Drug Safety Evaluation

1014 Pages·2002·5.823 MB·English

by  Shayne Cox Gad

DRUG SAFETY
EVALUATION
DRUG SAFETY
EVALUATION
SHAYNE C. GAD
A John Wiley & Sons, Inc., Publication
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LibraryofCongressCataloging-in-PublicationData:
Gad,ShayneC.,1848-
DrugSafeteyevaluation=ShayneC.Gad.
p.cm.
Includesindex.
ISBN0-471-40727-5(cloth:alk.paper)
1.Drugs—Toxicology.2.Drugs—Testing.I.Title.
RA1238.G3342002
6150.19—dc21
PrintedintheUnitedStatesofAmerica.
10 9 8 7 6 5 4 3 2 1
To Spunky Dustmop, who always listens
so well and is always there.
CONTENTS
Preface ix
About the Author xi
Chapter 1 Strategy and Phasing for Drug Safety Evaluation in the
Discovery and Development of Pharmaceuticals 1
Chapter 2 Regulation of Human Pharmaceutical Safety 30
Chapter 3 Information Sources: Building and Maintaining Data
Files 99
Chapter 4 Screens in Safety and Hazard Assessment 112
Chapter 5 Acute Toxicity Testing in Drug Safety Evaluation 130
Chapter 6 Genotoxicity 176
Chapter 7 Subchronic and Chronic Toxicity Studies 237
Chapter 8 Developmental and Reproductive Toxicity Testing 258
Chapter 9 Carcinogenicity Studies 297
Chapter 10 Safety Assessment of Inhalant Drugs 335
Chapter 11 Irritation and Local Tissue Tolerance in Pharmaceutical
Safety Assessment 367
vii
viii CONTENTS
Chapter 12 Special Concerns for the Preclinical Evaluation of
Biotechnology Products 404
Chapter 13 Formulations, Routes, and Dosage Designs 442
Chapter 14 Occupational Toxicology in the Pharmaceutical Industry 505
Chapter 15 Immunotoxicology in Pharmaceutical Development 527
Chapter 16 Large Animal Studies 595
Chapter 17 The Applicatioin of In Vitro Techniques in Drug Safety
Assessment 634
Chapter 18 Pharmacokinetics and Toxicokinetics in Drug Safety
Evaluation 691
Chapter 19 Safety Pharmacology 737
Chapter 20 Evaluation of Human Tolerance and Safety in
Clinical Trials: Phase I and Beyond 764
Chapter 21 Postmarketing Safety Evaluation: Monitoring,
Assessing, and Reporting of Adverse Drug Responses
(ADRs) 831
Chapter 22 Statistics in Pharmaceutical Safety Assessment 862
Appendix A Selected Regulatory and Toxicological Acronyms 971
Appendix B Definition of Terms and Lexicon of Clinical
Observations in Nonclinical (Animal) Studies 975
Appendix C Notable Regulatory Internet Addresses 979
Appendix D Glossary of Terms Used in the Clinical Evaluation
of Therapeutic Agents 990
Index 997
PREFACE
Drug SafetyEvaluation hasbeen written withthecentralobjectiveofpresentingan
all-inclusivepracticalguide for thosewhoareresponsibleforensuringthesafetyof
drugs and biologics to patients, health care providers, those involved in the
manufacture of medicinal products, and all those who need to understand how the
safety of these products is evaluated.
Thispracticalguidepresentsaroadmapforsafetyassessmentasanintegralpart
of the development of new drugs and therapeutics. Individual chapters also address
specific approaches to evaluating hazards, including problems that are encountered
and their solutions. Also covered are the scientific and philosophical bases for
evaluation of specific concerns (e.g., carcinogenicity, development toxicity, etc.) to
provide both understanding and guidance for approaching new problems. Drug
Safety Evaluation is aimed specifically at the pharmaceutical and biotechnology
industries. It is hoped that the approaches and methodologies presented here
will show a utilitarian yet scientifically valid path to the everyday challenge of
safety evaluation and the problem-solving that is required in drug discovery and
development.
Shayne C. Gad
Cary, North Carolina
ix
ABOUT THE AUTHOR
Shayne C. Gad, Ph.D. (Texas, 1977), DABT, ATS, has been the Principal of Gad
Consulting Services since 1994. He has more than 25 years of broad based
experience in toxicology, drug and device development, document preparation,
statistics and risk assessment, having previously been Director of Toxicology and
Pharmacology for Synergen (Boulder, CO), Director of Medical Affairs Technical
Support Services for Becton Dickinson (RTP, NC) and Senior Director of Product
SafetyandPharmacokineticsforG.D.Searle(Skokie,IL).Heisapastpresidentand
council member of the American College of Toxicology and the President of the
Roundtable of Toxicology Consultants. He has previously served the Society of
Toxicology on the placement, animals in research [twice each], and nominations
committees,aswellaspresidentoftwoSOTspecialtysections(OccupationalHealth
andRegulatoryToxicology)andofficerofathird(ReproductiveandDevelopmental
Toxicity).HeisalsoamemberoftheTeratologySociety,BiometricsSociety,andthe
American Statistical Association. Dr. Gad has previously published 24 books, and
more than 300 chapters, papers and abstracts in the above fields. He has also
organizedandtaughtnumerouscourses,workshopsandsymposiabothintheUnited
States and internationally.
DrugSafetyEvaluation.ShayneC.Gad
Copyright2002JohnWiley&Sons,Inc.
ISBN:0-471-40727-5
1
STRATEGY AND PHASING FOR DRUG
SAFETY EVALUATION IN THE
DISCOVERY AND DEVELOPMENT OF
PHARMACEUTICALS
1.1. INTRODUCTION
Thepreclinicalassessmentofthesafetyofpotentialnewpharmaceuticalsrepresents
aspecialcaseofthegeneralpracticeoftoxicology(Gad,1996,2000;Meyer,1989),
possessing its own peculiarities and special considerations, and differing in several
ways from the practice of toxicology in other fields—for some significant reasons.
Because of the economics involved and the essential close interactions with other
activities, (e.g., clinical trials, chemical process optimization, formulation develop-
ment,regulatoryreviews,etc.),thedevelopmentandexecutionofacrisp,timelyand
flexible, yetscientifically sound,program is a prerequisitefor success. The ultimate
aim ofpreclinicalassessmentalso makes it different. Agood pharmaceuticalsafety
assessment program seeks to efficiently and effectively move safe, potential
therapeutic agents into, and support them through, the clinical evaluation, then to
registration, and, finally, to market. This requires the quick identification of those
agentsthatarenotsafe.Atthesametime,theverybiologicalactivitywhichmakesa
drug efficacious also acts to complicate the design and interpretation of safety
studies.
Pharmaceuticals, unlike industrial chemicals, agricultural chemicals, and envir-
onmentalagents,areintendedtohavehumanexposureandbiologicalactivity.And,
unlike these materials and food additives, pharmaceuticals are intended to have
biological effects on the people that receive them. Frequently, the interpretation of
results and the formulation of decisions about the continued development and
1
2 STRATEGYANDPHASINGFORDRUGSAFETYEVALUATION
eventual use of a drug are based on an understanding of both the potential adverse
effects ofthe agent (its safety)and its likely benefits, aswell as thedose separation
between these two (the ‘‘therapeutic index’’). This makes a clear understanding of
dose-response relationships critical, so that the actual risk=benefit ratio can be
identified. It is also essential that the pharmacokinetics be understood and that
‘‘doses’’ (plasma tissue levels) at target organ sites be known (Scheuplein et al.,
1990). Integral evaluation of pharmacokinetics are essential to any effective safety
evaluation program.
The development and safety evaluation of pharmaceuticals have many aspects
specifiedbyregulatoryagencies,andthishasalsotendedtomaketheprocessmore
complex [until recently, as ICH (International Conference on Harmonization) has
tendedtotakehold]asmarketshavetrulybecomeglobal.Anextensivesetofsafety
evaluations is absolutely required before a product is ever approved for market.
Regulatoryagencieshaveincreasinglycometorequirenotonlytheestablishmentof
a ‘‘clean dose’’ in two species with adequate safety factors to cover potential
differences between species, but also an elucidation of the mechanisms underlying
such adverseeffects as are seen at higher doses and are not well understood. These
regulatory requirements are compelling for the pharmaceutical toxicologist (Traina,
1983;Smith,1992).Thereisnot,however,asetmenuofwhatmustbedone.Rather,
much(particularlyintermsofthetimingoftesting)isopentoprofessionaljudgment
and is tailored for the specific agent involved and its therapeutic claim.
Thediscovery,development,andregistrationofapharmaceuticalisanimmensely
expensive operation, and represents a rather unique challenge (Zbinden, 1992). For
every 9000 to 10,000 compounds specifically synthesized or isolated as potential
therapeutics, one (on average) will actually reach the market. This process is
illustrated diagrammatically in Figure 1.1. Each successive stage in the process is
more expensive, making it of great interest to identify as early as possible those
agentsthatarenotlikelytogotheentiredistance,allowingaconcentrationofeffort
on the compounds that have the highest probability of reaching the market.
Compounds ‘‘drop out’’ of the process primarily for three reasons:
1. Toxicity or (lack of) tolerance.
2. (lack of) efficacy.
3. (lack of) bioavailability of the active moiety in man.
Early identification of poor or noncompetitive candidates in each of these three
categoriesisthusextremelyimportant(Fishlock,1990),formingthebasisfortheuse
of screening in pharmaceutical discovery and development. How much and which
resources to invest in screening, and each successive step in support of the
development of a potential drug, are matters of strategy and phasing that are
detailedinalatersectionofthischapter.Invitromethodsareincreasinglyproviding
new tools for use in both early screening and the understanding of mechanisms of
observedtoxicityinpreclinicalandclinical studies(Gad,1989b,2001),particularly
withthegrowingcapabilitiesandinfluenceofgenomicandproteomictechnologies.