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For personal use only; all rights reserved

Fundamentals of Clinical Research

for Radiologists
Harald O. Stolberg1
Geoffrey Norman2
Randomized Controlled Trials
Isabelle Trop3

P receding articles in this series

have provided a great deal of in-
formation concerning research
design and methodology, including research
The 19th century saw many major ad-
vances in clinical trials. In 1836, the editor of
the American Journal of Medical Sciences
wrote an introduction to an article that he
protocols, statistical analyses, and assess- considered “one of the most important medi-
ment of the clinical importance of radiologic cal works of the present century, marking the
research studies. Many methods of research start of a new era of science,” and stated that
design have already been presented, includ- the article was “the first formal exposition of
ing descriptive studies (e.g., case reports, the results of the only true method of investi-
case series, and cross-sectional surveys), and gation in regard to the therapeutic value of
some analytical designs (e.g., cohort and remedial agents.” The article that evoked
case-control studies). such effusive praise was the French study on
Case-control and cohort studies are also bloodletting in treatment of pneumonia by
called observational studies, which distin- P. C. A. Louis [2, 3].
guishes them from interventional (experi- Credit for the modern randomized trial is
Received June 14, 2004; accepted after revision mental) studies because the decision to seek usually given to Sir Austin Bradford Hill [4].
July 2, 2004.
one treatment or another, or to be exposed to The Medical Research Council trials on strep-
Series editors: Nancy Obuchowski, C. Craig Blackmore,
Steven Karlik, and Caroline Reinhold.
one risk or another, was made by someone tomycin for pulmonary tuberculosis are rightly
other than the experimenter. Consequently, regarded as a landmark that ushered in a new
This is the 12th in the series designed by the American
College of Radiology (ACR), the Canadian Association of the researcher’s role is one of observing the era of medicine. Since Hill’s pioneering
Radiologists, and the American Journal of Roentgenology. outcome of these exposures. By contrast, in achievement, the methodology of the random-
The series, which will ultimately comprise 22 articles, is experimental studies, the researcher (experi- ized controlled trial has been increasingly ac-
designed to progressively educate radiologists in the
methodologies of rigorous clinical research, from the most menter) controls the exposure. The most cepted and the number of randomized
basic principles to a level of considerable sophistication. powerful type of experimental study is the controlled trials reported has grown exponen-
The articles are intended to complement interactive
software that permits the user to work with what he or she
randomized controlled trial. The basic prin- tially. The Cochrane Library already lists more
has learned, which is available on the ACR Web site ciples of randomized controlled trials will be than 150,000 such trials, and they have be-
(www.acr.org). discussed in this article. come the underlying basis for what is currently
Project coordinator: G. Scott Gazelle, Chair, ACR called “evidence-based medicine” [5].
Commission on Research and Technology Assessment; History of Randomized Controlled Trials
staff coordinator: Jonathan H. Sunshine, Senior Director
for Research, ACR. The history of clinical trials dates back to General Principles of Randomized
1
Department of Radiology, McMaster University Medical approximately 600 B.C. when Daniel of Judah Controlled Trials
Centre, 1200 Main St. W, Hamilton, ON L8N 3Z5, Canada. [1] conducted what is probably the earliest re- The randomized controlled trial is one of the
Address correspondence to H. O. Stolberg.
corded clinical trial. He compared the health simplest but most powerful tools of research. In
2
Department of Clinical Epidemiology and Biostatistics, effects of the vegetarian diet with those of a essence, the randomized controlled trial is a
McMaster University, Hamilton, ON L8N 3Z5, Canada.
royal Babylonian diet over a 10-day period. study in which people are allocated at random
3
Department of Radiology, Hôpital Saint-Luc, 1058 St. The trial had obvious deficiencies by contem- to receive one of several clinical interventions
Denis St., Montreal, QC H2X 3J4, Canada.
porary medical standards (allocation bias, as- [2]. On most occasions, the term “intervention”
AJR 2004;183:1539–1544
certainment bias, and confounding by divine refers to treatment, but it should be used in a
0361–803X/04/1836–1539 intervention), but the report has remained in- much wider sense to include any clinical ma-
© American Roentgen Ray Society fluential for more than two millennia [2]. neuver offered to study participants that may

AJR:183, December 2004 1539

 Stolberg et al.

have an effect on their health status. Such clini- cases, randomized controlled trials may not be procedure. They must first define the rules
cal maneuvers include prevention strategies, feasible because of financial constraints or be- that will govern allocation and then follow
screening programs, diagnostic tests, interven- cause of the expectation of low compliance or those rules strictly throughout the entire
tional procedures, the setting in which health high drop-out rates. study [2]. The crucial issue is that after the
care is provided, and educational models [2]. Many randomized controlled trials involve procedure for randomization is determined,
Randomized controlled trials in radiology can large sample sizes because many treatments it should not be modified at any point during
play a major role in the assessment of screen- have relatively small effects. The size of the ex- the study. There are many adequate methods
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ing programs, diagnostic tests, and procedures pected effect of the intervention is the main de- of randomization, but their common element
in interventional radiology [6–13]. terminant of the sample size necessary to is that no one should be able to determine
Randomized controlled trials are used to conduct a successful randomized controlled ahead of time to which group a given patient
examine the effect of interventions on particu- trial. Obtaining statistically significant differ- will be assigned. Detailed discussion of ran-
lar outcomes such as death or the recurrence ences between two samples is easy if large dif- domization methods is beyond the scope of
of disease. Some consider randomized con- ferences are expected. However, the smaller the this article.
trolled trials to be the best of all research de- expected effect of the intervention, the larger the Numerous methods are also available to en-
signs [14], or “the most powerful tool in sample size needed to be able to conclude, with sure that the sample of patients is balanced
modern clinical research” [15], mainly be- enough power, that the differences are unlikely whenever a small predetermined number of
cause the act of randomizing patients to re- to be due to chance. For example, let us assume patients have been enrolled. Unfortunately, the
ceive or not receive the intervention ensures that we wish to study two groups of patients who methods of allocation in studies described as
that, on average, all other possible causes are will undergo different interventions, one of randomized are poorly and infrequently re-
equal between the two groups. Thus, any sig- which is a new procedure. We expect a 10% de- ported [2, 28]. As a result, it is not possible to
nificant differences between groups in the out- crease in the morbidity rate with the new proce- determine, on most occasions, whether the in-
come event can be attributed to the dure. To be able to detect this difference with a vestigators used proper methods to generate
intervention and not to some other unidenti- probability (power) of 80%, we need 80 patients random sequences of allocation [2].
fied factor. However, randomized controlled in each treatment arm. If the expected difference
trials are not a panacea to answer all clinical in effect between the two groups increases to
questions; for example, the effect of a risk fac- 20%, the number of patient required per arm de- Bias in Randomized Controlled Trials
tor such as smoking cannot ethically be ad- creases to 40. Conversely, if the difference be- The main appeal of the randomized con-
dressed with randomized controlled trials. tween the groups is expected to be only 1%, the trolled trial in health care derives from its po-
Furthermore, in many situations randomized study population must increase to 8,000 per tential for reducing allocation bias [2]. No
controlled trials are not feasible, necessary, treatment arm. The sample size required to other study design allows researchers to bal-
appropriate, or even sufficient to help solve achieve power in a study is inversely propor- ance unknown prognostic factors at baseline.
important problems [2]. Randomized con- tional to the treatment effect squared [23]. Stan- Random allocation does not, however, pro-
trolled trials are not appropriate for cancer dard formulas are available to calculate the tect randomized controlled trials against
screening, a situation in which the outcome is approximate sample size necessary when de- other types of bias. During the past 10 years,
rare and frequently occurs only after a long signing a randomized controlled trial [24–26]. randomized controlled trials have been the
delay. Thus, although the test for appraising subject rather than the tool of important, al-
the ultimate value of a diagnostic test may be beit isolated, research efforts usually de-
a large well-designed randomized controlled Randomization: The Strength of the signed to generate empiric evidence to
trial that has patient outcomes as the end point Randomized Controlled Trial improve the design, reporting, dissemina-
[16], the trial should presumably be per- The randomization procedure gives the ran- tion, and use of randomized controlled trials
formed after other smaller studies have exam- domized controlled trial its strength. Random in health care [28]. Such studies have shown
ined the predictive value of the test against allocation means that all participants have the that randomized controlled trials are vulnera-
some accepted standard. same chance of being assigned to each of the ble to multiple types of bias at all stages of
An excellent example of the controversies study groups [27]. The allocation, therefore, is their workspan. A detailed discussion of bias
that can arise with randomized controlled tri- not determined by the investigators, the clini- in randomized controlled trials was offered
als is an overview of the publications on cians, or the study participants [2]. The pur- by Jadad [2].
mammography screening. The most impor- pose of random allocation of participants is to In summary, randomized controlled trials
tant references concern the article by Miet- assure that the characteristics of the partici- are quantitative, comparative, controlled ex-
tinen et al. [17] linking screening for breast pants are as likely to be similar as possible periments in which a group of investigators
cancer with mammography and an appar- across groups at the start of the comparison studies two or more interventions by admin-
ently substantial reduction in fatalities and (also called the baseline). If randomization is istering them to groups of individuals who
the responses that it elicited [18–22]. done properly, it reduces the risk of a serious have been randomly assigned to receive each
Randomized controlled trials may not be imbalance in known and unknown factors that intervention. Alternatively, each individual
appropriate for the assessment of interventions could influence the clinical course of the par- might receive a series of interventions in ran-
that have rare outcomes or effects that take a ticipants. No other study design allows investi- dom order (crossover design) if the outcome
long time to develop. In such instances, other gators to balance these factors. can be uniquely associated with each inter-
study designs such as case-control studies or The investigators should follow two rules vention, through, for example, use of a
cohort studies are more appropriate. In other to ensure the success of the randomization “washout” period. This step ensures that the

1540 AJR:183, December 2004

 Fundamentals of Clinical Research for Radiologists

effects from one test are not carried over to daily practice. Although both explanatory and ventions is determined at random. This de-
the next one and subsequently affect the in- pragmatic approaches are reasonable, and sign, obviously, is appropriate only for
dependent evaluation of the second test ad- even complementary, it is important to under- chronic conditions that are fairly stable over
ministered. Apart from random allocation to stand that they represent extremes of a spec- time and for interventions that last a short
comparison groups, the elements of a ran- trum, and most randomized controlled trials time within the patient and that do not inter-
domized controlled trial are no different combine elements of both. fere with one another. Otherwise, false con-
from those of any other type of prospective, Efficacy or effectiveness trials.—Random- clusions about the effectiveness of an
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comparative, quantitative study. ized controlled trials are also often described in intervention could be drawn [29].
terms of whether they evaluate the efficacy or Factorial design.—A randomized con-
effectiveness of an intervention. Efficacy refers trolled trial has a factorial design when two or
Types of Randomized Controlled Trials
to interventions carried out under ideal circum- more experimental interventions are not only
As Jadad observed in his 1998 book Ran- stances, whereas effectiveness evaluates the ef- evaluated separately but also in combination
domised Controlled Trials [2]: fects of an intervention under circumstances and against a control [2]. For example, a 2 × 2
similar to those found in daily practice. factorial design generates four sets of data to
Over the years, multiple terms have Phase 1, 2, 3, and 4 trials.—These terms analyze: data on patients who received none
been used to describe different types of describe the different types of trials used for of the interventions, patients who received
randomized controlled trials. This termi- the introduction of a new intervention, tradi- treatment A, patients who received treatment
nology has evolved to the point of tionally a new drug, but could also encom- B, and patients who received both A and B.
becoming real jargon. This jargon is not pass trials used for the evaluation of a new More complex factorial designs, involving
easy to understand for those who are embolization material or type of prosthesis, multiple factors, are occasionally used. The
starting their careers as clinicians or for example. Phase 1 studies are usually con- strength of this design is that it provides more
researchers because there is no single ducted after the safety of the new interven- information than parallel designs. In addition
source with clear and simple definitions tion has been documented in animal to the effects of each treatment, factorial de-
of all these terms. research, and their purpose is to document sign allows evaluation of the interaction that
the safety of the intervention in humans. may exist between two treatments. Because
The best classification of frequently used Phase 1 studies are usually performed on randomized controlled trials are generally ex-
terms was offered by Jadad [2], and we have healthy volunteers. Once the intervention pensive to conduct, the more answers that can
based our article on his work. passes phase 1, phase 2 begins. Typically, the be obtained, the better.
According to Jadad, randomized con- intervention is given to a small group of real
trolled trials can be classified as to the as- patients, and the purpose of this study is to Randomized Controlled Trials Classified According to
pects of intervention that investigators want evaluate the efficacy of different modes of the Number of Participants
to explore, the way in which the participants administration of the intervention to patients. Randomized controlled trials can be per-
are exposed to the intervention, the number Phase 2 studies focus on efficacy while still formed in one or many centers and can in-
of participants included in the study, whether providing information on safety. Phase 3 clude from one to thousands of participants,
the investigators and participants know studies are typically effectiveness trials, and they can have fixed or variable (sequen-
which intervention is being assessed, and which are performed after a given procedure tial) numbers of participants.
whether the preference of nonrandomized in- has been shown to be safe with a reasonable “N-of-one trials.”—Randomized con-
dividuals and participants has been taken chance of improving patients’ conditions. trolled trials with only one participant are
into account in the design of the study. In the Most phase 3 trials are randomized con- called “n-of-one trials” or “individual patient
context of this article, we can offer only a trolled trials. Phase 4 studies are equivalent trials.” Randomized controlled trials with a
brief discussion of each of the different types to postmarketing studies of the intervention; simple design that involve thousands of pa-
of randomized controlled trials. they are performed to identify and monitor tients and limited data collection are called
possible adverse events not yet documented. “megatrials.” [30, 31]. Usually, megatrials
Randomized Controlled Trials Classified According to require the participation of many investiga-
the Different Aspects of Interventions Evaluated tors from multiple centers and from different
Randomized Controlled Trials Classified According to
Randomized controlled trials used to evalu- Participants’ Exposure and Response to the countries [2].
ate different interventions include explanatory Intervention Sequential trials.—A sequential trial is a
or pragmatic trials; efficacy or equivalence tri- These types of randomized controlled trials study with parallel design in which the number
als; and phase 1, 2, 3, and 4 trials. include parallel, crossover, and factorial designs. of participants is not specified by the investiga-
Explanatory or pragmatic trials.—Explan- Parallel design.—Most randomized con- tors beforehand. Instead, the investigators
atory trials are designed to answer a simple trolled trials have parallel designs in which continue recruiting participants until a clear
question: Does the intervention work? If it each group of participants is exposed to only benefit of one of the interventions is observed
does, then the trial attempts to establish how one of the study interventions. or until they become convinced that there are
it works. Pragmatic trials, on the other hand, Crossover design.— Crossover design re- no important differences between the inter-
are designed not only to determine whether fers to a study in which each of the partici- ventions [27]. This element applies to the
the intervention works but also to describe all pants is given all of the study interventions in comparison of some diagnostic interventions
the consequences of the intervention and its successive periods. The order in which the and some procedures in interventional radiol-
use under circumstances corresponding to participants receive each of the study inter- ogy. Strict rules govern when trials can be

AJR:183, December 2004 1541

 Stolberg et al.

stopped on the basis of cumulative results, in a randomized controlled trial but have a limitations of the research methods of ran-
and important statistical considerations come clear preference for one of the study inter- domized controlled trials is growing. A ma-
into play. ventions. At least three types of randomized jor barrier hindering the assessment of trial
Fixed trials.—Alternatively, in a fixed controlled trials take into account the prefer- quality is that, in most cases, we must rely on
trial, the investigators establish deductively ences of eligible individuals as to whether or the information contained in the written re-
the number of participants (sample size) that not they take part in the trial. These are port. A trial with a biased design, if well re-
will be studied. This number can be decided called preference trials because they include ported, could be judged to be of high quality,
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arbitrarily or can be calculated using statisti- at least one group in which the participants whereas a well-designed but poorly reported
cal methods. The latter is a more commonly are allowed to choose their preferred treat- trial could be judged to be of low quality.
used method. Even in a fixed trial, the design ment from among several options offered Recently, efforts have been made to im-
of the trial usually specifies whether there [32, 33]. Such trials can have a Zelen design, prove the quality of randomized controlled
will be one or more interim analyses of data. comprehensive cohort design, or Wennberg’s trials. In 1996, a group of epidemiologists,
If a clear benefit of one intervention over the design [33–36]. For a detailed discussion of biostatisticians, and journal editors published
other can be shown with statistical signifi- these designs of randomized controlled tri- “CONSORT (Consolidated Standards of Re-
cance before all participants are recruited, it als, the reader is directed to the excellent de- porting Trials)” [38], a statement that re-
may not be ethical to pursue the trial, and it tailed discussion offered by Jadad [2]. sulted from an extensive collaborative
may be prematurely terminated. process to improve the standards of written
reports of randomized controlled trials. The
Randomized Controlled Trials Classified According to The Ethics of Randomized Controlled
CONSORT statement was revised in 2001
the Level of Blinding Trials
[39]. It was designed to assist the reporting
In addition to randomization, the investi- Despite the claims of some enthusiasts for of randomized controlled trials with two
gators can incorporate other methodologic randomized controlled trials, many important groups and those with parallel designs. Some
strategies to reduce the risk of other biases. aspects of health care cannot be subjected to a modifications will be required to report
These strategies are known as “blinding.” randomized trial for practical and ethical rea- crossover trials and those with more than two
The purpose of blinding is to reduce the risk sons. A randomized controlled trial is the best groups [40]. Although the CONSORT state-
of ascertainment and observation bias. An way of evaluating the effectiveness of an inter- ment was not evaluated before its publica-
open randomized controlled trial is one in vention, but before a randomized controlled tion, it was expected that it would lead to an
which everybody involved in the trial knows trial can be conducted, there must be equi- improvement in the quality of reporting of
which intervention is given to each partici- poise—genuine doubt about whether one randomized controlled trials, at least in the
pant. Many radiology studies are open ran- course of action is better than another [16]. journals that endorse it [41].
domized controlled trials because blinding is Equipoise then refers to that state of knowl- Recently, however, Chan et al. [42]
not feasible or ethical. One cannot, for exam- edge in which no evidence exists that shows pointed out that the interpretation of the re-
ple, perform an interventional procedure that any intervention in the trial is better than sults of randomized controlled trials has em-
with its associated risks without revealing to another and that any intervention is better than phasized statistical significance rather than
the patient and the treating physician to those in the trial. It is not ethical to build a trial clinical importance:
which group the patient has been random- in which, before enrollment, evidence suggests
ized. A single-blinded randomized controlled that patients in one arm of the study are more The lack of emphasis on clinical
trial is one in which a group of individuals likely to benefit from enrollment than patients importance has led to frequent miscon-
involved in the trial (usually patients) does in the other arm. Equipoise thus refers to the ceptions and disagreements regarding
not know which intervention is given to each fine balance that exists between being hopeful the interpretation of the results of clinical
participant. A double-blinded randomized a new treatment will improve a condition and trials and a tendency to equate statistical
controlled trial, on the other hand, is one in having enough evidence to know that it does significance with clinical importance. In
which two groups of individuals involved in (or does not). Randomized controlled trials some instances, statistically significant
the trial (usually patients and treating physi- can be planned only in areas of uncertainty results may not be clinically important
cians) do not know which intervention is and can be carried out only as long as the un- and, conversely, statistically insignificant
given to each participant. Beyond this, tri- certainty remains. Ethical concerns that are results do not completely rule out the
ple-blinded (blinding of patients, treating unique to randomized controlled trials as well possibility of clinically important effects.
physicians, and study investigators) and as other research designs will be addressed in
quadruple-blinded randomized controlled subsequent articles in this series. Hellman Limitations of the Research Methods Used in
trials (blinding of patients, treating physi- and Hellman [37] offered a good discussion Randomized Controlled Trials
cians, study investigators, and statisticians) on this subject. The evaluation of the methodologic qual-
have been described but are rarely used. ity of randomized controlled trials is central
to the appraisal of individual trials, the con-
Reporting of Randomized Controlled
Randomized Controlled Trials Classified According to duct of unbiased systematic reviews, and the
Nonrandomized Participant Preferences Trials
performance of evidence-based health care.
Eligible individuals may refuse to partici- The Quality of Randomized Controlled Trial Reporting However, important methodologic details
pate in a randomized controlled trial. Other Awareness concerning the quality of re- may be omitted from published reports, and
eligible individuals may decide to participate porting randomized controlled trials and the the quality of reporting is, therefore, often

1542 AJR:183, December 2004

 Fundamentals of Clinical Research for Radiologists

used as a proxy measure for methodologic randomized controlled trials has significantly 8. Fontana RS, Sanderson DR, Woolner LB, et al.
quality. High-quality reporting may hide im- increased in both diagnostic and interven- Screening for lung cancer: a critique of the Mayo
Lung Project. Cancer 1991;67[suppl 4]:1155–1164
portant differences in methodologic quality, tional radiology. Examples of randomized
9. [No authors listed]. Impact of follow-up testing
and well-conducted trials may be reported controlled trials in diagnostic imaging in- on survival and health-related quality of life in
badly [43]. As Devereaux et al. [41] ob- clude the works of Gottlieb et al. [48] and breast cancer patients: a multicenter randomized
served, “[h]ealth care providers depend upon Kaiser et al. [49]. Examples of interventional controlled trial—the GIVIO Investigators. JAMA
authors and editors to report essential meth- randomized controlled trials are the studies 1994;271:1587–1592
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odological factors in randomized controlled by Pinto et al. [50] and Lencioni et al. [51]. 10. Jarvik JG, Maravilla KR, Haynor DR, Levitz M,
trials (RCTs) to allow determination of trial Randomized controlled trials are equally Deyo RA. Rapid MR imaging versus plain radi-
ography in patients with low back pain: initial re-
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sults of a randomized study. Radiology
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The most important limitations of re- fortunate, and controversy over this issue 11. Kinnison ML, Powe NR, Steinberg EP. Results of
search methods include the following: continues to this day [52, 53]. On the other randomized controlled trials of low-versus high-
Insufficient power.—A survey of 71 ran- hand, positive developments have occurred, osmolality contrast media. Radiology 1989;170:
domized controlled trials showed that most such as the work of the American College of 381–389
12. Rosselli M, Palli D, Cariddi A, Ciatto S, Pacini P,
of these trials were too small (i.e., had insuf- Radiology Imaging Network. Writing for
Distante V. Intensive diagnostic follow-up after
ficient power to detect important clinical dif- this group, Berg [54] has offered a commen- treatment of primary breast cancer. JAMA 1994;
ferences) and that the authors of these trials tary on the rationale for a trial of screening 271:1593–1597
seemed unaware of these facts [44]. breast sonography. 13. Swingler GH, Hussey GD, Zwarenstein M. Ran-
Poor reporting of randomization—A study Radiologists have a great deal to learn about domised controlled trial of clinical outcome after
of 206 randomized controlled trials showed randomized controlled trials. Academic radiol- chest radiograph in ambulatory acute lower-respi-
ration infection in children. Lancet 1998;351:
that randomization, one of the main design fea- ogists who perform research and radiologists
404–408
tures necessary to prevent bias in randomized who translate research results into practice 14. Cochrane Library Web site. Available at:
controlled trials, was poorly reported [45]. should be familiar with the different types of www.update-software.com/abstracts/
Other limitations.—Additional limitations these trials, including those conducted for di- ab001877.htm. Accessed September 10, 2004
identified by Chalmers [46] were inadequate agnostic tests and interventional procedures. 15. Nystrom L, Rutqvist LE, Wall S, et al. Breast can-
randomization, failure to blind the assessors Radiologists also must be aware of the limita- cer screening with mammography: overview of
to the outcomes, and failure to follow up all tions and problems associated with the meth- Swedish randomised trials. Lancet 1993;341:
973–978
patients in the trials. odologic quality and reporting of the trials. It is
16. Duffy SW. Interpretation of the breast screening
our hope that this article proves to be a valu- trials: a commentary on the recent paper by
able source of information about randomized Gotzsche and Olsen. Breast 2001;10:209–212
Intent to Treat
controlled trials. 17. Miettinen OS, Henschke CI, Pasmantier MW,
A method to correct for differential drop- Smith JP, Libby DM, Yankelevitz DF. Mammo-
out rates between patients from one arm of graphic screening: no reliable supporting evi-
the study and another is to analyze data by Acknowledgments dence? Lancet 2002;359:404–405
the intent to treat—that is, data are analyzed We thank Alejandro Jadad for his support 18. Tabar L, Vitak B, Chen HHT, Yen MF, Duffy SW,
Smith RA. Beyond randomized controlled trials:
in the way patients were randomized, regard- and Monika Ferrier for her patience and sup-
organized mammographic screening substantially
less of whether or not they received the in- port in keeping us on track and for preparing reduces breast carcinoma mortality. Cancer 2001;
tended intervention. The intent to treat the manuscript. 91:1724–1731
correction is a form of protection against bias 19. Hoey J. Does mammography save lives? CMAJ
and strengthens the conclusions of a study. A 2002;166:1187–1188
detailed discussion of the assessment of the 20. Norman GR, Streiner DL. Biostatistics: the bare
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The reader’s attention is directed to earlier articles in the Fundamentals of Clinical Research series:
1. Introduction, which appeared in February 2001 8. Exploring and Summarizing Radiologic Data, January 2003
2. Framework, April 2001 9. Visualizing Radiologic Data, March 2003
3. Protocol, June 2001 10. Introduction to Probability Theory and Sampling
4. Data Collection, October 2001 Distributions, April 2003
5. Population and Sample, November 2001 11. Observational Studies in Radiology, November 2004
6. Statistically Engineering the Study for Success, July 2002
7. Screening for Preclinical Disease: Test and Disease
Characteristics, October 2002

1544 AJR:183, December 2004