Table Of ContentSafety Evaluation of
Biotechnologically-derived
Pharmaceuticals:
Facilitating a Scientific Approach
CMRInternationalWorkshop Series
MonitoringforAdverseDrugReactions
Editors: S.R. WalkerandA. Goldberg
Long-TermAnimalStudies
TheirPredictiveValueforMan
Editors: S.R. WalkerandAD. Dayan
Medicinesand Risk/BenefitDecisions
Editor: SR. WalkerandA.W. Asscher
QualityofLife:AssessmentandApplication
Editors: S.R. WalkerandRM. Rosser
InternationalMedicinesRegulations
AForwardLookto1992
Editors: SR. WalkerandJ.P. Griffin
AnimalToxicityStudies: TheirRelevanceforMan
Editors: CE. LumleyandS.R. Walker
CreatingtheRight Environmentfor DrugDiscovery
Editor: S.R Walker
CurrentIssuesinReproductiveandDevelopmentalToxicology
CananInternationalGuidelinebeAchieved?
Editors: CE. Lumleyand SR. Walker
TheCarcinogenicityDebate
Editors:JAN. McAuslane, CE LumleyandS.R Walker
TheRelevanceofEthnicFactorsintheClinicalEvaluationofMedicines
Editors: S.R Walker, C.E. LumleyandJAN. McAuslane
ImprovingtheRegulatory ReviewProcess: Industryand Regulatory
Initiatives
Editors: CE. LumleyandS.R. Walker
Improvingthe Regulatory ReviewProcess:AssessingPerformanceand
SettingTargets
Editors:JAN. McAuslaneand S.R. Walker
Workshop Series
Safety Evaluation of
Biotechnologically-derived
Pharmaceuticals:
Facilitating a Scientific
Approach
Ediled by
Susan A. Griffiths and Cyndy E. Lumley
Centre for Medicines Research International
Carshalton, Surrey, UK
Proceedings of a CMR IlItemational Workshop held al AslldoWlI Park Hotel,
Wych Cross, UK, February 1997
SPRINGER SCIENCE+BUSINESS MEDIA, B.V.
A catalogue record for this book is available horn the British Library
ISBN 978-94-010-6043-1 ISBN 978-94-011-4876-4 (eBook)
DOI 10.1007/978-94-011-4876-4
Copyright
© 1998 by Springer Science+Business Media Dordrecht
Origina1ly published by Kluwer Academic Publishers in 1998
Softcover reprint ofthe hardcover Ist edition 1998
Ali rights reserved. No part of this publication may be reproduced, stored in a retrieval
system, or transmitted in any form or by any means, electronic, mechanical, photocopying,
recording or otherwise, without prior permission from the publishers, Springer Science+
Business Media, B.V.
Lasertypeset by Martin Lister Publishing Services, Bolton-le-Sands, Camforth, Lancs.
Contents
Preface vii
Foreword - ProfessorGiuseppeVicari xi
Notes onContributorsandChairmen xiii
1 Designingnon-clinicalsafetyevaluationprogrammes:
Theviewoftheclinician
John Lipani 1
2 Designingnon-clinicalsafetyevaluationprogrammes:
Theviewofthetoxicologist
Maggie Dempster 7
3 Companystrategiesfor designingnon-clinicalsafety
evaluationprogrammes: ResultsofaCMRInternational
survey
Susan Griffiths 17
4 Influenceofregulatorysystems: AviewpointoftheUS
FDAprocess
JoyA. Cavagnaro 31
5 Influenceofregulatorysystems: TheEuropeanCPMP
perspective
Per Sjoberg 39
6 Biotechnologically-derived pharmaceuticalsinJapan:
Presentand future prospects
Tohru Inoue 51
7 Designingnon-clinicalsafetyevaluationprogrammes for
colonystimulatingfactors, growthfactors and
hormones: Apersonalview
DouglasM. Morton 65
v
SafetyEvaluationofBiotechnologically-derivedPharmaceuticals
8 Designingnon-clinicalsafetyevaluationprogrammes for
interferonsand interleukins: Apersonal view
Grushenka H.I. Wolfgang, Sharon Chen, Martin Giedlin, 79
Rene Braeckmanand DaleJohnson
(ThispaperwaspresentedattheWorkshopbyDaleJohnson)
9 Designingnon-clinical safetyevaluationprogrammesfor
monoclonal antibodiesfor therapeutic use: Apersonal
view
PeterBugelski 103
10 Designingnon-clinical safetyevaluationprogrammesfor
gene therapy products: Apersonal view
James MacDonald, RichardMorrisseyandJames Patrick 115
11 Recommendationsand the way forward 129
12 Designingnon-clinicalsafetyevaluationprogrammesfor
colonystimulatingfactors, growthfactors and
hormones: Recommendationsand thewayforward
Jennifer SimsandFelixdela Iglesia 133
13 Designingnon-clinical safetyevaluationprogrammesfor
interferons and interleukins: Pastexperiencesand
recommendationsfor future products
Joy A. Cavagnaroand Timothy Anderson 139
14 Designingnon-clinical safetyevaluationprogrammesfor
monoclonal antibodies: Recommendationsand theway
forward
James Green andJohn Purves 151
15 Designingasafetyevaluationprogrammefor gene
therapy products: Recommendationsand theway
forward
Peter Harris andAnthony Dayan 159
Appendix1: PreclinicalSafety Evaluationof 169
Biotechnology-Derived Pharmaceuticals:
ICHStep 4HarmonisedTripartiteGuideline
AppendixII: ListofParticipants 189
Index 193
vi
Preface
The Thirteenth CMR International Workshop, held in February
1997, provided an opportunity for international experts to discuss
the approaches used, and difficulties encountered, in designing
scientifically-based non-clinical safety evaluation programmes for
biotechnologically-derived pharmaceuticals. This two-day meet
ing brought together toxicologists and clinicians, from 32 pharma
ceutical and biotechnology companies, and regulators and regula
tory advisors from the European Medicines Evaluation Agency
and 9countries: Denmark, France,Germany, Italy,Japan, theNeth
erlands, Sweden, the UK and the USA. Ata time whena guideline
to provide general principles for designing internationally accept
able preclinical safety evaluation programmes for biotechnology
products was being developed under the auspices of ICH (the
International Conference on Harmonisation of Technical Require
ments for Registration of Pharmaceuticals for Human Use), it was
timely to debate the application of these principles to specific
productclasses.
The foundation for the discussions was setby a clinician and a
toxicologist describing the information required from a safety test
ing programme of biotechnologically-derived pharmaceuticals.
This was followed by regulatory viewpoints from the USA,
Europe and Japan. Four speakers then presented proposals on the
design of non-clinical safety evaluation programmes for colony
stimulating factors, growth factors and hormones; interferons and
interleukins; monoclonal antibodies for therapeutic use; and gene
therapy products. After the plenary discussion, the participants
split up into four syndicate groups for several hours of further
discussion and debate on the approaches that should be taken for
each of these product classes. Although, inevitably, there were
differences of opinion, the conclusions which were presented
vii
SafetyEvaluationofBiotechnologically-derivedPharmaceuticals
subsequently to the whole group, were remarkably consistent.
There was a general endorsement of the ICH draft guideline,
which was at Step 3 of the ICH process at that time, and it was
agreed that detailed annexes for different types of product are not
feasible due to the diversity of biotech products. There was con
sensus by both regulators and the industry that genotoxicity and
carcinogenicity studies are not usually appropriate for biotech
products. In addition, there was agreement on general principles
for the safety testing of gene therapy products, which are not
included in the ICH guideline. Finally, the participants recognised
that companies should not contribute to increased regulatory
expectations by conducting studies which are more suitable for
small molecule chemicals, without adequate scientificjustification.
These recommendations, arising from a forum in which experts
from a wide range of companies and agencies were present, were
taken into consideration for the final ICH S6 guideline which was
agreed atICH4inBrusselsinJuly1997.
The workshop also provided an opportunity for industry and
regulatory experts to share their experiences of designing safety
evaluation programmes for specific product classes. This type of
interaction isparticularlyimportantbecauseindividualcompanies
and regulatory authorities may have little experience with these
compoundsdue tothe relatively smallnumber ofbiotechproducts
which have been marketed to date. In addition, the case-by-case
approach taken to designing safety evaluation programmes for
biotechnologically-derivedpharmaceuticalshas led to inconsisten
cies in the information on non-clinical safety testing requested by
regulatorsintheUSA, EuropeandJapan. Theeditorshope that the
publication of these proceedingswill provide support for industry
toxicologists to press for a scientific approach to the safety evalu
ation of biotech products, and give regulators the confidence not
to requeststudies tobeconductedwhich are part ofthe traditional
programme for smallmolecule chemicals,unless thereis appropri
ate scientificjustification.
We would like to thank all the Authors and Participants for
making the meeting such a stimulating debate. Special thanks go
viii
Preface
to the Rapporteurs andChairmen ofthe syndicate groupsfor pull
ing together the views into the consensus recommendations docu
mented in these proceedings. We are also indebted to Sandra Cox,
whose work as administrator and compiler made a considerable
contribution to the quality ofthis publication, and toSaraTownsend
for so capably handling all the administrative arrangements for
the meeting.
Susan Griffiths
CyndyLumley
December 1997
ix
