2. CLINICAL STUDY AND
BASIC CONCEPT
What is a Clinical Trial?
A clinical trial (clinical research) is a research study in human
volunteers (preclinical trail – in animals) to answer specific
health questions.
Carefully conducted clinical trials are the fastest and safest
way to find treatments that work in people and ways to
improve health.
3. CLINICAL STUDY AND
BASIC CONCEPT
Types of clinical trials
Treatment trials
Prevention trials
Diagnostic trials
Screening trials
Quality of Life trials
4. CLINICAL STUDY AND
BASIC CONCEPT
Clinical trials, FDA approval
Before a company initiates clinical trials (i.e. testing
in humans), it must conduct extensive experiments in
animal and human cells and in live animals
(Preclinical Trial)
If this stage of testing is successful, the company files
an Investigational New Drug (IND) application with
the Food and Drug Administration (FDA) to request
permission to conduct clinical trials.
5. CLINICAL STUDY AND
BASIC CONCEPT
Clinical Trials
Preclinical F Phase I Phase II Phase III F FDA Phase IV
testing I I
L L
E E
Years 3.5 1 2 3 2.5 12 Additional
I N To post
N D tal marketing
D A testing
Test Lab and 20 to 80 100 to 300 1000 to Review
at at
population Animal healthy patient 3000 process/
Studies volunteers volunteers patient Approval
F volunteers F
D D
A A
Success 5000 5 enter trials 1
rate compounds approved
evaluated
6. CLINICAL STUDY AND
BASIC CONCEPT
Preclinical trials
Trial carried out on to the animal species
Objective: To evaluate safety, toxicity and tolerance data (by applying
the factor for conversion of animal data to human data)
Study
Drug metabolism pathway
PK of the drug
PK-PD relation
Protein binding
Tissue distribution
Development of methodology for quantification of drug and
metabolite in biological fluid
Long term toxicity
Placental transfer kinetic
7. CLINICAL STUDY AND
BASIC CONCEPT
Phase 1
Trial carried out on healthy volunteers except AIDS or Cancer.
Study
Dose-concentration (in plasma)-response-toxicity study
IV, single dose study (for checking bioavailability)
Radioactive tracer study (for evaluation of first pass metabolism)
Evaluation of suitability of preclinical animal model (to predict
pharmacological effect in human)
Effect of food
8. CLINICAL STUDY AND
BASIC CONCEPT
Phase 2
First time trial on patient and conducted in OPEN manner
Study
Evaluation of difference in PK and PD between the healthy
volunteer and patient
To search new therapeutic effect of the drug
9. CLINICAL STUDY AND
BASIC CONCEPT
Phase 3
Study
Search less common side effect of drug (which is conc.
independent)
Comparison with the marketed drug
Drug-drug interaction
Study in special population like age, sex race etc.
Develop the dosage form
10. CLINICAL STUDY AND
BASIC CONCEPT
Phase 4
Post marketing surveillance
Not well planned study but random study
Some rare side effect or toxicity may come out
11. GOOD CLINICAL PRACTICE
Good Clinical Practice (GCP) is an international ethical and
scientific quality standard for designing, recording and reporting
trials that involve the participation of human subjects.
Compliance with this standard provides public assurance that the
rights, safety and well being of trial subjects are protected,
consistent with the principles that have their origin in the
Declaration of Helsinki, and that the clinical trial data are
credible.
Regulations tell you what you are required to do by law. Guidelines
tell you the best way to do it
12. GOOD CLINICAL PRACTICE
FDA GCP Regulations
Regulations contained in 21 CFR Part 50, 56, and 312
Part 50 (applies to consenting of subjects),
Part 56 (applies to IRB responsibilities) and
Part 312 (applies to IND submissions, sponsor responsibility, and investigator
responsibility)
GCP Guidelines- International Conference on Harmonization
The objective of ICH GCP Guidelines is to provide a unified standard for
European Union, Japan and United States to facilitate the mutual acceptance of
clinical data by the regulatory authorities in the jurisdiction.
Published by the FDA in Federal Register in May, 1997
Adopted by all parties as GCP standard (considered law in European Union;
considered “final guidance” in the US)
Based on the Declaration of Helsinki
13. GOOD CLINICAL PRACTICE
Some important terms (Glossary)
Investigator
Sponsor
Subject /Trial Subject
Investigator’s Brochure
Non Clinical Study
Protocol
Blinding (Masking)
Institutional Review Board (IRB)
Adverse Event (AE)
Serious Adverse Event (SAE)
14. GOOD CLINICAL PRACTICE
Elements of GCP
IRB
Investigator
Sponsor
Clinical trial protocol and protocol amendments
Investigator Brochure
Essential documents
15. GOOD CLINICAL PRACTICE
Institutional review board (IRB) or Independent Ethics
Committee (IEC)
It consists of reasonable number of members, who collectively
have qualifications and experience to review and evaluate the
science and medical aspects as well as ethics of proposed trials.
It should perform the functions in accordance with written
procedures, maintain written records of its activities and
minutes of its meetings and should comply with GCP.
Acts as a safe guard to the rights of the trial subject
Should consider the qualification of the investigator for the
proposed trial
Should conduct continuing review of each ongoing trial at
intervals appropriate to the degree of risk.
16. GOOD CLINICAL PRACTICE
Investigator
Qualified to perform study should have
Appropriate education, training and experience to assume responsibility
and should provide evidence of such qualifications.
Sufficient time to devote to study timelines.
Personally conduct or supervise study.
Adequate and qualified staff and facilities.
Awareness of and compliance with GCP.
Familiar with the investigational product and inventory.
Adherence to protocol requirements.
Inform subject’s primary physician
Ensure adequate medical care for SAEs.
Maintained records should be accurate, complete, legible and timely.
17. GOOD CLINICAL PRACTICE
Investigator-Communication with IRB
Obtaining written and dated IRB approved consent form
Submission of Investigational Brochure
Ongoing communication
Report of SAEs
IND Safety Reports
Significant protocol deviations
The investigator should submit written summaries of the status of
the trial to the IRB annually or more frequently, if requested by
the IRB
18. GOOD CLINICAL PRACTICE
Investigator- Communication with the Sponsor/CRO
Reporting of any AEs or SAEs
Notification of changes in staff and address
Retention of all pertinent study information and records until
notified in writing that records are no longer required
Coordination of publication plans
If trial is blinded, the investigator should promptly document
and explain to the sponsor any:
Premature unblinding
Accidental unbliniding
Unblinding due to serious adverse events
19. GOOD CLINICAL PRACTICE
Investigator-Communication with Study Subjects
Obtaining valid written informed consent
The information language should be non-technical and understandable to
the subject/LAR/impartial
Provide subject a copy of a fully executed consent
Provide subject with any new information
Answer questions at any time
The investigator must inform the subject when medical care is needed for
inter-current illness(es) of which investigator becomes aware.
It is recommended that the investigator inform subject’s primary physician
about subject’s participation in study.
If subject wishes to withdraw from the study, the investigator should make
reasonable effort to ascertain the reasons – while fully respecting the
subject’s rights.
20. GOOD CLINICAL PRACTICE
Investigator- Investigator – Compliance with Protocol
The investigator should conduct the trial in compliance with:
The protocol agreed to by the sponsor
If required, protocol agreed to by the regulatory authority(ies)
Ultimately given approval by the IRB
The investigator should not implement any deviation from, or changes of
the protocol without:
Agreement by the sponsor
Prior review and documented approval from the IRB of an amendment
Exception: where necessary to eliminate an immediate hazard (s) to trial
subjects or when the changes involve only logistical or administrative aspects of
the trial. However, as soon as possible, the implemented deviation or change,
the reason for it, and, if appropriate, the proposed protocol amendment(s)
should be submitted to:
The IRB for review and approval
To the sponsor for agreement
If required, to the regulatory authorities
21. GOOD CLINICAL PRACTICE
Investigator – Investigational Products
It is the investigator’s responsibility for investigational product(s) accountability at
the trial site
The investigator or person who is designated by the investigator should maintain
records of:
o The product(s) delivery to the site
o The inventory at the site
o The use by each subject
o The return to the sponsor or disposition of unused products
The records should include:
Date, quantities, batch/serial numbers, expiration dates and the unique
code numbers assigned to the product(s) and subjects
Products should be stored as specified by the sponsor and in accordance with
applicable regulatory requirements
Should explain to the subject:
Correct use of the product
Should check at appropriate intervals that the subject is following the instructions properly
to use the product
22. GOOD CLINICAL PRACTICE
Investigator – Records and Reports
Records should be accurate, complete, legible and
timely pertinent to the data reported to the sponsor
in the CRFs (Case Report Forms) and other required
reports
All corrections to a CRF should be dated, explained
and should not obscure the original entry whether the
entry is written or electronic changes or corrections.
The investigator should retain records of the changes
and corrections.
23. GOOD CLINICAL PRACTICE
Investigator’s Brochure
For investigational (not FDA-approved) drug trials
Summary of significant physical, chemical,
pharmaceutical, pharmacological, toxicological,
pharmacokinetic, metabolic, and clinical information
that is relevant to the investigational product
Relevant animal and clinical studies, adverse events, etc.
24. GOOD CLINICAL PRACTICE
FDA Form 1572 – to initiate clinical trials
Investigator agrees to comply with conditions required by FDA for use of
investigational articles
“Contract” that the investigator signs/dates
“Warning: A willing false statement is a criminal offense”
Content of Form 1572
Principal Investigator name/address
Name/address of site(s) of study conduct
Name/address clinical labs (local/central)
Name/address IRB
Names of key personnel with study participant contact
Submit CVs of key personnel (signed/dated) listed in form
25. GOOD CLINICAL PRACTICE
Progress Reports
The investigator should submit written summaries (where
required by applicable regulatory requirements) of the trial’s
status to the institution.
The investigator should submit written summaries of the status of
the trial to the IRB annually or more frequently, if requested by
the IRB
The investigator should promptly provide written reports to the
sponsor and the IRB and where required by the regulatory
authorities, the institution on any changes significantly affecting
the trial and/or increasing the risk to subjects.
26. GOOD CLINICAL PRACTICE
Safety Reporting
All serious adverse events (SAE) should be reported immediately to the sponsor except
for those SAEs that the protocol or other document identifies as not needing immediate
reporting
The immediate and follow up reports should identify Subjects by unique code numbers
assigned to trial, but not with identifiers (name, address, identification numbers)
The immediate reports should be followed promptly by detailed, written reports
Adverse events and/or laboratory abnormalities identified in the protocol as critical to
safety evaluations should be reported to the sponsor within the time periods specified by
the sponsor in the protocol
For reported deaths, the investigator should supply the sponsor and the IRB with any
additional requested information (e.g., autopsy reports and terminal medical reports)
27. GOOD CLINICAL PRACTICE
Premature Termination or Suspension of a Trial
If the trial is suspended or prematurely terminated for any reason the investigator
should promptly Inform the trial subjects, should assure appropriate therapy and
follow-up and where required, should inform the regulatory authorities and the
IRB
If the investigator terminates or suspends a trial without prior agreement of the
sponsor, the investigator should inform the institution, regulatory authorities(if
required), the sponsor and the IRB with detailed written explanation of the
termination or suspension
If the sponsor terminates/suspends a trial, the investigator should promptly inform
the institution (per applicable regulatory requirements) and the IRB and provide
written explanation of the termination/suspension
If the IRB terminates/suspends its approval, the investigator should inform the
institution and the investigator should promptly notify the sponsor and provide the
sponsor with a detailed written explanation of the termination or suspension
28. GOOD CLINICAL PRACTICE
Final Report
Upon the completion of the trial, the investigator should
inform and provide the IRB and the sponsor:
All required reports
Summary of the trial’s outcome
Reports to regulatory authorities if applicable
29. GOOD CLINICAL PRACTICE
Records Retention Requirements
Essential documents should be retained until at least two (2) years after the last
approval of a marketing application in an ICH region.
These documents should be retained, however, if required by the applicable
regulatory requirements (state or federal) or by an agreement with the sponsor.
It is the responsibility of the sponsor to inform the investigator as to when these
documents no longer need to be retained.
Upon request of the monitor, auditor, IRB or regulatory authority, the
investigator/institution should make available for direct access all requested
trial-related records.
