phase iii clinical trials - 2014-15

DESIGN OF PHASE III

TRIALS Dr Anil Vangala

PRMB1038

[email protected]

Phases of Clinical Trials

Pre-clinical studies:

Animal and laboratory studies - What it is and what does it do?

Phase I

Pharmacokinetics, pharmacodynamics, dosage, metabolism and safety - What is the dose?

Phase II

Safety and effectiveness - Does it work and is it safe?

Phase III

Pre-marketing data to establish efficacy and safety against current gold standard treatment - Is it better?

Phase IV

Post-marketing examination of long-term side-effects, efficacy and evaluation of uses, dosage, use in various populations/ethnicities etc. - Long term usage and what else can it do?

Phase III Clinical Trial Objectives

To demonstrate or confirm therapeutic effect

To confirm the preliminary evidence accumulated in

Phase II that a drug is safe and effective for use in the

intended indication and recipient population

To provide an adequate basis for marketing approval

To further explore the dose-response relationship

To explore the drugs use in wider populations, in different stages of disease or in combination with another drug.

Design of Clinical Trials

Randomisation - 1

What is Randomisation? It is the process of assigning clinical trial participants to treatment

groups. Randomisation gives each participant a known (usually equal) chance of being assigned to any of the groups.

Why Randomise? At the end of a clinical trial, the explanation for the difference in

outcomes between treatment groups The intervention exhibits a real effect

The difference is solely due to chance

There is a systematic difference (selection or accidental bias) between the groups due to factors other than the intervention.

Randomisation aims to obviate the third possibility so as to provide a precise and valid treatment comparison and it also provides basis for statistical tests.


Randomisation - 2

Methods of randomisation

Simple randomisation

Tossing a coin; A (heads), B (tails).

List assigning next subject to treatment is usually achieved using a

sequence of random numbers from a statistical textbook, or a computer

generated sequence made before trial starts.

A for digits 0-4

B for digits 5-9

0 5 2 7 8 4 3 7 4 1 6 8 3 8 5 1 6 9 6

A B A B B A A B A A B B A B B A B B B


Randomisation - 3

Permuted block randomisation

Blocks having equal numbers of As and Bs (A=intervention, B=control) are used with the order of treatments within the block

being randomly permuted. A block of four has 6 different possible

arrangements of 2 As and 2 Bs.

A random number digit assigns a block of treatment which sets

the allocation order for the first four subjects and the process is

repeated.


Randomisation - 4


Randomisation - 5

Stratified Allocation

It further restricts chance imbalances by ensuring treatment

groups are as alike as possible.

For example, in a trial of chemotherapy for breast cancer,

suitable stratification factors might be menopausal status and

oestrogen receptor (ER) status. In this case we have 4 strata:

Premenopausal and ER +ve

Premenopausal and ER ve

Postmenopausal and ER +ve

Postmenopausal and ER -ve


Randomisation - 6 A set of permuted blocks is generated for those who are

premenopausal and ER +ve, another set for those who are premenopausal and ER ve and so on.

Stratification adds to the trial credibility as it ensures treatment balance on these known prognostic factors allowing easy interpretation of outcomes without adjustments.

The minimisation method

Used when we have very large number of strata.

Determine new subject factor status.

Count no. of subjects with those factors on each treatment-allocate to balance up scores (so give new patient the treatment which gives the smallest total sum).

If sums for A and B are equal then one would use simple randomization to assign the treatment.


Randomisation - 7

Example of Randomisation using the minimization method

Status after 34 participants have been randomised to the trial Characteristic Treatment A Treatment B

Site 1 7 8 Site 2 * 10 9 ER +ve * 5 6 ER ve 12 11 < 50 8 9 50 * 9 8 Total 17 17

The next participant (no.35) is from site 2, ER +ve, > 50. Subtotals for treatment A is 10+5+9 = 24, and for treatment B is 9+6+8= 23. So participants will be allocated treatment B.


Randomisation - 7

Concealment of the randomisation process It is very important that those responsible for recruiting people into

trial are unaware of the group to which a participant will be allocated, should that subject agree to be in the study (allocation concealment)

For multicentre clinical trials, centre randomisation by telephone, fax or internet.

For single centre clinical trials, pharmacy staff may undertake randomisation (as not involved with trial)

Sealed envelopes opened in sequence.

A clinical trial report should clarify who generated the sequence (statisticians or randomisation software), the method used and how concealment was achieved and monitored.


Randomisation - 8

Checklist for choosing a randomisation strategy

How many subjects and clinical sites are planned?

Are 24h randomisation services required?

How will randomisation be implemented, central, remote local, bedside?

Who will generate the sequence and by which method: random number lists, computer?

Is a stratified or simple randomisation needed?

If stratified, how many strata and levels within each stratum are required?

What balancing strategy should be chosen: simple, permuted blocks, minimisation?

What measures are taken to guarantee allocation concealment?

Who is going to monitor successful implementation (the balance of treatment allocation) during recruitment?

Design of Clinical Trials Blinding -1

Open patient, doctor, pharmacy and sponsor know what is being used.

Blinded patient does not know

Double-blind patient, doctor and sponsor do not know

Clinical trials are often double-blinded so as to minimise any potential bias and to ensure that subjective assessments and decisions are not affected by knowledge of treatment assignment.

Design of Clinical Trials Blinding - 2

The justification for double-blind trials

The patient (psychological effect , attendance compliance and cooperation)

The treatment team (intensity of patient examination, continuance of trial therapy, dose modification)

The evaluator (need to be objective)

The importance and feasibility of making a trial double-blind depends on the disease, type of therapy, method of evaluation, and resources available.


Conduct of double-blind trial

Matched placebos (colour, texture, taste (capsules),

shape and size); Majority are for oral drug therapy.

Think of clinical trials determining the dose of a new

drug

Coding and randomisation (allocation concealment)

Breaking the code (triple-blind)


When is blinding feasible?

Ethics: the double-blind procedure should not result in any harm or undue risk to a patient

Practicality: for some treatments it would be totally impossible to arrange a double-blind trial

Avoidance of bias: one needs to assess just how serious the bias might be without blinding

Compromise: sometimes partial blinding (e.g. independent blinded evaluators) can be sufficient to reduce bias in treatment comparison

Design of Clinical Trials Types of Controls - 1 Control groups can be classified on the basis of :

The type of treatment used

Placebo

No treatment

Different dose or regimen of the study treatment

A different active treatment

The method of determining who will be in the

control group

randomisation or

by selection of a control population separate from the

population treated in the trial (external or historical

control)

Design of Clinical Trials Types of Controls - 2

In general can have 5 control groups

The first 4 are concurrently controlled (both control and test groups

are chosen from the same population and treated concurrently),

usually with random assignment to treatment; they are distinguished

by the type of control treatment used e.g. Placebo concurrent control,

no treatment concurrent control, dose-response concurrent control

and Active (positive) concurrent control.

External (including historical) control groups, regardless of the

comparator treatment are considered together as the fifth type.

Design of Clinical Trials Crossover Trials - 1

Patient receives both arms of study at different stages, within patient study. Subjects are randomly allocated to study arms where each arm consists of a sequence of two or more treatments given consecutively. The simplest model is the AB/BA study. Subjects allocated to the AB study arm receive treatment A first, followed by treatment B, and vice versa in the BA arm.

Crossover trials allow the response of a subject to treatment A to be contrasted with the same subject's response to treatment B. Removing patient variation in this way makes crossover trials potentially more efficient than similar sized, parallel group trials in which each subject is exposed to only one treatment. In theory treatment effects can be estimated with greater precision given the same number of subjects.

The trials are usually double-blind Good patient cooperation is important to ensure correct

medication and evaluation.


Crossover trials are generally restricted to the study of short term outcomes in chronic diseases or processes because the disease or process needs to persist long enough for the investigator to expose the subject to each of the experimental treatments and measure the response.

The principal drawback of the crossover trial is that the effects of one treatment may "carry over" and alter the response to subsequent treatments. The usual approach to preventing this is to introduce a washout (no treatment) period between consecutive treatments which is long enough to allow the effects of a treatment to wear off. A variation is to restrict outcome measurement to the latter part of each treatment period.


In practice this means that, for the same number of participants, a crossover design is likely to be more powerful. However, crossover trials are not always appropriate. Some questions you should ask

Is the condition of the patients chronic and stable?

Does the intervention provide temporary relief, and not permanent change?

Can the outcome be repeated in the second period if it occurs in the first?


Might the effect of the first intervention last into the second treatment period?

Does the trial go on long enough for drugs to have effects and outcomes to occur?

When analysing data from crossover trials, need to show that there is no period effect and no carryover effects for the data to be valid.

The best advice is therefore to avoid using a crossover design if there is any good reason to suppose that carry over effects are likely to occur

References

A concise guide to clinical trials, Allan K. Hackshaw ;c2009

ebook available

2 hard copies - shelved at: 615.50724 HAC (Penrhyn Road campus

library)

Design and Analysis of Clinical Trials Concepts and

Methodologies 3rd ed.. Shein-Chung Chow ;Jen-Pei Liu ;2013

ebook available

phase iii clinical trials - 2014-15

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