Table Of ContentClinical Trials Design
in Operative and Non
Operative Invasive
Procedures
Kamal M.F. Itani
Domenic J. Reda
Editors
123
Clinical Trials Design in Operative and Non
Operative Invasive Procedures
Kamal M.F. Itani Domenic J. Reda
(cid:129)
Editors
Clinical Trials Design
in Operative and Non
Operative Invasive
Procedures
123
Editors
KamalM.F. Itani Domenic J.Reda
Department ofSurgery, Department ofVeterans Affairs,
VABostonHealthCare System CooperativeStudies Program
BostonUniversity andHarvard Medical Coordinating Center
School HinesVAHospital
West Roxbury,MA Hines, IL
USA USA
ISBN978-3-319-53876-1 ISBN978-3-319-53877-8 (eBook)
DOI 10.1007/978-3-319-53877-8
LibraryofCongressControlNumber:2017932081
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To Gheed, Fawzi and Karim for their
continuous and unwavering support.
To VA Boston Health Care system, its
patients andstaff for being part of my clinical
trials.
Kamal Itani
To the three Mary’s in my life.
Domenic Reda
Foreword I
Ihighly recommend thenew text on“Clinical TrialsDesign inOperativeandNon
Operative Invasive Procedures” edited by Drs. Itani and Reda. Dr. Itani is a rec-
ognizedsurgicalclinicaltrialistfromtheBostonVAMedicalCenter,andDr.Reda
istheDirectoroftheDepartmentofVeteransAffairsCooperativeStudiesProgram
Coordinating Center located in Hines, Illinois. Together they have a wealth of
experience in designing, coordinating and conducting clinical trials, which is
reflected in the depth and breadth of coverage in this book. The book is an out-
growth of clinical trials courses offered by the American College of Surgeons and
the VA Cooperative Studies Program in which they participated and helped to
organize. Many of the chapter authors have also participated in these courses, and
the book represents a culmination of their considerable expertise in clinical trials.
The text is very encompassing in its coverage, providing a comprehensive
resource for any investigator wanting to design, coordinate, execute and analyze a
clinical trial. The text is replete with numerous “real world” examples that were
carefully chosen to illustrate the concepts being presented. While the text contains
material one wouldnormally expect tofind about thedesign,conduct and analysis
ofclinicaltrials,italsocontainsinformationonuniquetopicsthatareoftenhardto
find in the published literature, particularly from one source. For example, the
chapter on mistakes in clinical trials “describes some of the mistakes that were
made and remedies tried in the design, implementation, conduct, and analysis of
over 60 clinical trials and observational studies.” The section on “Considerations
Specific to Surgical or Procedural Trials” covers a wide array of issues related to
studies being conducted in this area, such as surgical training, recruitment and
retention, and clinical equipoise, an often overlooked ethical principle in trial
design. The chapter on “Publication” highlights issues that investigators need to
consider prior to submitting their works for publication, such as having up-to-date
protocols and statistical analysis plans (SAP). Many journals now require submit-
tingthestudyprotocolandallprotocolamendments,along withtheSAP,withthe
manuscript submission. Reviewers and editors will look at these documents to
ensure that the manuscript is consistent with the protocol, particularly the analytic
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viii ForewordI
plan. Another relevant chapter involves “Remote Monitoring of Data Quality,”
which provides a thorough discussion and overview of the U.S. Food and Drug
Association’s (FDA) guidance on risk-based monitoring (RBM). Because of the
increased cost of doing clinical trials and the current capabilities to effectively
monitortrialdataoff-site,RBMisbecomingstandardpracticeinmanyclinicaltrial
settings.
A particularly important topic covered in the book is the chapter on “Trial
Registration and Public Access to Data.” Trial registration has been mandated by
several national and international authorities, including the U.S. FDA (via
ClinicalTrials.gov), World Health Organization (WHO), and International
Committee of Medical Journal Editors (ICMJE). Registration is also required for
publication in many journals, e.g., ICMJE requires trial registration as a condition
forpublicationofresearchresultsgeneratedbyaclinicaltrial.Equallyimportantis
the reporting of trial results. In the U.S., trial results require posting on
ClinicalTrials.gov within one year of ascertaining the primary outcome on the last
patient. Thus, investigators need to be mindful of these registration and reporting
requirements and plan their trial accordingly.
Another unique feature of the book is the chapter on “Economic Evaluations,”
which gives acogent overview ofgeneral economicprinciples relevant toalltrials
and illustrates them with data from two randomized trials. The chapter concludes
with a summary of the lessons learned and recommendations for future research.
So, why this book? While there are many texts on clinical trials, there are none
thatIknowofthattargetthisaudience.Thebookcoversmanyuniqueissuesrelated
to the design, conduct and analysis of clinical trials involving invasive operative
and non-operative procedures that would be relevant to surgeons and interven-
tionalists planning trials in this area. Because the book provides comprehensive
coverage on many topics not covered elsewhere, it will also be an important
resourceforthosewhoparticipateinclinicaltrialsonmanydifferentlevels,suchas
investigators,pharmacists,studycoordinators,statisticians,healtheconomists,data
managers, and regulatory affairs experts.
Peter Peduzzi, Ph.D.
Professor of Biostatistics, Yale School of Public Health;
and
Director, Yale Center for Analytical Sciences
and Yale Data Coordinating Center
Foreword II
I write a Foreword to this book from the perspective of someone who started out
like you, as a surgeon and then, later in my career, crossed the line into the very
different world of being the clinical editor of JAMA. I went from being worried
about anastomotic leaks and wound infections to how to manage hypertension in
elderlypatientsorwhatmedicationsshouldbeusedfordiabetes.Transitioningfrom
surgeontoJAMAeditorwastough-JAMAisknownforitsmethodologicalrigorin
the review process of research manuscripts-resulting in me being exposed to an
intensityofresearchmanuscriptreviewslikenoneIexperiencedinmymanyyears
asanacademicsurgeon.Animportantmisconceptionwasdispelledalongtheway.
Ihadalwaysassumedthattherewasamuchmoresubstantialbodyofhighquality
evidence to support treatment decisions in non-surgical fields such as internal
medicineorpediatricsthanwehadtoguideusinsurgery.Nottrue.Certainly,there
aremanymorerandomizedtrialsinvestigatingtheeffectsofmedicationsandother
sorts of treatments used by non-interventionalists, but even with these trials, con-
siderable uncertainty exists regarding the best treatment approaches for many dis-
eases even when there are numerous RCTs examining various disease entities.
Even though surgeons have done fewer high-quality clinical trials than inves-
tigatorsfromotherdisciplines,someofthemhavehadremarkableeffectresultingin
substantial improvements in patient care. One breast cancer surgery trial after
another showed that less surgery than believed to be necessary resulted in equiv-
alentoutcomes.Inthespanoftwogenerationsofsurgeons,breastcancertreatment
transformedfromthedisfiguringradicalHalsteadmastectomytolumpectomywith
radiation to leaving known tumor behind in the axilla of women with sentinel
lymphnodepositivecancers.Surgeonslearnedviaaremarkablywelldesignedtrial
that accounted for all the pitfalls of clinical trials of interventions that not all
laparoscopic approaches are better than their open counterparts-at least for groin
hernia operations. Yet, probably the biggest improvement in surgical care in our
lifetimes was the introduction of laparoscopic cholecystectomy, which completely
replaced the open operation without a single high-quality RCT being necessary.
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x ForewordII
Not all surgical questions require proof of their utility by performing clinical
trials.Yet,whentheyarenecessarytheyshouldbeperformedcorrectlysothattheir
results are definitive. At JAMA, we review an unfortunately large number of
clinicaltrialsthatwedonotpublishbecauseofbasicflawsinthedesign,execution
oranalysisofclinicaltrials.Thus,thetext“ClinicalTrialsDesigninOperativeand
Non Operative Invasive Procedures” by Itani, Reda, and colleagues is a welcome
addition totheclinical methodologyliterature.Thetextiscomprehensivecovering
allaspectsoftrialdesignandanalysisandthevariousadministrativeaspectsoftrial
execution such as IRB considerations, budgeting, funding and getting the trial
published.Importantemergingconceptssuchasadaptivetrialdesignandmolecular
markers and genomic testing are covered.
From a journal editor’s perspective, how would I use this book? Of course, all
the chapters are useful, but there are certain topics that investigators should pay
particularattentionto.Thesearechapterscoveringmaterialdiscussingtopicswhere
wecommonlyseemistakesinjournalarticlesubmittedtoJAMA.Trialregistration
is covered in Chap. 42. Dr. Lucero correctly points out that journals require reg-
istrationforanystudyinvolvinganintervention.Fromourperspective,intervention
is not limited to a drug or device. Even quality assurance studies involve an
intervention of sorts and requires registration. One of the most common problems
we encounter with research manuscripts at JAMA is studies that have incorrect
sample size estimation-either because of inadequate consideration of a clinically
meaningful difference between groups or inflation of the expected difference in
order to keep the number of enrolled subjects small. Investigators trying to sort
through these issues will find Chap. 16 particularly helpful.
Missingdataeitherfrominadequatefollowupofpatientsornotacquiringallthe
necessary data when the patients are seen, are common and frequently not ade-
quately considered in clinical research. Chapter 19 with its section on multiple
imputation will be helpful in this regard. Many of the common errors we see are
summarized in Dr. William Henderson’s chapter on mistakes in clinical trials
(Chap.43).Dr.Hendersonisaveryexperiencedtrialistandhisperspectiveofwhat
can go wrong with a clinical trial deserves serious consideration by young trialists
so that they may avoid the pitfalls of their forbearers.
ThesearejustasamplingofchaptersinthisbookandIhavehighlightedonlya
fewoftheproblemsweseeatJAMAthatmightberectifiedhadinvestigatorsgiven
serious consideration to a book like this one. Clinical research is hard. There are a
myriadofpitfallsthatanyclinicalinvestigatorcanencounteronthewaytoanswering
importantclinical questions.Careful consideration ofthematerial presentedinthis
bookwillhelpinvestigatorsnegotiatethecomplexitiesofclinicalresearch.
Edward H. Livingston, MD, FACS, AGAF
Deputy Editor for Clinical Reviews and Education
JAMA, Chicago, IL, USA
Preface
Prospective randomized trials evaluating drugs are commonly performed and the
results published. Procedures are more likely to be evaluated using small
prospective studies without controls usually limited to a few centers or a single
investigatorexpertintheprocedure,througharetrospectiveevaluationofaseriesof
subjects with the intervention or through a retrospective case control study with
matchingcontrols.Theenthusiasmfornewtechnology,newtoolsamongsurgeons
andinterventionistsandtheFDAprocessofallowingthembasedonpatient safety
are the major drivers for embracing new technology, procedures and diagnostic
tools without proper evaluation for effectiveness, cost and long term results.
Surgeonsinparticularhavebeencriticizedfortheirlackofscientificapproachin
evaluating procedures and new technology. Although well designed, properly
conductedclinicaltrialshavebeenpublishedinthelasttwodecadesinthesurgical
andnon-operative proceduralfields, thosespecialtiesarestillbehind othermedical
and pharmaceutical specialties in conducting properly constructed clinical trials.
The Department of Veteran Affairs research system was among the first to
implement multi-center randomized trials in the various fields of medicine. The
Cooperative Studies Program was specifically set up for the purpose of supporting
such trials. Some of the largest and most impactful studies have come out of that
program. In parallel, the VA Cooperative Studies Program collaborated with the
American College of Surgeons to develop a course in the design, conduct and
analysis of clinical trials which was sponsored by the American College of
Surgeonsmostlyforsurgeons.AsimilarcoursewassubsequentlyofferedintheVA
toVAclinicalinvestigators.Severaloftheauthorsofthisbookhaveparticipatedin
eitherorbothcoursesandhavebeenencouragedbyparticipantsinthesecoursesto
comeupwiththisbook.Thisbookcoversallclinicalandstatistical aspectsforthe
proper planning, conduct, funding and publication of a clinical trial. It is our hope
that this book will be a good reference for any investigator or sponsor planning a
clinical trial, especially in the surgical and the non operative invasive fields.
West Roxbury, USA Kamal M.F. Itani
Hines, USA Domenic J. Reda
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