2016-01-20 Magnus Kjaer

Introduction to clinical trials

One Definition of Clinical TrialNIH 2014

A research study in which one or more human subjects are prospectively assigned to one or more interventions to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes

NIH: National Institutes of Health (US)

One of many definitions

Key words

Experimental unitHuman subject

InterventionTreatment

Evaluate

Subject from a target population.

Pharmaceutical, diet, procedure, diagnostic, device, program, placebo.

Assessment of (clinical) effect, but also adverse events, lab variables, vital signs, quality of life, health economy.

The Wheel of Science

Research question

Experiment

Data

Conlusion

Drug discovery - Drug development

discovery; refinement; chemical & biological characterisation

safety & toxicity in animals; formulation development

volunteer studies; patient studies regulatory process

marketing

post registration

monitoring

Lessons &

development

Discovery=find new compound: Development=convert it to a useful drug

The path to a new medicineYears 1 162 3 4 5 6 7 8 9 10 11 12 13 14 15

No. of compounds Up to 10,000 10-15 1-8 1-3 1

First patentapplication

Clinical trialapplication

Product licenceapplication

Drug Discovery Drug Development Target and leadidentification

Leadoptimisation Concept testing

Developmentfor launch Launch

Clinical DevelopmentPhase I12-150people

Phase II50-1000people

Phase III500-5,000people

Phase IV studies continue

Product lifecycle support

Toxicology and pharmacokinetic studies(absorption, distribution, metabolism, excretion)

Pharmaceutical and analytical development

Process chemistry and manufacturing

Registration and regulatory affairs

Sales and marketing (preparation, promotion, advertising and selling)

Phase I

The drug seems reasonably safe in animal studies, but has never been tested on humans

What do we want to know?

How can we find that out?

Phase I trials

• Explorative

• Focus on:

• Tolerability

• Safety

• Pharmacokinetics (how the body affect the drug)

• Efficacy if possible (biomarkers)

• Interaction with other drugs

• Food interaction

Phase I50-150people

Phase II100-200people

Phase III500-15000people

Phase IV studies continue

Phase I trials

• 50-150 healthy people (often males)

• Increase dose levels – ascending doses

• Single dose – Single ascending dose (SAD) study

• Repeated dose – Multiple ascending dose (MAD) study

• ADME (Absorption, Distribution, Metabolism Excretion)

• QT studies

• Bridging studies, Pharmacokinetics in other populations

Phase I50-150people

Phase II100-200people

Phase III500-15000people

Phase IV studies continue

Phase II

The drug seems to be reasonably safe in humans and there is some sign of an effect on something.

What do we want to know next?

How can we find that out?

Phase II trials

• Show some type of efficacy – biomarker

• Selection of dose or doses – “optimal dose”

• Safety and tolerability in patients

• Pharmacokinetics in patients

Phase I50-150people

Phase II50-1000people

Phase III500-5,000people

Phase IV studies continue

Phase II trials

• 50-1000 patients

• Longer studies – 2 week to one year

• Often complicated design

• Extensive monitoring

• Effect in special populations or target population

Phase I50-150people

Phase II50-1000people

Phase III500-5,000people

Phase IV studies continue

Phase III

The drug seems resonable safe to give to patients and we have and idea of which dose to use.

What do we want to know now?

How can we find that out?

Phase III trials

• Clinical relevant effect is verified

• Study population is equal to the target population

• Forms the basis of the NDA, New Drug Application

• Confirmative

• Lot of regulations

Phase I50-150people

Phase II100-200people

Phase III500-15000people

Phase IV studies continue

Phase III trials

• Large trials 500-20000 patients

• Study duration 6 months to 3-5 years

• Sub-groups start to be established

• Special features and problem can be visable

Phase I50-150people

Phase II100-200people

Phase III500-15000people

Phase IV studies continue

Phase IV

Our drug is approved for use on patients for a specific indication and target population.

What’s next?

Phase IV trials

• New populations

• New indications

• Marketing

• Often large 500-30000 patients

• Further investigation of efficacy and safety post approval

Phase I50-150people

Phase II100-200people

Phase III500-5,000people

Phase IV studies continue

Planning of Clinical ProgramsLine of Sight

• Planning of phase I

• Understanding of what to do in phase II and III

• Planning of phase II

• Understanding of what to do in phase III

The Clinical Study Process

OutlineOutlineClinical Study

ProtocolClinical Study

Protocol

Statistical Analysis Plan

Statistical Analysis Plan

Study Conduct

Data CaptureStudy Setup

Statistical Analysis

Clinical Study Report

Clinical Study Report

PublicationsPublications

Clean File

T i m e

Preparation of statistical analysis

Data base lock

Observational studies

Data is collected for a set of patients without randomisation

Prospective: Data is collected after the objectives are set

Retrospective: Data is collected before the objectives are set

timenow

data collection analysis interpretation

timenow

data collection analysis interpretation

Where to look for information

ICH (international Conference on Harmonisation)

FDA (Food and Drug Agency)

EMEA (European Medicines Agency)

Cochrane Collaboration

http://www.ich.org/products/guidelines.html

http://www.fda.gov/

http://www.emea.europa.eu/

http://www.cochrane.org/index.htm

ICH

• Quality• Efficacy• Safety• Multidiciplinary

ICH Quality guidelines

Harmonisation achievements in the Quality area include pivotal milestones such as the conduct of stability studies, defining relevant thresholds for impurities testing and a more flexible approach to pharmaceutical quality based on Good Manufacturing Practice (GMP) risk management.

ICH safety guidelines

ICH has produced a comprehensive set of safety Guidelines to uncover potential risks like carcinogenicity, genotoxicity and reprotoxicity. A recent breakthrough has been a non-clinical testing strategy for assessing the QT interval prolongation liability: the single most important cause of drug withdrawals in recent years.

•S7A: Safety Pharmacology Studies for Human Pharmaceutical•S7B: The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT prolongation) by Human Pharmaceutical

ICH efficacy guidelinesThe work carried out by ICH under the Efficacy heading is concerned with the design, conduct, safety and reporting of clinical trials. It also covers novel types of medicines derived from biotechnological processes and the use of pharmacogenetics/genomics techniques to produce better targeted medicines.

ICH Efficacy Guidelines

•Clinical Safety E1-E2F•Clinical Study Reports E3•Dose Reponse Studies E4•Ethnic Factors E5•Good Clinical Practise E6•Clinical Trials E7-E11•Clincal Evaluation of a Therapeutic Category E12•Clincal Evaluation E14•Pharmacogenomics E15-E16•Cross Cutting Topics E17

ICH Efficacy Guidelines

•E7: Studies in Support of Special Populations, Geriatrics•E8: General Considerations for Clinical Trials•E9: Statistical Principles for Clincal Trials•E10: Choice of Control Group and Related Issues •E11: Clinical Investigation of Medicinal Products in the Pediatric Population

Chapter 1 Reading instructions

• 1.1 What are clinical trials: Read

• 1.2 History of clinical trials: Less important

• 1.3 Regulatory process and requirements: Read page 14

• 1.4 Investigational new drug application: Read page 17–20

• 1.5 New drug application: Less important

• 1.6 Clinical development plan and practise: Read

• 1.7 Aims and structure of this book: Skip