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CLINICAL TRIALS AND IT Dave Henry BSc(Hons) MBA

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CONTENTS

• History and Background to Clinical Trials

• Pharmaceutical Development & Industry Challenges

• The Clinical Trial Process

• How does IT fit in?

• Software Validation

• Clinical & Regulatory IT Systems

• Data Standards

• The Future

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FIRST CLINICAL TRIAL

• 1747 James Lind and Scurvy Trial

• 12 Sailors in 6 groups

• Group on Oranges & Lemons

cured with in 6 days

• Published 1753

• 50 years later Limes adopted as

standard by the Royal Navy

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1937 ELIXIR SULFANILAMIDE INCIDENT

• Treats streptococcal infections

in tablet & powder form

• Liquid form used Diethylene

glycol, normally used in

antifreeze

• 100 People died from this

deadly poison

• 1938 of the Federal Food, Drug,

and Cosmetic Act, Basis for

FDA regulation of drugs

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THALIDOMIDE DISASTER 1957-1961

• The drug was marketed as a mild

sleeping, pill safe even for

pregnant women from 1957

• Popular for treating nausea and

morning sickness

• Caused thousands of babies

worldwide to be born with

malformed limbs

• Withdrawn in November 1961

• Never approved by the FDA

• Additional reproductive toxicity

animal testing mandated

• Used subsequently for Leprosy

and Cancer treatment

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WHY CLINICAL TRIALS?

• Develop new medicines/devices and ensure Patient

Safety

• New treatments

• Better treatments

• Safer treatments

• Cheaper treatments

• 1946 First Randomized Curative Trial - The Randomized

Controlled Trial of Streptomycin for Tuberculosis

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REGULATORS AND REGULATIONS

• UK – MHRA Medicines &

Healthcare products Regulatory

Agency

• Europe – EMEA/EMA European

Medicines Agency

• USA – FDA Food & Drug

Administration

• Japan – MHLW Ministry of

Health, Labour and Welfare

• Plus another 80+ Regulators

Worldwide

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REGULATIONS

• Regulations require sponsors to

• Prove Efficacy

• Prove Safety

• Protect Patients

• Ensure Ethics

• Ensure Patient Informed Consent

• Declaration of Helsinki 1964 ( Extended 1947 Nuremberg Code)

• Good Clinical Practice (GCP)

• International Council on Harmonisation (ICH) of Technical Requirements for

Pharmaceuticals for Human Use

• US Code of Federal Regulations 21 CFR Part 11

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PHARMACEUTICAL DEVELOPMENT

Discovery Preclinical Clinical Approval Marketing/

Post Market

Generic Approval

• Target Identification & Validation

• Chemistry

• Pharmacology

• Pharmacokinetics

• Toxicology

• Pharmaceutics

• Pilot Manufacturing

• Target Identification & Validation

• Chemistry

• Pharmacology

• Pharmacokinetics

• Toxicology

• Pharmaceutics

• Pilot Manufacturing

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PHARMACEUTICAL DEVELOPMENT

Phase I Phase

II Phase

III Phase IV

Discovery Preclinical Clinical Approval Marketing/

Post Market

Generic Approval

• Between 10-80 Healthy Volunteers/Subjects

• Pharmacokinetics – Effect of body on drug

• Pharmacodynamics – Effect of drug on body

• Safety

• Between 10-80 Healthy Volunteers/Subjects

• Pharmacokinetics – Effect of body on drug

• Pharmacodynamics – Effect of drug on body

• Safety

• First test against disease in Patients

• Short duration

• Limited numbers 100-300

• Small number of Sites 1-10

• Comparisons with existing treatment

• First test against disease in Patients

• Short duration

• Limited numbers 100-300

• Small number of Sites 1-10

• Comparisons with existing treatment

• Large numbers of patients 1,000-80,000

• Large number of Sites 30-6,000

• Long term safety and efficacy

• ‘Normal’ conditions of use

• Large numbers of patients 1,000-80,000

• Large number of Sites 30-6,000

• Long term safety and efficacy

• ‘Normal’ conditions of use

• Registered product/indication

• Post-marketing surveillance

• Larger population use

• Safety Adverse Reaction Monitoring

• Registered product/indication

• Post-marketing surveillance

• Larger population use

• Safety Adverse Reaction Monitoring

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PHARMACEUTICAL DEVELOPMENT

> 1$ Billion > 1$ Billion

10,000

Test

Compounds

10,000

Test

Compounds <5 Test Compounds <5 Test Compounds 1 Approved 1 Approved

<250

Test

Compounds

<250

Test

Compounds 40% Funded 40% Funded

Phase I Phase

II Phase

III Phase IV

Discovery Preclinical Clinical Approval Marketing/

Post Market

Generic Approval

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INDUSTRY CHALLENGES

• Limited patent lifetime of 20 years after discovery before generics

• Industry struggling with reduced return on R&D investment

• Even after Regulatory Approval, Healthcare provider funding?

• Canada CADTH 84% Drugs Rejected or Restricted

• UK NICE 60% Restricted/No Market Access (National Institute for Health and Care Excellence)

• Need to demonstrate economic as well as clinical value

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CLINICAL TRIAL PROCESS

•Design

•Set Up

•Clinical

•Reporting/Post Clinical

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GCP – GOOD CLINICAL PRACTICE

An International, ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. Compliance with these standards provides public assurance that the rights, safety and well being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki and the clinical trial data are credible.

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DESIGN

•Protocol

•CRF

•Supplies

•Costs

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CASE REPORT FORM (CRF)

• Primary record of clinical trial

data, different for each trial

• Traditionally multi-part NCR

form in booklets

• Electronic Versions in use for

last decade

• EDC Electronic Data Capture

• Still a lot of manual paper in

use, transcribed by nurse or

study coordinator

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SET UP

• Investigators and Sites

•Financial Agreements

•Approvals

•Drug Handling

•Supplies

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APPROVALS

•Regulatory

• International (EU, ICH)

• National (FDA)

•Ethical

• National

• Regional

• Local

• Informed Consent

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CLINICAL

•Enrolment/Recruitment

•Patients

•Monitoring

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REPORTING/POST CLINICAL

• ‘Final’ Database

•Statistical Analysis

•Final Report

•Publications

•Archiving

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HOW DOES IT FIT IN?

•Pre IT

• Manual

• Duplication

• Time

•Advantages of IT

• Information in one place

• Information only needs to be entered once

• Access to ‘current’ information

• Speeds up process

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CLINICAL TRIAL IT COMPLICATIONS

• Computer system validation and audit, GCP and GAMP

• More demanding than ISO-9001 for test, verification & validation

• Authentication, Electronic signature and Audit requirements 21 CRF Part 11

• Regulator and Client Audits

• Doing Agile/SCRUM and SAFe in a regulated environment

• Some systems could potentially kill patients (wrong dose)

• Many independent actors: Sponsor, Sub contractors, Investigators,

Ethics Committees, Hospitals, Labs, Patients

• Challenges

• Convergence of different types of system

• Much of the data is replicated

• Data standards evolving

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GXP SOFTWARE VALIDATION

• Standard Operating Procedures

(SOPs)

• Traceability of Requirements,

Design and Testing

• Installation qualification (IQ)

• Operational qualification (OQ)

• Performance qualification (PQ)

• Formal sign off of validation

documentation

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IT SYSTEMS - GENERIC

• Corporate Project & Resource Planning

• High level plans across business functions like Manufacturing, Clinical, Regulatory,

Marketing and Sales

• Clinical Trial == 6 Tasks/Milestones

• Corporate Finance

• MRP, Supplies Manufacture and Distribution

• Document Management

• Portal and Identity Management

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CLINICAL & REGULATORY IT SYSTEMS

Imaging

Safety

Statistical

Analysis

ECOA

Lab Data

Regulatory

Information Mgt Validation of

instruments

RTSM/IVRS

EDC

CTMS

☠

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CLINICAL & REGULATORY IT SYSTEMS

• Clinical Trial Management and Administration (CTMS)

• Planning & Tracking, Clinical Monitoring, Issue Management & Finance

• Clinical Electronic Data Capture (EDC) and Data Management

• Electronic CRF, Clinical Data Entry, Validation and Cleaning and Data Lock

• Clinical Randomisation and Trial Supply Management (RTSM/IVRS)

• Delivering Trial Supplies to Sites, allocation of Patients to Drug Packs (randomisation),

emergency code break

• eCOA electronic Clinical Outcome Assessments

• Measure a patient’s symptoms, overall mental state, or the effects of a disease or

condition on how the patient functions

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CLINICAL & REGULATORY IT SYSTEMS

• Clinical Medical Imaging

• Validation, Analysis, Measurement and review of MRI & CAT Images

• Safety Reporting

• Recording of Adverse Events, coding and reporting to Regulatory Authorities

• Lab Data Systems

• Integration of data from Central Laboratories

• Statistical Analysis (SAS)

• Analysis of Cleaned & Locked Data, Breaking Randomisation, Statistical Reporting

• Regulatory Information Management

• Collation and electronic submission of all Discovery, Pre-clinical & Clinical Registration

documents required for Regulatory Submission, Approval and ongoing product

maintenance

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REGULATORY SUBMISSION

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DATA STANDARDS AND COMMON DATA MODEL

• System integration

• Heterogeneous applications

• Different data models & semantic

• Inconsistent identifiers for shared objects

• study, site, investigator, subject, visit

• shared across most applications

• entered separately today, with need for data reconciliation

• Inconsistent study set-up

• One protocol – different interpretations

=> Different configuration/programming

• Different data “standard” value sets and libraries (EDC, Labs, MI, eCOA, …)

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1

3

2

CDM for all

systems

Core Services

with CDM

MDR (with

sponsor variations)

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DATA STANDARDS IN PHARMA

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CLINICAL TRIALS AND IT FUTURES

• Clinical Trials are evolving to a more flexible adaptive designs

• Adoption of Big Data and collection of data direct from Patients

• Consolidation of Clinical applications to workflow driven solutions

• Adoption of wider data standards in Pharma Industry

• Collection of data direct from GP & Hospital Electronic Medical

Record (EMR) Systems

• Minimise Test and Release overhead while maintaining validated

state

• Public Cloud Adoption

• Data Privacy challenges and Geographic Location of data

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THANK YOU