To ensure that drugs are safe for humans, drug testing is done as follows:

 Drugs are initially developed and evaluated in the laboratory to ensure that
each drug possesses the desired characteristics and actions.

 If a drug appears to have the desired properties, it is then tested in animals

to determine what, if any, side effects the drug may cause. A wide range of
doses are administered to test for side effects, both at the estimated human
dose level as well as in large overdoses to determine possible toxic effects.

 The candidate drug is also given to pregnant animals to determine whether

it has any adverse effects on the developing fetus. This is to help determine
whether the drug would be safe for pregnant women.

 If the candidate drug appears to be safe in test animals, it is then ready to be

tested in humans.
 The only way if a new compound will be safe and effective in
humans is to test it in humans.

 Clinical trials are the part of development where the safety

and efficacy of the product are tested in human volunteer

 A clinical trial is a prospective study that evaluates the

effects of one or more interventions against a control.

 A health intervention can either be a drug, a medical device,

treatment, technique, or combination of treatments

 Clinical trials are research studies in which people help

doctors find ways to improve health and cancer care.

 Clinical trials are subjected to stringent regulation to protect

the safety and rights oh these volunteers

 Clinical trials should be conducted

 In accordance with the ethical principles that have their
origin in the Declaration of Helsinki (Revised 1996) which
lays down “the recommendations guiding physicians in
biomedical research involving human subjects”

 Consistent with good clinical practice requirements

 International ethical and scientific standard for the design,
conduct, performance, monitoring, auditing, recording, analyses
and reporting of clinical trials that involve the participation of
human subjects
 In US, GCPs are regulations that protect the right and safety of
human subjects and ensure the scientific quality of clinical trials
of drug safety and eficacy.
 Compliance with GPR provides public assurance that
 The rights, safety, well-being and confidentiality of trial
subjects are protected, consistent with the principles of the
Declaration of Helsinki
 And data and reported result are credible and accurate.

 To discover or verify the clinical effects of an investigational

product(s)

 To identify any adverse reactions to an investigational

product(s)

 To study absorption, distribution, metabolism, and excretion of

an investigational product(s) with the object of ascertaining its
safety and/or efficacy.
 Prevention Trials
 test new approaches, such as medicines, vitamins, or supplements,
 trials may be examining ways to prevent cancer in people who have
never had it, or in people who have had a cancer previously and are at
risk for another.

 Screening Trials
 These trials are testing the best ways to try to find a disease eg. cancer
at it's earliest stage
 So that chances of cure are higher, and the amount of treatment needed
will be less.

 Treatment Trials
 test new treatments (like a new cancer drug, new approaches to surgery
or radiation therapy, new combinations of treatments, or new methods
such as gene therapy)

 Benefits
 Clinical trials that are well-designed and well-executed are the best approach
for eligible participants to play an active role in their own health care.
 Gain access to new research treatments before they are widely available.
 Obtain expert medical care at leading health care facilities during the trial.
 Help others by contributing to medical research.

 Risks
 There are risks to clinical trials.
 There may be unpleasant, serious or even life-threatening side effects to
experimental treatment.
 The experimental treatment may not be effective for the participant.
 May require more of their time and attention including trips to the study site,
more treatments, hospital stays or complex dosage requirements.
  Clinical trials are essential to the safe development of
medications

 Because, without clinical studies, new drugs and treatments

could not be approved.

 No matter how promising a new treatment looks when

tested with lab animals, it cannot be used to treat people
until it has been carefully evaluated through the several
phases of a clinical study

 Most improvements in the diagnosis, treatment and care of

patients with cancer have resulted from clinical trials.

 Clinical trials provide opportunities

 To learn how well new treatments work
 To compare them with established techniques and
medications
 To learn where there are advantages and disadvantages to
a new therapy.

 Clinical trials are the most effective tool for assessing positive
and negative effects of a health intervention.

 They enable improvements of quality of care through

comparing alternative treatments
  People react to the same exposure or treatment in different
ways; what may affect one person may not affect another.

 When a new intervention is evaluated, it is essential to

consider if the observed responses are consistent with this
natural variation, or whether there really is a treatment
effect.

1.Subjects are followed forward in time - prospective

2. Employ one or more interventions

 may be prophylactic, diagnostic, therapeutic agent,
devices, regimens or procedures

3.Must have a control group which must be similar to the

intervention group at baseline
 The outcome of subjects given the new intervention is
always compared with that in a group who are not
receiving the new intervention
 A control group normally receives the current standard of
care, no intervention or placebo.
 A placebo is an inactive pill, liquid, or powder that has no treatment value.

 In clinical trials, experimental treatments are often compared with placebos to

assess the treatment's effectiveness.

 The placebo is given to one group of participants, while the drug being tested is
given to another group.

 The results obtained in the two groups are then compared to see if the
investigational treatment is more effective in treating the condition.

 PLACEBO EFFECT
 A physical or emotional change, occurring after a substance is taken or
administered, that is not the result of any special property of the substance.
 The change may be beneficial, reflecting the expectations of the participant
and, often, the expectations of the person giving the substance.

4.Human Subjects
 Concerns regarding subject safety.
 Issues of research ethics and informed consent
 Informed consent
▪ subject voluntarily confirms his willingness to participate
▪ after having been informed of all aspects of the trial that are
relevant to the subject’s decision to participate, including the
purpose of the trial.
▪ It should be freely given and documented by means of a written,
signed and dated and witnessed
5. The ideal clinical trial includes both the randomization of
subjects and blinding of subjects and care providers

 Randomization
 Each participant is randomly assigned to receive either the
study treatment or a placebo.
 Each participant has the same chance of receiving any of the
interventions under study
 Allocation is carried out using a chance mechanism so that
neither the participant nor the investigator will know in
advance which will be assigned

 Blinding
 The subjects involved in the study do not know which
study treatment they receive
 To eliminate bias which might be introduced by either the
participating subject or care providers
 Double blind - neither the subject nor anyone involved in
giving the treatment is aware of which treatment was
given.
 Single blind -only the subject is blind to the treatment
they have received
 Phase 1
 The first introduction of proposed drugs into humans
 Include 20 to 80 healthy volunteers
 But sometimes small number of patients with illness to be
treated or tested (e.g toxic drugs such as anticancer agents
are first tested in small numbers of patients)
 Conducted in dedicated medical facilities where subject are
monitored during experiment
 The purpose to evaluate the safety of the agent

 The first test in humans consist of a single dose that is

significantly lower (on weight basis) than those at which adverse
effects were observed in animals

 This is followed by studies in which the dose is escalated to

determine the maximum tolerated dose

 Unpleasant side effects are common in phase 1 trials because

the studies are intended to evaluate the maximum tolerated
dose

 If the maximum tolerated dose is below the expected

therapeutic dose, then the drug fails and will not further
developed
 Phase II
 Drugs meets safety requirement of Phase I, enters Phase II
 Performed in usually 100 to 300 of patients with condition
the drug is expected to treat
 To demonstrate clear drug activity and tolerance of the
new compound in patients with a mild to moderate
disease conditions
 Patients are randomly assign to receive either new drug or
placebo (formulation without the active ingredients)
 The new drug may also be compared to the best existing
treatment rather than a placebo

 Phase III
 To confirm therapeutic benefits of the new drug on the
targeted patients
 Involving the order of 1000 to 3000 patients
 Is critical to establish that the drug has desired effects
 The safety is continuous evaluated, adverse reaction are
monitored, analysis the risks and benefits, drug
interaction and other data
 Require rigorous statistical demonstration of clinical
safety and patient benefit to ensure approval of the
therapeutic
 Phase II and III are normally double blinded
 Neither the volunteers nor the clinicians know who is
receiving the actual drug and who is receiving the placebo
or standard treatment
 Double blinded avoid results that are due to the
psychological expectations of the participants and limit
the potential for the investigators to bias the result
intentionally or unintentionally.

 Ethics refers to moral principles governing human character

and conduct.

 Research investigators should be aware of the ethical, legal

and regulatory requirements for research on human subjects
in Malaysia as well as applicable international requirements.
 Respect for Persons
 Implies the duty to obtain informed consent from study
participants and to maintain confidentiality on their behalf.
 Individuals should be treated as autonomous.
 Those with diminished autonomy need protection.

 Beneficence
 Beneficence demands a favourable balance between the
potential benefits and harms of participation
 Secure the well being of the individual
 Benefit for society/class of patients

 Justice
 Treat persons fairly.
 Equally share the risks and benefits
 Researchers must ensure that the vulnerable not be
exploited and that eligible candidates who may benefit
from participation not be excluded without good cause.
1. Good research design
 Randomization
 may be a problem if the treatment is known (or perceived )
superior to placebo
 trial may be unethical

 Placebo control
 problems of an acceptable placebo
 deprivation of treatment

 Monitoring of the trial

 how to handle available data as it accrues
 Safety monitoring committee

2. Competent investigators
 Researchers should be capable and suitable to undertake the
study.
 Studies beyond the capability of the investigators are not
likely to be properly conducted or achieve credible results

3. Favorable balance of harm and benefit

 Welfare of the subject/physician's obligation to his patient –
 Societal good
 4. Informed consent
 cannot always be obtained e.g. minor (infants), comatose
subjects, mentally incompetent, prisoners, emergency
procedures, pregnant women/fetus

5. Equitable selection of subjects

6. Compensation for research related injury

 The use of placebos is occasionally remarkably successful in

therapeutics, but the practice is more difficult to justify
morally in the experimental situation.
 The controlled use of a placebo necessarily involves the
deception of patients and this raises some complex issues
 The basic circumstances when placebo trials are ethical and
perhaps necessary are:
 when there is no alternative to the experimental treatment
available – for example it may be right to include a placebo
control in the evaluation of a drug intended for the
treatment of AIDS, for which there is no known cure
 when the effect of adding a new treatment to an established
one is under study.