test drug compares with the placebo or standard drug.

Phase III
Phase III (Therapeutic confirmatory studies):
 Duration---≤5 years
 Participants---300 to 3000 patients.
 Main objective is proving or confirming the clinical
efficacy with no unacceptable safety concerns.
 To do this the investigators use a process called
randomization
 According to FDA approximately 25 to 30% of
medications move on to phase 4.

Phase III
 Phase III studies are 2 types:
 Phase IIIA or prior NDA studies:
 With the efficacy and safety data obtained from the
phase II trials, phase III a trials are initiated.
 Most of the phase III studies are conducted in phase III
a trials like non inferiority trials, long term safety
studies.

Phase III
 Most of the studies producing the information
supporting the patient information leaflet/ label along
with post marketing commitments. Some studies may
also conducted in special population depend upon the
drug/disease.
 Most of the times drug candidate compared with an
active comparator. If there is a lack of standard
treatment for target disease, drug candidate compared
with the placebo. This phase done before getting the
first indication approval.

Phase III
Phase IIIB or After NDA studies: This phase starts
after getting first approved indication from regulatory
authority and before getting the marketing approval/
launch of the drug.
 These are additional studies which gather additional
information like long term safety and drug effect on
quality of life etc.
 The intention of these studies is to produce the data
supporting the publications and marketing claims.

Phase IV
Phase IV (Pharmacovigilance studies):
 The phase 4 trials also referred to as post marketing
surveillance and as the name suggests, it is conducted
after the drug is already marketed and available to the
public.
 The main objective of this phase is to check the drug
performance in real life scenarios, to study the long
term risks and benefits of using the drug to discover
any rare side effects.
 If any rare adverse event observed in larger population
the drug must be withdrawn from the market.

Best practices for clinical trial operations
To conduct clinical trials efficiently and effectively
from start to finish, there are number of factors to
consider. These factors in trials can have impact on
outcome the clinical trial. The following are a few best
practices for clinical operations.
Pre Trial Due Diligence:
 Protocol: Before starting the trial, the most important
factor is understanding the protocol and what it
requires from a logistical standpoint.

 This understanding must come from a comprehensive
assessment, considering the protocol from the
perspective of the site, investigator, coordinator and
patient.
 Evaluating the protocol from the perspective is
particularly important, as understanding the logistical
requirements from their point of view will help with
the recruitment of patients willing and able to commit
to participating in the trial from start to finish.

 Site Selection: Once understanding the protocol is
complete, it will be easier to begin the site selection process
and start considering what type of sites you will need for
the trial such as private practices, specialized clinics,
hospitals, group practices etc.
 Site distribution should also be considered. It is
beneficial for sites to be geographically diverse so the trial
is accessible to more patients. Consider how each region
might affect the study. For example does the population of
an area fluctuate throughout the year or does it remain
steady? How might the whether within the region impact
your trial?

 Pre feasibility assessments can help provide a
critical snapshot of the current landscape for your trial
before the trial begins. Are there sites interested and
available to participate in your trial? The information
received from pre feasibility assessments can provide
the baseline for developing initial assumptions
regarding recruitment and enrollment.

 In the pre feasibility assessments, a site’s proposed
recruitment methods can be collected. This
information can be used to determine which methods
of recruitment would be ideal. Should social media be
considered or would the trial be better suited for more
traditional methods, such as print, TV or radio
advertising

 Risk assessment: An initial risk assessment should also be
conducted during the pretrial phase. Risks can affect each
stage of the trial. By identifying and categorizing risks from
the beginning, sponsors can be aware of potential risks to
begin determining whether to accept, avoid, mitigate or
transfer these risks.
 Consider non protocol risks. For example, have the sponsor
and CRO ever worked together? If the sponsor and CRO do
not have an established working relationship, risk
mitigation may be needed for each party to have a clear
understanding one another’s responsibilities, expectations,
needs and treatment.

 Risk mitigation may also be necessary if the CRO
and/or Sponsor have never worked with the vendors
selected for the trial. Clarifying pathways of
communication is key to managing these
relationships---knowing from the start who to contact
and how to communicate across project team
members from the sponsor, CRO and vendors can help
avoid future confusion, delays and unnecessary back
and forth.

 Training-Finally during the pre trial phase training
should be considered both training of site personnel
and project team members. Again, understanding the
protocol is key in determining how much training is
needed and the best way to deliver that training.
Recording trainings is best practice. By recording live
trainings, site personnel and project team members
can complete initial or refresher self paced training by
reviewing the recordings independently.

 CRA: During the pre trial phase consideration should
be given to whether Clinical Research Associates will
be involved in the study start up activities. Involving
CRA’s in study start up activities early on is beneficial
for training purposes.

Trial Maintenance and Close out:
 The two key factors to consider during trail
maintenance are enrollment and data: ensuring each
site is enrolling patients that meet all eligibility criteria
and ensuring accurate data is being collected.
 Enrollment: The actual enrollment of subjects is
slower than the projected enrollment data. Study level
material should be developed and made available to
sites from study start to facilitate enrollment for your
trial.

 Bringing site personnel together to discuss enrollment
and share successes, failures, challenges and best
practices can help identify enrollment trends and
challenges. Conducting site recruitment calls/ visit to
collect detailed information regarding sites
recruitment and enrollment activities provides
valuable information regarding enrollment activity.

 Enrollment should be monitored frequently at both
the site and study level. Actual enrollment should be
compared to the projected enrollment data regularly. If
your trial is not meeting the projected enrollment
goal, the projected enrollment may need to be re
evaluated and updated.

 Data: Gathering clean data is among the most
important steps to a successful clinical trial. Sites can
be found, patients can be recruited, but if the data is
inaccurate, it will not be of use to the sponsor.
 Data is also a key factor to consider during trial close
out. However the primary focus from a clinical
operations perspective is data cleaning to meet the
database lock milestone.

 CRA’s should collaborate directly with data
management to ensure data is monitored and cleaned
on an ongoing basis.
 Data management should provide status trackers or
reports routinely that outline the current status of CRF
data review---what queries are open, what data has
been SDVed, what data has been frozen etc.

Nuremberg Trials
 Nuremberg trials were a series of 13 trials carried out in
Nuremberg, Germany, between 1945 and 1949. The
defendants, who included Nazi party officials and high
ranking military officers along with German industrialists,
lawyers and doctors were indicted on such charges as
crimes against peace and crimes against humanity.
 In these trials involuntary subjects are involved most of
whom were imprisoned Jews, Poles, Russians and Roma.
The verdict included a section entitled “Permissible
Medical Experiments” now called the Nuremberg Code
that addressed fundamental issues on the use of human
subjects in medical research

Tuskegee Syphilis Study
 In 1932 the public health service working with
Tuskegee Institute began a study to record the natural
history of Syphilis in hopes of justifying treatment
programs for blacks. It was called the “Tuskegee study
of Untreated Syphilis in the Negro male.
 The study was conducted without the benefit of
patient’s informed consent. Researchers told the men
they were being treated for bad blood, a local term
used to describe several ailments, including Syphilis,
anaemia and fatigue. In truth they did not receive the
proper treatment needed to cure their illness.

Tuskegee Syphilis Study
 The subjects undergone free medical examinations
and they provide free meals, transportation and burial
insurance.
 On July 1972, the public learned that, over the course
of the previous 40 years experiment had allowed
hundreds of African American men with Syphilis to go
untreated even after Penicillin was discovered as a cure
for Syphilis.

Nuremberg Code
 The Nuremberg code was introduced in August 1947,
after Nuremberg trials. It attempted to give clear rules
about what was legal and what was not when
conducting human experiments.
 The code consists of ten points.
1) The voluntary consent of the human subject is
absolutely essential.
2) The experiment should be such as to yield fruitful
results for the good of society, unprocurable by other
methods or means of study and not random and
unnecessary in nature.

Nuremberg Code
3) The experiment should be so designed and based on
the results of animal experimentation and a
knowledge of the natural history of the disease or
other problem under the study, that the anticipated
results will justify the performance of the experiment.
4) The experiment should be so conducted as to avoid all
unnecessary physical and mental suffering and injury.

Nuremberg Code
5) No experiment should be conducted, where there is
an priori reason to believe that death or disabling
injury will occur, except perhaps, in those experiments
where the experimental physicians also serve as
subjects.
6) The degree of risk to be taken should never exceed
that determined by the humanitarian importance of
the problem to be solved by the experiment.

Nuremberg Code
7) Proper preparation should be made and adequate
facilities provided to protect the experimental subject
against even remote possibilities of injury, disability or
death.
8) The experiment should be conducted only by
scientifically qualified persons. The highest degree of
skill and care should be required through all stages of
the experiment of those who conduct or engage in the
experiment.

Nuremberg Code
9) During the course of the experiment, the human subject
should be at liberty to bring the experiment to an end, if he
has reached the physical or mental state, where
continuation of the experiment seemed to him to be
impossible
10) During the course of the experiment, the scientist in
charge must be prepared to terminate the experiment at
any stage, if he has probable cause to believe, in the
exercise of the good faith, superior skill and careful
judgement required of him, that a continuation of the
experiment is likely to result in injury, disability or death to
the experimental subject.

Belmont Report
 Belmont report was published in 1979, in this the basic
guidelines are intended to prevent ethical problems
related to research. It is commissioned by the US
Government in response to ethical failures in medical
research, such as the Tuskegee Syphilis Study. The
Belmont report was written by a panel of experts and
proposes following three principles.
 Respect for persons
 Beneficence
 Justice

Belmont Report
 Respect for persons consists of two distinct principles
–individuals should be treated as autonomous and
individuals with diminished autonomy should be
entitled to additional protections.
 The principle of respect for persons is interpreted to
mean that researchers should, if possible, received
informed consent from participants and the Belmont
report identifies 3 elements of informed consent such
as information, comprehension and voluntariness.

Belmont Report
 The principle of Beneficence is behind efforts by
researchers to minimize risks to participants and
maximize benefits to participants and society.
 The principle of justice addresses the distribution of
the burdens and benefits of research. That is it should
not be the case that one group in society bears the
costs of research while another group reaps its
benefits. Issues of justice arise most strongly around
questions about the selection of participants.

Declaration of Helsinki
 The world medical association (WMA) has developed
the Declaration of Helsinki as a statement of ethical
principles to provide guidance to physicians and other
participants in medical research involving human
subjects.
 The Declaration was the first document to require that
biomedical research involving humans conform to
generally accepted scientific principles

Declaration of Helsinki
 The Declaration specifies information that must be
given to the subject before consent is obtained,
including all foreseeable risks and discomforts, the fact
that he or she may withdraw at any time, and a
complete description of the study protocol.

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