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CLINICAL TRIALS
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WHAT ARE CLINICAL TRIALS?
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Clinical trials are a set of procedures in medical
research conducted to allow safety and efficacy data to be
collected for health interventions.
The international conference on harmonization defines a
clinical trials as “Any investigation in humans subjects
intended to discover or verify the clinical, pharmacological
and/or other pharmacodynamic effects of an investigational
product, and/or to identify any ADR to an investigational
drugs, and/or to study ADME of drug with the objective of
ascertaining the safety and efficacy”. This is also termed as
randomized control trial
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WHAT ARE CLINICAL TRIALS?
 Research
studies involving people
 Try to answer scientific questions and
find better ways to prevent, diagnose, or
treat disease
 Translate results of basic scientific
research into better ways to prevent,
diagnose, or treat disease
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DIFFERENT TYPES
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OF
CLINICAL TRIALS
Treatment trials - test new treatment, new
combinations of drugs, or new approaches to
surgery or radiation therapy (for people with a
particular disease).
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,
vitamins, vaccines, minerals or lifestyle changes.
Screening 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
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DRUG DEVELOPMENT PROCESS
Investigational New drug (IND)
 Pre clinical studies (animal studies)
 USFDA- ask for
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Description of drug
Chemistry
Preclinical information
Any previous human study
Investigators Brochure
Clinical development plan
Protocol and Investigator submission for first Phase-1
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PRECLINICAL TESTING
Is the drug safe?
 Affects other body systems?
 Effective dose range?
 Pharmacodynamics?
 Pharmacokinetics?
 Is the drug a carcinogen?
 Is the drug a teratogen?
 Long term animal studies confirms cancer or
birth defects.
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DIFFERENT PHASES OF CLINICAL
TRIALS
Clinical trials are conducted in phases. The trials at each phase
have a different purpose and help scientists answer different
questions:
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In Phase I trials, researchers test a new drug or treatment in a
small group of healthy people ( 20 -50) for the first time to evaluate
its safety, determine a safe dosage range.
In Phase II trials, the study drug or treatment is given to a
selected group of patients (100 – 300) to see if it is effective and to
further evaluate its safety.
In Phase III trials, the study drug or treatment is given to a large
group of patients ( 1000 – 3000) to confirm its effectiveness,
monitor side effects, compare it to commonly used treatments, and
collect information that will allow the drug or treatment to be used
safely.
In Phase IV trials, post marketing studies delineate additional
information including the drug’s risks, benefits and optimal use.
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CLINICAL TRIALS TIMELINE ( 605 BC - 1986 AD )
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605 - 562 BC :
The first clinical trial was carried out by King Nebuchadnezzar II .
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1537 :
It was by chance surgeon Ambroise Pare
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 Governments,
regulatory departments, research
organizations, medical professional bodies, and
health care providers emphasize legislation on
ethical conduct of clinical trials.
 Post-World
War II Nuremburg war crimes trials,
more specifically the "Doctors' Trial."
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"DOCTORS' TRIAL."
 The
Medical Case, U.S.A. (the Doctors' Trial) 1946-47.
 Twenty-three
accused.
 War
German doctors and administrators
crimes and crimes against humanity.
 Medical
experiments and medical procedures on
prisoners and civilians.
 >Twelve
series of medical experiments concerning 10
TURNING POINT
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Emerged the Nuremburg Code - basic principles to be
observed when conducting research involving human
subjects.
Subsequently formed the basis for international
guidelines on medical research, such as the
Declaration of Helsinki.
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DECLARATION OF HELSINKI
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June 1964 –The 18th WMA (World Medical Association)
General Assembly at Helsinki, Finland.
Declared ethical principles to provide guidance to
physicians and other participants in medical research
involving human subjects.
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CIOMS
 Council
for International Organizations and
Medical Sciences (CIOMS) produced detailed
guidelines (originally published in 1993 and
updated in 2002).
 Address
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complex issues including
HIV/AIDS research,
availability of study treatments after a study ends,
women as research subjects,
safeguarding confidentiality,
compensation for adverse events,
guidelines on consent.
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ICH-GCP
 To
provide unified standard for European Union
(EU), Japan and United States in facilitating
mutual acceptance of clinical data-International
Conference on Harmonisation (ICH).
 Good
Clinical Practice (GCP) guidelines was
developed with consideration of Australia,
Canada, Nordic countries and WHO.
 GCP
guidelines are like north star in the sky; we
may never reach there but aim to reach (way to
go).
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CLINICAL DEVELOPMENT PLAN
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A successful clinical research process requires a
lot of money, time, human and other resources
and careful planning.
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IMPORTANT TERMS:
INVESTIGATIONAL NEW DRUG (IND): A new drug, antibiotic drug,
or biological drug that is used in a clinical investigation. It also includes a
biological product used in vitro for diagnostic purposes.
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INSTITUTIONAL REVIEW BOARD (IRB):
A committee of physicians, statisticians, researchers, community
advocates, and others that ensures that a clinical trial is ethical and that
the rights of study participants are protected. All clinical trials must be
approved by an IRB before the begin of study.
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NEW DRUG APPLICATION (NDA): An application submitted by the
manufacturer of a drug to the FDA - after clinical trials have been
completed - for a license to market the drug for a specified indication.
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STUDY TEAM AT TRIAL SITE
Study Team at Trial Site include:
Investigator, Co- Investigator, Study Coordinator,
Nurse, Pharmacist.
 Unblinded Personnel (Coordinator/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.
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Individual Member of the Study Team can be delegated specific Trial Duties
such as:
• 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
• Reporting of SAE ( Adverse Events )
• Logistics Management
• Resolution of Data Enquiries
• Patient’s Visit Scheduling, Protocol Compliance & Follow Up
• Maintenance of Site Master File.
• Compliance with GCP & Regulatory Guidelines
• Tracking of Payments / Study Grants
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REVIEW OF ETHICS COMMITTEE OPERATIONS
The Composition of EC must have 7 Members
The Chairman of EC should be from outside of the Institution ( Non
Affiliated member ).
The Quorum of EC should have min. 5 Members ( Medical Scientist /
Pharmacologist, Clinician, Theologian / Social Scientist / Ethicist, Legal
Expert, Lay person. )
No CT should be initiated at any Site without obtaining written NOC from
the respective EC.
If any Investigator or Study team Member is a part of EC, they should
abstain from voting on their research proposal.
Version Number of all the essential trial documents approved by EC should
be clearly mentioned on the approved letter.
All serious & unexpected ADR should be reported to EC within 7 working
days of their occurrence.
EC should maintain its records for at least 5 years after the completion
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termination of the study
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SOURCE DOCUMENT
Source data/documents refer to the documents where the
information’s on patient’s medical condition and treatment is recorded
for the first time.
SD should contain accurate, authentic, and complete information on
patient’s medical condition, laboratory results, treatment administered,
adverse events & corrective medications.
SD should have proper control & access.
Should reveal what was done & when
All the information regarding patient’s Physical Laboratory, Medical
Tests should be kept in one file with valid signatures & dates of the
concerned personnel.
SD should be properly archived for preservation.
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Electronic data for SD should be ensured for Security, Validation &
Back up control.
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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
Lockable Trial Rooms / Storage Cabinets
Lockable Cabinets, Fridge
National or Internationally accredited Laboratories
Well defined Quality control standards
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SITE EVALUATION
Ensurence of Non Disclosure of Agreement by the Site / Investigator as per Sponsor /
CRO.
Maintain Confidentiality of Information given by Sponsor / CRO to the Site /
Investigator.
Sponsor / CRO evaluates the Site, reviews the Qualification of Study Team
Members.
Evaluates Composition,Operations, EC Operating System, Source Documentation
Practices & Infrastructures of the Site.
PROCESS OF SITE EVALUATION
 Sponsor / CRO approaches the investigator site for discussing a Clinical Trial
Proposal
 Investigator’s concensus / approval is obtained based on Study Protocol
discussion
 NDA is executed between Investigator & Sponsor/CRO Investigator
 Provides his details on Study Feasibility Questionnaire
 If Investigator’s response is satisfactory & meets the expectations of Sponsor /
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CRO, Site Evaluation Visit ensured.
 Site is either selected / rejected based on the report of Site Evaluation done by
Sponsor / CRO Representative
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SITE ACTIVATION
Sponsor/CRO forwards the following documents to the Clinical Investigator for
Review & Completion:
1. Study Protocol
2. Patient Information Sheet & PIC (English & Vernacular)
3. Investigator Brochure
4. Case Record Form
5. Insurance / Indemnity Certificate
6. Patient Diaries / Questionnaire
7. Format of Undertaking by Investigator
8. Draft of CTA between Investigator & Sponsor / CRO
9. Regulatory Clearance ( DCGI ) NOC
10. No. of copies of above documents for EC application
Site is selected for CT after successful Evaluation of the Site by the Sponsor / CRO.
Careful CTA drafting & Suggestions can avoid issues like, Payment Delays, Frequent
Amendments, Retain Dedicated Study personnel.
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Investigators Training Meeting is conducted to provide a uniform understanding of
Protocol & process to all the Participants.
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SITE INITIATION VISIT
Site Initiation Visit by Sponsor verifies that Investigator
& his Team are Trained on the Study Requirements.
1. Essential Trial Documents
2. Roles & Responsibilities of each Team Member
3. Facilities, Role of Sponsor, Study Time lines
4. ICF & CRF
5. SAE / ADR Reporting
6. EC – NOC Application Requirements
7. Source Documents
8. Study Drug Storage / Accounatbility
9. Randomization Procedures
10. Data Management
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11. Audits / Inspections & Archival
SUBJECT ENROLLMENT & ICF ADMINISTRATION
 ICF is a procedure to take the consent of the participant after being
completely briefed about the Trial & Outcome, etc.
 Sponsor has the responsibility to detail all the risks, regulatory needs
& procedures of the Trial in the ICF in vernacular of the subject.
 The subject & the Investigator obtaining the ICF must sign the ICF
with date at the appropriate places.
 One copy of the signed ICF should be given to the subject and ICF
should be obtained by the Investigator.
 In case the Subject is illiterate, one impartial person should be present
during ICF discussion & signing.
 Any amendment done in the obtained ICF should be subjected to EC
approval & the subject should be re- consented.
 Only EC approved ICF should be used for all enrollment.
 Data required in the Protocol should be carefully recorded in the 26
source documents & later transcribed in the CRF.
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MAINTENANCE OF SOURCE DOCUMENTS
Source Documents should tell the complete story of the trial
& aid in reconstruction of total information.
 CRFs as SD refer to Quality of Life Questionnaire,
Evaluation Scales, Patient demographics and it should be
mentioned in the protocol.
 Documentation of all Transactions of the Study Drug would
lead to 100% drug accountability
 Incomplete & Inappropriate SD can lead to Audit Issues &
well maintained SD helps in reconstruction of the Study at
any point of time.
 All SD are required to be archived for a specific period of 1015 years after completion of the Study for future Audit. 27
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A Good Source Document should be able to address the
following. :
1. ICF Process
2. Pre-existing Conditions & Relevant History
3. Laboratory Reports & Results
4. Efficacy Evaluations
5. Adverse Events & Corrective Medication
6. Drug Accountability
7. Progress Notes
8. Ongoing Patient’s Status
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“BOOMING CLINICAL TRIALS MARKET IN
INDIA”
RNCOS E-SERVICES PVT LTD.
DATED: FEB 05, 2008
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Indian clinical trials market is expected to grow at rate of
nearly 36% between 2006 and 2011 to register revenues
worth US$ 546 Million in future.
India by 2011 will be conducting more than 15% of the
total global clinical trials.
India presently lacks in GCP trained investigators
(which are less than 1000). Their demand is projected to
reach between 3000 and 6000 by 2010.
The salaries of a clinical data specialist and Medical
writer in India are around 15% and 9% respectively of29
what they get in the US.
FUTURE OF CLINICAL RESEARCH
 India
is rapidly emerging as the hub for
global clinical research because:India's huge heterogeneous patient population of
more than 1.1 billion.
 largest pool of patients suffering from Cancer,
Diabetes , Hypertension , Asthma ,Tropical
infections and degenerative diseases.
 Patient doctor ratio is high.
 Qualified and Efficient healthcare professionals.
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ADVANTAGES INDIA
Patient diversity
 Patient heterogeneity
 World class medical infrastructure
 Familiarity with western medical facilities
 English competency
 Cost competency ( patient recruitment, shorter
timelines, manpower etc.,)
 ICH / GCP guidelines implementation
 Project management competencies
 Central lab facilities ( Internationally, nationally
accredited)
 Regulatory guidelines and government policies –
helping clinical research in India ( MOH, DCGI,
ICMR etc.,)
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