phase iii and iv clinical trials methodology and...

Helping the people of Canada maintain

and improve their health

Aider les Canadiens et les Canadiennes

à maintenir et à améliorer leur santé

Phase III and IV Clinical Trials

Methodology and Design

August 22, 2007

•8:45-11:45

Nora Wolfson MD

Biologics and Genetic

Therapies Directorate

August 5, 2015

Helping the people of Canada maintain

and improve their health

Aider les Canadiens et les Canadiennes

à maintenir et à améliorer leur santé

August 22, 2007

•8:45-11:45

Nora Wolfson, MD

Biologics and Genetic

Therapies Directorate

August 5, 2015

Disclaimer: The information within this presentation

is based on the presenter's expertise and

experience, and represents the views of the

presenter for the purposes of a training course

Health Products and Food Branch

Goals of Clinical Trials:

• Increase knowledge

• Obtain Safety/Efficacy data

• Justify/confirm use for an indication to

get market approval

3


Study Design

As described in ICH E6 (Guideline for Good Clinical

Practice, Section 6.4, Trial Design): “The scientific

integrity of the trial and the credibility of the data from

the trial depend substantially on the trial design”

A description of the trial design should include a

specific statement of the primary endpoints and the

secondary endpoints, if any, to be measured during

the trial

4


Design

A good clinical trial design will be:

simple

measure important clinical parameters

precise (reduce errors of chance),

eliminate bias

provide validity

5


Clinical Trials

•Are classified in different phases:

Phase I

Phase II

Phase III

Phase IV

6


Clinical Trials• Phase I: PK, PD, early measurement of drug activity, MTD-

Healthy volunteers or target population – Single, ascending

doses – Small sample size – Short duration

• Phase II: -Exploratory Trials- Evidence of drug’s efficacy –

Safety risks – Target population –placebo/active controlled –

Larger sample size – Longer duration

• Phase III: -Confirmatory Trials- Effectiveness – Safety –

Target population – Randomized-controlled, 2, 3 treatment arms

– Much larger sample size - Duration: years

• Phase IV: Monitor ongoing Safety/Efficacy – Target population

– Uncontrolled - Very large sample size (after the product is

approved) (Post-market Surveillance, real clinical setting)

7


Written Protocol should describe:

(before the study starts )

• Objectives

• Design

Methods to minimise bias: R & B

• Endpoints

• Patient population

• Selection of Control Group

• Number of Subjects

• Response Variables

• Conduct

• Analysis (analytical approaches to common problems including early

study withdrawal and protocol violations, should be incorporated).

8


Study Design Considerations

Primary endpoint: is directly related to the primary

objective of the trial (there should be one primary

endpoint)

Should be supported by evidence that it can provide a

valid and reliable measure of a clinically relevant and

important benefit in the target population

Should be carefully selected as it is the variable used

when estimating the sample size

9


Study Design ConsiderationsMultiple primary endpoints:

May be desirable in some trials

Should be clearly pre-specified: how the results will be

interpreted; i.e.: what is considered necessary to achieve

the trial objectives

Type I error (making false positive conclusions) should be

addressed because of the potential for multiplicity problems

(arising from numerous comparisons made)

“The usual concern with multiplicity is that, if not properly handled, unsubstantiated claims for the effectiveness of a drug may be made as a consequence of an inflated rate of false positive conclusions.”

10



Secondary endpoints:

Should be pre-defined in the protocol, and their role in the interpretation of the trial results should be clearly stated, for example, are they considered part of the confirmatory strategy for the trial?

11



Description of the type of trial design:

Parallel group design: most common for confirmatory trials

subjects randomised to one of two or more arms

Crossover design:

each subject randomised to a sequence of one or more treatments, and hence acts as his own control (disadvantage: treatment must be short acting –no carry-over effect)

(Group A: Drug then control;

Group B: control then Drug)

12



Description of the type of trial design:

Factorial designs: two or more treatments evaluated simultaneously through the use of varying combinations of treatments

Groups: 1) A; 2)B; 3) A+B; 4) Placebo

Adaptive: Allow for initial uncertainties in trial designed to be confirmed/adapted during the trial in a pre-planned manner

maintaining validity and integrity

13



Trial designed to show superiority:

• placebo-controlled trial

• active control treatment

Important parameter: is the effect size

Defined as the treatment effect to be detected in a clinical trial, corresponding to the smallest difference between the treatment groups that is considered to be of clinical value

14



Trial designed to show equivalence:

a test treatment differs from the standard active treatment by an amount that is clinically unimportant (the equivalence margin)

Trial designed to show non-inferiority:

a test treatment is not less effective than a standard

active treatment by a small predefined margin (the non-

inferiority margin)

15



Non-Inferiority and equivalence trials should have:

• Assay sensitivity (AS): is the ability of a trial to distinguish an

effective treatment from a less effective treatment

Factors that reduce AS:

poor compliance with therapy

Poor responsiveness of the study population

Concomitant medications

Poor diagnostic criteria

Inappropriate measures of drug effect

Biased assessment of the endpoint

• Fairness of comparison

• Validity

16



17

• Statistical

issues are

complex

• Highly

recommended

that a

statistician be

involved in

reviewing all

aspects of the

CT

http://www.google.ca/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCN20hO2IgccCFRIWkgodEasLHg&url=http%3A%2F%2Fthebetterbtu.blogspot.com%2F&ei=uSi5VZ10kqzIBJHWrvAB&bvm=bv.99028883,d.aWw&psig=AFQjCNH3yD3Q14gK_imGI6DmlkuqPwqqZA&ust=1438283120283626

http://www.google.ca/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCN20hO2IgccCFRIWkgodEasLHg&url=http%3A%2F%2Fthebetterbtu.blogspot.com%2F&ei=uSi5VZ10kqzIBJHWrvAB&bvm=bv.99028883,d.aWw&psig=AFQjCNH3yD3Q14gK_imGI6DmlkuqPwqqZA&ust=1438283120283626


Study Design ConsiderationsMeasures to minimize or avoid bias

• Blinding:• Double-blind approach: (optimal but not always practical)

• If a double-blind approach is not possible, the measures to minimise

bias should be clearly specified in the clinical trial protocol, especially for

open-label trials

• Randomization:Introduces a chance element in assigning treatments

Distribution of prognostic factors is similar (comparable groups)

Should be described in detail in the protocol

Provides the statistical basis for evaluating treatment effect

18



• Sample Size (power): should be large

enough to provide a reliable answer to

the questions being addressed

• Required number of subjects usually

based on the primary endpoint

19


Study Conduct ConsiderationsTrial Conduct:

• Protocol should provide data of good quality

• Adherence to the study protocol is essential.

• Crucial for an adequate evaluation of the efficacy and safety of the

ID

Trial Monitoring

• Essential in generating quality data

Interim analysis (IA)

• Requires unblinded access to treatment group assignment and

comparative treatment group information

• The statistical plan for the IA should be described in the protocol to

avoid bias

20


Study Conduct Considerations

Changes that occur during the conduct of the

trial should be clearly justified and carefully

documented in a formal amendment to the

protocol

21


Statistical Considerations

Should include:

• Methods and timing for:

assessing-recording- and analysing efficacy

• Sample size determination

• Methods and timing for planned interim

analysis

• Handling of missing data

• How multiplicity will be addressed

22


Phase III Clinical Trials Regarded as Confirmatory clinical Trials

Are designed to evaluate the efficacy of an investigational drug and

gather more information about safety in the target population (closer to

the real clinical setting)

Controlled or uncontrolled

Larger sample (several hundreds to thousands of

patients)

Target population

Risk/Benefit assessment

Requires statistical analysis

23


Phase III Clinical Trials

• Phase III studies are intended to provide an

adequate basis for marketing approval.

• May also further explore:

the dose-response relationship,

the drug's use in wider populations,

the drug’s use in different stages of

disease

The drug’s use in combination with

another drug.

24


Success of a confirmatory clinical trial will

depend on the appropriateness of:

Study design

Study conduct

Analysis of trial results

ICH 8: Clinical trials should be designed,

conducted and analysed according to sound

scientific principles to achieve their objectives;

and should be reported appropriately.

25


Phase IV

• They are post marketing studies

• General population

• No limit duration

• Safety monitoring

• Good to identify:

• Drug interactions

• Uncommon ADRs

26


Phase IV

• Performed after drug approval and related to the

approved indication

• Are important for optimising the drug's use.

• Could be any type but should have valid

scientific objectives.

• Usually include additional:

drug-drug interaction

dose-response

safety

27


• ICH E8 General Considerations for

Clinical Trials

• Outlines studies for Special Populations:

• Pregnant Women

• Nursing Women

• Children

• ICH E7 addresses issues for geriatric patients

• ICH E5 patients from different ethnic groups

28


Useful References ICH Topic E 6 (R1): Guideline for Good

Clinical Practice (2002)

ICH E8: General Considerations for Clinical

Trials (1997)

ICH Topic E9: Statistical Principles for

Clinical trials (1998)

ICH Topic E10: Choice of Control Group

and Related Issues in Clinical Trials (2000)

29


Acknowledgements

• Dr. Norman Viner

• Dr. Catherine Njue

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Thank you

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