Clinical Trials

1. Importance of clinical trials
Dr Sharanya Sreekumar
Postgradute Student
Public Health Dentistry

2. Contents
• Introduction
• Historical perspective
• Importance of clinical trial
• Types of clinical trials
• Design of clinical trial
• Phases of clinical trial
• Important regulations and guidelines
• New clinical trial regulations rules in India
• PHACT
• Conclusion
• References
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3. Introduction
• Trial is from the Anglo–French term, meaning to try. Broadly, it
refers to the action or process of putting something to a test or
proof.
• Clinical is from clinic, from the French cliniqu´ e and from the
Greek klinike, and refers to the practice of caring for the sick at
the bedside.
• Broadly clinical trial refers to any testing done on human beings
for the sake of determining the value of a treatment for the sick
or for preventing disease or sickness.
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4. Historical perspectives
• First trial was carried by James Lind for treatment of scurvy .
12 scurvy
patients in the
year 1747
cider
Elixir of
vitriol
Vinegar
Sea water
Orange and
lemons
Barley water
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5. • Johannes Fibiger’s 1898 study of diphtheria antitoxin in 484
patients in Copenhagen, alternate allocation entailed treating
every other patient.
• Alternate allocation considered as ancestor of RCT
• By 1940’s Sir Austin Bradford Hill brought out strict concealed
randomization of patients to treatment or control groups.
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6. Importance of clinical trial
• A clinical trial is a research study that tests a new medical
treatment or a new way of using an existing treatment to see if it
will be a better way to prevent and screen for diagnose or treat
a disease.
• Trials are said to be controlled if the effect of a treatment is
measured against a comparison treatment administered over
the same time period and under similar conditions.
• Uncontrolled trials
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7. Types of clinical trial
• Treatment trials
• Prevention trials
• Diagnostic trials
• Screening trials
• Quality of Life or Supporting care trials
• Genetic trials
• Compassionate use clinical trials: critical ill patients
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8. CHIM ( Controlled Human Infection Model )
• CHIM (for malaria, Controlled Human Malaria Infection, CHMI)
provides a platform to reasonably evaluate the protective efficacy
of a vaccine candidate without going out for larger trials.
• The term “Controlled” in CHMI reflects the requirement of highly
controlled settings such as well-characterised parasite strains,
effective drug(s) for infection elimination and highly efficient
diagnostic system for stringent monitoring.
• The term “infection” reflects that the experimental protocol intends
to induce controlled infection and not cause disease.
• The term “Human” reflects that the subject will be human, as with
any clinical vaccine research evaluating protective efficacy.
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9. Design of clinical trial
• Parallel study design
• Cross over study design
• Factorial study design
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10. Parallel group design
• A parallel group design is a complete randomized design in which
each patient receives one and only one treatment in a random
fashion
• Run in periods : Before patients enter a clinical trial, a run-in (or
lead-in) period of placebo, no active treatment, dietary control, or
active maintenance therapy (e.g., diuretic and/or digoxin in heart
failure studies) is usually employed prior to randomization
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11. Advantages of Run in Periods
• It acts as a washout period to remove effects of previous
therapy.
• It can be used to obtain baseline data and to evaluate if patient
fulfils study entry criteria.
• It can be used as a training period for patients, investigators and
their staff
• It can be used to estimate and compare the magnitude of
possible placebo effects between groups.
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12. Cross over design
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13. Factorial study design
• Factorial study design are commonly used to test multiple
treatments in a single study
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15. What to do before a clinical trial?
• For any new drug to enter in clinical trial, it must pass preclinical
studies.
• Preclinical studies involve in vitro (i.e. test-tube or Laboratory)
studies and trials on animal populations.
• Wide range of dosages of the study drug is given to animal
subjects or to an in-vitro substrate in order to obtain
preliminary efficacy, toxicity and pharmacokinetic information.
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16. Phase 0 clinical trial
• The Phase 0 clinical trial is the latest designation for the
exploratory, First-In-Humans trials conducted according to the
FDA 2006 Guidance on exploratory Investigational New Drug
(IND) studies.
• The purpose of Phase 0 trial is to aid in a “go versus no-go”
decision making process
• Drug’s fate early in the development process, using relevant
human models rather than relying on sometimes inconsistent
animal data.
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17. There are three types of Phase 0 clinical trials:
• Clinical trials to determine drug pharmacokinetics (also known
as microdose trials),
• To establish pharmacologically relevant doses
• To study the mechanisms of action ( pharmacodynamics )
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18. Advantages
1. Early selection of promising compounds
2. Unsuitable molecules can be eliminated earlier
3. Risk of human toxicity is less
4. Approximate drug dosage can be established
Disadvantages
1. Difficult to motivate human subjects
2. Certain drugs have different metabolism at microdosing and
clinical ( larger ) doses
3. Ethical issues
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19. Phase 1 clinical trial
• Phase I trials are the first stage of testing in human subjects.
Normally, a small (20-80) group of healthy volunteers will be
selected.
• This phase includes trials designed to assess the safety
(pharmacovigilance), tolerability, pharmacokinetics, and
pharmacodynamics of a drug.
• These trials are often conducted in an inpatient clinic, where
the subject can be observed by full-time staff.
• The subject who receives the drug is usually observed until
several half-lives of the drug have passed.
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20. Safety in phase 1 trials
• It is evaluated by observing any adverse events , ECG, vital
signs, and physical examination
• Special attention given to changes in liver and renal function
tests
• Any clinical chemistry changes observed during animal studies
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21. • The selection of initial dose is based on results of preclinical
studies
• Phase I trials most often include healthy volunteers.
Different kinds of phase 1 studies
• SAD ( Single Ascending Dose): MTD
• MAD( Multiple Ascending Dose)
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22. Information obtained from Phase I studies
• Maximum tolerated dose
• Nature of adverse reactions that can be expected
• Preliminary characterization of the drug
• Accumulation of parent drug/ metabolites
• Bioavailability in presence of food
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23. Phase 2 trials
• Once the initial safety of the study drug has been confirmed in
Phase I trials
• Phase II trials are performed on larger groups (20-300)
• It is designed to assess how well the drug works, as well as to
continue Phase I safety assessments in a larger group of
volunteers and patients.
• Duration of phase 2 trials can be months or years
• It will have more stringent inclusion criteria
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24. • Phase 2 trials gives a successful design for phase 3 trials which
carried out in multiple centres
• Key factors to be learned from phase 2 is
1. To obtain optimal safety dosing regimen
2. To obtain a clinical end point
3. To prove clinical efficacy
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25. Phase 2 trials divided into
• Phase 2a( how drug should be given and how often)
• Phase 2b ( how well drug works at prescribed doses )
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26. Information obtained from Phase IIa studies
• Dose-response
• Efficacy
• Effect Size
• Adverse events (ADR of special interest)
• Biomarker profiling
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27. Information obtained from Phase IIb studies
• Proves primary hypothesis
• Frequency
• Additional ADR
• Identifying confounding factors
• Type of patients more responsive to treatment
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28. Phase 3 ( Confirmatory trials)
• Phase 3 is the primary basis for marketing approval.
• Phase 3 is carried out in multiple centers and involves a sample
size of 1000 to 3000.
• They require more complex , experienced , diverse and
collaborative team to conduct them.
• Phase 3 usually involves randomization and masking ( blinding )
• Require a prior review by IRB and continual oversight by an
independent group ( Data safety and monitoring committee)
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30. BARI Trial ( Bypass Angioplasty Revascularization
Investigation)
• BARI was multicenter clinical trial designed to assess long term
safety and efficacy of CABG or PTCA.
• This trial involve 14 enrollment centers 4 satellite sites, a clinical
coordinating center and separate ECG and radiographic central
laboratory.
• It took 1 year to plan the trial.
• Over a 3yr period 25,000 people were screened.
• Participants were followed for 8 years.
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31. Who’s who in a clinical trial
• Experienced –clinician scientists
• Research designer / biostatistician
• Research assistants
• Data collectors
• Data analyzers
• Clinical trialists/ methodologist
• Site coordinators
• Bioethicists
• Participants
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32. Key elements in phase 3 trials
• Basically all Phase 3 trials will have a manual of procedures
(MOP)
• In MOP they include the all procedures to be carried out
throughout the trial
• Clinical protocol is the most important part
• It can be modified and it should be recorded
• It can also act as the historical record of the trial
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33. Masking procedures( Blinding )
• Single masked studies
• Double masked studies: most frequently done
• Triple masked
• Unmasked studies or open label studies : in which all are
aware of the study eg: a new restorative material.
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34. Trial end point
• It is the objective measurement that reflects the impact or
effect of an intervention
• Primary end point : it can be single or combination of events
eg: children’s amalgam trial uses a composite neurobehavioral
endpoint as it measures memory, attention, and motor/visual
skills.
• Surrogate endpoint : it is another measure in place of an
endpoint. i.e biomarker in place of long term assessment eg
tooth loss and periodontal disease
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35. Stopping rules
• A stopping rule specifies the conditions under which a trial will
be stopped before its planned completion
• It should be clearly specified in MOP.
Stopped early for 2 main reasons
 Statistical criterion has been met , determined by monitoring
board
 Out of concern of safety of participants .
 Eg: CAST trial( cardiac arrhythmia suppression trial) stopped
uneventful death of patients using IND( investigational new
drug ) studies compared with placebo.
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36. Control groups in phase 3 trials
Three essential types
• No-treatment
• Placebo control
• Current standard of care : most appropriate control
intervention in a trial.
• It helps researchers analyze current new treatment is superior
or equivalent.
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37. Information obtained from Phase III studies
• Definitive proof of efficacy
• Additional safety data in large patients
• Adverse effects with longer duration of treatment
• Information for package insert and labeling of medicine.
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38. Phase 4 trials
• Phase IV trial is also known as Post Marketing Surveillance Trial.
• Phase IV trials involve the safety surveillance (pharmacovigilance)
and ongoing technical support of a drug after it receives
permission to be sold.
• The safety surveillance is designed to detect any rare or long-term
adverse effects over a much larger patient population and longer
time period than was possible during the Phase I-III clinical trials.
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42. ICH GCP Guidelines
• It is a set of standards used internationally for the conduct of
clinical trials.
• The guidelines aim to ensure that the "rights, safety and well
being of trial subjects are protected".
• The declaration of Helsinki of the World Medical Association
(1964) codifies recommendation for guidance of doctors in
clinical research.
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43. • Principles of ICH GCP
1. Clinical trials should be conducted in accordance with the ethical
principles
2. Before trial the risk benefit analysis should be done
3. The rights, safety, and well being of the trial subjects should be the
most important consideration
4. Should be scientifically sound, and described in a clear, detailed
protocol.
5. IRB / IEC approval
6. Informed consent should be mandatory
7. Confidentiality of record should be protected
8. Systems with procedures that assure the quality of every aspect of the
trial should be implanted 43

44. Regulatory approval for India
• The Drug Controller General of India (DCGI) requires a
confirmatory Phase III study that includes a proportion of local
patients.
• The Central Drug Standard Control Organization (CDSCO) handles
the approval process.
• Apart from the CDSCO approval, DCGI has given rights to each
state’s drug control authority to regulate the manufacture, sale
and distribution of drugs.
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45. • Challenges emerged between 2011-2013, when the Supreme
Court of India had asked for several justifications from the
Health Ministry around the conduct and continuance of
clinical trials in India
• New Drugs Advisory Committee (now as SEC) , Technical
Committee and Apex Committee to examine applications for
clinical trials in India.
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46. • The SEC( Subject Expert Committee) acts as a gateway in the
clinical trial approval process by advising the DCGI in the following
matters:
• To undertake in-depth evaluation of non-clinical data, including
pharmacological toxicological data, clinical trial data (Phase I, II,
III, and IV) furnished by the applicant for approval of new drug
substances of chemical and biological origin, global clinical trials,
fixed-dose combinations and those of two or more drugs.
• Defining roadmap for research industry for appropriate
development of new drugs relevant to Indian population.
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49. PHACT (Public Health Alliance for
Clinical Trials )
• Ellen Morgan, Christian Sacher and Yaw Asare-Aboagye are the founders
of Public Health Alliance for Clinical Trials (PHACT).
• Public Health Alliance for Clinical Trials (PHACT) is the first non-profit
Clinical Research Organization (CRO) dedicated to conducting clinical
trials for products to treat diseases that affect the poorest people in
developing countries.
• They collaborate with non-profit organizations to assist in reducing
research costs, thus enabling clinical trials.
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50. Conclusion
• With globalization the internet trials are being carried out in
the world now a days. So harmonization between countries
become a necessary factor for successful outcome of world
wide trials.
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51. References
• W V Giannobile, Clinical Research in Oral Health,2010. Wiley –
Blachwell; 1st edi.
• Information about clinical trial. Available from : URL
http://www.temple.edu/pascope/about_trials.html
• Clinical trial wikipedia, the free encyclopedia. Available from: URL
http://en.wikipedia.org/ wiki/clinical_trial.
• Kulkarni S. K., Hand Book of Experimental Pharmacology, 3rd ed,
Vallabh Prakashan New Delhi, 2004, 21. 4
• S.Peter Essentials of Public Health Dentistry , 5th edi.2015
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