clinical trials history and types

1. CLINICAL TRIALS
HISTORY AND TYPES
PRESENTED BY
PAVAN REDDY
2ND SEM M.PHARM (PHARMACOLOGY)
COPS ,DSU

2. Introduction to clinical trials
A clinical trial or study is defined by the International
Conference on Harmonisation Principles of Good Clinical
Practice (ICH GCP) as being any investigation in human
subjects intended to discover or verify the clinical,
pharmacological and/or other pharmacodynamic effects of
an investigational product(s), and/or to identify any adverse
reactions to an investigational product(s), and/or to study
ADME of an investigational product(s) with the object of
ascertaining its safety and/or efficacy.

3. History of CT before 1750
Persian physician and philosopher, Avicenna
 In The Canon of Medicine, he laid down rules for the
experimental use and testing of drugs and wrote a precise
guide for practical experimentation in the process of
discovering and proving the effectiveness of medical drugs
and substances.
He laid out the following rules and principles for testing
the effectiveness of new drugs and medications.

4. History
Perhaps the first ever clinical trial was
James Lind’s demonstration in 1753 that
citrus fruits cured scurvy.
 He compared the effects of various
different acidic substances ranging from
vinegar to cider, on groups of sailors, and
found that the group who were given
oranges and lemons had largely
recovered from scurvy after 6 days.

5. Why do we need clinical trial?
Clinical trials also allow testing and monitoring of the effect
of a treatment on a large number of people to ensure that
any improvement as a result of the treatment occurs for
many people and is not just a random effect for one person.
Most modern medical treatments are a direct result of
clinical research

6. Why clinical trials standardized?
Untill 19th century there was no proper standard image for conducting
trials.
On literature review it was found that that there was no focus on
ethical consideration from year 1930 to 1960
 During the clinical trials as a consequence, there were tragedies
associated with high morbidity and mortality. Potential rationale behind
all these tragedies were non scientific conduct, misinterpretation of
safety data, inadequate preclinical data on safety and efficacy,
victims treated as guinea pigs, lack of pharmaco-vigilance evidence, lack
of attentiveness in clinical researchers engaged in patient care,
inappropriate patient consent, hindrance/slow withdrawal even

7. Reasons
• No scientific knowledge and
lack of integrity of trials
• No approved Protocol
• Lack of ethical considerations
• Patient consent not received
• Lack of preclinical studies for
safety and efficacy
• Participation in trials against
subject’s willingness

8. Tragedies
TUSKEGEE SYPHILIS STUDY (1932-
1972) :
In Albama
Conducted for 40 yrs
Participants were not informed
about studies
Aim was to investigate the
progression of syphilis
National research act founds
national commission on for the
protection of human subjects
SULFANILAMIDE DISASTER 1937
East virginia
Death of 100
Sulfanilamide as antibacterial for
streptococcal infection
Federal Food and Drug Act, 1938
was established in response to this
tragedy making the premarketing
safety data for novel drugs
mandatory.

9. Regulatory bodies
USA : FDA
UK : MHRA (medicines and healthcare products regulatory agency)
EU : EMEA (European medicines agency)
INDIA : CDSCO (Central drugs standard control organization)

10. Phases of Drug Development

12. Phase IV of Clinical Trial
Post Marketing Trials
Objectives :
-fulfill post approval regulatory requirements
-differentiate the new drug from other marketed
products

13. Pre-clinical studies
Preclinical studies involves in-vitro and in-vivo (animal or cell culture)
Therapeutic index (safety and efficacy evaluation)
 PHARMACOKINETICS study of a drug
 toxicity information.
These studies help pharmaceutical companies to decide whether a
drug candidate has scientific merit for further development as an
investigational new drug (IND)

14. IND Application
Once preclinical studies
indicated the safety and
efficacy of a drug an IND
application has to be filed
with regulatory authorities
For obtaining regulatory
approval for phase 1, 2 and 3
clinical evaluation
Contents of IND appn:
Preclinical data ( all data from animal
studies)
Info on composition & source of drug
Chemical & manufacturing info
Proposed clinical plans & protocol
Ethical committee clearance

16. Phase 0/ Microdosing
Study of new drug in micro doses to derive pk info in
human before undertaking phase1 studies is called phase 0
Objective: To obtain preliminary pk data
Preclinical data: sub acute toxicity in one species by 2 ROA
Micro dose: less than1/100 of the dose of a test substance
calculated to produce pharmacological effect with a max
dose 100 micrograms

17. Phase I
First stage of testing in human subjects
Designed to assess the safety, tolerability, PK and PD of
drug
20-25 volunteers
Duration : 6-12 months
Aim : to determine maximum tolerated dose (MTD) of the
new treatment

18. Phase II
Consists of 20-300 subjects
To confirm effectiveness, monitor side effects and further
evaluate safety
Duration: 6 months to several years
First in patients who have the disease that the drug Is
expected to treat
For new actions of a marketed drug, start with phase2

19. Phase II
Sometimes phase II is
subdivided into IIA and IIB
Phase IIB specifically
designed to study
efficacy(how well the drug
works at the prescribed
doses
Phase IIA aimed to assess
dosing requirements(how
much drug should be given)

21. Phase III
(Most typical kind of study: Therapeutic Confirmatory)
Phase III are randomized controlled multicenter trials on large
patient groups (300-3000) or more depending upon the
disease/medical condition studied.
Phase III has two key goals:
1. To demonstrate the therapeutic efficacy of the drug in a
representative sample of the population at which the treatment
is targeted.
2. To demonstrate the safety and tolerability of the drug in a
sufficient large sample of the population at which the drug is
targeted.

22. Phase IV(post marketing
surveillance)
Within a regulatory framework, Phase IV trials are generally considered as
‘post-registration’ trials: that is, trials of products that already have a
marketing authorization.
No fixed duration or patient population
Helps to detect rare ADRs, drug interactions and also to explore new uses for
drugs
Phase IV is used to indicate the set of clinical studies performed after the
approval indications and restrictions imposed by the Summary of Product
Characteristics.

23. Periodic safety update reports
To be submitted by the manufacturer every 6 months for 2
years and then annually for next 2 years after marketing
approval
Harmful effects discovered may result in a drug being no
longer sold, or restricted to certain uses

24. Aims of phase IV
Comparisons between the new treatment and frequently used current
treatment
Pharmaco-economic assessments, intended to extend the information
obtained in phase I
Pharmacodynamic assessments

26. Phase Objectives
I The earliest types of studies that are carried out in humans. They are
typically done using small numbers of healthy subjects and are to investigate
pharmacodynamics, pharmacokinetics and toxicity.
II Carried out in patients, usually to find the best dose of drug and to investigate
safety.
III Generally major trials aimed at conclusively demonstrating efficacy.
They are sometimes called confirmatory trials and, in the context
of pharmaceuticals, typically are the studies on which registration of a new
product will be based.
IV Studies carried out after registration of a product. They are often for marketing
purposes as well as to gain broader experience with using the new product.

27. References
Textbook of clinical trials, wiley
General considerations for clinical trials, current step
4 version dated 17 july 1997
www.clinicaltrials.gov
https://www.nccn.org/patients/resources/clinical_trials/p
hases.aspx