Clinical trials involve research studies that assign participants to medical interventions to evaluate their effects. There are various phases of clinical trials. Phase 0 involves micro-dosing to determine pharmacokinetics. Phase I tests safety on healthy volunteers. Phase II evaluates dosing and efficacy on patients. Phase III tests larger groups to confirm efficacy and monitor safety compared to standard treatments. Phase IV occurs after approval to further monitor long-term safety and efficacy. The document outlines the goals and timeline of each phase in the drug development and approval process.

1. CLINICAL
TRIALS
Dr. Nilesh Siddhawar,
JR1, Dept. of Pharmacology,
VNGMC, Yavatmal

2. • Introduction
• Aims and Objectives
• History
• Drug development process and Phases
• Phases of clinical Trials
• Conclusion

3. Clinical trials
Any research study that prospectively assigns human participants or group
of humans to one or more health related interventions to evaluate the effect
on health outcomes

4. AIMS AND OBJECTIVES
• Discovering and confirming the role of new drugs for
the future pharmacotherapy
• To evaluate safety and efficacy of experimental drug
relative to its adverse drug reactions
• To change behaviour,habbits or other lifestyle factors
• Licensing process of a new drug

5. History
• The first documented experiment resembling a clinical trial was conducted by
King Nebuchadnezzar
• He ordered people to eat only meat and drink only wine, a diet he believed would
keep them healthy .
• He permitted the dissenters to instead follow a diet of legumes and water — but
only for 10 days, after which he would assess their health.
• When experiment ended, the bean-loving people appeared better nourished than
the mandated meat-eaters, so the king allowed them to continue their diet

6. The first person to conduct a parallel-arm medical experiment was British physician
Dr. James Lind.

7. • Lind selected 12 ill sailors and divided them into
groups of 2. All the subjects displayed similar
symptoms.
• Men were given the same rations, but each pair
received a different scurvy treatment: either cider,
a few drops of a weak acid, vinegar, sea-water,
nutmeg and barley water, or oranges and lemons.
• After 6 days, the ship's supply of fruit was spent,
but by then ; the 2 men on the citrus treatment
were already back on their feet

8. • The word Placebo first appeared in medical literature in the early
1800s.
• 1863 that US physician Austin Flint conducted the first medical
experiment comparing a dummy remedy to an active treatment.
• He treated 13 patients suffering from rheumatism with an herbal
extract instead of an established remedy.
• The first widely publicized randomized clinical trial was a 1948
test of streptomycin for treating pulmonary tuberculosis

9. International clinical trials day is celebrated
on 20th May
• In 1906: FDA was founded.
• In 1923: Concept of randomization.
• In 1943: The UK Medical Research Council’s (MRC)
trial to treat the common cold is the first double blind
controlled study.

10. Types of Clinical Trials
1. Treatment Trials
2. Prevention Trials
3. Diagnostic trials
4. Screening Trials
5. Quality of life Trials

11. 1. Drug discovery :
-During which the candidate molecules are chosen on the basis of their pharmacological
properties
2. Preclinical :
-During which a wide range of animal studies are performed, e.g. Pharmacokinetic,
pharmacodynamic and toxicity studies
3. Clinical Trial :
-During which the lead compound is evaluated for efficacy, safety, and adverse effects in
human volunteers and patients
DRUG DEVELOPMENT PROCESS

12. Drug Discovery
• Drug, target or targeted chemical moiety is identified
and then validated.
• Lead compound is identified
• Lead compound optimisation

13. PRECLINICAL EVALUATION
1. Toxicity Testing
2. PK &PD
3. Pharmacological effects
Time required: 1.5-
3yrs
IEC
approva
l

14. Pre-clinical Evaluation Phase (Animal Studies)
• Wide range of animals studies are performed
• Involves screening, evaluation, pharmacokinetics and short-term
toxicity in animals
• The aim is to satisfy all the requirements that are needed before a
compound is considered fit to be tested for first time in humans
• Pre-clinical phase usually require – 2 to 4 yrs. for completion

15. TOXICOLOGICAL STUDIES
• Acute toxicity : 2 animal species
• Subacute toxicity : 2 animal species
• Chronic toxicity : 2 animal (1 rodent and other non rodent)
Special toxicity:
i. Effect on reproductive performance
ii. Teratogenicity
iii. Carcinogenicity (Same dose for 2 yrs)
iv. Mutagenicity
v. Local toxicity: dermal, ocular, vaginal etc

17. CORE COMPONENTS OF CLINICAL TRIALS
• Involve human subjects
• Must have method to measure intervention
• Focus on unknowns: effect of medication, any adverse reaction
• Must review existing scientific data & build on that knowledge
• Test a certain hypothesis
• Study protocol must be built on sound & ethical consideration
• Control for any potential biases

18. Different Phases Of Clinical Trials

19. Phase 0
• Administration of single sub therapeutic doses
• Small number of healthy subjects (10 to 15)
• Limited dosing duration(< 7 days )
• No therapeutic or diagnostic intent
• Provides agent's pharmacodynamics and pharmacokinetics
• Assist in the go vs no-go decision making process of drug.

21. Advantages –
• Save the investment
• Shorten development timeline
• Improve the efficiency and success of
subsequent trials
• Require lesser preclinical testing data.
Limitations-
• False negative results can lead to
discontinuation of promising drug
• Non linear pharmacokinetic if present
can create problems in dose
extrapolation

22. Investigational New Drug
Application• When the new drug passes the pre-clinical pharmacological screening, the manufacturer
may file a ‘Investigational new drug’ (IND)to an authorized drug control body.
• In UK- CSM
• In USA- FDA
• In INDIA- Drugs controller general, Govt. of India, New Delhi.

23. Phase I
• Limited number (25-100 in number) Healthy volunteers
• If drug has excessive toxicity, volunteers with particular disease can be used.
• To determine appropriate dose range with regard to safety and toxicity
• Used to document pharmacokinetics of drug
• Take 9-18 months to complete.
• It is open label or non-blind trial.

24. • Three different kinds of phase I trials include:
• Single ascending dose studies
• Multiple ascending dose studies
• Food effect

25. SINGLE ASCENDING DOSE STUDIES (SAD)
• Small groups (3) of subjects are given a single dose of the drug while they are
observed and tested for a period of time.
• If no adverse effects, dose is escalated with 3 new healthy subjects
• If toxicity is observed then 3 more subjects are given the same dose and if found
toxic, the dose is considered as Max. Tolerated dose (MTD).

26. Multiple Ascending Dose (MAD)
• To understand the pharmacokinetics and pharmacodynamics of multiple doses of the
drug.
• A group of patients receives multiple low doses of the drug
• Samples ( blood, and other fluids) are collected at various time points
• Analyzed: how the drug is processed within the body.

27. Food effects
• To investigate any differences in absorption of the drug by the body, caused by eating
before the drug is given.
• It is a crossover study, with volunteers being given two identical doses of the drug while
being fasted, and after being fed

28. Once a drug has shown to be safe, then it must be tested for efficacy.
Phase II
• Relatively limited (150-350) patients
• Focus on dose response, dosing schedule and issues related to
preliminary safety and efficacy
• Often involve hospitalized subjects who can be closely monitored
• Take 1-3 yrs to complete
• Additional animal testing could be done simultaneously for long
term safety information.

29. Phase II clinical trial is again divided into
1) Phase II a-
• Potential therapeutic benefits, side effects and adverse effects are observed
• Main obejective – to estabilish a dose response,type of patient,frequency of dosing and
other characterastics of safety and efficacy.
• Ususally single blind trial &involve small no. Of patients (upto 200)
2) Phase II b-
• It usually represent most rigorous demonstration of medicines efficacy.
• Large no. of patients (200-400) in double blind manner.

30. ● Large scale multicentred (heterogenous
population),Randomised ,Double blind ,Cross over trial .
● Large number of patients : 1000 – 5000 .
● Make comparison between new treatment and standard
therapy / placebo
● Lasts an average of 5 – 6 years.
● Further estabilish safety and efficacy and possible drug and
food interactions.
Phase III

31. New Drug Application
• Sponsor submits “New Drug Application” for marketing approval
• NDA contains extensive data on test product efficacy and safety and may include
copies of individuals subject data forms.
• Once DRA receives NDA it is distributed to FDA review group.
• FDA review group responsible for safety and efficacy of pharmaceutical agents,
medical devices.
• FDA reviewers are also responsible for drug classification.

32. Subset of Phase III Trials
Phase III a –
• Conducted prior to submission of “ New drug Application”.
• Generate additional data on safety and efficacy in relatively large no.
of patients
• Often provide information for package insert and labelling of drug.
Phase III b-
• Conducted after submission of NDA but prior to drugs approval
and launch
• It supplement earlier trials or may be directed toward new type of
trials

33. Phase IV
• Conducted after drug is marketed
• Evaluation of different formulations, dosages, duration of treatment ,drug
interactions and other drug comparison.
• Monitor ongoing safety in large populations and identify additional uses
• It include sample size in thousands.
• Has no fixed duration.
• During New drug status period manufacturer are expected to submit PSUR
to Drug controller authority.

34. ● Extension of phase IV clinical trials
● Phase V is a growing term used in the literature of translational
research
● It refers to comparative effectiveness research and community-
based research
● It is used to signify the integration of a new clinical treatment into
widespread clinical practice
Phase V Clinical Trials

35. Guidelines for Clinical Trials of New Drug
New drug discovered in India: Phase 0 to IV
New drug discovered outside India: After submitting Phase I data to
licencing authority permission then granted to conduct Phase II &
subsequently phase III trials or repeat phase I trials
If drug is already marketed in other countries,phase III data should
generally be obtained on at least 100 patients distributed in 3-4
centers to confirm safety and efficacy in Indian patients

36. Bioethical code of Conduct
• Nuremberg Code 1947
• Declaration of Helsinki 1964
• ICMR Guidelines
• WHO & CIOMS Guidelines
• UNESCO Guidelines

37. Principles of Ethics
1. Principle of autonomy: Welfare and rights need to be respected
2. Principle of beneficence & non-maleficence: Minimise harms and
enhance benefits
3. Principle of Justice: Fair distribution of scarce resources and respect for
morally acceptable laws

38. Rules for Ethical Clinical Research-
1. Essentiality
2. Scientific validity
3. Favourable risk-benefit ratio
4. Fair subject selection
5. Voluntariness , informed consent
6. Non-exploitation
7. Privacy and confidentiality
8. Professional competence
9. Accountability and transparency

39. IEC/IRB -
To safeguard the welfare and rights of the participants and to ensure Universal Ethical
values
Composition:
• 8-12 members
• Chairman should be from outside institution
• Member secretary from same institution
• Other members are medical/Non-medical or lay persons

40. Use of Placebo
• Placebo controls results in d/t associated smaller sample size less
expensive and more rapid trials
• Several authors have argued that placebo control trials are invariably
unethical
• Comparison of new treatment with old treatment is sufficient to
establish efficacy
• They are allowed if disease is mild or no satisfactory treatment is
available for disease

41. Conclusion
• The final outcome of clinical trials is improved clinical medicine.
• After preclinical development, investigational new drug passes through
clinical phases I, II, III and IV.
• These phases provide in detail explanation of pharmacokinetic,
pharmacodynamic profile and side effect which may be harmful or
beneficial, adverse effect and post marketing surveillance.
• Clinical trial are conducted in human volunteers for confirmation of useful
properties of new drug.

43. 1. Collier R. Legumes, lemons and streptomycin: A short history of the
clinical trial. CMAJ : Canadian Medical Association Journal.
2009;180(1):23-24. doi:10.1503/cmaj.081879.
2. Mahan, Vicki L. "Clinical trial phases." International Journal of Clinical
Medicine 5.21 (2014): 1374.
3. Principles of Pharmacology, HL Sharma , KL Sharma 3 rd edition
4. Postgraduate topics in pharmacology, Rituparna Maiti, 2nd edition
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