Chapter 8 Clinical Trials

8/8/2019 Chapter 8 Clinical Trials

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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.

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Chapter 8 Clinical Trials