Clinical trials involve several phases to test a drug's safety and efficacy. Phase I trials test safety in healthy volunteers. Phase II trials test dosage and side effects in patients. Phase III trials test efficacy in large patient groups. Legal and procedural aspects require ethics committee approval, informed consent, and regulatory oversight. Clinical trials involve clinical investigators, institutions to host the trial, sponsors to fund the trial, and regulatory authorities to provide legal approval. The clinical trial protocol, informed consent process, and role of ethics committees are important to protect patient rights and welfare in clinical research.

1. Clinical Trials
Scientific Aspects
AND
Legal & Procedural Aspects
ATHAR SHAMIM
M.PHARM 2nd
sem

2. Scientific Aspects of Clinical Trial
Phases of Clinical Trial
• Phase I : First in man  safety
• Phase II : First in patient dose, dosage form
• Phase III : Efficacy, ADRs
• Post marketing surveillance or Phase IV :
Evaluation in the real clinical setting

3. Phase I• Objectives
1. To assess a safe & tolerated dose
2. To see if pharmacokinetics differ much from animal to
man
3. To see if kinetics show proper absorption, bioavailability
4. To detect effects unrelated to the expected action
5. To detect any predictable toxicity
– Inclusion criteria
– Healthy volunteers : Uniformity of subjects: age, sex,
nutritional status [Informed consent a must]
– Exception: Patients only for toxic drugs Eg AntiHIV,
Anticancer
– Exclusion criteria
– Women of child bearing age, children,

4. Phase I contd
• Methods:
– First in Man : Small number of healthy volunteers
– First in a small group of 20 to 25
– Start with a dose of about 1/10 to 1/5 tolerated animal
dose
– Slowly increase the dose to find a safe tolerated dose
– If safe  in a larger group of up to about 50 –75
– No blinding
– Performed by clinical pharmacologists
– Centre has emergency care & facility for kinetics
study
– Performed in a single centre
– Takes 3 – 6 months [ 70% success rate]

5. Phase II
• First in patient [ different from healthy volunteer]
• Early phase [20 – 200 patients with relevant disease]
– Therapeutic benefits & ADRs evaluated
– Establish a dose range to be used in late phase
– Single blind comparison with standard drug
• Late phase [ 50 – 500]
– Double blind
– Compared with a placebo or standard drug
• Outcomes
– Assesses efficacy against a defined therapeutic endpoint
– Detailed P.kinetic & P.dynamic data
– Establishes a dose & a dosage form for future trials
• Takes 6 months to 2 years [ 35% success rate]

6. Phase III
• Large scale, Randomised, Controlled trials
• Target population: 250 – 1000 patients
• Performed by Clinicians in the hospital
• Minimises errors of phases I and II
• Methods
– Multicentric  Ensures geographic & ethnic variations
– Diff patient subgroups Eg pediatric, geriatric, renal impaired
– Randomised allocation of test drug /placebo / standard drug
– Double blinded:
– Cross over design
– Vigilant recording of all adverse drug reactions
– Rigorous statistical evaluation of all clinical data
• Takes a long time: up to 5 years [25% success]

7. Cross over design
Group Week 1 Week2 Week3
I Standard Placebo Test
II Placebo Test Standard
III Test Standard Placebo
* A wash out period of a week between two weeks
of therapy

8. New drug application
• The New Drug Application (NDA) is the vehicle
through which drug sponsors formally propose
that the FDA approve a new pharmaceutical for
sale and marketing.
• Goal of the NDA are to provide enough
information to permit FDA reviewers to establish
the following:

9. Cont…..
• Is the drug safe and effective in its proposed use(s) when used
as directed, and do the benefits of the drug outweigh the risks?
• Is the drug’s proposed labeling (package insert) appropriate, and
what should it contain?
• Are the methods used in manufacturing (Good Manufacturing
Practice, GMP) the drug and the controls used to maintain the
drug’s quality adequate to preserve the drug’s identity, strength,
quality, and purity?
• Once approval of an NDA is obtained, the new drug can be
legally marketed starting that day

10. Phase IV or Post marketing
Surveillance
• No fixed duration / patient population
• Starts immediately after marketing
• Report all ADRs
• Helps to detect
– rare ADRs
– Drug interactions
– Also new uses for drugs [Sometimes called Phase V]

12. Clinical Trial: Legal & Procedural
aspects
Elements of a Clinical Trial
• Aim or objective
• Protocol : study design
• Ethics committee clearance
• Regulatory approval whenever required
• Informed consent
• Implementation of protocol
• Collection of data
• Compilation of data, analysis and interpretation
• Report writing

13. Participating Parties in Clinical Trial
1. Patient / Healthy volunteer
2. Clinical Pharmacologist, Clinical Investigator
& team: [Qualified and competent]
3. Institution where trials are held : [Approval
required]
4. Ethical Review Board or Institutional Ethical
Committee:
5. Sponsor
6. Regulatory Authorities:

14. Functions of participating parties
– [1] Patient / Healthy volunteer : Subject of
the trial
– [2] Clinical Pharmacologist, Clinical
Investigator & team:
– Conducts the clinical trial; reports all adverse
events
– [3] Institution where trials are held :
– Provides all facilities [Approval required]

15. Functions of parties contd.
– [4] Ethical Review Board or Institutional Ethical
Committee:
– Supervises and monitors every step;
– Safeguard the welfare and the rights of the
participants
– [5] Sponsor :
– Pays for all expenses;
– Appoints competent investigators,
– Ships all drugs for the trial,
– Files all papers to legal / regulatory authorities,
– [6] Regulatory Authorities:
– Legal authority on the outcomes of the trial

16. Clinical Trial Protocol• Title & Abstract
• Introduction
– General statement of purpose
– Complete Preclinical results on animal study
– Clinical data if available
– Time frame
• Goals: Primary & secondary objectives
• Study Design:
– Type of study
– Recruitment criteria : Exclusion & Inclusion criteria
– Randomisation criteria and Sample size
– Duration of study
• Data Analysis:
– Case report forms, Statistical Analysis, Bibliography

17. Informed Consent
• Informed consent form:
– Voluntary
– Explained in simple nontechnical language
– Translated in the native language of the subject
– Comprehensive information regarding the trials
• Benefit of new therapy over existing ones
• Alternative treatments available
– All possible adverse reactions
– Freedom to withdraw from the trial
• at any time,
• without giving any reason

18. Institutional Ethical Committee
– Independent
– Competent
– 5 – 7 members; 5 required for quorum.
– Member Sec from same Institution
– Others: A mix of medical non-medical,
scientific & non-scientific including lay public
– Multidisciplinary & Multisectorial

19. Responsibilities of IEC
1. To protect the dignity, rights & well being of
patients / volunteers
2. Ensure a competent review of the protocol
3. Advise on all aspects of welfare & safety
4. Ensure scientific soundness of the proposal

20. The composition of IEC
1. Chairperson
2. 1-2 basic medical scientists.
3. 1-2 clinicians from various Institutes
4. One legal expert or retired judge
5. One social scientist / representative of NGO
6. One philosopher / ethicist / theologian
7. One lay person from the community
8. Member Secretary
– Individuals from other institutions if required
– Adequate representation of age, gender, community,

21. Problem areas
• Compensation in drug related injuries
– Mild and Severe
• Patient Rights
– Confidentiality of data
– Right to withdraw
• Collection procedures & amount of biological material
taken
• Compensation & Insurance claims
• Sending bio-material abroad
• Selection of Patients

22. References
• Brunton L. J. et al., Goodman & Gilman’s The Pharmacological Basis of
Therapeutics, 11th
ed., 2006,Mc Graw Hill Publishers, pp 117-119
• Tripathi K.D., “Essentials of Medical Pharmacology” , 6th
ed., 2008, Jaypee
Publishers, pp 71-73, 77
• Ali Asgar et. al., “Clinical Trials and Health Care Policies”, 2005, Jamia
Hamdard, pp 5-8, 22-25
• Rang H.P. et al., Rang & Dale’s Pharmacology, 6th
ed., 2008, Churchill
Livingstone, pp 92-95, 784-785
• http://clinicaltrials.gov/ct2/info/understand#Q01
• http://en.wikipedia.org/wiki/Clinical_trial
• http://cdsco.nic.in/html/schedule-y%20(amended%20version-2005)%20original.htm