Clinical trials in Medicine, protocol and responsibility

1. Clinical Trials
Scientific Aspects
AND
Legal & Procedural Aspects
@drmansoor (pharmd)

2. “clinical trial” means
an investigation in a human subject which is
intended to discover or verify the clinical,
pharmacological or other pharmacodynamics
effects of an investigational drug product or to
identify any adverse reactions to an
investigational drug product;

3. Types of Clinical Trials:
(as defined by the National Institutes of Health)
 Treatment Trials - test new treatments, new
combination of drugs or new approaches to
surgery or radiation.
 Prevention Trials - look for better ways to prevent
diseases.

4. Types of Clinical Trials:
 Diagnostic Trials - determine better tests or
procedures for diagnosing a particular disease or
condition.
 Screening Trials - test the best way to detect or
treat diseases.
 Quality of Life Trials - explore and measure ways to
improve the comfort and quality of life of people with
a chronic illness.

6. Clinical Trials are Done in
Phases:
 First, a Pre-Clinical Trial must
be done before the Clinical
Trial starts.
 Preclinical trial – research
on a new drug or a new
medical device or procedure,
usually done on animals, to
learn about mechanisms of
action, determine how well the
treatment works, and see if it
is safe to test on humans.

7. 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

9. 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,

10. 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]

11. 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 [Only patient knows] 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]

12. 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]

13. 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

14. 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]

15. 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

16. 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:

17. 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]

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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,

24. 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

25. Research Concepts
 In many studies, the new drug is
compared to a placebo. A placebo is a
product that looks like the new drug, but it
does not have the active ingredient in it.
People do not know that they are getting
the placebo.
 Sometimes the test compares the new
treatment against an existing treatment to
see if better results can be obtained.

26. Research Concepts
 Blind and Double Blind Trials are frequently
done.
 A Blind Trial is a trial in which the patients do not
know if they are receiving the treatment or a
placebo.
 A Double Blind Trial is a trial in which the
patients and the researchers do not know who is
receiving the treatment.
 Why would the above be good ideas?

27. Research Concepts
 Randomization is the process by which patients
are assigned a group for the Clinical Trial.
 Groups are assigned randomly, not purposefully.
 Some people will receive the new treatment, some
may receive an already approved treatment, and
some may receive a placebo.
 If one treatment is found superior, the trial is
stopped so that the fewest patients possible
receive the less beneficial treatment.

28. Use of Placebo Control
The “placebo effect” is well documented
Could be
No treatment + placebo
Standard care + placebo
Matched placebos necessary so patients & investigators
cannot decode the treatment assignment
eg. Vitamin C trial for common cold
Placebo was used, but was distinguishable
Many on placebo dropped out of study – not blinded
Those who knew they were on vitamin C reported fewer
cold symptoms and duration than those on vitamin who
didn't know

29. NDA UG
An application for authorisation to conduct a clinical trial shall be made by a sponsor
who shall be
(a) the holder of the patent of the drug;
(b) a licensed person;
(c) the manufacturer of the drug; or
(d) an agent of the holder of the patent or the manufacturer, of the
drug.
Where an application for authorisation to conduct a clinical trial is made by an agent,
the agent shall submit a power of attorney attesting to the appointment as an agent
or a letter of authorisation

30. The application shall be accompanied by the following —
(a) the clinical trial protocol;
(b) evidence of approval of the clinical trial by the Uganda National Council of Science
and Technology or an institution approved by the Uganda National Council for
Science and Technology;
(c) the investigator’s brochure or prescribing information data sheet
(d) a declaration by the principal investigator made using
(e) a declaration by the monitor made
(f) the financial declaration by the sponsor and the principal investigator
(g) the information to be provided to the subjects and the written consent forms of the
subjects;
(h) valid evidence of the insurance of the subjects;
(i) pharmaceutical data on the dosage form of the investigational medicinal
(j) capacity building plans for the training of the staff to be involved in the clinical trial;
(k) the prescribed fees; and
(l) any other requirement as may be determined by the Authority.