A N E W S L E T T E R F O R

T H O S E I N V O L V E D I N

C L I N I C A L T R I A L S

CRAdvisor, Issue 48, 2000

ISSN 1369-9407

48I S S U E

page 2

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8 J U N E 2 0 0 0

“Audits themselves are not and cannot

be quick fixes. Fundamental and systematic

GCP deficiencies continue to be found by

auditors at an alarming rate” reported

Nigel Crossland in the May 2000 issue of

GCP Journal (Vol 7 No 2).

Investigator site audits usually focus on

documentation (comparing site documentation

with the requirements of ICH GCP Guidelines

section 8), trial procedures, facilities, laboratories

and pharmacies. Deficiencies are expected and

so are corrections. Unfortunately investigators

do not appear to learn from previous errors as

the same problems are found over and over

again.‘There is a continued failure to adequately

communicate the requirements of GCP to

groups such as investigators, research nurses,

medical technicians, pharmacists and Ethics

Committees’ writes Mr Crossland.

His comments are supported by a variety

of deficiencies found in recently undertaken

audits of investigational sites. The deficiencies

included:

IN THIS ISSUE

• Investigator site audits reveal deficiencies

• UK competitiveness as a clinicalresearch country receives major boost

• Status of ICH products in Europe,Japan and USA

• Steps in the ICH implementationprocess

48UK Government to‘save’ clinical trials?The loss of trials to other countries is of major

concern to the UK pharmaceutical industry and

has led to action by the UK government.

Speaking at the 11 May UK Chapter meeting of

the Association of Clinical Research Professionals,

Dr Richard Tiner of the ABPI announced that the

task force had been established to review the

competitiveness of the UK pharmaceutical

industry. The task force is to be chaired by

Minister of Health, Lord Hunt.The delays

caused by the much criticised ethics review

process will be high on the agenda.

Poor GCP compliance by investigator is stillmajor source of concern!

page 2 © Canary Publications 2000

• Use of inappropriate consent forms (eg. adult

forms being used for children)

• Inadequate, absent, unavailable and inconsistent

source records

• Widespread deficiencies in product account-

ability procedures and documentation

• Review and evaluation of adverse events by

non-medical staff due to over-delegation

• Out-of-date investigator brochure at study

site

• Inadequate documentation of delegated

responsibilities

• Out-of-date laboratory accreditation

certificates and normal ranges

• Recorded data able to be changed without

evidence on site measuring equipment

• Documents left uncorrected at study

close-out

• Improper archiving and storage of trial

documentation at study site.

Poor communication between sponsor and

investigator has also been observed. Mr Crossland

reports that “Audit findings and recommendations

that are relevant to the investigator appear not

to be adequately communicated to the investigator

site.There is too much reliance on discussions held

during the site exit meeting. Relying on such a

relatively informal route for providing detailed

audit information is quite inadequate for the

needs of busy investigators”.

More effective communication of audit findings

are suggested as a method of improving GCP

compliance.“As audit findings should be reviewed

objectively with the intention of understanding non-

compliance issues and learning from them, a new

attitude must be taken; this being the introduction of

QA programmes supported by written procedures

for audits and correction of deficient activities”.

Source: Article by Nigel Crossland, Quality and ManagementConsultant, Crossland Consultancy in GCPJ 2000, Vol 7, No 2

page 1▲

12 Golden GCP Rules for Investigators10 Golden Rules for Pharmacists

ICH GCP Guidelines Indexed PocketbookThe poster provides a daily visual reminder of the need to complywith GCP. The Golden Rules book is easy to read with illustrations,bullet points and key guidelines.The ICH pocketbook contains a

unique index to help readers find that critical requirement.

Golden rules book or poster £7 eachBook/poster combination £10 per set

ICH GCP Guidelines book £5

A small price to pay for compliance at the study site

Canary Publications, PO Box 9, Guildford, Surrey GU2 5GY, UK Order by email: books@canarybooks.com

Rule 8Rule 8

for Pharmacists

by Dr David Hutchinson

Graphics by: Neil Mountain & Vanessa Fellows Copyright: © Dr David Hutchinson, 1999

First edition, June 1999 published by Canary Publications, a Division of Canary Ltd, PO Box 9, Surrey Research Park, Guildford, Surrey, GU2 5GY, UK

All rights reserved. No part of this poster may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic,

electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without prior written permission of the publisher.

Telephone: 07000-CANARY (226279) Fax: 07000-FAXBACK (329222) E-mail: info@canarybooks.com

Design and Print; DCPrint, Farnham, Surrey

Discuss and

agree requirements with the

investigator and study monitor

Set up

study-specific

storage areas,

records and files

Keep a log of

medication returned

by the

subject

Keep a detailed

log of trial medication

received from the sponsor

Rule 5Rule 5

Rule 4Rule 4

Rule 2Rule 2

Rule 1Rule 1

Rule 6Rule 6

Rule 7Rule 7

Rule 3Rule 3

Obtain, read and

adhere to the study protocol

Allocate subject

medication

in strict numerical order

Regularly check

the condition of stock

Rule 9Rule 9

Maintain

study blinding

Rule 10Rule 10

Only destroy trial medication

with the sponsor’s authorisation

For further information, read the book.....

Keep accurate and

detailed dispensing recordsISBN 0 9531174 4 8 Author: Dr David Hutchinson

All the rules are explained in detail in this easy to read, practical

book with illustrations.

Canary

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10for Pharmacists

GOLDEN GCP RULES

David Hutchinson

10

Rule 10Rule 10

by Dr David Hutchinson Graphics by: Neil Mountain & Vanessa Fellows Copyright: © Dr David Hutchinson, 1999

First edition, June 1999 published by Canary Publications, a Division of Canary Ltd, PO Box 9, Surrey Research Park, Guildford, Surrey, GU2 5GY, UK

All rights reserved. No part of this poster may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic,

electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without prior written permission of the publisher.

Telephone: 07000-CANARY (226279) Fax: 07000-FAXBACK (329222) E-mail: info@canarybooks.com

Design and Print; DCPrint, Farnham, Surrey

Rule 1

for Investigators

Rule 1

Rule 2Rule 2Select, train and keep a log of study personnel

Rule 3Rule 3Rule 8Rule 8Report serious adverse

events immediately to sponsor

Rule 5Rule 5

Rule 4Rule 4

Rule 6Rule 6

Rule 7Rule 7

Rule 9Rule 9

Rule 11Rule 11

Rule 12Rule 12Keep everyone fully Informed

Study site meeting in progress

Ethics Committee meeting in progress

SPONSOR

Laboratory samples- focus on sample quality- review results

SPONSOR

INVESTIGATOR

PHARMACIST

SPONSOR

INVESTIGATOR

PHARMACIST

SUBJECT

Meticulously document product accountability

1212

For further information, read the book.....

ISBN 0 9531174 3 X Author: Dr David Hutchinson

All the rules are explained in detail in this easy to read, practical

book with illustrations.

Record data

correctly

Obtain Ethics Committee approval before starting & get the written informed

consent of all subjects before they take part

Maintain good trial files & archives

Know and strictly follow the study protocol

Ensure study equipment is adequate

Diligently collect & record reliable data. Keep all source documents

Predict recruitment accurately and keep an up to date subject enrolment log

Canary

12for Investigators

GOLDEN GCP RULES

David Hutchinson

12

1010for PharmacistsGOLDEN GCP RULES

David Hutchinson 1212for Investigators

GOLDEN GCP RULES

David Hutchinson

ICH GCPGuidelines

IN

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BOOKS AND POSTERS TO PROMOTE GCP COMPLIANCE AT THE STUDY SITE

BOOKS AND POSTERS TO PROMOTE GCP COMPLIANCE AT THE STUDY SITE

ICH GCP

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A small price to pay for compliance at the study site

INDEXED

CRAdvisor, Issue 48, 2000 page 3

Many of the tripartite harmonised ICH

guidelines have now been implemented

(Step 5) in Europe, Japan and the USA. Several

products are still awaiting adoption after

finalisation (Step 4) and others are in the

consultation phase (Steps 2–3). In this article

we review the status of each of the ICH

products in the efficacy ‘E’ classification that

relate to trials on human medicines.

E1: The Extent of Population Exposureto Assess Clinical SafetyThe guideline on The Extent of Population Exposure

to Assess Clinical Safety for Drugs Intended for Long-

term Treatment of Non-Life-Threatening Conditions

was finalised (Step 4) in October 1994.This gives

recommendations on the numbers of patients and

duration of exposure for the safety evaluation of drugs

intended for the long-term treatment of non-life-

threatening conditions.Implementation (Step 5):EU: Adopted by CPMP, November 94, issued asCPMP/ICH/375/95Japan:Adopted May 95, PAB/PCD Notification No. 592USA: Published in the Federal Register, Vol. 60, 1 March, 1995,page 11270

E2: Clinical Safety Data ManagementE2A: Definitions and Standards for

Expedited Reporting

Finalised (Step 4) in October 1994.This gives

standard definitions and terminology for key aspects

of clinical safety reporting. It also gives guidance on

mechanisms for handling expedited (rapid) reporting

of adverse drug reactions in the investigational

phase of drug development.Implementation (Step 5):EU:Adopted by CPMP, November 94, issued asCPMP/ICH/377/95Japan:Adopted March 95, PAB/PCD Notification No. 227USA: Published in the Federal Register, Vol. 60, No. 40,1 March, 1995, pages 11284–11287

E2B: Data Elements for Transmission of

ADR Reports

Finalised (Step 4) in July 1997.This extends E2A to

standardise the data elements for the transmission of

all types of individual case safety reports, regardless

of source and destination.Implementation (Step 5):EU:Adopted by CPMP, September 97, issued asCPMP/ICH/287/95. Japan: Not yet publishedUSA: Published in the Federal Register, Vol. 63, No. 10,15 January, 1998, pages 2396–2404

E2C: Periodic Safety Update Reports

Finalised (Step 4) in November 1996.This gives

guidance on the format and content of safety

updates, to be provided to regulatory authorities, at

intervals, after products have been marketed.The

guideline is intended to ensure that the world-wide

safety experience is provided to authorities at

defined times after marketing with maximum

efficiency and avoiding duplication of effort.Implementation (Step 5):EU:Adopted by CPMP, December 96, issued asCPMP/ICH/288/95. Japan:Adopted March 97, PAB/PSDNotification No.32. USA: Published in the Federal Register, Vol.62, No. 96, 19 May, 1997, pages 27469–27476

E3: Clinical Study ReportsStructure and Content of Clinical Study Reports

Finalised (Step 4) in November 1995.This allows a

single compilation of world-wide core clinical study

reports, for inclusion in applications.This ensures

more efficient generation of data and submission

to the regulatory authorities.Implementation (Step 5):EU:Adopted by CPMP, December 95, issued asCPMP/ICH/137/95. Japan:Adopted May 96, PAB/PCDNotification No. 335. USA: Published in the Federal Register,Vol. 61, 17 July, 1996, page 37320

E4: Dose-Response Information toSupport Drug RegistrationFinalised (Step 4) in March 1994.This gives

recommendations on the design and conduct of

The current status of ICH products in the‘efficacy’ classification

page 4

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page 4 © Canary Publications 2000

studies to assess the relationship between dose,

blood levels and clinical response in the early stages

of the clinical development of a new drug.These

trials are pivotal to the clinical development of a new

drug and harmonisation means that they only need to

be carried out once, to meet regulatory requirements.Implementation (Step 5):EU:Adopted by CPMP, May 94, issued as CPMP/ICH/378/95Japan:Adopted July 94, PAB/PCD Notification No.494USA: Published in the Federal Register, Vol. 59, No. 216,9 November, 1994, pages 55972–55976

E5: Ethnic Factors in the Acceptabilityof Foreign Clinical DataFinalised (Step 4) in February 1998.This addresses

the intrinsic characteristics of the drug recipient and

extrinsic characteristics associated with environment

and culture, which are likely to impact on the

results of clinical studies carried out in different

ethnic groups.Status of Implementation (Step 5):EU:Adopted by CPMP, March 1998, as CPMP/ICH/289/95,comes into operation, September 1998. Japan:Adopted August98, PMSB/ELD Notification No. 672, PMSB Notification No.739USA: Published in the Federal Register, Vol. 63, No. 111,10 June, 1998, page 31790 in force September 1998

E6: Good Clinical Practice: GCP:Consolidated GuidelineFinalised (Step 4) in May 1996.This document sets

out a standard for the conduct of clinical trials,

covering aspects of preparation, monitoring,

reporting and archiving of clinical trials and

incorporating addenda on the Essential Documents

and on the Investigator’s Brochure which had been

agreed earlier through the ICH process.Implementation (Step 5):EU:Adopted by CPMP, July 96, issued asCPMP/ICH/135/95/Step5, Explanatory Note and Comments to the above, issued as CPMP/768/97. Japan:Adopted March97, PAB Notification No. 430, MHW Ordinance No. 28USA: Published in the Federal Register, Vol. 62, No. 90, 9 May,1997, pages 25691–25709

E7: Clinical Trials in SpecialPopulations: GeriatricsFinalised (Step 4) in June 1993.This gives

recommendations on the special considerations

which apply in the design and conduct of clinical

trials on medicines that are likely to have significant

use in the elderly.

Implementation (Step 5):EU:Adopted by CPMP, September 93, as CPMP/ICH/379/95.Japan:Adopted December 93, PAB/NDD Notification No. 104USA: Published in the Federal Register, Vol. 59, No. 102,2 August, 1994, pages 39398–39400

E8: General Considerations for Clinical TrialsFinalised (Step 4) in July 1997.This sets out the

general scientific principles for the conduct,

performance and control of clinical trials.The

guideline addresses a wide range of subjects in the

design and execution of clinical trials and in the

evaluation of the scientific validity of protocols.Implementation (Step 5):EU:Adopted by CPMP, September 97, as CPMP/ICH/291/96Japan:Adopted April 1998, PMSB/ELD Notification No. 380USA: Published in the Federal Register, Vol. 62, No. 242,17 December, 1997, page 66113

E9: Statistical Principles for Clinical TrialsAdopted in February 1998.The issues in a bio-

statistical guideline affect each and every clinical

trial contained in a dossier and the guideline is in-

tended to overcome the differences in the level of

detail required in the different ICH regions, which

can be an obstacle to the general acceptance of

analyses and conclusion from clinical trials.Implementation (Step 5):EU:Adopted by CPMP, March 1998, as CPMP/ICH/363/96Japan:Adopted November 1998, PMBS/ELD Notification No.1047. USA: Published in the Federal Register, Vol. 63, No. 179,16 September, 1998, page 49583 in force September 1998

page 5

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page 3▲

CRAdvisor, Issue 48, 2000 page 5

page 4▲

E10: Choice of Control Group inClinical TrialsThe ICH guideline was released for consultation

under Step 2 of the process. It addresses the choice

of control groups in clinical trials needed for an

approval of a dossier with respect to efficacy and

safety.At present, there are major differences in

practice and attitudes toward the need for placebo

controlled trials (or other trials in which a difference

between treatments is shown) and the acceptability

of active control equivalence trials as evidence of

efficacy and safety.This difference applies both to

determinations of intrinsic efficacy and to the need

for comparison with other drugs.Consultation (Step 3):EU: Released for consultation in CPMP/ICH/364/96, June1999, deadline for comments December 1999 Japan: Released for consultation, PAB/PCD Notification No. 992, 22 June 1999, deadline for comments on 22 September 1999USA: Published in the Federal Register, Vol. 64, No. 185,24 September, 1999, pages 51767–51780

E11: Clinical Investigation of MedicinalProducts in the Pediatric PopulationThe ICH guideline was released for consultation

under Step 2 of the process in October 1999.This

addresses the conduct of pediatric trials on medi-

cines.The existing guidances are based on differing

assumptions and propose different strategies, scien-

tific principles and regulatory standards.The objective

of ICH Guideline will be to facilitate the development

of safe and effective use of medicinal products in

children and help eliminate the current difficulties

encountered by companies operating internationally.Consultation (Step 3):EU: Released for consultation, November 1999, issued asCPMP/ICH/2711/99. Japan: Released for consultation,PAB/PCD Notification No. 1831, 17 December 1999, deadlinefor comments on 31 March 2000. USA:To be notified

Guidelines for Clinical Evaluation byTherapeutic CategoryThe ICH Efficacy Guidelines to date have focused

on guidance which can be applied to all therapeutic

classes of drugs, but there are, in some therapeutic

classes, individual drug evaluation guidelines among

the three regions. Differences between guidelines

can result in obstacles to the mutual use and

acceptance of clinical data. At the Steering

Committee meeting in September 1998, it was

agreed that this should be adopted as a new area of

work for ICH, with the first such guideline being

undertaken as a “pilot study” to assess the feasibility

of extending work in this area.

E12A: Principles for Clinical Evaluation of New Antihypertensive DrugsThis document provides a set of “Principles”of Clinical

trials, focusing on the type of study designs and

development phase which are common to all three

ICH regulatory authorities. Since there are a few major

differences in the requirements of the three regions,

this document should be considered as an “ICH

Principle Document”rather than an “ICH Guideline”.

It will not be subject to the usual ICH Step Procedures

leading to a fully harmonised document. Comments

received on this document will be forwarded to the

three regulatory authorities for consideration.

Source: ICH web site at: <www.ifpma.org/ich.html>. Copies ofall ICH documents can be downloaded from this site.

Steps in the ICHimplementation processStep 1 – consensus buildingAn initial draft or guideline is prepared and circulated forcomment by members of an expert working group (EWG)within fixed deadlines.The document is eventually signedoff by members of the EWG and submitted to the ICHSteering Committee.

Step 2 – start of regulatory action.This step is reached when the ICH Steering Committeeagrees with the document prepared by the EWG.Agreementis reached on the basis that the EWG has reached sufficientconsensus on the technical issues.

Step 3 – regulatory consultationThe guideline leaves the ICH process and passes through theusual wide ranging regulatory consultation channels in thethree regions.The parties exchange comments and come toan agreement on the content of a single harmonised text.

Step 4 – adoption of the textIf all the regulatory and industry parties are in agreement and the consensus of the text agreed at Step 2 has not beenchanged the document is adopted and signed off by theSteering Committee.

Step 5 – implementationImplementation in Europe, Japan and the USA is carried outusing the usual national/regional procedures.

page 6 © Canary Publications 2000

Editor: Dr David Hutchinson

Principal Writer: Gillian Devine (GD)

Subscriptions & Advertising: Neil MountainCorrespondents:Gitte Raaschou Beck (Denmark) Irene Herod (UK)

Eugen Chicevic (Central Europe) Ilian Ivanov (Bulgaria)

Paul-Etienne Chipp (Switzerland) Mikhail Kandalov (Russia)

Bettina Klesse (South Africa) Hisashi Uematsu (Japan)

Leny Aiach Telles Correa (Brazil) Paul Marcus (UK)

Donna Cullen (USA) Alexey Melkov (Russia)

Jorge Cúneo (Argentina) Volker Peinke (Germany)

Valerie Fletcher (UK) Marc Robin (Germany)

Francois Geelen (Germany) Sam Tong (UK)

M Khurram Zaki Khan (Pakistan) Maria Galikova (Slovakia)

Lisbeth Tofte Hemmingsen (Denmark) Nigel Dent (UK)

Joris Bannenberg (Netherlands) Cecil Nick (UK)

Pamela Charnley Nickols (UK) Sheelagh Corcoran (UK)

Jean-Michel Andrieux (France) Laura Brown (UK)

Kym Prieto (Europe)

Contact us by e-mail: editor@cradvisor.co.uk

Literature regularly reviewed includes:

QA Journal JRSMQUASAR (BARQA publication) Pharmaceutical ReviewClinical Trials Advisor ScripApplied Clinical Trials The TimesMCA Eurodirect publications EFGCP NewsletterCRFocus AIOPI NewsletterGCP Journal The StatisticianThe Monitor MAILPharmaceutical Physician NLN NewsletterDIA Journal FDA Warning LettersBulletin of Medical Ethics ESRA Rapporteur

Web sites regularly reviewed includes:

EMEA, EFPIA, FDA, MCA, IFPMA,ICH, DGIII (European Commission)

Aims & Scope:To keep readers informed of:• changes in regulations, codes of practice, guidelines and

new clinical research procedures• clinical research methodology, statistical and legal issues• news from important meetings and conferences• correspondence, questions and answers, the grapevine,

solutions to problems• important information in other publications and on

the Internet• training courses, jobs and other opportunities.To provide information on:• ICH developments and progress• inspection and audit findings and their avoidance.

Published by: Canary Ltd, PO Box 9, Guildford, Surrey GU2 5GY, UK Telephone: 07000-CANARY (226279) or +44 1483 295910Fax: 07000-FAXBACK (329222) or +44 1483 295911

© Canary Publications 2000

All rights reserved. No part of this publication may be copied, transmitted, reproducedin any way without the written permission of the publisher.

Disclaimer:Whilst we try to ensure that information published is correct, the Editors,Advisors or publishers accept no liability for losses or damages arising.You shouldalways seek a second opinion before acting on any information provided.

Design: LIMA Graphics, Frimley, Surrey, UKPrint: Surrey Litho, Great Bookham, Surrey, UK

News in brief

Revision of the Declaration of HelsinkiAfter wide consultation of patient representative groups, the public and physician organisations, theWorkgroup on the Revision of the Declaration of Helsinki will consider the comments received at the end of March 2000.The workgroup members, Drs. NancyDickey, Judith Kazimirski and Kati Myllymaki plan topresent an interim report to the WMA Council during May 2000.Source:World Medical Association web site:<www.wma.net>.

Orphan medicinal productsIt is now possible for sponsors to submit applications fororphan medicinal product designation in the EuropeanUnion.The EMEA committee responsible for this processheld a meeting on 16 May 2000 to discuss the procedures.Sponsors should notify EMEA of their intention to submit asearly as possible and at the latest 2 months prior to plannedsubmission date. Sponsors are requested to follow draftguidelines ENTR/6283/00 for the format and content ofapplications. For further information contact Dr PatrickLeCourtois at the EMEA.

EMEA guidance on contraceptivetrialsThe Committee for Proprietary Medicinal Products (CPMP)have issued a note for guidance on the clinical investigationof steroid contraceptives in women.The adopted guidancecomes into force in August 2000.This latest documentreplaces the guidelines on this subject issued in February 1987.

Quality of trials in Europe vs. USAACRP’s European President David Hutchinson has announced that a key note lecture at the association’s 3rd annual conference to be held in Prague (5–6 October)will be given by Dr Bette Barton.As well as being a key member of the ICH Steering Committee, Dr Barton was formerly Head of the FDA’s Division of ScientificInvestigations. She will compare FDA inspection findings in Europe and USA. For more information about the ACRP conference contact Eileen Moynihan,ACRP London Office: tel: +44 020 7987 4741, email:<EiMoynihan@aol.com>.