CLINICAL TRIALS

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 WHAT ARE CLINICAL TRIALS?

 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 2
 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 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

 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:

 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 7

information including the drug’s risks, benefits and optimal use.
CLINICAL TRIALS TIMELINE ( 605 BC - 1986 AD )
 605 - 562 BC :
The first clinical trial was carried out by King Nebuchadnezzar II .

 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 German doctors and administrators

accused.

 War crimes and crimes against humanity.

 Medicalexperiments and medical procedures on

prisoners and civilians.

 >Twelve series of medical experiments concerning 10

TURNING POINT

 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

 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
 Councilfor International Organizations and
Medical Sciences (CIOMS) produced detailed
guidelines (originally published in 1993 and
updated in 2002).

 Address 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. 13
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).

 GoodClinical 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
 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.

 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.

 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
 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.
 Electronic data for SD should be ensured for Security, Validation & 21

Back up control.
 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
 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.
 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 25

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.
 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 10-
15 years after completion of the Study for future Audit. 27
 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

 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

 Indiais 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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