Clinical trialThe Way We Make Progress

Against Disease

Prof. Ashry Gad Mohamed

Prof. of Epidemiology

College of Medicine & KKUH

Definition

a clinical trial is defined as a planned experiment on humans. the setting is in health institutions environment and it usually involves patients.

Rationale

Before a new treatment method is made available to the public it must be studied and tested for safety and effectiveness.

Each treatment must be tested in increasingly larger numbers of people to determine the effects in a large range of people. (Phases)

Each study must follow a rigorous study plan with protections for participants. (protocol)

RCT is the gold standard for evidence.

Fields of clinical trials

Quality of life

Therapy

Prognosis

PreventionDiagnosis

Compliance

Clinical trial

Treatment Trials

• What new treatments can help people with a particular disease?

• What is the most effective treatment for people with that disease?

Treatment Trials

• Many treatment trials compare two or more different approaches to treating a disease

• Participants will take either:– The best accepted

treatment– A new treatment

Prevention Trials

What approaches can prevent healthy people from developing disease?

Prevention Trials

Two kinds, that ask participants to either:1. Do something2. Take something

Basic terms in clinical trial

• Investigators

• Participants

• Intervention

• Outcome

Phases of clinical trial

Phase 1

Prerequisite: In vitro data support the

hypothesis

Who? Healthy volunteers or hopeless cases

How many? Small group (20 – 80)

Why? To determine the best way to give

people the drug.

How often should be given?

What is the safest dose?

(Safety & metabolism in human)

Phase 2

Why? Drug effectiveness in particular

indication.(How well the drug

works?)

Short term common side effects.

Therapeutic pilot study

WHO? Larger group of patients

(100- 300).

Phase 3Why? Confirm effectiveness.

Short & long term side effects.

Double blind randomized placebo controlled trials

How many? Hundreds or thousands

patients.

Approval

Phase 4

When? Post marketing surveillance.

Why? Different populations.

Long term side effects.

Never end.

Steps of clinical trial

1-Formulation of the hypothesis.• Hormone replacement treatment (HRT) and

Breast cancer.

• Trial of Vitamin D and calcium supplementation and hip fracture.

• Use of statins for the prevention of Myocardial Infarction.

• Use of the oral contraceptive pill and deep vein thrombosis (DVT).

2-Definition of

Reference population.

Experimental population.

Necessary sample size.

inclusion criteria.

exclusion criteria.

3- Informed consent

A process by which a subject voluntarily confirms his/her willingness to participate in a particular trial after having been informed of all aspects of the trial that are relevant the subjects decision to participate.

Protecting Patients’ Safety

Informed Consent Before agreeing to take part, patients have the right to understand all that is involved in a clinical trial:

• Procedures and treatments

• Tests• Possible risks and benefits

Protecting Patients’ Safety

Institutional Review Board

• Committee made up of experts

Benefits of Taking Part

Possible benefits:• Patients will receive, at a minimum, the

best standard treatment• If the new approach is proven to work,

patients may be among the first to benefit• Patients have a chance to help others

and improve health care

Risks of Taking Part

Possible risks:

• Unknown side effects or other risks

• New treatment may not help every participant

• Costs

4-Allocation of regimens

Intervention versus Placebo

Current treatment

Nothing

Randomization

Aim

Methods

Variants of clinical trials:• 1-Parallel design: Parallel groups design: each patient

receives only one treatment.

Follow up

Ref. Pop. Sample

Intervention

Control

OUTCOME

2-Crossover design: each patient receives all/both treatments in random order, often with a washout period between treatments•Disease: Chronic, incurable stable disease.•Intervention: rapid onset & short duration

Treat. A

Treat. B

Treat. A

Treat. B

washoutperiod

1st treatmentperiod

2nd treatmentperiod

3-Factorial Design

Sample

Drug A Placebo

Drug B Placebo Drug B Placebo

Clinical trial & number of participants

• 1-Mega Trial Thousands of patients Multiple centers Statistical power Generalization

• 2-Sequential trial No specified sample size Continuous recruitment Clear benefit / no difference

• 3- Fixed size trial

Most common

Study power

• 4- N of one

Every physician

Routine work

BlindingOne or more of the people involved in the

trial is unaware of the intervention.

1- Open trial

2- Single- blind trial

3- Double blind trial

4-Double blind double dummy trial

5- Triple and quadruple blind

Collection of baseline data

• Disease, medical & demographic characteristics.

• Similarity in all aspect except intervention.

Follow up• Quantity• Quality• Compliance

Outcome

• Objective Vs subjective.

• Surrogate Vs hard outcome.

Analysis

60 45

15

Intension to treat analysis.

15/ 60 =0.25 =25%

Protocol analysis.

15/45 = 0.33 =33%

Relative RiskGroupoutcomeTotal

positiveNegative

Interventionaba +b

Controlcdc +d

Measures of effect size 1-Relative risk (RR)

–Is the ratio of the risk of a given event in one group of subjects compared to another group

Experimental Event Rate (EER) ----------------------------------------------- Control Event Rate (CER )

EER: The percentage of intervention group who experienced outcome in question. ( a/(a + b))

CER: The percentage of control group who experienced outcome in question. (c /( c + d))

2-Relative risk reduction (RRR)

–The proportion of the initial or baseline risk which was eliminated by a given treatment/intervention or by avoidance of exposure to a risk factor

–RRR= (CER – EER) / CER

3-Absolute risk reduction (ARR)

–The difference in risk of a given event, between

two groups

–ARR= CER - EER

4-Number Needed to Treat (NNT)

–It is defined as the number needed to treat in order to prevent one additional adverse event (e.g. death)

–NNT = 1/ ARR

–Its clinical importance depends on Initial probability of the outcome.

RR=(18/64) / (29/65) = 0.281/0.446 =0.63 =63%

95% CI= 0.39 – 1.01 Source: N Engl J Med 1992; 326: 1527-1532.

InterventionOutcomeTotal

Deathsurvival

Ligation184664

sclerotherapy293665

2-Absolute Risk Reduction (ARR): ARR= CER - EER =(29/65) – (18/64) =0.446 – 0.281 = 0.165 = 16.5% 3-Relative Risk Reduction (RRR)

RRR= (CER – EER) / CER =(0.446 – 0.281) / 0.446 =0.165 / 0.446 = 0.37 = 37% i.e. Legation decreases the risk of death by 37%

4-Number Needed to Treat (NNT):

NNT = 1/ ARR = 1 / 0.165 = 6.06 =6 patients You have to treat 6 patients by ligation to save one life

Over 17000 patients suspected of having acute myocardial infraction were randomised to receive treatment (1) oral aspirin or (2) no aspirin. The table below presents results for vascular mortality at five weeks:

17187153671820total

860075841016no aspirin

85877783804aspirin

totalnot dieddied

ARR (for dying) = I(804/8587) – (1016/8600)I =0.024(24 deaths may possibly be prevented for each 1000 patients)

RR (for dying) = (804/8587) / (1016/8600) = 0.79(those taking aspirin are at a lower risk of dying)

RRR(for dying) = RR x 100% = 21%(aspirin reduced the risk of death at 5 weeks by 21%)

NNT= 1/ARR =42

Source:A-Z of medical statistics

Example

• A multi-centre, randomised placebo-controlled trial of the beta blocking drug Timolol, reported the number of deaths in 18 months of follow-up among patients who had recently suffered a myocardial infarction.

(New England Journal of Medicine. 1981;304: 801-7).

Calculations

1) Risk (timolol) = 98/945 = 0.104 (10.4%)2) Risk (placebo) = 152/939 = 0.162 (16.2%)

1) ARR = 0.162 – 0.104 = 0.058 95% CI (0.028, 0.089)

6) NNT = 1/0.058 [100/5.8] = 17 people

diedsurvived

timolol98847945

placebo152787939

Ethical issues

• Informed consent

• Confidentiality

• Stopping rules

Independent monitoring group

Clear existence of benefits

Clear existence of harm