A GUIDE TO CLINICAL DRUG RESEARCH
`
`edited by
`
`ADAM COHEN
`Professorof Clinical Pharmacology,
`University of Leiden,
`Leiden, The Netherlands
`and
`Directorof the Centre for Human Drug Research,
`Leiden University Hospital,
`Leiden, The Netherlands
`
`and
`
`JOHN POSNER
`Clinical Pharmacologist
`Glaxo Wellcome PLC
`Beckenham, Kent, UK
`
`Sheppard Library
`Massachusetta@iiitege of Pharme
`ang
`ai
`eRe Toalth Soienoes
`
`179 Ld
`Avenue
`
`na
`
`R
`Kluwer Academic Publishers
`DORDRECHT/BOSTON/LONDON
`
`
`
` .
`
`AstraZeneca Exhibit 2051 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00905
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017-01912
`
`

`

`oo,
`
`1995
`
`95-8825
`
`Ref.
`| RM
`Library of Congress Cataloging-in-Publication Data
`1. J 301.27
`; De
`A guide to clinical drug research / edited by Adam CohenandJohn "7.7. 3.
`se
`oe _
`-685
`Posner
`cm.
`p.
`Coat
`1995
`Includes index.
`uo a
`ISBN 0-7923-3508-2 (HB : alk. paper)
`.
`1. Drugs--Research.
`1. Cohen, Adam.
`Il. Posner, John.
`[DNLM: 1, Clinical Trials--methods.
`2. Research Design. QV771 nel
`G946 1995]
`—
`RM301.27.G85
`615’ . 19--de20
`DNLM/DLC
`for Library of Congress
`
`
`
`ISBN 0-7923-3508-2
`i
`
`Published by Kluwer Academic Publishers,
`P.O. Box 17, 3300 AA Dordrecht, The Netherlands
`
`Sold anddistributed in the USA and Canada by
`Kiuwer Academic Publishers,
`101 Philip Drive, Norwell, MA 02061, USA
`
`In all other countries, sold and distributed by
`Kluwer Academic Publishers Group
`P.O. Box 322, 3300 AH Dordrecht, The Netheriands
`
`
`
`Printed on acid-free paper
`
`All Rights Reserved
`© 1995 Kluwer Academic Publishers
`No part of
`the material protected by this copyright notice may be reproduced or utilized in any
`form or by any means,electronic or mechanical, including photocopying, recording or by any information
`storage andretrieval system, without written permission from the copyright owner.
`
`Printed in the Netherlands
`
`AstraZeneca Exhibit 2051 p. 2
`
`

`

`iinetiaaoe
`Sagresit
`q
`
`3
`
`Whatdoesthe investigator need
`to know aboutthe drug?
`
`
`
`q
`
`i
`a
`
`
`
`| Aninvestigator may be asked to conduct a study with a new__Introduction
`
`4
`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 PhaseII or III, when there is already a considerable
`amountofclinical data available.
`on the
`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 phasetrials.
`Whenan investigator is approached by a sponsoring pharma-
`ceutical companyfor thefirst 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’sintentionswill help to put the study
`which the investigator
`is béing 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-centretrial, in which caseit is quite usual to have
`an investigator’s meeting, whencritical decisions about the drug
`— such as primary end points, interim analyses and the remit of
`data safety monitoring committees — are made.
`
`|
`4
`
`
`
`4
`
`|
`
`
`
`Drug developmentis traditionally divided into four phases:
`Phase I: Clinical pharmacology.
`Studies in healthy volunteers or patients, according to the
`class of drug andits safety, to determine:
`Pharmacodynamics (biological effects) where practicable,
`tolerability, safety, and efficacy, if in patients
`Pharmacokinetics: absorption, distribution, metabolism
`and excretion
`
`Phasesof drug
`development
`
`17
`
`
`
`AstraZeneca Exhibit 2051 p. 3
`
`

`

`
`
`
`
`cbtSassEancneanjconnecericeag
`
`Contents of Inv
`
`* General de
`Physical prc
`Chemicalpr
`Solubility
`Formula
`
`* Pre-clinical
`* Pharmac
`Specific 5
`General|
`Safety pr
`Metabolis
`* Toxicolo
`Single do
`Repeat d
`Mutageni
`Carcinog
`Reprodui
`
`Pharmacet
`Purity
`Percent anc
`Formulatior
`Vehicle
`In vitro diss:
`Stability
`Shelf life
`Light and hi
`
`Clinical se:
`* Clinical|
`Safety
`Tolerabili
`Pharmac
`Bioavaila
`Metaboli:
`Dynamic
`Interactic
`Special¢
`* Clinical
`Dose-rar
`Placebo-
`Active cc
`Overalls
`
`3 /WHAT DOES THE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG?
`
`PhaseIJ: 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 comparatortrials
`PhaseIV: Post-registration
`Marketing or user studies
`Expandclinical 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-druginteraction studies, may occurat 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 contentis 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 providea 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 mayfind this
`section rather daunting and unless he has a good grounding in
`pharmacology, manyof the terms will be confusing. Readers are
`directed to some of the standard texts for further information.
`
`18
`
`
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`AstraZeneca Exhibit 2051 p. 4
`
`

`

`G?
`
`cs: dose-ranging
`for efficacy and
`
`1 large numbers,
`Is
`
`efficacy; further
`ith other active
`
`ial approach to
`ractice. Phase I
`imme, but some
`2 studies, studies
`nal disease, and
`ous stages in the
`hases II and III
`attempt to save
`\erapeutic trials,
`
`uld provide the
`containing the
`odently of the
`| can serve as a
`e is informed of
`‘ety of the drug.
`‘upplemented by
`the sponsoring
`
`wre on which the
`ssed.
`
`for development
`sted in man. An
`1e may find this
`ad grounding in
`ing. Readers are
`‘information.
`
`
`
`
`
`
`
`
`
`
`
`Contents of Investigator’s brochure
`
`Box 3.1
`
`* 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 pharmacology
`Metabolism and pharmacokinetics
`Toxicology
`Single dose studies
`Repeat dosestudies, including maximal repeatable dose
`Mutagenicity:in vitro / in vivo
`Carcinogenicity or oncogenicity (if appropriate)
`Reproductive studies (if appropriate)
`
` WHAT DOESTHE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG? /3
`
`Pharmaceutical section
`Purity
`Percent and type of impurity
`Formulation
`Vehicle
`In vitro dissolution
`Stability
`Shelf life
`Light and heatstability
`
`Clinical section
`* Clinical pharmacology (Phase1)
`Safety
`Tolerability
`Pharmacokinetics
`Bioavailability
`Metabolism (including radio-labelled studies
`Dynamics(biologicaleffect)
`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
`
`

`

`species. It is important to appreciate some general peculiarities of different
`
`
`
`
`
`In vivo whole animal experiments may be done onavariety of
`A knowled
`animals are
`
`20
`
`AstraZeneca Exhibit 2051 p. 6
`
`3/ WHAT DOES THE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG?
`
`In vivo
`pharmacology
`
`Most new substancesare either enzymeinhibitors, or recept-
`or antagonists or agonists. Biochemical experiments are con-
`ducted to demonstrate activity, potency andspecificity. 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.
`
`responses
`
`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.
`* 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 response between 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 considerationis
`the second orthird 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 evidenceoflocalirritancy.
`* 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 measuresofvariability.
`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.
`
`explain. Fos
`dominated t
`the parasyn
`Bronchocon
`testing anti
`histaminepl
`
`The specific
`monstration
`General ph
`which may¢
`or or enzym:
`
`* The spec:
`receptor|
`* The selec
`sub-types
`: The orde
`action of
`in differe:
`
`In this insta
`centrations
`betweentar;
`
`This section
`conscious u:
`the cardiov
`animals. Tt
`determine a
`rate and de
`usually perf
`differ from
`studied. Ho
`simple test
`interference
`observation:
`considerable
`behavioural
`
`

`

`G?
`
`ditors, or recept-
`iments are con-
`scificity. In vitro
`preparations to
`on of action and
`‘tigator needs to
`re defined at the
`
`drug efficacy are
`1man. There are
`iunimals; at best,
`esponse can be
`ticular attention
`
`amic
`
`responses
`
`s when the drug
`licate poor bio-
`lite.
`similar models.
`Ist 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
`2.
`, to ensure a
`ients, even from
`ray little heed to
`es of variability.
`use the fewest
`onvincing, if the
`
`: on a Variety of
`sral peculiarities
`
`
`
`
`
`
`
`WHAT DOESTHE INVESTIGATOR NEED TO KNOW ABOUTTHE 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
`histamineplays 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 receptorsites.
`
`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
`
`21
`
`
`
`AstraZeneca Exhibit 2051 p. 7
`
`

`

`Regulatory Authority has approved the trial application. The investigator mu
`
`Sanetaaiaeeeereee|
`
`3 / WHAT DOES THE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG?
`
`
`
`
`
`Toxicology
`
`22
`
`- 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 (i:e. 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.
`Manysponsoring companies now undertakeinvestigation of the
`routes of hepatic metabolism in isolated human microsomes or
`liver slices. With thecurrent state of knowledge, the objective is
`to determine whether the drug is metabolised by enzymesof the
`P-450 class and to predict and perhaps preclude the need for
`drug-drug interaction studies in man.
`Plasma concentration data in animal modelsis 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
`changingfield.
`Thus,
`the investigator must not only satisfy himself that
`sufficient
`toxicology has been conducted, but also that his
`
`to identify the
`that the requisit
`The toxicolo
`divided into the
`- Mutagenicity
`General toxic
`Carcinogenic
`* Reproductive
`* Additional o
`cology, anti;
`metabolites.
`
`The objective o
`is to administer
`dose levels
`to
`' behaviour, gene
`haematological
`«
`on individual
`sponsoring com
`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:
`routes in 2 mai
`the routes used
`oral, the seconc
`systemic expos
`minimum of 1:
`rodent species,
`one month tox
`’ permissible.
`Up to seven
`in a rodent and
`in man requires
`countries and J.
`one month tox:
`studies.
`The investig
`quirements hav
`been informed
`
`AstraZeneca Exhibit 2051 p. 8
`
`

`

`WHAT DOES THE INVESTIGATOR NEED TO KNOW ABOUTTHE 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 proposedclinical route, andifthisis
`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.
`Upto 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 monthstoxicology in two species for EU
`countries and Japan;the USAis different in thatit 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 heen met and that the regulatory authority has
`been informed about them, as appropriate. What does he need
`
`23
`
`
`
`AstraZeneca Exhibit 2051 p. 9
`
`
`
`
`
`
`G?
`
`ce
`
`likely organ
`
`m concentration
`ax)
`
`iver, renal, lung,
`
`1 ‘
`
`their respective
`yuld be wary of
`1 is generated in
`ly a primate) and
`; from which the
`nacokinetics and
`
`improves with a
`smical series, but
`the two in man.
`vestigation of the
`in microsomesor
`e, the objective is
`xy enzymes of the
`ude the need for
`
`is is also valuable
`ty experiments. It
`produce wanted
`vat produce toxic
`) to establish the
`more valuable if
`and toxicological
`
`re are regulatory
`to be performed
`ntity to man and
`‘try
`to country.
`armonising these
`EU, but this is a
`
`tisfy himself that
`ant alea tliat his
`. application. The
`
`

`

`
`
`ace eaeeae
`
`3/ WHAT DOES THE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG?
`
`Table 3.1
`
`
`
`Single dose toxicity requirements
`P| Marketing requirements
`2 species (1 rodent,
`1 non rodent other
`than rabbit)*
`
`Clinicaltrial requirements
`Sameasfor marketing?
`:
`
`
`Proposed
`“clinical
`
`“duration
`
`USA
`
`3 species(including
`1 non rodent)°
`
`Sameas for marketing®
`
`® MHW:Guidelinesfortoxicity studies of drugs, 1989.
`5 MHW:Generalguidelinesfor clinical evaluation of new drugs (draft 4),
`August 1988.
`° PMA:Guidelines for the assessment of drug and medical device safety
`in animals, February 1977.
`4 CPMP:Single dose toxicity, February 1987.
`© CPMP: Recommendationsfor the developmentof nonclinical testing
`strategies (draft 7), July 1990.
`Reproduced with permission of Dr M. D. Scales.
`
`
`
`
`>3 months
`>6 months
`
`a.MHW:Guidel
`5 PMA:Guideli
`‘in animals, Fe
`
`© CPMP: Repe:
`
`
`
`Table 3.2 Repeated dosetoxicity requirements in support of clinical
`studies
`
`Proposed
`duration of
`
`Minimum toxicology requirement
`
`1 day
`2 weeks
`3 days
`[28 days]
`.
`1 month
`7 days
`
`4 weeks 3months|Phase I-II: 4 weeks
`PhaseIll: 13 weeks
`.
`
`[14 days]
`
`[90 days]
`[180 days]
`
`30 days
`> 30 days
`> 1 month
`> 3 months
`
`6 months
`
`PhaseI-Il: 13 weeks
`PhaseIll: 26 weeks
`
`
`
` epeated dose
`
`
`
` arcinogenicit
`
`
`> 6 months
`
`12 months
`
`*
`
`In the absenceof specific guidance on toxicology requirementsin
`support ofclinicaltrials in Japan,? the Japanese marketing
`requirements?are utilized according to customary practice.
`8 MHW:Guidelinesfor toxicity studies of drugs, 1989.
`> PMA:Guidelines for the assessmentof drug and medical device safety
`in animals, February 1977.
`° CPMP: Recommendations for the development of nonclinical testing
`strategies (draft 7), July 1990.
`4 MHW:Generalguideline for clinical evaluation of new drugs (draft 4),
`August 1988.
`
`24
`
`
`
`
`
`PMA: Guideli
`in animals, Fe
`MHW:Guidel
`MHW:Gener:
`_August 1988,
`CPMP: Carcil
`‘CPMP: Reco
`
`“Strategies (dr.
`
`AstraZeneca Exhibit 2051 p. 10
`
`

`

`
`
`
`
`equirements
`
`marketing?
`
`
`marketing®
`
`
`marketing?®
`
`
`
`drugs (draft 4),
`
`
`
`inical testing
`
`
`al device safety
`
`of clinical
`
`
`[14 days]
`
`[28 days]
`
`
`
`[90 days]
`
`[180 days]
`
`
`ical device safety
`
`rclinical testing
`
`
`
`
`
`drugs (draft 4),
`
`
`
`
`tirements in
`sting
`atice.
`
`
`
`WHAT DOES THE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG? /3
`
`Table 3.3
`
`Repeated dosetoxicity requirements in support of marketing
`
`
`Minimum toxicology requirement
`
`
`
`Proposed
`
`clinical
`
`
`
`duration
`
`
`
`2 weeks
`{ day
`
`
`
`
`2 weeks
`
`3 days
`
`
`4 weeks
`1 month
`
`
`7 days
`
`
`
`13 weeks
`3 months
`4 weeks
` 3 months
`
`
`
`30 days
`6 months
`
`
`> 30 days
`
`
`6 months
`> 1 month
`
`
`
`26 weeks
`
`
`3 months
`
`52 weeksor longer
`
`
`> 3 months
`
`
`
`as above
`12 months
`as above
`
`
`> 6 months
`
`
`@ MHW:Guidelinesfortoxicity studies of drugs, 1989.
`b PMA:Guidelines for the assessment of drug and medical device safety
`
`in animals, February 1977.
`© CPMP: Repeated dose toxicity, October 1983.
`
`
`Table 3.4
`
`
`
`Carcinogenicity
`
`
`
`Marketing requirements
`Clinicaltrial requirements
`
`
`
`Recommendedfor most
`Only whenthere is cause
`
`
`drugs? exceptiosin prac-
`for concern”
`
`
`
`tice being drugs intended
`for short term use only
`
`
`
`
`
`[Recommended(but not
`Whenthere is causefor
`always done) prior to
`concern or when long
`
`
`
`PhaseIll for drugs
`term clinical useis
`
`
`
`according to market
`expected”
`
`
`
`requirementscriteria®
`
`
`
`[Recommended as per®
`Whenthere is cause for
`
`marketing requirements *]
`concern or when long
`
`
`
`but not usually doneprior
`term clinical use is
`
`
`
`to long term clinical studies
`expected
`
`
`
`unless suspicions arise
`
` ety
`
`
`
`in animals, February 1977.
`b MHW: Guidelinesfortoxicity studies of drugs, 1989.
`© MHW: General guidelinesforclinical evaluation of new drugs(draft 4),
`
`August 1988.
`
`
`d CPMP:Carcinogenic potential, October 1983.
`@ CPMP: Recommendations for the development of nonclinical testing
`
`strategies (draft 7), July 1990.
`
`
`
`
`
`
`25
`
`
`
`AstraZeneca Exhibit 2051 p. 11
`
`

`

`De reneeaaE
`
`TalGregPETTITTeKteereeTaareREEPEEoe SEE
`
`aeeer
`
`3 / WHAT DOESTHE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG?
`
`Evidence of
`Should mi
` Clinical trial requirements
`
`investigatio1
`have a “no:
`Japan|3 test package?
`{‘Fundamentalpart’ of test
`- dosing is cei
`package prior to Phase |]°
`
`Table 3.5 Genetic toxicity
`
`Marketing requiremenis
`
`
`
`
`
`
`&@ MHW:Guidelinesfor toxicity studies of drugs, 1989.
`> MHW:General guidelines for clinical evaluation of new drugs (draft 4),
`August1988.
`° CPMP:Testing of medicinal products for their mutagenic potential,
`February 1987.
`
`
`4 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 moresensitive 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 numberthat 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.
`
`AstraZeneca Exhibit 2051 p. 12
`
`
`
`26
`
`
`
`
`USA
`
`EU
`
`No specific
`recommendations
`
`No specific
`
`recommendations [3/4 test package
`3/4 test package°®
`
`recommended? butonly
`Ames(and often micronu-
`cleus) test routinely done
`
`
`
`
`
`
`
`The carcinoge:
`‘genotoxicity a)
`(Scales et al.
`
`duration of u:
`
`fequirements.'
`
`
`- Test for gen
`Amestest).
`
`Test for cl
`
`*-vitro (for ex
`‘Test for ge
`
`the mouse |
`In vivo tes
`micronuclei
`
`
`
`
`
`
`naddition, di
`yreted to meal
`he patient’s
`‘onducted in t
`The mutage
`
`
`In
`érformed.
`
`cterial test,
`Vivo test fo:
`
`The USA ]
`
`of drugs, |
`
`cept an Ame
`In summar’
`a new mok
`
`md micronuc!
`Forfirst ac
`‘ause for cor
`genicity studic
`
`apan require:
`
`
`
`

`

`
`
`IG?
`
`WHATDOES THE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG? /3
`
`ial requiremenis
`
`
`
`ental part’ of test
`orior to Phase1]
`
`ic
`ndations
`
`
`
`vackage
`nded® but only
`
`id often micronu-
`
`it routinely done
`
`
`2w drugs (draft 4),
`
`Itagenic potential,
`
`ion clinical testing
`
`
`
`elf that he can
`man being? The
`udies are:
`
`nsitive species.
`iensitive species.
`istorical controls.
`group and the
`: start and finish
`rform sequential
`iree month study
`vailable.
`z periods, i.e. the
`f parent and,
`if
`
`in based on well
`'§ are notoriously
`yr Is:
`
`‘kg) between the
`and the proposed
`3t be taken of the
`excretion which
`| man.
`
`Mutagenicity
`
`Evidence of adequate tissue exposure to the drug.
`in certain
`Should minor
`fluctuations or
`even trends
`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 al. 1992). Before marketing all drugs, regardless of
`duration of use require four genotoxicity tests to satisfy EU
`requirements. Thesetests are:
`
`- Test for gene mutations in bacteria (for example the so-called
`Amestest). »
`Test for chromosomal aberrations in mammalian cells in
`vitro (for example human lymphocytes).
`- Test for gene mutations in eukaryotic systems (for example
`the mouse lymphomaassay).
`In vivo test for genetic damage (for example the rodent
`micronucleustest).
`
`:
`
`In addition, drugs to be used chronically, which is usually inter-
`preted to mean for over six month orintermittently 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 micronucleustest, 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 Amesand micronucleustest for PhaseI clinicaltrials.
`In summary, the investigator who is asked to conduct a study
`on a new molecular entity should expect to see a negative Ames -
`and micronucleustest (i.e. one in vitro and onein vivotest).
`Forfirst 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 malefertility.
`
`27
`
`
`
`AstraZeneca Exhibit 2051 p. 13
`
`

`

`
`
`:
`
`i
`:
`
`|
`
`
`
`3 / WHAT DOESTHE INVESTIGATOR NEED TO KNOW ABOUT THE DRUG?
`
`Local toxicity
`
`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
`drugis given in a large volume andinto a bigger vessel in man.
`Investigators need to be fully reassured about thepre-clinical
`safety of a new molecular entity andto realise that if they have
`concerns, thenit is likely their ethics review committee will also
`be concerned.
`It
`is preferable to obtain extra data and
`reassurance from the sponsorat this stage, rather than risk an
`ethics committee refusal.
`
`
`it: is the inv
`
`-gtructions aré
`
`
`
`Pharmaceutics 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 ‘shelflife’ 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 bio-
`availability. This could, theoretically, result in a different tissue
`exposure in man than in animals, which could render the
`pharmacology and toxicology studies unreliable, independently
`of any inherent differences in drug action between animals and
`man. The investigator needs to be alert to this possibility. It is
`unusual for a sponsoring drug company to repeat any of the
`pre-clinical studies with a new formulation given only to man,
`but the two formulations should at least show similar in vitro
`dissolution characteristics.
`Some new substances for example some intravenous cephalo-
`sporins, have to be prepared immediately before administration.
`
`Usually these preparat