Lawrence M. Friedman Curt D. Furberg
`David L. DeMets
`
`Fundament~.ls of
`clinical Trials
`Third Edition
`
`~1
`
`~ ;S~ ~ . . -
`•
`.. ' ..
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1095-0001
`
`

`

`Curt D. Furberg
`Department of Public Health Services
`Wake Forest University
`Bowman Gray School of Medicine
`Winston-Salem, NC 27109
`USA
`
`Lawrence M. Friedman
`Division of Epidemiology and
`Clinical Applications
`National Heart, Lung, and
`Blood Institute
`National Institute of Health
`Bethesda, MD 20802
`USA
`
`David L. DeMets
`Department of Biostatistics and
`Medical Informatics
`University of Wisconsin
`Madison, WI 53792
`USA
`
`Library of Congress Cataloging-in-Publication Data
`Friedman, Lawrence M., 1942—
`Fundamentals of clinical trials /Lawrence M. Friedman, Curt D.
`Furberg, David L. DeMets. — 3rd ed.
`p.
`cnn.
`Includes bibliographical references and index.
`ISBN 0-387-98586-7 (pbk.: alk. paper)
`1. Clinical trials. I. Furberg, Curt. IT. DeMets, David L.,
`1944—
`III. Title.
`[DNLM: 1. Clinical Trials. 2. Research Design. W 20.SF911f
`1998]
`R853.CSSF75 1998
`615.5'072—dc21
`
`98-26138
`
`This is a reprint of an edition published by Mosby.
`
`ISBN 0-387-98586-7
`
`Printed on acid-free paper.
`
`O 1998 Springer-Verlag New York, Inc.
`All rights reserved. This work may not be translated or copied in whole or in part without the
`written permission of the publisher (Springer-Verlag New York, Inc., 175 Fifth Avenue, New
`York, NY 10010, USA), except for brief excerpts in connection with reviews or scholarly
`analysis. Use in connection with any form of information storage and retrieval, electronic
`adaptation, computer software, or by similar or dissimilar methodology now know or hereafter
`developed is forbidden.
`The use in this publication of trade names, trademarks, service marks and similar terms, even if
`the are not identified as such, is not to be taken as an expression of opinion as to whether or not
`they are subject to proprietary rights.
`
`Printed in the United States of America. (EB)
`
`15 14 13 12 11
`
`Springer-Verlag is a part of Springer Science+Business Media
`
`springeronline.com
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1095-0002
`
`

`

`36
`37
`40
`41
`42
`
`45
`
`45
`45
`47
`49
`~50
`~50
`~54
`~55
`
`~57
`
`C~iAPT.ER
`
`Introduction to C ' 'cal Trials
`
`The evolution of the clinical trial dates from the eighteenth century.10,Ss Lind, in
`his classical study on board the Salisbury, evaluated six treatments for scurvy in 12
`patients. One of the two who were given oranges and lemons recovered quickly and
`was fit for duty after 6 days. The second was the best recovered of the others and
`was assigned the role of nurse to the remaining 10 patients. Several other compara-
`five studies were also conducted in the eighteenth and nineteenth centuries. 'The
`comparison groups comprised literature controls, other historical controls, and con-
`current controls.s5
`The concept of randomization was introduced by Fisher and applied in agricul-
`tural research in 1926.$ The first clinical trial that used a form of random assignment
`of subjects to study groups was reported in 1931 by Amberson et al.z After careful
`matching of 24 patients with pulmonary tuberculosis into comparable groups of 12
`each, a flip of a coin determined which group received sanocrysin, a gold com-
`pound commonly used at that time. The British Medical Research Council trial of
`streptomycin in patients with tuberculosis, reported in 1948, was the first to use
`random numbers in the allocation to experimental and control groups.42, 5$
`The principle of blindness was also introduced in the trial by Amberson et a1.2
`The patients were not aware of whether they received intravenous injections of
`sanocrysin or distilled water. In a trial of cold vaccines in 1938, Diehl et x1.26 referred
`to the saline solution given to the subjects in the control group as a placebo.
`It is only in the past few decades that the clinical trial has emerged as the pre-
`ferred method in the evaluation of medical interventions. Techniques of implemen-
`ta,tion and special methods of analysis have been developed during this period.
`Many of the principles have their origins in work by Hill.z',4~,4',4$
`Because the authors of this book have all spent formative years at the National
`Institutes of Health (l~I~, it is also pertinent to cite a series of papers that reviews
`the history of clinical trials development at the NIH.*
`The purpose of this chapter is to define clinical trials; review the need for them;
`and discuss timing, phasing, and ethics of clinical trials.
`
`*References 13, 36, 40, 43, 66
`
`1
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1095-0003
`
`

`

`2 Fundamentals of Clinical Trials
`
`FUNDAMENTAL POINT'
`A properly planned and executed clinical trial is a powerful experimental
`technique for assessing the effectiveness of an intervention.
`
`WHAT IS A CLINICAL 'TRIA.L?
`
`A clinical trial is defined as a prospective study comparing the effect and value
`of interventions) against a control in human beings. Note that a clinical trial is
`prospective, rather than retrospective. Study participants must be followed forward
`in time. They need not all be followed from an identical calendar date. In fact, this
`will occur only rarely. Each participant, however, must be followed from a well-
`defined point, which becomes time zero or baseline for the study. This contrasts
`with acase-control study, a type of retrospective study in which participants are
`selected on the basis of presence or absence of an event or condition of interest. By
`definition, such a study is not a clinical trial. People can also be identified from hos-
`pital records or other data sources and subsequent records can be assessed for evi-
`dente of new events. This is not considered to be a clinical trial since the partici-
`pants are not directly observed from the moment of initiation of the study and at
`least some of the follow-up data are retrospective.
`A clinical trial must employ one or more intervention techniques. These may be
`"prophylactic, diagnostic or therapeutic agents, devices, regimens, procedures, etc. "62
`Intervention techniques should be applied to participants in a standard fashion in an
`effort to change some aspect of the participants. Follow-up of people over time
`without active intervention may measure the natural history of a disease process,
`but it does not constitute' a clinical trial. Without active intervention the study is
`observational because ~o experiment is being performed.
`A clinical trial must contain a control group against which the intervention
`group is compared. At baseline, the control group must be sufficiently similar in rel-
`evant respects to the intervention group so that difFerences in outcome may reason-
`ably be attributed to the action of the intervention. Methods for obtaining an appro-
`priate control group are discussed in Chapter 4. Most often a new intervention is
`compared with best current standard therapy. If no such standard exists, the people
`iti the intervention group may be compared with people who are on no active inter-
`vention. "1Vo active intervention" means that_ the participant may receive either a
`placebo or no intervention at all. Obviously, participants in all groups may be on a
`variety of additional therapies and regunens; so-called concomitant interventions,
`which may be either self-administered or prescribed by others (e.g., private physi-
`cians).
`For purposes of this book, only studies on human beings will be considered as
`clinical trials. Certainly, animals (or plants) may be studied using similar techniques.
`
`'
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1095-0004
`
`

`

`Introduction to Clinical Trials 3
`
`However, this book focuses on trials in people, and each clinical trial must therefore
`incorporate participant safety considerations, into its basic design. Equally important
`is the need for, and responsibility of, the investigator to fully inform potential partic-
`ipants about the trials.60~ 63
`Unlike animal studies, in clinical trials the investigator cannot dictate what an
`individual participant should do. He can only strongly encourage participants to
`avoid certain medications or procedures that might interfere with the trial. Since it
`may be impossible to have "pure" intervention and control groups, an investigator
`may not be able to compare interventions, but only intervention strategies. Strategies
`refer to attempts at getting all participants to comply to the best of their ability with
`their originally assigned intervention. When planning a trial, the investigator should
`recognize the difficulties inherent in studies with human subjects and attempt to esti-
`mate the magnitude of participants' failure to comply strictly with the protocol.
`As discussed in Chapters 5 and 6, the ideal clinical trial is one that is randomized
`and double-blinded. Deviation from this standard has potential drawbacks that will
`be discussed in the relevant chapters. In some clinical trials compromise is unavoid-
`able, but often deficiencies can be prevented by adhering to fundamental features of
`design, conduct, and analysis.
`Several people distinguish between demonstrating efficacy of a.n intervention
`and effectiveness of an intervention. The former refers to what the intervention
`accomplishes in an ideal setting; the latter to what it accomplishes in actual prac-
`tice, taking into account incomplete compliance to protocol. As discussed. in Chap-
`ter 16 and elsewhere, our preferred analytic approach emphasizes the importance
`of the concept of effectiveness. Only in special circumstances, will the focus of the
`clinical trial described in this book be on efficacy.
`
`CLINICAL TRYAL I,HA~SES
`
`While we focus on the design and analysis of randomized trials comparing the
`effectiveness of one or more interventions with a control, several steps or phases of
`clinical research must occur before this comparison can be implemented.
`
`Phase I studies
`.Although usefiil preclinical information may be obtained from in vitro studies or
`animal models, early data must be obtained in humans. T'he first step, or phase in
`developing a drug or a biologic is to understand how well it can be tolerated in a
`small number of individuals..Although it does not meet our definition of a_ciinical
`trial, this phase is commonly called a phase I trial. People who participate in phase I
`trials have typically already tried and failed to improve on the existing standarel
`interventions. Most phase I designs are relatively simple. One of the first steps in
`
`~imental
`
`Zd value
`1 trial is
`forward
`'act, this
`~ a well-
`:ontrasts
`ants are
`:rest. By
`~om hog-
`. for evi-
`partici-
`y and at
`
`may be
`s, etc. "62
`on in an
`rer time
`process,
`study is
`
`vention
`~r in rel-
`reason-
`1 appro-
`:ration is
`people
`ve inter-
`either a
`be on a
`entions,
`e physi-
`
`iered as
`uuques.
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1095-0005
`
`

`

`~I,
`
`~~
`
`4 Fundamentals of Clinical Trials
`
`evaluating drugs is to estimate how large a dose can. be given before unacceptable
`toxicity is experienced by patients.'" This dose i~ usually referred to as the maximally
`tolerated dose, or MT'D. Much of the literature has discussed how to extrapolate ani-
`anal model data to the starting dose in humans74 or how to step-up the dose levels to
`achieve the MTD. ~Ss Storer and DeMets describe,83 there is a sparsity of phase I
`design literature; somewhat surprising since the goals are not dissimilar from those
`of bioassay methods for which a large literature exists.
`In estimating the MTD in cancer drug development, the investigator usually
`starts with a very low dose and escalates the dose until a prespecified level of toxic-
`ity in patients is obtained. Typically, a small number of patient, usually three, are
`entered sequentially at a particular dose. If no specified level of to~city is observed,
`the next predefined higher dose level is used. If unacceptable to~city is observed in
`of the three patients, an additional number of patients, usually three, are treated
`~y
`at the same dose. If no further toxicity is seen, the dose is escalated to the next
`higher dose. If additional unacceptable toxicity is observed, then the dose escalation
`is terminated and that dose, or perhaps the previous dose, is declared to be the
`1VITD. This particular design assumes that the MTD occurs when approximately one
`third of the patients experience unacceptable toxicity. Variations of this design
`exist, but most are similar.
`Some investigators`~~65,8z have recently proposed more sophisticated designs that
`specify a sampling scheme for dose escalation and a statistical model for the estimate
`of the MTD and its standard error. The sampling scheme must be conservative in
`dose escalation so as not to overshoot the MTD by very much, but at the same time
`be efficient in the number of patients studied. Many of the proposed schemes use a
`step-up/step-d.own approach; the simplest being to step-up with a single patient until
`to~city is first observed. Further increase or decrease in the dose level depends on
`whether or not to~city is observed at a given dose. Dose escalation stops when the
`process seems to have converged around a particular dose level. Once the data are
`generated, a dose response model is fit to the data and estimates of the MTD can be
`obtained as a function of the specified probability of a toxic response.
`
`Phase II studies
`Once the MTD is established, the next goal is to evaluate whether the drug has
`any biologic activity or effect and to estimate the rate of adverse events. If the
`design of the phase I trial has not been adequate, the investigator may evaluate the
`drug for activity at too low or high a dose. Thus, the phase II design depends on the
`quality and adequacy of the phase I study. The results of the phase II trial will; in
`turn, be used to design the comparative phase ICI trial. The statistical literature for
`phase II trials is also quite limited.**
`
`*References 3> 16, 38, 82, 83, 96
`**References 23, 29, 35, 37, 45, 78, 94
`
`of
`toy
`m`
`pa
`t~
`20
`cal
`res
`hay
`5
`~d~
`fro
`pat
`the
`gar
`
`asp
`effi
`ably
`Ust
`wh
`cor
`the
`
`~~'
`
`assn
`pray
`is s
`mai
`stuc
`
`P~~'
`pray
`nec
`ma3
`s~
`sary
`pha
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1095-0006
`
`

`

`Introduction to Clinical Trials 5
`
`One of the most commonly used phase II designs in cancer is based on the work
`of Gehan,35 which is a version of a two-stage design. In the first stage the investiga-
`for attempts to -rule out drugs that have no or little biologic activity. For example, he
`may specify that a drug must have some minimal level of activity, say,' in 20% of
`patients. If the estimated activity level is less than 20%, he chooses not to consider
`this drug further, at least not at that MTD. If the estimated activity level exceeds
`20%, he will add more patients to get a better estimate of the response rate. A typi-
`cal study for ruling out a 20% or lower response rate enters 14 patients. If no
`response is observed in the first 14 patients, the drug is considered not likely to
`have a 20% or higher activaty level. That is, failure 14 times in a row would happen
`S% or less if the drug were truly effective 20% or more of the time. T'he number of
`additional patients added depends on the degree of precision desired, but ranges
`from 10 to 20. Thus a typical cancer phase II trial might include fewer than 30
`patients to estimate the response rate. As is discussed in Chapter 7, the precision of
`the estunated response rate is important in the design of the comparative trial. In
`general, phase II trials are smaller than they ought to be.
`OthersZ9,5Z,8z have proposed phase II designs that .have more stages or a sequential
`aspect. Some73~94 have considered hybrids of phases II and III designs to enhance
`efficiency. While these designs have desirable statistical properties, the most vul~er-
`able aspect of phase II, as well as phase I studies, is the type of patients enrolled.
`Usually, patients entered in phase II trials have more exclusion criteria than those
`who will be considered in the phase III comparative trials. Furthermore, the out
`come in the phase II trial (e.g., tumor response) may be different from that used in
`the definitive comparative trial (e.g., survival).
`
`Phase II~//IV trials
`
`The phase III trial is the clinical trial defined above. It is generally designed to
`assess the effectiveness of the new intervention and thereby, its role in clinical
`practice. As noted, the intervention need not be a drug, but the term phase III trial
`is stifll commonly applied. The focus of this text is on phase III trials. However,
`many design assumptions for phase III trials depend on a series of phase I and II
`studies.
`Phase III trials of chronic conditions or diseases often have a short follow-up
`period for evaluation, relative to the time the intervention might be used in clinical
`practice. In addition, they focus on effectiveness, but knowledge of safety is also
`necessary to evaluate fully the proper role of an intervention. A procedure or device
`may fail after a few years and have adverse sequelae for the patient. Thus long-term
`surveillance of an intervention believed to be effective in phase III trials is neces-
`sary. Such long-term studies, which do not involve control groups, are referred to as
`phase N trials.
`
`(e
`Cy
`d-
`o
`I
`.e
`
`y
`
`~e
`i,
`n
`d
`:t
`n
`e
`e
`n
`
`t
`,,
`1
`
`~
`
`11
`
`
`
`i
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1095-0007
`
`

`

`1
`
`6 Fundamentals of Clinical Trials
`
`A, clinical trial is the clearest method of determining whether an intervention has
`the postulated effect. Only seldom is a disease or condition so completely chara.cter-
`ized that people fully understand its natural history aid can say, from a knowledge
`of pertinent variables, what the subsequent course of a group of patients will be.
`Even more rarely can. a clinician predict with certainty the outcome in individual
`patients. By .outcome is meant not simply that an individual will die, but when, and
`under what circumstances; not simply that he will recover from a disease, but what
`complications of that disease he wi11 suffer; not simply that some biologic variable
`has changed, but to what extent the change has occurred. Given the uncertain
`knowledge about disease course and the usual large variations in biologic measures,
`it is often difficult to say on the basis of uncontrolled clinical observation whether a
`new treatment hay made a difference to outcome, and if it has, what the magnitude
`i~. A clinical trial offers the possibility of such judgment because there exists a con-
`trol group—which, ideally, is comparable to the intervention group in every way
`except for the intervention being studied.
`The consequences of not conducting appropriate clinical trials at the proper time
`can be serious or costly. An example is the continued uncertainty as to the efficacy
`and safety of digitalis in congestive heart failure. Only recently, after the drug has
`been used for more than 200 years, has a large clinical trial evaluating the effect of
`digitalis on mortality been mounted.$' Intermittent positive pressure breathing
`became an established therapy for chronic obstructive pulmonary disease without
`good evidence of benefits..Much later, one trial suggested no major benefit from this
`very expensive procedure.g~ Similarly, high concentration of oxygen was used for
`therapy in premature infants until a clinical trial demonstrated its harm." A clinical
`trial can determine the incidence of adverse effects of complications of the interven-
`tion. Few interventions, if any, are entirely free of undesirable effects. However, drug
`toxicity might go unnoticed without the systematic follow-up measurements
`obtained in a clinical trial of sufficient size. The Cardiac Arrhythmia Suppression Trial
`documented that commonly used antiarrhythmic drugs were harmful in patients
`who had had a myocardial infarction and raised questions about routine use of an
`entire class of antiarrhythmic agents.z8
`In the final evaluation, an investigator must compare the benefit of an interven-
`tion with its other, possibly unwanted effects to decide whether, and under what cir-
`cumstances, its use should be recommended. The cost implications of an int~rven-
`tion, particularly if there is limited benefit, must also be considered. Thrombolytic
`therapy has been repeatedly shown to be beneficial in acute myocardial infarction.
`The cost of different thrombolytic agents, however, varies several-fold. ire the added
`benefits of the most expensive agents worth the extra. cost? Such assessments are
`not statistical. They must rely on the judgment of the investigator and the physician.
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1095-0008
`
`

`

`Introduction to Clinical Trials 7
`
`It hay been argued, most commonly and most forcefully by those suffering from
`and interested in the acquired immunodeficiency syndrome (.AIDS), that traditional
`clinical trials are not the sole legitimate way of determining whether interventions
`are usefial.14,53,'~ This is undeniably true, and clinical trial researchers need to be will-
`ing to modify, when necessary, aspects of study design or management. If the
`patient community is unwilling to participate in clinical trials conducted along tradi-
`tional lines, or iri ways that are scientifically pure, trials are not feasible and no infor-
`rr~ation will be forthcoming. Investigators need to involve the relevant communities
`or populations at risk, even though this could lead to some compromises in design
`and scientific purity. Investigators need to decide when such compromises so invali-
`date the results that the study is not worth conducting. It should be noted that the
`rapidity with which trial results are demanded, the extent of community involve-
`ment, and the consequent effect on study design can change as knowledge of the
`disease increases, as at least partially effective therapy becomes available, and as
`understanding of the need for valid research designs, including clinical trials, devel-
`ops. This has happened to some extent with AIDS trials.
`Clinical trials are conducted because it is expected that they will influence
`practice.* It is undoubtedly true that the influence depends on numerous factors,
`including direction of the findings, means of dissemination of the results, and exis-
`tence of evidence from other relevant research. However, well-designed clinical
`trials can certainly have pronounced effects on clinical practice.51
`There is no such thing as a perfect study. A well thought-out, well-designed,
`appropriately conducted and analyzed clinical trial, however, is an effective tool.
`While even well-designed clinical trials axe not infallible, they can provide a sounder
`rationale for intervention than is obtainable by other methods of investigation. On
`the other hand, poorly designed and conducted trials can be misleading. Also, with-
`out supporting evidence, no single study ought to be definitive. When interpreting
`the results of a trial, consistency with data from laboratory, animal; epiclemiolo~ic,
`and other clinical research must be considered.
`
`FRO~I.EElO~I~ IN THE TIMING OF A 'g'IdIAL
`
`Onee drugs and procedures of unproved clinical benefit have become part of gen
`eral medical practice, performing an adequate clinical trial becomes difficult ethically
`ar~d logistically. Some people advocate instituting clinical trials as early as possible in
`the evaluation of new therapies.20~$' T'he trials, however, must be feasible. Assessing
`feasibility takes into account several factors. Before conducting a trial, an investigator
`needs to have the necessary knowledge and tools. He must knew something about
`
`*References 4, 5, 33, 34, 51, 69, 75
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1095-0009
`
`

`

`~' I
`
`s
`
`''~
`
`i
`'~
`
`"'
`
`8 Fundamentals of Cluucal Trials
`
`the safety of the intervention and what outcomes to assess and have the techniques to
`do so. Well-run clinical trials of adequate magnitude are costly and should be done
`only when prel~min ry d nc
`a evi e e of th effica of an intervention looks romis'
`e
`cy
`p
`mg
`enough to warrant the effort and expenses involved.
`,Another aspect of timing is consideration of the relative stability of the interven
`tion. If active research will be likely to make the intended intervention outmoded iti
`a short time, studying such an intervention may be inappropriate. This is particularly
`true in long-term clinical trials or studies that take many months to develop. One of
`the criticisms of trials of surgical interventions has been that surgical methods are
`constantly being improved. Evaluating an operative technique of several years past,
`when a study was initiated, may not reflect the current status of surgery.''°~~°
`These issues were raised in connection with the Veterans Aciministraxion study of
`coronary artery bypass surgery.59 The trial showed that surgery was beneficial in sub-
`groups of patients with left main coronary artery disease and three vessel disease, but
`not overall.25,5~,85 Critics of the trial argued that when the trial was started, the surgical
`techniques were still evolving. Therefore, surgical mortality in the study did not reflect
`what occurred in actual practice at the end of the long-term trial. In addition, there
`were wide differences in surgical mortality between the cooperating clinics, which
`may have been related to the experience of the surgeons. Defenders of the study maur
`twined that the surgical mortality in the Veterans Administration hospitals was not very
`different from the national experience at the time.22 In the Coronary Artery Surgery
`Study," surgical mortality was lower than in the Veterans Administration trial, reflect
`ing better technique. The control group mortality, however, was also lower.
`Review articles show that surgical trials have been successfully undertaken.",~
`While the best approach would be to postpone a trial until a procedure has reached
`a plateau and is unlikely to change greatly, such a postponement will probably
`mean waiting until the procedure has been widely accepted as efficacious for some
`3.ndication, thus making it impossible to conduct the trial. However, as noted by
`Chalmers and Sacks,21 allowing for improvements in operative techniques in . a clini
`cal trial is possible. As in all aspects of conducting a clinical trial, judgment must be
`used in determining the proper time to evaluate an intervention.
`
`ETHICS OF CLINICAL Z'~~IAIS
`
`People have debated the ethics of clinical trials for as long as they have been
`done. The arguments have changed over the years and perhaps become more
`sophisticated, but in general, they center around the issues of the physicia~'~ obliga-
`tions to his patient vs. societal good, informed consent, randomization, and the use
`of placebo.* Studies that require ongoing intervention or studies that continue to
`
`'"References 6, 9, 12, 15, 44, 49, 57, G7, 71, 72, 76, 80, 92, 93, 95
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1095-0010
`
`

`

`Introduction to Clinical Trials 9
`
`'s to
`one
`
`~~g
`
`Ten-
`
`~ ~
`arly
`of
`are
`ast,
`
`enroll participants after trends in the data have appeared have raised some of the
`controversy.3z,5',~` The indicated references argue a number of these issues.
`We take the view that properly designed and conducted clinical trials are ethi-
`cal. Awell-designed trial can answer important public health questions without
`impairing the welfare of individuals. There may, at times, be conflicts between a
`phg~sician's perception of what is good for his patient, and the needs of the trial. In
`such instances, the needs of the participants must predominate.
`Proper informed consent is essential. The requirements of the U.S. Department
`of Health anal Human Services are reasonable ones.63 Also pertinent are the Interna-
`tional Ethical Guidelines for Biomedical Research Involving Human Subjects.24,54 Sev
`eral investigators have shown that simply adhering to legal requirements does not
`of
`ensure informed consent.'~,41 In many clinical trial settings, though, true informed
`pub-
`consent can be obtained.s° Sometimes, during a trial, important information derives
`,but
`from either other studies or the trial being conducted, which is relevant to the
`ical
`informed consent. In such cases, the investigator is obligated to update the consent
`lest
`form and notify current participants in an appropriate manner. A trial of antioxi-
`ere
`dents in Finnish male smokers indicated that beta carotene and vitamin E may have
`ich
`been harmful with respect to cancer or cardiovascular disease, rather than. benefi-
`~ cial.86 Because of those findings, investigators of other ongoing trials of antioxidants
`informed the participants of the results and the possible risks. Not only is it an ethi-
`e1'Y
`er5'
`cal stance, but swell-informed participant is usually a better trial participant. The
`pct
`situations where participant enrollment must be done immediately, in comatose
`patients, or in highly stressful circumstances and where the prospective participants
`are minors or not fully competent to understand the study are more complicated
`and may not have optimal solutions.
`The use of finders fees, that is, payment to physicians for referring participant
`to a clinical trial investigator, is inappropriate in that it might lead to undue pressure
`on a prospective participant.56 This differs from the common and accepted practice
`of paying investigators a certain amount for the effort of recruiting each enrolled
`participant. Even this practice becomes questionable if the amount of the payment
`is so great as to induce the investigator to enroll inappropriate participants.
`Randomization has generally been more of a problem for physicians and investi-
`gators than for participants.'$ T'he objection to random assignment should only apply
`if the investigator believes that a preferred therapy exists. If that is the case, he
`should not participate in the trial. On the other hand, if he truly cannot say that one
`treatment is better than another, there should be no ethical problem with randoraliza-
`tion. Such judgments regarding efficacy obviously vary among investigators. Because
`it may be unreasonable to expect that an indi~iclual investigator have no preference,
`not only at the start of a trial but during its conduct, the concept of "clinical
`equipoise" has been proposed.30 In this concept, the presence of uncertainty as to
`the benefits or harm from an intervention among the expert medical community
`
`"'~`
`ied
`
`~lY
`me
`
`by
`~-
`be
`
`en
`•re
`~a-
`se
`
`to
`_
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1095-0011
`
`

`

`10 Fundamentals of Clinical Trials
`
`rather than in the investigator, is justification for a clinical trial. Similarly, the use of
`a placebo is acceptable if there is no known best therapy and. in other special. cir-
`cumstances (e.g., the commonly used therapy is poorly tolera.ted).3' Of course, all
`participants must be told that there is a specified probability, for example, 50%, of
`their receiving placebo. The use of a placebo also does not imply that control group
`participants will receive no treatment. In many trials, the objective is to see whether
`a new intervention plus standaxd care is better or worse than a placebo plus stan-
`dard care. In all trials, there is the ethical obligation to allow the best standard care
`to be used.
`The issue of how to handle accumulating data from an ongoing trial is a difficult
`one, and is discussed in Chapter 15. With advance understanding by both
`participants and investigators that they will not be told interim results, and that
`there is a responsible data monitoring group, ethical concerns should be lessened, if
`not totally alleviated.
`There has been concern about falsification of data and entry of ineligible, or
`even phantom participants in clinical trials.',' We condemn all such data fabrication.
`It is important to emphasize that confidence in the integrity of the trial and its
`results is essential to every trial. If, through intentional or inadvertent actions, that
`confidence is impaired, not only have the participants and potentially others in the
`community been harmed, the trial loses its raxionale and ability to influence science
`and medical practice. Chapter 10 covers issues of data quality assurance.
`
`STUDY PROTOCOL
`
`Every well-designed clinical trial requires a protocol. The study protocol can be
`viewed as a written agreement between the investigator, the participant, and the
`scientific community. The contents provide the background, specify the objectives,
`and describe the design and organization of the trial. Every detail explaining how
`the trial is carried out does not need to be included, provi