Emerging study designs - The need of real world evidence

to validate safety and efficacy results

from clinical trials

Symposium

Drug Research Academy

March 14 2018

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Atheline Major-Pedersen MD, PhDSafety Surveillance, Global SafetyNovo Nordisk A/S

The views and opinions expressed in this presentation do not necessarily represent the official policy or position of Novo Nordisk A/S

Disclaimer

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Out of scope: Data Sources

Definitions

• Randomized clinical trials/explanatory

• Observational

• Emerging

Study designs

Agenda

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Pharmacoepidemiology and Pharmacovigilance- Definitions

PharmacoepidemiologyThe study of the uses and effects of drugs in well defined populations.

Strom, Brian (2006)

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Pharmacoepidemiology

PharmakonDrug

EpiUpon/Among

DemosPeople or District

LogosStudy

PharmacovigilanceThe science and activities relating to the detection,assessment, understanding and prevention of adverse effects or any other drug-related problems.WHO

Pharmacovigilance

PharmakonDrug

VigilareKeep watch

Pre-approval drug lifecycle and pharmacovigilance activities

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Randomized Clinical Trials

Adapted from FDA

Randomized Clinical Trials

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Reduces

bias

and

confounding

(Internal validity)

Unpredictability

•Trial subjects have the same chance of receiving any of the interventions

•Allocation is carried out using a chance mechanism so that neither the subject nor the investigator will know in advance which will be assigned

Balance

•Treatment groups are of similar size and constitution

•Treatment groups only differ in the intervention each group receives

Randomized Clinical Trials –highly controlled environment

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Trial population

Relatively small size

Narrow

(selective)

Indications for use

Proposed indication for use

(specific)

Duration of trial

Relatively short

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Health policy decision-makers- becoming increasingly dependent on

real world evidence in conjunction with clinical trial data

Real World

Progression of evidence requirements -directing to inclusion of real world evidence

Decision-makers

Need of real world evidence to validate safety and efficacy results from clinical trials

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Trial population

Relatively small size

Narrow

Indications for use

Proposed indication for use

Duration of trial

Relatively short

RCTs

Drug lifecycle and pharmacovigilance activities14MAR2018 10

Randomized Clinical Trials

Adapted from FDA Div. of PV Webinar March 2017

Observational

•Spontaneous/voluntary reporting of cases • Post marketing studies (voluntary or required) • Active surveillance

&Effectiveness

Review of traditional observational study designs

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Observational Studies

Descriptive

e.g. case seriesAnalytical

Ecological

Cross-sectional

Case-control

Cohort

Ref. ENCePP

Limitations of observational studies

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Effect modifier

Effect modifier

Limitations of pre-approval CTRs and observational studies 14MAR2018 13

Trial population

Relatively small size Narrow

Indications for use

Proposed indication for use

Duration of trial Relatively short

Hybriddesigns

Emergingdesigns

Explanatory – Pragmatic Continuum of trial designs

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Explanatory (RCTs)

Pragmatic Trials

Table adapted from CONSORT and Practihc groups BMJ 2008;337:a2390doi: 10.1136/bmj.a2390

Hybrid designs

Aim:

to ensure high generalizability of the results

Designed to help choose between options of care

External validity

(PRAGMATIC aim)

Randomization

(reduce bias, confounding,

effect modifiers)

Internal validity

(EXPLANATORY element)

Emerging study designs- Hybrid studies

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Pragmatic trial designs

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Pragmatic Trials

Increase external validity

- generalizable to the usual care

setting

Large Simple Trials

“Simple” refers to data structure –

not to data collection, or study complexity

Randomized Database Trials

Database/registry-based prospective randomized clinical

trials (RRCTs)

- Combine the advantages of

randomization and observational

database/registry-based studies.www.consort-statement.org

http://www.encepp.eu/standards_and_guidances

RCTs

Drug lifecycle and pharmacovigilance activities14MAR2018 17

Randomized Clinical Trials Observational

•Spontaneous/voluntary reporting of cases • Post marketing studies (voluntary or required) • Active surveillance

&Effectiveness

HybridPragmatic

Designing interventional trials along the pragmatic-explanatory continuum – tailored to the research need along the drug´s life cycle

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“The choice of epidemiological methods toanswer a research question is based on

principles rather than on rules.These principles may provide opportunities for

creativeness and new innovative methods, when appropriate and needed.”

(ENCePP)

BACK-UP

SLIDES

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Example of RRCT set-up

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The integrated platform for RRCTs in the Swedish Heart Failure Registry

RCTs vs RRCT vs Registry-based study designs14MAR2018 21