GUIDELINES FOR ETHICAL CONDUCT IN THE CARE OF HUMAN SUBJECTS (CLINICAL PHASE) IN DRUG TESTING

CLINICAL TRIALS

• According to WHO

• type of research that studies new tests and treatments and evaluates their effects on human health outcomes

• carefully designed, reviewed and completed, and need to be approved before they can start.

• People of all ages can take part in clinical trials, including children.

CLINICAL TRIALS

are conducted to collect data regarding the safety and efficacy of new drug and device development.

CLINICAL RESEARCH

refers to studies, or trials, that are done in people.

PHASE I

limited to determining toxicity at a range of dosages

TERMINAL ILLNESSES

efficacy assestment

Phase Il and IlI

Clinical efficacy in large sample of patients

Phase IV

Assess efficacy and side ffects in specific patient population

PROTOCOL

Trials follow a specific study plan, called a ? that is developed by the researcher or manufacturer

Phase I

all patients receives the drug unblinded - open label trial

Phase Il and III

drug is compared to placebo or alternative tx, patients receive one of the tx during the entire trial - parallel design

PARALLEL STUDY

when 2 groups of treatments are given so that one group receives only placebo or standard of care treatment while another group receives only the drug

CROSSOVER STUDY

when each subject receives a placebo, followed by a washout period, and then receives the drug or visa versa

Factorial design

• used to compare different types and combinations of drug therapy

• Allows comparisons between single drug therapies and combination of two drugs combined

Crossover design

• allows patients to receive more than one drug treatment or dosage level during the course of the trial

• Assumption: drug therapy does not have a carry-over effect between the different tx period.

“Washout period”

• placebo or no medication

• Depends on DOA or rate of elimination of trial drugs

• Issue: sufficient to eliminate carry-over effect

During the washout period

• trial data and clinical measures are collected to assess the impact of previous tx

• Considered as baseline data for subsequent tx

• Efficient in regards to no. of patients required to collect a data

POSTMARKETING SURVEILLANCE (PHASE IV)

• Non-experimental (observational)

• Case —control and Cohort- drug therapy is not assigned by the researcher

Control of the intervention

critical component of the trial

ASSIGNMENT OF THE INTERVENTION

• Cause and effect of the relationship between the drug therapy and clinical outcomes can be established

• Accomplished through randomization-computer programs or number lists - assures that assignment to tx intervention are unbiased

• In most trials, patients have equal chance of receiving each tx

• Some trials is designed to have imbalance In tx assignment. Ex. 2:1 or 3:1

Stratified randomization

• used to adjust for potential differences in response between specific patient groups or trial sites.

• Characteristics of concern (type or severity of illness, gender, age, race or study site)- patients are randomized base on their strata.

STRATIFIED RANDOMIZATION

This assures equal numbers of patients with this characteristics are assigned to each trial tx.

BLOCKED RANDOMIZATION

• Sample size for a specific number of patients is established so that equal number of patients are assigned to each treatment group.

• It avoids imbalance in enrollment between treatment groups as trial progresses.

• Keep size of each group similar over entire study

CLINICAL PROTOCOLS

is used to control the application of intervention

PROTOCOL ADHERENCE

monitored throughout the trial

APPLICATION OF INTERVENTIONS

• Designed to address most potential contingencies that occur during the trials

• Deviations form protocol are documented

• Repeated deviations in the protocol by a and discussed particular site may result in disciplinary action such as removal from participation in the trial.

MEASUREMENT OF TRIAL OUTCOMES

• Use of special type of measurement tool or instrument is used to measure outcomes, training of all trial personnel regarding use of the instrument is performed prior to trial start-up.

• Use of an Assessment tool

INCLUSION

identify patient groups specified by trial objectives

EXCLUSION

eliminate patients who might be harmed, unlikely to survive, who will not receive the tx due to allergy, concomitant illness or contraindication

Phase I

healthy volunteers (life threatening diseases)

Phase Il and Ill

w/ disease, patients who will likely benefit from the study

FEASIBILITY

• Dependent: trial purpose, intended application of trial results and access to trial sites and patients

• Overall trial cost and timeline - primary objective and sample size

• Number of patients available, percentage likely to meet the inclusion and exclusion criteria

FEASIBILITY OF CONDUCTING THE TRIAL

Trial purpose: type of outcome

Outcomes of mortality

lengthy observation

Outcomes that intended to be generalized

need broad inclusion and exclusion criteria

TRIAL OUTCOMES MEASUREMENTS

affects the type and quantity of data required, additional testing requirements

CONTRACT RESEARCH ORGANIZATION (CROs)

helps identify patients and provide access to patients

BLINDING

• Involves disguising of drug therapy to the patient and health professionals to minimize bias

• Controlled trial

• Single, Double, Triple

• Achieve by developing dosage forms of active and placebo that are indistinguishable (size, shape, etc.)

• must not significantly alter the drug release characteristics, physical stability of dosage forms, chemical stability of active component

• In vitro tests for dissolution

• Labeling used is indistinguishable

• Disadvantage- affect pt. adherence

SINGLE BLINDING

only patient is unaware of which tx grouped they are assigned

DOUBLE BLINDING

both patient and health professional evaluating the effect and collecting data are unaware of trial drug assignment

TRIPLE BLINDING

additional blinding of the biostatistician and Data Safety and Monitory Board > comparative safety and efficacy

DOUBLE DUMMY APPROACH

involves preparation of a separate matching placebo for each drug product

TRIAL DRUG PACKAGING

• Package sizes (count per bottle and number of bottles per kit) are designed to meet trial requirement of dosage adjustments, clinic visit period, visit window and dosing frequency

• Helps maintain the blinding of study

• Database is maintained which provides correspondence between bottle number and treatment assigned

• Complicated dosage regimen- blister card dosage is used- help improved adherence and direct/timely feedback

Institutional Review Board (IRB)

asses trial protocol

Health Insurance Portability and Accountability Act of 1996 (HIPAA)

provides that patients be informed of their rights to maintain the privacy of health information

INTENTION TO TREAT ANALYSIS (ITA)

• It means that even if the patient has stopped taking the medication, did not complete the assigned tx, or has been switched to an active alternative therapy, the data from the patient is included in the original tx group to which pt is randomized.

• Lessen the likelihood of finding a difference between the treatments

• It more analogous to what happens outside the clinical trial situation.

• It is the statistical feature of clinical trials

ADJUSTMENT T0 MULTIPLE COMPARISON

Lowering the statistical boundary at which the researcher will consider the results significantly different

SUBGROUP ANALYSIS

• Once data is obtained, researchers re-analyzed data from different perspectives

• Ex: dividing the data into several different patient groups