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Therapeutics

 Clinical Trials

Clinical trial : A properly planned and executed clinical trial is a powerful experimental technique for assessing the effectiveness of an intervention. A prospective study comparing the effect and value of interventions against a control in human subject .A well-planned protocol document is critical for  conducting a clinical trial, and strict adherence to the document is essential.

  Ethical issues in clinical trials involve the protection of participants, disclosure of conflicts of interest, accurate and timely reporting of results, and prompt reporting of adverse events

Objective Tools for Evaluation of clinical trials :

Diagnostic tests

Screening modalities

Prevention strategies

Therapeutic interventions

Essential features of clinical trials : 

A. Subjects are followed forward in time - prospective

B. Employ one or more interventions - may be prophylactic, diagnostic, therapeutic agent, devices, regimens or procedure

C. Must have a control group which must be similar to the intervention group at baseline  . The control group is selected to be as similar to the study group as is possible in virtually all respects

Phases of Clinical trials : Phases of Clinical Drug Development

 Phase 0 (pre-clinical/non-clinical)  

Phase I - evaluates dose and toxicity , First study with humans

Phase II - assesses drug activity . Estimates of efficacy

Phase III: Randomized, standard of care comparison of two or more therapies

Phase II and III regulatory trials in drug and vaccines for malaria and HIV. Academic proof of concept trails.

 Large phase IV surveillance studies.

D. Human Subjects - concerns regarding subject safety. - issues of research ethics and informed consent

E. The ideal clinical trial includes both the randomization of subjects and blinding of subjects and care providers. Randomization allows for the equal allocation of potential confounders and effect modifiers between the two study groups. These are factors which are possibly unknown or unpredictable at the onset of the study.Blinding attempts to eliminate bias which might be introduced by either the participating subject or care providers - Single Blinding - Double Blinding 

Other Characteristics of clinical trials

A. Need :

1 . Most definitive method of determining whether an intervention has the postulated effect                          

2. Uncertainty regarding diseases and their natural history and therapy and its positive and negative effects

3. The consequences of not conducting appropriate clinical trial can be serious and costly in the long run.              Examples: - Use of CPAP in COPD patients - Use of digitalis in congestive heart failure - Uncontrolled use of high concentrations of O2 in premature neonates 

B. Timing

1 . Must be performed before drugs or interventions have become part of routine medical practice                        

 2. Early in the development of new therapies, but                 

3. Only after sufficient knowledge is available concerning efficacy and safety   

4. Should not be conducted if therapy will be outmoded before or shortly After the trial has concluded 

C. Ethics: 

1 . Three fundamental ethical principles regarding research:

1. A . Respect for Persons - individuals should treated as autonomous. Those with diminished autonomy need protection.

    

B . Beneficence - - Secure the well being of the individual - Benefit for society/class of patients

 C . Justice - treat persons fairly. Equally share the risks and benefits

Ethical Norms dictate that there should be:

a .Good research design (1) Randomization - may be a problem if the treatment is known (or perceived ) to be superior to placebo - trial may be unethical (2) Placebo control - problems of an acceptable placebo - deprivation of treatment (3) Monitoring of the trial - how to handle available data as it accrues - Safety monitoring committee

b. Competent investigators

c. Favorable balance of harm and benefit - Welfare of the subject/physician s obligation to his patient - Societal good

d. Informed consent - cannot always be obtained e.g. minor (infants), comatose subjects, mentally incompetent, prisoners, emergency procedures, pregnant women/fetus

e. Equitable selection of subjects

f. Compensation for research related injury 

Scientific Issues in clinical trials :

Hypothesis: Is the question addressed by the study important?                                Study population: What are the eligibility criteria for subject inclusion and exclusion?

–Disease type and stage

–Functional performance status

–Number and type of prior therapies

–Organ function: liver, kidney, bone marrow

Endpoints: Which parameters will be measured?

–Remission rate, progression-free survival, overall survival( e.g. in cancer trials )

–Quality of life, symptom control                                  

–Ancillary studies: blood and tissue levels of drug and target inhibition, imaging of tumor size, and metabolism

Biostatistical considerations

–Appropriate study design

–Numbers and types of patients 

Clinical Trial Design

The question:

Is it relevant?

Is it feasible? (Can it be answered?)

Is it worth it?                                             

What study endpoints will provide the answer?

What else can we learn?

The population:Is it representative? Is it significant? Is it available?

The Control

Types of controls:

–Historical

–Pair matched

–Contemporaneous

Randomization

Stratification: balancing major variables

Placebo use and blinding

The Hypothesis

How we answer the trial question?

Null hypothesis

Alternate hypothesis

One-tailed and two-tailed hypotheses

The p value represents the probability of obtaining the observed result if the null hypothesis is true.

One-tailed alternate hypothesis ?one-sided p value

Two-tailed alternate hypothesis ?two-sided p value

What makes Clinical Trial different from ‘Standard of Care’

Involves human subjects

Test an ‘intervention’ – be it a product, procedure or health care sytem….in order to improve standard of care!

Measures effects over a period of time

Most have a comparison CONTROL group

Must have method to measure intervention

Focuses on unknowns: effect of intervention

Must be done before medication is part of standard of care

Standard of Care all about clinical judgement decision/flexibility – trials need all to stick with the protocol, no deviation – within your clinical judgement

Types of Medical Research Studies

Non-directed Data Capture :Vital Statistics

Directed Data Capture & Hypothesis Testing : Cohort Studies, Case Control Studies.

Clinical Trials

Investigation of  Treatment/Condition

Drug Trials

Evidence Based Medicine (EBM)

EBM is defined as : The conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients. The practice of EBM means integrating individual clinical expertise with the best available external clinical evidence from systematic research

Sources of Evidence:

Primary Evidence include : Randomised controlled trials ,Observational studies , Descriptive studies , Case reports.

Secondary Evidence:  Meta analysis  , Systematic reviews ,Summary reviews Respected opinions

Tertiary Evidence – Clinical Guidelines

In general the evidence include :

1 .Systematic reviews and meta-analyses

2 . Randomized controlled trials with definitive and clinically significant effects

3 . Randomized controlled trials with non-definitive results

4 . Cohort studies

5 . Case-control studies

6 . Cross-sectional surveys

7 . Case reports

Key Results in a Trial:

Experimental event rate = EER

Control event rate = CER

Relative risk (RR) = EER/CER

Relative risk reduction (RRR) = Relative risk - 1

Absolute risk reduction (ARR) = EER – CER

Number needed to treat (NNT) is the number of patients that need to be treated (for a specific time period) to prevent one event

NNT = 1/ARR

Example :  

CAPRIE was a randomised, blinded, international trial designed to assess the relative efficacy of clopidogrel (75 mg once daily) and aspirin (325 mg once daily) in reducing the risk of a composite outcome cluster of ischaemic stroke, myocardial infarction, or vascular death

ARR  = 5.32-5.83 = -0.51%

RR =  0.0532/0.0583 = 0.913

RRR = 0.913-1 = -0.087 or -8.7%

NNT = 1/0.0051 = 196