Clinical Trials: Dr. Tina Saldanha

Clinical Trials
Dr. Tina Saldanha

History
 Every drug on the market today goes through a testing process
known as a clinical trial
 Under the watchful eye of researchers, individuals volunteer to try

new drugs and therapies
 These structured trials help researchers understand the effects of a

new drug
 The notion of testing new medications goes back thousands of years
 Over time, physicians and researchers refined the concept of clinical

trials
 Today, the Food and Drug Administration (FDA) requires clinical

trials for all drug approval
Clinical trials….since biblical times
 Nebuchadnezzar and Daniel (562 BC): diet of meat and wine
compared to bread, water and legumes
 Avicenna (1025 AD) in his encyclopedic ‘Canon of Medicine’:

describes some interesting rules for the testing of drugs. He
suggests that in the clinical trial a remedy should be used in its
natural state in disease without complications
 Surgeon, Ambroise Pare (1537): unintentionally carried out a clinical

trial comparing standard treatment of boiling oil vs mixture of egg
yolk, turpentine and oil of rose for treatment of open wounds in
soldiers.
 James Lind (1747): conducted the first controlled clinical trial
(comparision of cider/vinegar/citrus fruits) on a group of sailors
suffering from scurvy
 Use of Placebo for the first time in clinical trials (1863): Placebos are
non-effective medical treatments (to “please” the patient) given to
control groups to compare the results with those from the new drug
Clinical trials history
 Randomization is introduced to clinical trials (1923): participants
randomly receiving one of the treatments, one being a placebo and
one being the new drug. Blind clinical trials, where neither group
knows which treatment they are receiving, also emerged in the 20th
century.
 Multicenter clinical trials are introduced (1944): multiple studies are

conducted at various sites all using the same protocol to provide
wider testing and better statistical data
 The Nuremberg Code (1947): outlines 10 basic statements for the

protection of human participants in clinical trials
 The Declaration of Helsinki (1964): outlines ethical codes for

physicians and protection of participants in clinical trials all over the
world
 The U.S. FDA is provided more authority and accountability (1988)

over the approval of new drugs and treatments
Clinical trials history
 The U.S. FDA is provided more authority and accountability (1988)
over the approval of new drugs and treatments
 The International Conference on Harmonization (ICH) is assembled

(1990): to bring uniformity to drug development requirements for
three global pharmaceutical markets: The EU, Japan and U.S. The
ICH initiatives promote increased efficiency in the development of
new drugs, improving their availability to patients and the public
 A Common Technical Document (CTD) is developed (2000): The

CTD acts as a standard dossier used in Europe, Japan and the U.S.
for proposing data gathered in clinical trials to respective governing
authorities
Evolution of Clinical trials in India
 India has a rich heritage of traditional medicine – Ayurveda. It is
likely that the indepth descriptions in the ayurvedic texts are based
on direct observations made by the ancient ayurveda experts.
 However, there is no recorded documentation in the ancient texts of

any clinical experiments
 Hence, relatively current history of medical research in India is

presented below:
 Indian Research Fund Association (IRFA) first meeting was held

(1911)
 Journal for Indian Medical research was initiated (1912)
 Several projects on beriberi, malaria, kala azar and indigenous

drugs were initiated (1918-1920)
 IRFA was redesignated as the Indian Council of Medical Research

(1949)
Evolution of Clinical trials in India
 Schedule Y of Drugs and Cosmetics Act (1988) established the
regulatory guidelines for clinical trial (CT) permission
 The schedule did force the industry to conduct Phase III clinical trials
for registration of a new drug and supported growth of a predominantly
generic Indian pharmaceutical industry
 The next major step has been revision of Schedule Y in Jan 2005
 Provided pragmatic definitions for Phase I to IV
 Schedule Y 2005 legalized Indian GCP guidelines of 2001
 Stipulated GCP responsibilities of ethics committee (EC), investigator

and sponsor and
 Suggested formats for critical documents e.g. consent, report, EC
approval, reporting of serious adverse event
 These amendments in Schedule Y have been a major step forward in
direction of GCP compliant trials and have provided the much-needed
regulatory support to GCP guidelines.
Clinical research- Types
Clinical research is studies in human volunteers to answer specific health

questions
Not all clinical research involves new treatments for a disease
 Intervention studies Treatment research (also called “clinical trials”)

generally involves an intervention such as medication, psychotherapy, new
devices, or new approaches to surgery or radiation therapy
 Prevention studies help to determine how we can better prevent a certain

disease or condition from occurring in healthy people. Different kinds of
prevention research may study medicines, vitamins, vaccines, minerals, or
lifestyle changes
 Diagnostic and screening studies look for better ways to detect and
diagnose disease
Clinical research- Types
Clinical research is studies in human volunteers to answer specific health
questions
Not all clinical research involves new treatments for a disease
 Behavioral research seeks to identify how certain behaviors are related to

a variety of diseases, and how these behaviors can be modified
 Quality of life studies look for ways to help those with chronic or incurable
diseases. Also known as “supportive care,” this research explores ways to
improve comfort and the quality of life for individuals with a chronic illness
 Genetic studies aim to improve the prediction of disorders by identifying

and understanding how genes and illnesses may be related. Explore ways
in which a person’s genes make him or her more or less likely to develop a
disorder.
 Epidemiological studies seek to identify the patterns, causes, and control

of disorders in groups of people.
Clinical research
 Some clinical research is “outpatient,” meaning that participants do not stay
overnight at the hospital
 Some is “inpatient,” meaning that participants will need to stay for at least
one night in the hospital or research center.
Clinical research
Clinical research- Phase I
 Phase 1 studies focus on the safety and pharmacology of a compound.
 During this stage low doses of a compound are administered to a small

group of healthy volunteers who are closely supervised
 In cases of severe or life-threatening illnesses, volunteers with the disease

may be used
 Generally, 20 to 100 volunteers are enrolled in a phase 1 trial and are

generally paid for participating
 These studies usually start with very low doses, which are gradually
increased
 The study is designed to determine the effects of the drug or device on

humans including how it is absorbed, metabolized, and excreted
 This phase also investigates the side effects that occur as dosage levels
are increased.
 On average, about two thirds of phase 1 compounds will be found safe

enough to progress to phase 2
Clinical research- Phase II
 Phase 2 studies examine the effectiveness of a compound.
 To avoid unnecessarily exposing a human volunteer to a potentially harmful
substance, studies are based on an analysis of the fewest volunteers needed
to provide sufficient statistical power to determine efficacy.
 Typically, phase 2 studies involve 100 to 300 patients who suffer from the
condition the new drug is intended to treat
 During phase 2 studies, researchers seek to determine

effective dose
method of delivery (eg, oral or intravenous)
dosing interval, as well as to
reconfirm product safety
 Patients in this stage are monitored carefully and assessed continuously
 Most phase II studies are randomized trials where one group of patients
receives the experimental drug, while a second "control" group receives a
standard treatment or placebo
Clinical research- Phase II
 Often these studies are "blinded" which means that neither the patients nor
the researchers know who has received the experimental drug
 This allows investigators to provide the pharmaceutical company and the

FDA with comparative information about the relative safety and effectiveness
of the new drug
 A substantial number of these drug trials are discontinued during phase 2

studies
 Some drugs turn out to be ineffective
 safety problems or
 intolerable side effects
 About one-third of experimental drugs successfully complete both Phase I and

Phase II studies.
Clinical research- Phase III
 Phase 3 trials are the final step before seeking FDA approval
 During phase 3, researchers try to confirm previous findings in a larger

population.
 These studies usually last from 2 to 10 years and involve thousands of

patients across multiple sites
 These studies are used to demonstrate further safety and effectiveness and
to determine the best dosage
 Despite the intense scrutiny a product receives before undergoing

expensive and extensive phase 3 testing, approximately 10% of
medications fail in phase 3 trials.
Clinical research-NDA (New DrugApplication)
 If a drug survives the clinical trials, an NDA is submitted to the regulatory
authorities
 An NDA contains all the preclinical and clinical information obtained during
the testing phase. Information on:
 Chemical makeup and manufacturing process
 Pharmacology and toxicity of the compound
 Human pharmacokinetics
 Results of the clinical trials
 Proposed labeling
 After receiving an NDA, the FDA completes an independent review and

makes its recommendations
Clinical research-NDA review process
 Application for drugs similar to those on the market are considered
standard, whereas priority applications represent drugs offering important
advances in addition to existing treatments.
 If during the review the FDA staff feels there is a need for additional
information or corrections, they will make a written request to the applicant
 During the review process it is not unusual for the FDA to interact with the
applicant staff
 Once the review is complete, the NDA might be approved or rejected
 If the drug is not approved, the applicant is given the reasons why and what
information could be provided to make the application acceptable
 Sometimes the FDA makes a tentative approval recommendation,

requesting that a minor deficiency or labeling issue be corrected before final
approval
 Once a drug is approved, it can be marketed

Clinical research-Phase IV
 Post marketing surveillance is important, because even the most well-
designed phase 3 studies might not uncover every problem that could
become apparent once a product is widely used
 Furthermore, the newproduct might be more widely used by groups that

might not have been well studied in the clinical trials, such as elderly
patients
 A crucial element in this process is that physicians report any untoward

complications
 Alternatively, a phase 4 study might be initiated by the sponsor to assess

such issues as the longer term effects of drug exposure, to optimize the
dose for marketing, to evaluate the effects in pediatric patients, or to
examine the effectiveness of the drug for additional indications
Clinical research-Phase IV
 Some approvals contain conditions that must be met after initial marketing,
such as conducting additional clinical studies
 For example, the FDA might request a post marketing, or phase 4, study to
examine the risks and benefits of the new drug in a different population or to
conduct special monitoring in a high-risk population
Clinical research: Recent concepts:
phase 0
 Phase 0 is also called as “microdosing” study and is the “first in humans
study”
 The objective is to derive PK information in humans before Phase I study
 Micro dose: less than 1/100 of the dose of a test sunstance calculated ot
produce the pharmacological effect is used (max dose less than or equal to
100 mg) ie. It is a subtherapeutic dose
 Small group of 10-20 patients

 Does not give information about safety efficacy but go/no go decision can
be taken

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Clinical Trials

Dr. Tina Saldanha

 Under the watchful eye of researchers, individuals volunteer to try

 These structured trials help researchers understand the effects of a

 The notion of testing new medications goes back thousands of years

 Over time, physicians and researchers refined the concept of clinical

 Today, the Food and Drug Administration (FDA) requires clinical

 Avicenna (1025 AD) in his encyclopedic ‘Canon of Medicine’:

 Surgeon, Ambroise Pare (1537): unintentionally carried out a clinical

 Multicenter clinical trials are introduced (1944): multiple studies are

 The Nuremberg Code (1947): outlines 10 basic statements for the

 The Declaration of Helsinki (1964): outlines ethical codes for

 The U.S. FDA is provided more authority and accountability (1988)

 The International Conference on Harmonization (ICH) is assembled

 A Common Technical Document (CTD) is developed (2000): The

 However, there is no recorded documentation in the ancient texts of

 Hence, relatively current history of medical research in India is

 Indian Research Fund Association (IRFA) first meeting was held

 Journal for Indian Medical research was initiated (1912)

 Several projects on beriberi, malaria, kala azar and indigenous

 IRFA was redesignated as the Indian Council of Medical Research

 Schedule Y 2005 legalized Indian GCP guidelines of 2001

 Stipulated GCP responsibilities of ethics committee (EC), investigator

Clinical research is studies in human volunteers to answer specific health

 Intervention studies Treatment research (also called “clinical trials”)

 Prevention studies help to determine how we can better prevent a certain

 Behavioral research seeks to identify how certain behaviors are related to

 Genetic studies aim to improve the prediction of disorders by identifying

 Epidemiological studies seek to identify the patterns, causes, and control

 During this stage low doses of a compound are administered to a small

 In cases of severe or life-threatening illnesses, volunteers with the disease

 Generally, 20 to 100 volunteers are enrolled in a phase 1 trial and are

 The study is designed to determine the effects of the drug or device on

 On average, about two thirds of phase 1 compounds will be found safe

 During phase 2 studies, researchers seek to determine

method of delivery (eg, oral or intravenous)

dosing interval, as well as to

reconfirm product safety

 Patients in this stage are monitored carefully and assessed continuously

 This allows investigators to provide the pharmaceutical company and the

 A substantial number of these drug trials are discontinued during phase 2

 intolerable side effects

 About one-third of experimental drugs successfully complete both Phase I and

 During phase 3, researchers try to confirm previous findings in a larger

 These studies usually last from 2 to 10 years and involve thousands of

 Despite the intense scrutiny a product receives before undergoing

 After receiving an NDA, the FDA completes an independent review and

 Once the review is complete, the NDA might be approved or rejected

 Sometimes the FDA makes a tentative approval recommendation,

 Once a drug is approved, it can be marketed

 Furthermore, the newproduct might be more widely used by groups that

 A crucial element in this process is that physicians report any untoward

 Alternatively, a phase 4 study might be initiated by the sponsor to assess

 The objective is to derive PK information in humans before Phase I study

 Small group of 10-20 patients

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