A GUIDE TO CLINICAL DRUG RESEARCH
`
`edited by
`
`ADAM COHEN
`Professor of Clinical Pharmacology,
`University of Leiden,
`Leiden, The Netherlands
`and
`
`Director of the Centre for Human Drug Research,
`Leiden University Hospital,
`Leiden, The Netherlands
`
`and
`
`JOHN POSNER
`Clinical Pharmacologist
`Glaxo Wellcome PLC
`Beckenham, Kent, UK
`
`Sheppard Libra -
`Massachuse g.
`
`‘
`
`Kluwer Academic Publishers
`
`DORDRECHT/ BOSTON/ LONDON
`
`
`
` .
`
`AstraZeneca Exhibit 2051 p. 1
`InnoPharma Llcensing LLC V. AstraZeneca AB IPR2017-00904
`Fresemus-Kabi USA LLC V. AstraZeneca AB IPR2017-01910
`
`

`

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`Ref.
`
`3 R M
`
`301.27
`' 685
`1995
`
`““"‘~““—-~-~—~~~'
`
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`_
`A guide to clinical drug research / edited’ by Adam Cohen and John
`~~
`Posner
`'
`"
`l
`.,~
`cm.
`p.
`Includes index.
`-
`ISBN 0-7923—3508-2 (HB : alk. paper)
`ll. Posner, John.
`1. Drugs--Research.
`l. Cohen, Adam.
`[DNLM2 1. Clinical Trials--methods.
`2. Research Design. QV771
`6946 19951
`'
`RM301.27.G85
`615’. 19--dc20
`DNLM/DLC
`for Library of Congress
`
`
`
`Library of Congress Cataloging-in-Publication Data
`
`,
`
`4
`
`-
`
`'
`
`1995
`
`95-8825
`
`ISBN 0-7923-3508-2
`____—__—__—___—_—_————————————-——-—-
`
`Published by Kluwer Academic Publishers,
`PO. Box 17. 3300 AA Dordrecht, The Netherlands
`
`Sold and distributed in the USA and Canada by
`KluwerAcademic Publishers,
`
`101 Philip Drive, Norvvell, MA 02061, USA
`
`In all other countries, sold and distributed by
`Kluwer Academic Publishers Group
`PO. Box 322, 3300 AH Dordrecht, The Netherlands
`
`
`
`Printed on acid-free paper
`
`All Rights Reserved
`© 1995 KluwerAcademic Publishers
`
`the material protected by this copyright notice may be reproduced or utilized in any
`No part of
`form or by any means, electronic or mechanical, including photocopying, recording or by any information
`storage and retrieval system, without written permission from the copyright owner.
`
`Printed in the Netherlands
`
`AstraZeneca Exhibit 2051 p. 2
`
`

`

`raga.‘...'_'..-'».:m.a;..<..
`
`
`jénsta
`
`$3
`
`What does the investigator need
`to know about the drug?
`
`3,
`"
`
`
`
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`3
`
`5%
`
` .
`
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`
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`3%;
`
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`
`
`
`An investigator may be asked to conduct a study with a new Introduction
`molecular entity which has never been administered to man
`before, or else has only been administered to a small number of
`subjects in Phase I studies. Alternatively, he may undertake a
`trial during Phase II or 111, when there is already a considerable
`amount of clinical data available.
`the
`on
`This
`chapter will
`concentrate predominantly
`information an investigator should know before embarking on a
`Phase I study, with some comment about extra data that should -
`be available to conduct later phase trials.
`When an investigator is approached by a sponsoring pharma-
`ceutical company for the first time, it is worth trying to establish
`the overall plan or strategy for the drug’s evaluation. The data
`may prove to be confidential, but even an outline of the
`sponsoring drug company’s intentions will help to put the study
`which the investigator
`is being requested to undertake,
`in
`context. It is not unusual for the sponsoring physician or the
`Clinical Research Associate to bring a research scientist with
`him on an early visit if the drug to be tested is at an early stage
`of development. At a later stage, the investigator may be taking
`part in a multi-centre trial, in which case it is quite usual to have
`an investigator’s meeting, when critical decisions about the drug
`— such as primary end points, interim analyses and the remit of
`data safety monitoring committees — are made.
`
`Drug development is traditionally divided into four phases:
`Phase I: Clinical pharmacology.
`Studies in healthy volunteers or patients, according to the
`class of drug and its safety, to determine:
`Pharmacodynamics (biological effects) where practicable,
`tolerability, safety, and efficacy, if in patients
`Pharmacokinetics: absorption, distribution, metabolism
`and excretion
`
`Phases of drug
`development
`
`17
`
`
`
`AstraZeneca Exhibit 2051 p. 3
`
`

`

`3 /WHAT DOES THE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG?
`
`
`
`Phase II: Clinical investigation
`,
`Studies in patients with the target disease
`Pharmacodynamics and pharmacokinetics: dose-ranging
`in expanding, carefully controlled studies for efficacy and
`safety
`Phase III: Formal therapeutic trials
`Randomised and controlled for efficacy in large numbers,
`safety, placebo and active comparator trials
`Phase IV: Post-registration
`Marketing or user studies
`Expand clinical experience for safety and efficacy; further
`formal therapeutic trials; comparisons with other active
`comparators
`
`This classification assumes a logical, sequential approach to
`drug development, which rarely occurs in practice. Phase I
`studies initiate the clinical development programme, but some
`clinical pharmacology trials, e.g. bioequivalence studies, studies
`in special risk groups, such as hepatic and renal disease, and
`drug-drug interaction studies, may occur at various stages in the
`execution of the clinical development plans. Phases II and III
`often overlap, as sponsoring drug companies attempt to save
`time by initiating long term parallel group therapeutic trials,
`before the dose-range is adequately defined.
`
`A responsible sponsoring drug company should provide the
`investigator with an Investigator’s Brochure containing the
`essential
`information on the drug,
`independently of
`the
`protocol. It is a confidential document, which can serve as a
`check list for the investigator to be sure that he is informed of
`all relevant data relating to the efficacy and safety of the .drug.
`Its content is listed in Box 3.1 and this may be supplemented by
`separate documents supplied on request from the sponsoring
`drug company — including publications.
`Key elements from the Investigator’s Brochure on which the
`investigator must be informed will now be discussed.
`
`The
`
`investigator’s
`brochure
`
`Pre-clinical
`
`evaluation
`
`Pharmacology
`
`This section should provide a scientific rationale for development
`of the drug and an hypothesis which is to be tested in man. An
`investigator reviewing this data for the first time may find this
`section rather daunting and unless he has a good grounding in
`pharmacology, many of the terms will be confusing. Readers are
`directed to some of the standard texts for further information.
`
`18
`
`Contents of lnv
`
`- General de:
`
`Physical prc
`Chemical pi
`Solubility
`Formula
`
`- Pre-clinical
`‘ Pharmac
`
`Specific;
`General;
`Safety pt
`Metabolis
`‘ Toxicolo
`
`Single do
`Repeatd
`Mutageni
`Carcinog
`Reprodw
`
`Pharmacei
`
`Purity
`Percent anc
`Formulatior
`Vehicle
`In vitro diss‘
`
`Stability
`Shelf life
`
`Light and ht
`
`Clinical sen
`
`- Clinicall
`Safety
`Tolerabili
`Pharmac
`Bioavaila
`Metaboli:
`
`Dynamic
`lnteractic
`
`Specialg
`- Clinical
`Dose-rar
`Placebo-
`Active cc
`Overalls
`
`
`
`AstraZeneca Exhibit 2051 p. 4
`
`

`

`G?
`
`
`
`WHAT DOES THE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG? / 3
`
`Contents of lnvestigator’s brochure
`
`Box 3.1
`
`for development
`
`:5: dose-ranging
`for efficacy and
`
`1 large numbers,
`is
`
`efficacy; further
`'ith other active
`
`ial approach to
`ractice. Phase I
`
`imme, but some
`3 studies, StUdieS
`nal disease, and
`ous stages in the
`hases II and III
`attempt to save
`terapeutic trials,
`
`uld provide the
`containing the
`ndently of the
`
`1 can servelas a
`e is informed of
`
`:"ety of the drug.
`:upplemented by
`the sponsoring
`
`ire on which the
`.ssed.
`
`
`
`
`
`3f
`
`33
`:5»
`
`
`
`sted in man. An
`1e may find this
`Dd grounding in
`ing. Readers are
`
`' information.
`.2,1~ l
`
`
`
`- General description of drug
`Physical properties
`Chemical properties including pH of solution
`Solubility
`Formula
`
`- Pre-clinical section
`
`‘ Pharmacology
`Specific pharmacology and biochemistry: in vitro / in vivo
`General pharmacology
`Safety pharmaéology
`Metabolism and pharmacokinetics
`Toxicology
`Single dose studies
`Repeat dose studies, including maximal repeatable dose
`Mutagenicity: in vitro / in vivo
`Carcinogenicity or oncogenicity (if appropriate)
`Reproductive studies (it appropriate)
`
`Pharmaceutical section
`Purity
`Percent and type of impurity
`Formulation
`Vehicle
`In vitro dissolution
`
`Stability
`Shelf life
`Light and heat stability
`
`Clinical section
`
`' Clinical pharmacology (Phase 1)
`Safety
`Tolerability
`Pharmacokinetics
`
`Bioavailability
`Metabolism (including radio-labelled studies
`Dynamics (biological effect)
`Interactions (kinetic and dynamic)
`Special groups
`Clinical research (Phases 2 & 3) — if available
`Dose-ranging studies
`Placebo-controlled studies
`
`Active comparator studies
`Overall safety and tolerability
`
`19
`
`
`
`AstraZeneca Exhibit 2051 p. 5
`
`

`

`
`
`3 / WHAT DOES THE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG?
`
`Most new substances are either enzyme inhibitors, or recept-
`or antagonists or agonists. Biochemical experiments are con-
`ducted to demonstrate activity, potency and specificity. In vitro
`experiments are carried out on isolated' tissue preparations to
`show the potency, specificity, selectivity, duration of action and
`concentration-response relationships. The investigator needs to
`be familiar with a few terms which are which are defined at the
`end of this chapter.
`'
`
`In vivo
`
`pharmacology
`
`
`(i
`
`20
`
`species. It is important to appreciate some general peculiarities of different
`
`Experiments on whole animals to demonstrate drug efficacy are
`devised to mimic or ‘model’ the target disease in man. There are
`no truly accurate models of disease states in animals; at best,
`they can give confidence that a dynamic response can be
`demonstrated. The investigator should pay particular attention
`to:
`
`' Route of administration used in the studies.
`' Concentrations
`achieved
`at which
`dynamic
`occurred.
`
`responses
`
`' Duration of the response.
`- Evidence for rebound or tachyphylaxis.
`- Discrepancies in response in the same species when the drug
`is given by different routes. This may indicate poor bio-
`availability, or formation of an active metabolite.
`- Discrepancies in responsebetween species in similar models.
`This is important in helping to estimate the first dose in man.
`Some animal models can predict the effective dose in\ man
`quite accurately, especially if the drug under consideration is
`the second or third in the class. Many receptor agonists and
`antagonists behave quite differently from one species to
`another and even receptor binding data in a subprimate or
`primate species which shows homology with man,
`is no
`guarantee of a similar response.
`' The vehicle used and evidence of local irritancy.
`- The design of the key studies. It is a surprising fact that,
`whilst clinicians pay great attention to study design, numbers
`of subjects studied, blinding procedures, etc.
`, to ensure a
`reliable experiment, many pre-clinical experiments, even from
`reputable pharmacology departments often pay little heed to
`power statements, blinding and even measures of variability.
`Whilst
`there is an understandable need to use the fewest
`possible animals, the experiment should be convincing, if the
`potential drug is to be given to human beings.
`
`In vivo whole animal experiments may be done on a variety of
`
`explain. For
`dominated l:
`
`the parasyn
`Bronchocon
`
`testing anti
`histamine p1
`
`The specific
`monstration
`
`General ph
`which may <
`01' 01‘ enzymi
`
`-
`
`' The spec:
`receptort
`. The selec
`sub-types
`- The orde
`action of
`in differei
`
`In this insta
`centrations
`
`between targ
`
`This section
`conscious u:
`the cardiov
`animals. Tl
`determine a
`
`rate and de]
`usually perf
`differ from
`studied. Ho
`
`simple test
`interference
`observation:
`considerable
`
`behavioural
`
`A knowled
`animals are
`
`AstraZeneca Exhibit 2051 p. 6
`
`

`

`G?
`
`
`
`WHAT DOES THE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG? / 3
`
`of different models which the sponsoring company should
`explain. For example, the cardiovascular system in the dog is
`dominated by vagal tone and drugs acting on the sympathetic or
`the parasympathetic systems may behave differently in man.
`Bronchoconstriction in the guinea pig (a species often used for
`testing anti-asthma drugs)
`is histamine-dependent, whereas
`histamine plays little or no role in asthma in man.
`
`The specific pharmacology described above relates to the de-
`monstration of a potentially valuable dynamic response in man.
`General pharmacology describes other biological
`responses
`which may or may not be mediated through that specific recept-
`or or enzyme system. The investigator will need to determine:
`
`General
`
`pharmacology
`
`- The specificity of the desired response in relation to other
`receptor types.
`‘
`The selectivity of the desired response in relation to receptor
`sub-types.
`_
`The order of magnitude of the desired response for inter-
`action of the drug with the same sub-types of receptors, but
`in different tissues.
`
`In this instance, he will be looking for a rank ordering of con-
`centrations of effect, with the widest possible separation
`between target and other receptor sites.
`
`This section describes the effects of the drug on the behaviour of
`conscious unrestrained animals, usually the cat or dog and on
`the cardiovascular and respiratory systems in unconscious
`animals. These tests are performed by trained observers to
`determine alterations in behaviour, sleep patterns, respiratory
`rate and depth, heart rate, ECG and blood pressure. They are
`usually performed in few animals with a placebo control and
`differ from general pharmacology,
`in that
`fewer doses are
`studied. However, there is some overlap between the two. A
`simple test of
`liver metabolism is often conducted,
`e.g.
`interference with phenobarbitone-induced sleeping time. The
`observations of an experienced animal experimentalist can be of
`considerable help to the investigator, as they may give hints of
`behavioural effects which may occur in man.
`
`Safety
`pharmacology
`
`A knowledge of the metabolism and pharmacokinetics in
`animals are helpful to the pre-clinical scientist in several ways:
`
`Metabolism and
`
`pharmacokinetics
`
`
`
`
`
`)itors, or recept-
`iments are con-
`
`:cificity. In vitro
`preparations to
`on of action and
`
`itigator needs to
`re defined at the
`
`drug efficacy are
`1 man. There are
`
`inimals; at best,
`esponse can be
`ticular attention
`
`amic
`
`responses
`
`s when the drug
`licate poor bio-
`)lite.
`
`similar models.
`.rst dose in man.
`ve dose in man
`consideration is
`
`tor agonists and
`one species to
`a subprimate or
`'ith man,
`is no
`
`.cy.
`
`rising fact that,
`design, numbers
`3.
`, to ensure a
`
`nents, even from
`
`way little heed to
`es of variability.
`use the fewest
`onvincing, if the
`.
`
`rI
`
`: on a variety of
`em] peculiarities
`
`
`
`AstraZeneca Exhibit 2051 p. 7
`
`

`

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`3 / WHAT DOES THE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG?
`
`- Determining the bioavailability and hence likely organ
`exposure
`
`- Determining the plasma half-life, maximum concentration
`(Cmax) and time to peak concentration (Tmax)
`~ Measuring clearance
`-
`- Determining the route of metabolism (ize. liver, renal, lung,
`etc. ) and presence of metabolites
`° Predicting potential drug interactions in man
`
`These data are not necessarily predictive of their respective
`equivalents in man, and the investigator should be wary of
`direct extrapolation. Usually, this information is generated in
`two species (most often rat and dog, occasionally a primate) and
`is of most value when available in the species from which the
`dynamic data is also generated, so that pharmacokinetics and
`dynamics can be correlated.
`Predictability of metabolism in man often improves with a
`second or third generation drug in a close chemical series, but
`even here, there can be discrepancies between the two in man.
`Many sponsoring companies now undertake investigation of the
`routes of hepatic metabolism in isolated human microsomes or
`liver slices. With the, current state of knowledge, the objective is
`to determine whether the drug is metabolised by enzymes of the
`P-450 class and to predict and perhaps preclude the need for
`drug-drug interaction studies in man.
`Plasma concentration data invanimal models is also valuable
`
`in comparing with those achieved in toxicology experiments. It
`is by comparison of dose in mg/kg which produce wanted
`pharmacological effect with dose in mg/kg that produce toxic
`effects in the most sensitive species, that help to establish the
`starting doses in man. This information is more valuable if
`plasma concentration from pharmacological and toxicological
`experiments are also available.
`
`there are regulatory
`The investigator should be aware that
`requirements for certain toxicological studies to be performed
`prior to administration of a new molecular entity to man and
`that
`these
`requirements vary _ from country to country.
`Considerable progress has been made in harmonising these
`practices between the USA, Japan and the EU, but this is a
`changing field.
`Thus,
`the investigator must not only satisfy himself that
`sufficient
`toxicology has been conducted, but also that his
`
`Toxicology
`
`22
`
`
`
`
`
`lll
`
`l l ilrl ll ii 1
`
`Regulatory Authority has approved the trial application. The investigator mu
`
`to identify the
`that the requisit
`The toxicolo
`
`divided into the
`
`- Mutagenicity
`- General toxi(
`
`Carcinogenic
`- Reproductivr
`' Additional 0
`
`cology, anti;
`metabolites.
`
`The objective 0
`is to administer
`dose levels
`to
`
`' behaviour, gene
`haematological
`on individual
`
`1
`
`‘
`
`sponsoring corr
`of the drug to
`maximal repeat
`studies with thi
`
`together with a
`for the EU, US
`and type of do
`3.1—3.5).
`Single dose 5
`routes in 2 ma]
`
`the routes used
`
`Oral, the secont
`
`systemic expo:
`minimum of 11
`
`rodent species,
`one month tox
`
`. permissible.
`
`Up to seven
`in a rodent and
`
`in man requires
`countries and J1
`one month tox:
`studies.
`
`The investig
`quirements hav
`been informed
`
`AstraZeneca Exhibit 2051 p. 8
`
`

`

`WHAT DOES THE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG? / 3
`
`General toxicology
`
`investigator must, having read the toxicological section, be able
`to identify the potential human toxicity that could arise, and
`that the requisite monitoring is included.
`The toxicology part of the investigator’s brochure is usually
`divided into the following sections:
`' Mutagenicity or genetic toxicology.
`° General toxicology: single and repeat doses.
`- Carcinogenicity.
`' Reproductive toxicology.
`' Additional or specialist toxicology studies, e.g. juvenile toxi-
`cology, antigenicity testing and toxicity testing of human
`metabolites.
`
`~
`
`The objective of this part of the drug development programme
`is to administer single and repeated doses of the drug at various
`dose levels
`to cohorts of animals and observe effects
`in
`behaviour, general well being, major organ function, effects on
`haematological and biochemical markers and at autOpsy, effects
`on individual organs and tissues. The usual regimen that a
`sponsoring company follows is to give rapidly increasing doses
`of the drug to two species, usually rat and dog, establish the
`maximal repeatable dose and then conduct formal repeat dose
`studies with this as the top dose and two or three lower doses,
`together with a vehicle control group. Regulatory requirements
`for the EU, USA and Japan are quite consistent in the length
`and type of dosing before drug administration to man (Tables
`3.1—3.5).
`Single dose studies in man require toxicological testing by 2
`routes in 2 mammalian species, usually rat and mouse. One of
`the routes used must be the proposed clinical route, and if this is
`oral, the second route is usually the intravenous one to ensure
`systemic exposure.
`In addition,
`repeat dose studies of a
`minimum of 14 days are also required in a rodent and non
`rodent species, typically rat and dog. Japan is different, in that
`one month toxicology is required before exposure to man is
`permissible.
`Up to seven days treatment in man requires 28 days exposure
`in a rodent and non rodent species. Up to four weeks treatment
`in man requires three months toxicology in two species for EU
`countries and Japan; the USA is different in that it requires only
`one month toxicology for 28 days exposure for Phase I and II
`studies.
`these re-
`The investigator needs to reassure himself that
`quirements have been met and that the regulatory authority has
`been informed about them, as appropriate. What does he need
`
`23
`
`
`
`AstraZeneca Exhibit 2051 p. 9
`
`
`
`
`:1'i
`'
`
`ll
`
`
`
`G?
`
`ce
`
`likely organ
`
`m concentration
`
`ax)
`
`iver, renal, lung,
`
`1
`
`' their respective
`)uld be wary of
`1 is generated in
`ly a primate) and
`i from which the
`
`nacokinetics and
`
`improves with a
`:mical series, but
`the two in man.
`
`vestigation of the
`in microsomes or
`
`e, the objective is
`)y enzymes of the
`ude the need for
`
`is is also valuable
`
`gy experiments. It
`produce wanted
`at produce toxic
`3 to establish the
`more valuable if
`
`and toxicological
`
`re are regulatory
`to be performed
`ntity to man and
`itry to country.
`.armonising these
`EU, but this is a
`
`tisfy himself that
`1.1.1.1: glen that hjs
`
`. application. The
`
`

`

`
`
`7 ”we 7 a....7.......W1~.—.m5s..7j
`
`3 / WHAT DOES THE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG?
`
`Single dose toxicity requirements
`
`- Marketing requirements
`2 species (1 rodent,
`1 non rodent other
`
`than rabbit)a
`
`Clinical trial requirements
`Same as for marketingb
`
`Proposed
`
`"clinical
`
`"duration
`
`Table 3.1
`
`
`
` epeated dos<
`Reproduced with permission of Dr M. D. Scales.
`
`
`
`
`USA
`
`3 species (including
`1 non rodent)°
`
`Same as for marketing6
`
`2 mammalian species“|
`
`Same as for marketing?e
`
`a MHW: Guidelines for toxicity studies of drugs, 1989.
`b MHW: General guidelines for clinical evaluation of new drugs (draft 4),
`August 1988.
`C PMA: Guidelines for the assessment of drug and medical device safety
`in animals, February 1977.
`0‘ CPMP: Single dose toxicity, February 1987.
`e CPMP: Recommendations for the development of nonclinical testing
`strategies (draft 7), July 1990.
`
`Table 3.2 Repeated dose toxicity requirements in support of clinical
`studies
`
`Proposed
`duration of
`
`Minimum toxicology requirement
`
`1 day
`3 days
`7 days
`4 weeks
`
`30 days
`> 30 days
`> 1 month
`> 3 months
`
`[14 days]
`
`[28 days]
`
`[90 days]
`[180 days]
`
`2 weeks
`‘
`Phase HI: 4 weeks
`Phase ill: 13 weeks
`
`-
`
`Phase Hi: 13 weeks
`Phase III: 26 weeks
`
`6 months
`
`> 6 months
`
`12 months
`
`'
`
`in the absence of specific guidance on toxicology requirements in
`support of clinical trials in Japan,d the Japanese marketing
`requirementsa are utilized according to customary practice.
`5‘ MHW: Guidelines for toxicity studies of drugs, 1989.
`b PMA: Guidelines for the assessment of drug and medical device safety
`in animals, February 1977.
`c CPMP: Recommendations for the development of nonclinical testing
`strategies (draft 7), July 1990.
`d MHW: General guideline for clinical evaluation of new drugs (draft 4),
`August 1988.
`
`”’3 months
`
`
`,> 3 months
`
`(>"6 months
`
`a \MHW: Guidel
`b PMA: Guideli
`
`‘ in animals, Fe
`
`° CPMP: Repe:
`
`
`
`
`
`arcinogenicit
`
`
`
`
`PMA: Guideli
`in animals, Fe
`MHW: Guidel
`MHW: Gener:
`
`
`
`
`
`”August 1988.
`CPMP: Carcil
`
`’ CPMP: Reco
`
`strategies (dr.
`
`24
`
`AstraZeneca Exhibit 2051 p. 10
`
`
`
`

`

`
`
`
`
`WHAT DOES THE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG? / 3
`
`
`
`Repeated dose toxicity requirements in support of marketing
`
`
`Minimum toxicology requirement
`
`equirements
`-m
`marketingb
`
`
`
`
`
`marketingc
`
`
`
`marketing?e
`
`
`Table 3.3
`
`
`1 day
`
`3 days
`
`
`1 month
`
`
`7 days
`
`3 months
`
`4 weeks
`
`
`30 days
`
`> 30 days
`
`
`
`
`6 months
`
`> 1 month
`
`
`26 weeks
`
`3 months
`
`
`52 weeks or longer
`
`
`> 3 months
`
`
`as above
`
`> 6 months
`12 months
`
`
`
`
`
`a MHW: Guidelines for toxicity studies of drugs, 1989.
`b PMA: Guidelines for the assessment of drug and medical device safety
`
`
`in animals, February 1977.
`
`c CPMP: Repeated dose toxicity, October 1983.
`
`
`
`Table 3.4
`
`Only when there is cause
`for concern b
`
`
`
`Carcinogenicity
`
`
`
`g {DHX"(D5.". 3(Q q(D.QE. _‘CD3(D3H.U)
`Clinical trial requirements
`
`
`Recommended for most
`
`
`
`
`drugs a exceptios in prac-
`
`tice being drugs intended
`for short term use only
`
`
`
`
` [Recommended (but not
`When there is cause for
`always done) prior to
`concern or when long
`
`
`
`Phase ill for drugs
`term clinical use is
`
`
`
`according to market
`expectedb
`
`
`
`requirements criteriac
`
`
`
`[Recommended as pere
`When there is cause for
`
`marketing requirements a]
`concern or when long
`
`
`
`but not usually done prior
`term clinical use is
`
`
`
`to long term clinical studies
`expected d
`
`
`
`unless suspicions arise
`
`ety
`
`in animals, February 1977.
`
`
`b MHW: Guidelines for toxicity studies of drugs, 1989.
`c MHW: General guidelines for clinical evaluation of new drugs (draft 4),
`August 1988.
`
`
`d CPMP: Carcinogenic potential, October 1983.
`e CPMP: Recommendations for the development of nonclinlcal testing
`
`strategies (draft 7), July 1990.
`
`
`
`drugs (draft 4),
`
`
`
`al device safety
`
`
`
`
`
`
`
`inical testing
`
`of clinical
`
`
`
`iirements in
`eting
`ctice.
`
`
`
`
`
`
`
`
`ical device safety
`
`tclinical testing
`
`drugs (draft 4),
`
`
`
`25
`
`
`
`AstraZeneca Exhibit 2051 p. 11
`
`

`

`vw::w-‘wwym:—~~—r;v~=:-rwf-.-~v,"* w'xr'rw-r—w‘ r—x-wgm V‘T’fi.""7"~"v‘l Wt :v'i“""‘-‘"TV'ZT£T‘ «a
`
`3 / WHAT DOES THE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG?
`
`Table 3.5 Genetic toxicity
`
`Japan
`
`USA
`
`EU
`
`3 test packagea
`
`
`Clinical trial requirements
`[‘Fundamental part’ of test
`package prior to Phase I]b
`
`No specific
`recommendations
`
`No specific
`recommendations
`
`
`
` Marketing requirements
`
`
`
`
`3/4 test packagec
`[3/4 test package
`
`recommendedd but only
`Ames (and often micronu-
`cleus) test routinely done
`
`
`a MHW: Guidelines for toxicity studies of drugs, 1989.
`
`b MHW: General guidelines for clinical evaluation of new drugs (draft 4),
`
`
`August 1988.
`
`
`C CPMP: Testing of medicinal products for their mutagenic potential,
`
`
`February 1987.
`
`
`d CPMP: Recommendations for the development of non clinical testing
`
`
`strategies (draft 7), July 1990.
`
`
`in the results to satisfy himself that he can
`to look for
`administer the drug for the first time to a human being? The
`essential points in the single and repeat dose studies are:
`
`The maximum tolerated dose in the mere sensitive species.
`- The ‘no effect’ repeatable dose in the more sensitive species.
`- The findings in the concurrent controls, or historical controls.
`° The number of animals studied in each group and the
`survival rate, i.e. compare the number that start and finish
`the experiment. Sometimes, companies perform sequential
`autopsies at, say, 2, 4 and 12 weeks in a three month study
`and these findings at each point should be available.
`° The tissue exposure at the end of the dosing periods, i.e. the
`AUC’s and peak plasma concentration of parent and,
`if
`available, major active metabolites.
`
`Estimation of ‘safety and tolerability.’ for man based on well
`conducted and fully reported toxicology studies are notoriously
`difficult, but what the investigator is looking for is:
`
`' Evidence‘ of considerable ‘overage’ (in mg/kg) between the
`‘no effect’ level in the most sensitive species and the proposed
`starting and top doses in man. Account must be taken of the
`absorption, distribution, metabolism and excretion which
`may differ between toxicological species and man.
`
`
`
`26
`
`Evidence of
`
`
`
`. Should mi:
`
`investigatior
`
`have a ‘no i
`
`
`
`, dosing is ce:
`
`
`
`
`
`The carcinogez
`‘g‘enotoxicity ai
`,(SCales et a1.
`
`"duration of u:
`
`requirements. '
`
`. Test for gen
`Ames test).
`Test for cl
`
`
`
`vitro (for ex
`Test for get
`
`the mouse 1
`In vivo tes
`~ ‘micronuclet
`
`"
`
`
`
`he patient’s
`
`onducted in t
`
`The mutage
`or drugs und
`
`thorities in
`
`est with anr
`vxpo‘sure. In .
`
`Indamental
`1
`erformed.
`In
`
`cterial test,
`
`vivo test f0]
`
`The USA 1
`
`naddition, d1
`"reted to meat
`
`
`
`of drugs, '
`cept an Ame
`In summarj
`
`
`
`
`
`
`
`
`For first ac
`'ause for cor
`g’enicity studit
`
`ive toxico
`
`apan require:
`
`
`
`AstraZeneca Exhibit 2051 p. 12
`
`

`

`IG?
`
`
`
`WHAT DOES THE IINVESTIGATOR NEED TO KNOW ABOUT THE DRUG? / 3
`
`ial requirements
`
`
`
`
`ental part’ of test
`
`orior to Phase I]b
`
` ic
`
`ndations
`
`
`
`tackage
`.
`nded‘”l but only
`
`id often micronu-
`
`:t routinely done
`
`
`
`
`
`
`
`
`3w drugs (draft 4),
`
`Itagenic potential,
`
`ion clinical testing
`
`elf that he can
`
`[man being? The
`udies are:
`
`nsitive species.
`:ensitive species.
`istorical controls.
`
`group and the
`: start and finish
`
`rform sequential
`tree month study
`vailable.
`
`g periods, i.e. the
`f parent and,
`if
`
`in based on well
`
`:3 are notoriously
`)r is:
`
`/kg) between the
`and the proposed
`;t be taken of the
`
`excretion which
`i man.
`
`Evidence of adequate tissue exposure to the drug.
`Should minor
`fluctuations or
`even trends
`
`in certain
`
`investigational parameters occur, that these are dose related,
`have a ‘no effect’ level and show evidence of recoVery after
`
`dosing is ceased.
`
`The carcinogenic potential of drugs is assessed by short-term
`genotoxicity and long-term oncogenicity studies in two species
`(Scales et a1. 1992). Before marketing all drugs, regardless of
`duration of use require four genotoxicity tests to satisfy EU
`requirements. These tests are:
`
`Mutagenicity
`
`- Test for gene mutations in bacteria (for example the so-called
`Ames test).
`:
`Test for chromosomal aberrations in mammalian cells in
`
`vitro (for example human lymphocytes).
`- Test for gene mutations in eukaryotic systems (for example
`the mouse lymphoma assay).
`In vivo test for genetic damage (for example the rodent
`micronucleus test).
`
`'
`
`In addition, drugs to be used chronically, which is usually inter-
`preted to mean for over six month or intermittently throughout
`the patient’s
`life, also require oncogenicity studies
`to be
`conducted in two species, usually rat and mouse.
`The mutagenicity studies required by Regulatory Authorities
`for drugs under development are not as well defined. The UK
`authorities in their published guidelines recommend an Ames
`test with and without metabolic activation before clinical
`exposure. In Japan,
`it
`is less clear. The guidelines state ‘the
`fundamental part’ of the genotoxicity programme should be
`performed. In practice, sponsors interpret
`this to mean one
`bacterial test, e.g. Ames plus the rodent micronucleus test, as an
`in vivo test for clastogenicity.
`The USA has no written recommendations for genotoxicity
`tests of drugs, but in practice, the FDA expects them; Usually they
`accept an Ames and micronucleus test for Phase I clinical trials.
`In summary, the investigator who is asked to conduct a study
`on a new molecular entity should expect to see a negative Ames -
`and micronucleus test (i.e. one in vitro and one in vivo test).
`For first administration studies in man assuming there is no
`cause for concern there is no necessity to conduct carcino-
`genicity studies. There are no specific requirements for repro-
`ductive toxicology to study the drug in males for EU and USA;
`Japan requires an assessment of male fertility.
`
`27
`
`
`
`AstraZeneca Exhibit 2051 p. 13
`
`

`

`”FT-W5- ~~r..—~—mr—- msflwvwwwm—wnww—WW~~~W—~—— T7.” fifw‘j““1*"¥1“‘tf7:""“'f"“j ms.- _‘“1‘:'" .» w ., ”vi—‘73?
`
`3 / WHAT DOES THE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG?
`
`
`
`
`
`Local toxicity
`
`Pharmaceutics
`
`28
`
`is the in\
`
`'structions are
`
`
`
`Studies should be conducted to demonstrate lack of irritancy by
`the route of administration to be used in man.
`It is not infrequent, for local reactions to occur following
`intravenous or intra-arterial administration into small vessels
`e.g. rat tail veins and for this reason the dog is a better model
`for man. These problems are frequently not an issue when the
`drug is given in a large volume and into a bigger vessel in man.
`Investigators need to be fully reassured about the pre-clinical
`safety of a new molecular entity and to realise that if they have
`concerns, then it is likely their ethics review committee will also
`be concerned.
`It
`is preferable to obtain extra data and
`reassurance from the sponsor at this stage, rather than risk an
`ethics committee refusal.
`
`material con
`" sed1n the h
`
`
` ‘The amox
`bviously de
`
`
`
`Oral preparations of new molecular entities are administered as
`solutions, suspensions, capsules or tablets. There are many
`standard vehicles for drugs,
`the choice depending on the
`physico-chemical properties of the drug. The investigator needs
`to satisfy himself that the carriers are inert, and that solutions
`given intravenously do not precipitate out after administration.
`For double blind studies with oral preparations, it is important
`that
`the taste and texture of the placebo is as identical as
`possible to the active formulation.
`Pharmaceutical preparations sometimes have to be stored
`under strict condition, away from direct sunlight and at a
`certain temperature. Products also have a ‘shelf life’ since they
`may degrade over time and require re-analysing for activity and
`purity. The investigator should check on these items.
`The early Phase I and even Phase II trials are frequently
`conducted with experimental formulations which will not be
`marketed. Furthermore, the trial formulation may differ from
`that used in the toxicology studies and have a different