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Clinical Trials in Surgery


Clinical Trials in Surgery Mazen S. Zenati, MD, MPH, Ph.D. University of Pittsburgh, Department of Surgery and Epidemiology ... – PowerPoint PPT presentation

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Title: Clinical Trials in Surgery

Clinical Trials in Surgery
  • Mazen S. Zenati, MD, MPH, Ph.D.
  • University of Pittsburgh,
  • Department of Surgery and Epidemiology

Modern Clinical Trials in History
  • Clinical trials began in 1800 onward to
    proliferate and more attention was paid to study
  • Placebos were first used in 1863
  • The idea of randomization was introduced in 1923.
  • The first trial using properly randomized
    treatment and control groups also featured double
    blind assessment was carried out in 1948 by the
    Medical Research Council, and involved the use of
    streptomycin to treat pulmonary tuberculosis..

The Need for Clinical Trials in Surgery
  • In surgery many plausible clinical theory are
    institutionalized into practice before as
    systematic risk-benefit, cost-effectiveness and
    long term quality of life have been measured and
  • Many surgical procedures implemented for years
    before we discovered the ineffectiveness to
    eventually discredited
  • Halsted radical mastectomy
  • Kidney decapsulation (for hypertension)
  • Uterine suspension
  • Legation of internal mammary arteries (for
    coronary insufficiency)

The Need for Clinical Trials in Surgery.. cont.
  • New surgical procedures are not regulated in the
    same way new drugs or devices are
  • New procedures can be approved in the hospital
    based on the surgeon ability to convince the
    patients and some time upper management of the
    potential benefit of the new idea or the
  • No enough cases or controls,
  • Protocols and IRB in many cases are often not
  • No proper documentation of the outcome in
    systematic manner
  • No real plan for study or follow up

The Unique Nature of Surgical Trials
  • Blinding of patients or Surgeon is almost
  • Placebo-controlled procedures are ethically
    controversial specially if invasive
  • The placebo effect is powerful in surgical
    procedures and should be identify
  • The bias of the investigator due to the need for
    that procedure or program to be successful
  • Patient selection, extra skills in performance,
    and extra care and attention (efficacious vs.

The Unique Nature of Surgical Trials.. cont.
  • Difficulty in selecting centers to represent the
    practicing community (VA sites vs. academic
  • Standardization across the sites is difficult
  • When we compare a well-established technique with
    an alternative, the skills and experience in the
    first might bias the comparison (the need for
    video tapes and operative reports for QC)

Clinical trial in Surgery Necessary for
  • To test the safety and efficacy of a new
    technology in the short and long term outcome
  • To test if the new technology is Cost effective
  • To test if the new technology is at least as
    effective and/or safe as existing proven
  • To test for the feasibility of implementing the
    new technology in relation to the needed
    skills/training, equipment, and other factors.

Barriers to Clinical Trials in Surgery
  • Underutilized due to difficulties in design and
  • The high cost hospitalization, operation,
    personnel, and related special method of data
    collection and analysis
  • Funding is difficult to obtain from public and
  • Peer-reviewers, IRB, and other over criticisms
    (protecting patients right and safety) delay the
    process and takes years that the timeliness of
    introduction may be lost

Barriers to Clinical Trials in Surgery.. cont.
  • Multicenter trials might starts in different
    point with unbalance recruitments)
  • Funding fro the industry carries its own risk of
    design and ownership
  • Mastering complex procedures related to learning
  • Consent documents very sensitive (the risk is
    more of an open ended format)

Forces Opposing Clinical Trials in Surgery
  • The magnitude of potential benefits might subside
    the necessity for wait and for the total prove
    through a clinical trial
  • The high risk might hold recruitment for a
    control clinical trial
  • The wide range and high number of potential
    recipients also a factor in determine the need
    compared to a rare disease that may require
    special surgical procedure.

  • When we deal with disease that carry very bad
    prognosis as in oncology, cardiology, and
    transplant where the intervention is highly
    morbid and invasive
  • The evidence-based medicine appraised by patients
    themselves and third-party payers might modify a
    total embracement traditionally done by the
    surgical community

Randomized Control Trial
  • Can we really have a controls in surgical
    clinical trials?
  • Controls is it
  • Not to operate on half of the patients?
  • Mock operation not related to the indication?
  • Can we really deny half of the patients in need
    for surgical interventions just for the sake of
  • Are we then doom half of them to their death?
  • But which half is that? (will be really exposed
    to a greater eventful hazard?)
  • The interventions one or the controls one do we
    really know?

The Basic design of randomized Controlled
Clinical Trial
Eligibility Criteria
Decline to Participate
Agree to Participate, Informed Consent
Controls Current standard No therapy/placebo
Intervention New surgical technique
Good Outcome
Bad Outcome
Good Outcome
Bad Outcome
Barriers to Performing Randomized Trials
  • Surgeon bias for or against specific procedures
  • Morbidity associated with surgery
  • The for granted acceptance of lesser forms of
    clinical evidence by the surgical community
  • Difficulties in recruitments
  • Ethics and legality consents

Threats of the Lack of Randomized Control Group
  • Internal validity related to the temporal trends
  • Surgical learning curve effects
  • Regression to the mean
  • The frequent lack of equipoise among surgeons
  • Amplifying the fact that the clinical practice
    outpaces research evaluation

RCT vs. Quasi-experimental Study Design
  • RCT minimize the measurable confounding that
    potentially biasing the study's conclusions.
  • RCT reduces selection bias
  • RCT however, restricts the generalizablity of the
    results because of the strict inclusion and
    exclusion criteria
  • Some worthy to consider designs in case of
    unlikely to achieve RCT
  • The use of properly selected nonrandomized
    control groups
  • Using pre and post comparisons

Bias and Validity
  • Bias Systematic error within the study that
    results in mistaken estimate of the effect of
    therapy on disease
  • Internal validity The ability of a trial to
    come to the correct conclusion regarding the
    question being studied
  • External validity The ability of trial to
    produce results that are generalizable to a
    larger population of patients with disease

Formulating Research Question
  • RCT to answer as narrow as a possible clinical
    research question
  • To answer an important question justifying
  • Recruitment of large number of patients,
  • The high expenses of the trial
  • The need to compare the exist of legitimate
    uncertainty between the effective of at least two
    therapies of the same disease (clinical
  • In surgery there are many patients avoid surgery
  • Many surgeons are and perhaps patients reluctant
    to relinquish the control of choice of treatment
    of deeply held beliefs of most appropriate
  • Ideal problems to study by RCT
  • Similar morbidity of the procedure using for
    example similar incisions
  • The disease has high morbidity, new procedure
    promise to improve outcome
  • Disease with current treatment result in
    potential long term morbidities that will may
    justify the risk for exploring a new choice

Issues in Formulating Research Question
  • What are the end points
  • Can these end points be accurately and reliably
  • What potential surrogate end points are available
    and at what expenses to the internal validity
  • All the above in consideration to practicality,
    expenses, and feasibility of RCT
  • Pragmatic trials vs. explanatory trials

Pragmatic vs. Explanatory
  • Pragmatic attempt to stimulate clinical
    realities more accurately. The outcomes can be
    easily generalized and accepted into clinical
  • Explanatory attempts to answer more specific and
    narrow question (strict inclusion and exclusion
    criteria, homogeneous population)

Eligibility Criteria
  • Inclusions and exclusions
  • Important to determine the external validity
  • The study population should not be too narrow or
    to broad
  • It is a balance between statistical advantage and
    the generalizability of the results
  • Pragmatic trial tend to be broader in inclusion
  • Explanatory trials are narrower in focus

Outcome Measurement in Surgery
  • Traditional outcome measures
  • Mortality
  • Measures
  • Mortality rate, crude mortality rates, specific
    mortality rates, adjusted mortality rates,
  • Morbidity
  • Measures
  • Prevalence, point prevalence, period prevalence,
    incidence, cumulative incidence, attack rate,
    incidence rate
  • Speed of recovery ICU LOS, Hospital LOS
  • Health related quality of Life
  • Measuring patients satisfactory

Example on Eligibility
  • A study in vascular surgery to compare between a
    newly MIT and the conventional approach in
    treating occlusive peripheral vascular disease of
    lower extremities
  • Inclusion criteria patientslt 65 yr with clinical
    and radiographic evidence
  • Randomly allocated for the above interventions
  • End points angiographic resolution of the
  • Typical patients may be older than 65 yr, lack of
    generalizability lower the external validity
  • Eligibility criteria should be more objectively
  • Severity of lesion, symptoms
  • Endpoint might not be the best to determinant of
    therapeutic success
  • Patient symptoms, activity levels, and wound
    healing (more appropriate and more relevant

Example on selecting Endpoint
  • A RCT to comparing between prothrombin complex
    concentrate and FFP in emergency need (surgery/
    trauma) for reversing the effect of warfarin. The
    INR has been suggested as an endpoint but the FDA
    did not accept the proposal and asked for more
    clinically related outcome. Any suggestion?
  • A RCT to test the effect of preoperative oral
    Citrulline on surgical wound healing . The speed
    of wound healing, strength of the healing or LOS
    was though of as endpoint outcomes. Anything
    wrong with these?

Sample Size
  • We might need in surgery to conduct first a pilot
    nonrandomized observational study on homogenous
    population to determine the differences
    anticipated in outcome between the randomized
    groups in case we do not have enough data
  • The above will be also a good source to estimate
    the variability in the outcome data i.e.
    standard deviation, or standard error
  • What is clinically relevant is more important of
    just statistically significant in power analysis
  • Statistical consultation in this regard is very
    essential and should be obtained early in the
    course of study preparation

Controls and Level of Evidence
  • Controls to increase the level of evidence
    without controls is just as case series study
    which is important in surgery to obtain all the
    descriptive analysis of outcome but will not
    provide evidence of superiority (biased)
  • Without control we can not account for the
    placebo effect
  • Without control we can not account for
    confounding variables
  • Historical controls might be used frequently in
    surgery when a prospective controls is beyond the
    reach, specially when performed by the same
    surgeon and in the same institution
  • Population and the time change in technology
    still differ

Controls and Level of Evidence
  • Variables that we usually match with in selecting
    controls in surgical trials beside all inclusion
    and exclusion criteria
  • Age, sex, BMI,
  • Comorbidities, preexisting illness
  • Disease stage, duration, severity, ISS, mechanism
    of injury, site
  • Surgeon, procedure
  • Others smoking, alcohol use, depression,
    insurance coverage, etc
  • Still the superior level of evidence attributed
    to RCT is contingent on a successful

Randomized Trial in Surgery
  • Random allocation of the subjects to the trial
  • Breaks the link between any unmeasured
    confounding variables and treatment status
  • Assume all differences in effect between
    treatment groups to be a result of the
    differences in treatment (absent confounding)
  • Randomization is the major challenge clinical
    trials in surgery and causes considerable
    weakness the design when not satisfactory
  • The Challenge is convincing patients to
    relinquish control of their care to random
    process by whether or not they receive surgery or
    even which kind of surgery they actually received
  • Randomized trials in surgery can be either
    Pragmatic or Explanatory

Pragmatic vs. Explanatory
  • It is similar to effectiveness vs. efficacy in
    drug trials where
  • Effectiveness is the ability of an intervention
    to accomplish its intended outcome in population
    under real-life circumstances
  • Efficacy Is the ability of an intervention to
    obtain its intended outcome under ideal situation
  • Most randomized trials in surgery tend to be
    categorized as pragmatic effectiveness,
    comparing surgical technique and outcome under
    usual clinical conditions

  • Stabilizes the internal validity of the study
  • Randomization process can be predicted by
    specific logistics and practical constraints of
    the study. The strong desire to operate or not
    by a resident my tempt for the selection bias.
  • The process must be truly unpredictable and
    concealed from the investigator. Allocate the
    patient to randomization after obtaining the
    consent. Using random number table/a computer
    generated and then enclosed in opaque, serially
    numbered enveloped.
  • Investigator selection bias in selecting the
    intervention to subjects whenever more than one
    patient is presented at the same time as in a
    busy trauma center for instance
  • Use distance randomization by phone or internet

Randomized Trials appear to annoy human
nature-if properly conducted, indeed they should
Randomization, cont..
  • Block Randomization to result equal distributed
    patients between the arms of the study
  • Stratified Randomization to assure certain
    traits are equal among treatment groups

Example on Randomization
  • In a busy trauma center, RCT took place to assess
    whether abdominal ultrasound or diagnostic
    peritoneal lavage was more accurate in diagnosing
    intra-abdominal injury after blunt trauma. In the
    ER a clinical indicator was used to determine the
    need for rapid abdominal assessment. If met, a
    resident would open the next opaque, serially
    numbered envelope stored in a designated folder
    in the ED to indicate which assessment would be
    used. In such busy trauma centers, two or more
    patients may presented simultaneously. At the end
    of trial, it was noted that, more often than not,
    diagnostic peritoneal lavage was performed on
    thinner patients!

Example on Randomization
  • Two cases or more at the same time might offer
    the busy resident an opportunity to open more
    than one envelope at once and subsequently decide
    which patients receive which assessment.
  • The process was corrupted by a third part
    motivated by self interest. Likely/hopefully not
    understanding the potential effects on the
    outcome of the trial.

Masking. Blinding
  • To prevent or reduce observation bias and placebo
  • Observation bias is systematic variation between
    the true outcome and the outcome observed
    (consciously or unconsciously)
  • Placebo effect exaggerate the effects of
    treatment based on their enthusiasm and
  • Single blinded treatment assignment is concealed
    from subject only
  • Double-blinded treatment assignment is concealed
    from both subject and the investigator who
    ascertains the study end point
  • Contrary to studies of pharmacologic therapies
    for a disease, blinding in surgery is not that
  • Logistic Challenges we do not have placebo
    surgery similar to placebo tablets. We have to
    use sham surgery
  • Ethical Challenges many of the sham-surgery
    interventions are considered unethical by todays

Masking. Blinding.. Cont.
  • Using blinded third party (not the operating
    surgeon) might be necessary
  • We could verify the effectiveness of blinding by
    asking all study participants to guess which
    treatment they had received.
  • If the patients guesses were no better than
    random chance.. indicated that the blinding
    remained successful
  • Oftentimes, it is not possible to perform a
    randomized trial in blinded fashion different
    surgical techniques, therapies, approaches, or

Example on Blinding
  • In 1959, Cobb et al. reported a RCT designed to
    determine if the internal mammary artery ligation
    was effective in the treatment of angina. The
    researchers enrolled 17 patients with classic
    symptoms and recorded preoperative severity of
    symptoms as well as stress test electrocardiogram
    data. The patients then underwent surgery. After
    the internal mammary arteries were isolated, an
    envelope was opened and directed to either ligate
    or simply end the operation. The patients were
    informed preoperatively that the ligation
    procedure was experimental, but they unaware of
    the randomized nature of the study. Post
    operatively data were collected and found that
    the patients undergoing the sham procedure had
    greater symptomatic relief than those undergoing
    ligation, and one patient in the sham group had
    reversal of stress test electrocardiogram
    abnormalities. Overall, patients in both groups
    showed only modest improvement.

Example on Blinding.. cont.
  • The importance of sham surgery, without it (as
    case series design) the author could incorrectly
    concluded that intervention had a merit
  • The differences might be related to
  • Placebo effect caused the improvement in both
  • Something beside the trial intervention caused
    the improvement
  • The observed benefit was part of the natural
    history of the disease

Patient Crossover and Intention-To-Treat Analysis
  • Intention-To-Treat Analysis Analyze the outcome
    based on the original randomization assignments,
    regardless of treatment actually received
  • The alternative Analyze the data based on the
    treatment actually received not by random
    allocation (as if here we are breaking the
    randomization introducing selection bias since
    crossover does not occur by chance)
  • A high crossover rates questioned the validity of
    the study
  • High crossover rates in surgical clinical trials
    is common
  • Especially in trials comparing surgical with
    medical interventions

Patient Crossover and Intention-To-Treat
Analysis.. cont.
  • There is a specific need to multiple statistical
    methods and mixed modeling techniques to deal
    with crossover
  • We stick with Intention-To-Treat Analysis
    approach whenever randomization is preserved and
    in order to keep the statistical assumptions
    valid for the analysis approaches
  • What is the nonrandom factor that caused patients
    to crossover
  • These nonrandom factors will biases the study

Example on Crossover
  • From 1972 through 1974, the Veterans
    Administration Coronary Artery Bypass Surgery
    Cooperative Study Group enrolled patients into a
    randomized study comparing coronary artery bypass
    surgery with medical therapy in patients with
    angina and radiographic evidence of CAD. Patients
    were randomized to receive either surgical or
    medical therapy. After 14 yr of follow up, 55 of
    patients assigned to receive medical therapy had
    crossed over to receive surgical treatment,
    whereas 6 of the patients assigned to receive
    surgical treatment decided to not undergo the
    procedure and were thus managed clinically.
    Should we analyze the data based on the
    intention-to-treat (original randomization) or
    analyze the data based on the treatment actually
    received (not by random allocation)?

Example on Crossover.. Cont.
  • Should we analyze based on the intention-to-treat
    with such large cross over. Is not that seem
    counterintuitive of the randomization process?
  • Should we accept to break the randomization and
    allowing the introduction of selection bias by
    analyzing according to the actual treatment

  • Surgeons have fallen behind the rest of medical
    community partly because of the challenges
    required to complete a valid randomized trial of
    surgical therapy
  • Clinical Trials in surgery is underutilized
  • Recent era of increase in medical evidence demand
    from policy maker and caregivers and even
    patients resulted in an increase in the demand of
    randomized clinical trials for publications and
    quality assurance. And partly due to our
    acceptance and reliance on lesser forms of
  • Clinical Trials in surgery is urgently needed
  • Randomized clinical trials in surgery are not
    easy but still can be accomplished with the
    appropriate planning and selecting suitable
  • Good controls, selection of end point,
    randomization, blinding are the keys for
    successful CT
  • We need to standardized the ascertainment of
    outcome, attempting to quantify outcome as
    objectively as possible
  • We also should minimize the potential observation
    bias and placebo effect by selecting the most
    appropriate design

Final Thoughts
  • Only until clinical trails in surgery became the
    gold slandered to prove safety and effectiveness
    of the treatment, the current practice will
    continue to be dominant by opinions or the
    enthusiasm for a procedure.
  • Still however the surgeon's Judgment will never
    be a dispensable
  • The results still need to be interpreted in light
    of the study design and clinical reasonableness
  • The better commitment to evidence-based medical
    practice and the persistence and the application
    of novel approaches to overcoming difficult
    methodological hurdles will be continuously
    necessary to advance medicine

References and recommended Reading
  • John Gallin, Principles and Practice of Clinical
    Research, Academic Press, 2002
  • H. Troidl, Surgical Research, Springer, 1987
  • David Machin, Text book of Clinical Trials,
    Wiley, 2006
  • John Wei, Clinical Research Methods for Surgeons,
    Humana Press, 2006
  • Friedman LM, Fundamentals of clinical
    Trials-Third Edition, PSH Inc, 1998
  • Ovid MEDLINE
  • http//
  • PubMed http//
  • FDA http//
  • Clinical Research Office for Surgery and Trauma
    (CROST), University of Pittsburgh, Department of
    Surgery http//

Clinical Trials in Surgery
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