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The only way if a new compound will be safe and effective inhumans is to test it in humans.
Clinical trials are the part of development where the safetyand efficacy of the product are tested in human volunteer
A clinical trial is a prospective study that evaluates theeffects 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 helpdoctors 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) whichlays down the recommendations guiding physicians inbiomedical research involving human subjects
Consistent with good clinical practice requirements
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International ethical and scientific standard for the design,conduct, performance, monitoring, auditing, recording, analysesand reporting of clinical trials that involve the participation ofhuman subjects
In US, GCPs are regulations that protect the right and safety ofhuman 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 trialsubjects are protected, consistent with the principles of theDeclaration 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 investigationalproduct(s)
To study absorption, distribution, metabolism, and excretion ofan investigational product(s) with the object of ascertaining its
safety and/or efficacy.
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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 atrisk 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 methodssuch as gene therapy)
Benefits
Clinical trials that are well-designed and well-executed are the best approachfor 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 toexperimental 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.
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Clinical trials are essential to the safe development ofmedications
Because, without clinical studies, new drugs and treatmentscould 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 severalphases of a clinical study
Most improvements in the diagnosis, treatment and care ofpatients 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 throughcomparing alternative treatments
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People react to the same exposure or treatment in differentways; what may affect one person may not affect another.
When a new intervention is evaluated, it is essential toconsider if the observed responses are consistent with thisnatural variation, or whether there really is a treatmenteffect.
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 theintervention group at baseline
The outcome of subjects given the new intervention isalways compared with that in a group who are notreceiving the new intervention
A control group normally receives the current standard ofcare, no intervention or placebo.
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A placebo is an inactive pill, liquid, or powder that has no treatment value.
In clinical trials, experimental treatments are often compared with placebos toassess the treatment's effectiveness.
The placebo is given to one group of participants, while the drug being tested isgiven to another group.
The results obtained in the two groups are then compared to see if theinvestigational treatment is more effective in treating the condition.
PLACEBO EFFECT
A physical or emotional change, occurring after a substance is taken oradministered, that is not the result of any special property of the substance.
The change may be beneficial, reflecting the expectations of the participantand, 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 arerelevant to the subjects decision to participate, including thepurpose of the trial.
It should be freely given and documented by means of a written,signed and dated and witnessed
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5. The ideal clinical trial includes both the randomization ofsubjects and blinding of subjects and care providers
Randomization
Each participant is randomly assigned to receive either thestudy treatment or a placebo.
Each participant has the same chance of receiving any of theinterventions under study
Allocation is carried out using a chance mechanism so thatneither the participant nor the investigator will know inadvance which will be assigned
Blinding
The subjects involved in the study do not know whichstudy treatment they receive
To eliminate bias which might be introduced by either theparticipating subject or care providers
Double blind - neither the subject nor anyone involved ingiving the treatment is aware of which treatment wasgiven.
Single blind -only the subject is blind to the treatmentthey have received
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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 betreated or tested (e.g toxic drugs such as anticancer agentsare 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 issignificantly 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 todetermine the maximum tolerated dose
Unpleasant side effects are common in phase 1 trials becausethe studies are intended to evaluate the maximum tolerateddose
If the maximum tolerated dose is below the expectedtherapeutic dose, then the drug fails and will not furtherdeveloped
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Phase II
Drugs meets safety requirement of Phase I, enters Phase II
Performed in usually 100 to 300 of patients with conditionthe drug is expected to treat
To demonstrate clear drug activity and tolerance of thenew compound in patients with a mild to moderatedisease 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 existingtreatment 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 aremonitored, analysis the risks and benefits, druginteraction and other data
Require rigorous statistical demonstration of clinicalsafety and patient benefit to ensure approval of thetherapeutic
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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 placeboor standard treatment
Double blinded avoid results that are due to thepsychological expectations of the participants and limitthe potential for the investigators to bias the resultintentionally or unintentionally.
Ethics refers to moral principles governing human character
and conduct.
Research investigators should be aware of the ethical, legaland regulatory requirements for research on human subjectsin Malaysia as well as applicable international requirements.
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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 thepotential 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 benefitfrom participation not be excluded without good cause.
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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 thestudy.
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
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4. Informed consent
cannot always be obtained e.g. minor (infants), comatosesubjects, mentally incompetent, prisoners, emergencyprocedures, pregnant women/fetus
5. Equitable selection of subjects
6. Compensation for research related injury
The use of placebos is occasionally remarkably successful intherapeutics, but the practice is more difficult to justifymorally 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 treatmentavailable for example it may be right to include a placebocontrol in the evaluation of a drug intended for thetreatment of AIDS, for which there is no known cure
when the effect of adding a new treatment to an established
one is under study.