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DOI 10.1007/s10067-013-2342-z
REVIEW ARTICLE
Received: 24 May 2013 / Accepted: 10 July 2013 / Published online: 23 July 2013
# Clinical Rheumatology 2013
Abstract There is an increasing concern over generalizabil- Keywords Eligibility criteria . Knee osteoarthritis .
ity of trial results. We investigated eligibility criteria of knee Randomized trial
osteoarthritis clinical trials. Eligible trials were randomized,
placebo-controlled trials that were identified by searches
in MEDLINE, SCOPUS, and the Cochrane Central Reg-
ister of Controlled Trials. We then attempted to extract Introduction
data on the eligibility criteria by employing predetermined
criteria. From 355 randomized knee osteoarthritis trials, Randomized trials are considered as an important mea-
we reviewed data categorized by non-osteoarthritis-related sure for evaluating efficacy of treatments on knee osteo-
and osteoarthritis-related factors. A variety of items were used arthritis [1]. The International Multidisciplinary Commit-
in the eligibility criteria. Regarding the non-osteoarthritis- tee of experts appointed by the Osteoarthritis Research
related factors, ethical considerations, such as inability to give Society International recently recommended treatment
an informed consent (79.4 %) or medical conditions potential guidelines based on scientific evidence from randomized
for risks by test treatments (56.0 %) or by participation in a trials [24]. Although well-conducted randomized trials
trial (57.2 %), were the common reasons for excluding pa- are expected to provide unbiased evidence, there are also
tients from a trial. Concerning the osteoarthritis-related fac- concerns over generalizability, that is, whether the results
tors, most of the trials did not specify age and symptom found from randomized trials are applicable to actual patient
severity. When trials specifying these items were investigated, care.
patients with 40 to 80 years in age and grade 2 in the Concerns regarding the generalizability have been de-
KellgrenLawrence scale were mostly included into a trial. scribed in a large number of studies [513]. For example,
For the pain intensity, patients with 2040 in the 100-mm when eligibility criteria from the prestigious randomized
visual analog scale and 68 in the WOMAC pain subscale trials that were funded by the National Institute for Allergy
were commonly enrolled into a trial. These findings warrant and Infectious Diseases were used, 067.6 % of participants
further investigation on the generalizability of trial results. in the largest longitudinal cohort of HIV-positive women
were found to be excluded [13]. Such findings support
caution in generalizing results from randomized trials to
Y. H. Koog : H. Wi : W. Y. Jung general population with target diseases.
Honam Research Center, Medifarm Hospital, Although broad eligibility criteria are usually recom-
Suncheon, South Korea mended to overcome these concerns [14, 15], controversy
exists regarding the use of broad criteria in knee osteoarthri-
Y. H. Koog (*)
Department of Oriental Medicine, Medifarm Hospital, tis. Broad eligibility criteria may enlarge the amount of
Suncheon, South Korea variation and thus increase sample sizes to detect clinical
e-mail: samlungchim@hanmail.net change [16]. Despite this controversy, no studies have inves-
tigated eligibility criteria in knee osteoarthritis to date. In this
W. Y. Jung
Department of Neurology, Medifarm Hospital, study, we attempted to examine the eligibility criteria used in
Suncheon, South Korea knee osteoarthritis clinical trials.
1570 Clin Rheumatol (2013) 32:15691574
Osteoarthritis-related reasonsa
Age, gender, treated leg, osteoarthritis
severity, pain status, etc.
a
Osteoarthritis-related reasons were based on previous studies [26, 27]
1570 Clin Rheumatol (2013) 32:15691574
Osteoarthritis-related reasonsa
Age, gender, treated leg, osteoarthritis
severity, pain status, etc.
a
Osteoarthritis-related reasons were based on previous studies [26, 27]
Clin Rheumatol (2013) 32:15691574 1571
route were examined more than those administered via in a large number of trials. When only trials reporting the
invasive routes. values were considered, most trials enrolled patients between
Non-osteoarthritis-related reasons for excluding patients 40 and 80 years in age and focused on patients with grade 2 in
from a trial are described in Table 3. Inability to give an the KellgrenLawrence scale. For the body mass index, most
informed consent was the most common reason (79.4 %) for of 32 trials reporting this index set 40 as maximum criterion.
excluding patients from trials, followed by recent experience Categories of pain-related reasons for enrolling patients
of other potential treatments (61.4 %). Medical conditions into a trial are presented in Table 5. Of 207 trials stating
that may cause risks by treat treatments or may be difficult to that painful knee was investigated, VAS was the commonest
interpret outcomes were also reported as reasons in more pain outcome. For the VAS, patients with more than 20
than 50 % trials. 40 mm were enrolled in 80.3 % of 132 trials. Regarding the
Categories of osteoarthritis-related reasons for enrolling Western Ontario and McMaster Universities Arthritis Index
patients into a trial are depicted in Table 4. With respect to (WOMAC) pain subscale, patients with more than 68 were
age or osteoarthritis severity, exact values were not specified enrolled in 42.1 % of 19 trials.
1572 Clin Rheumatol (2013) 32:15691574
Table 2 Trial characteristics Table 4 Categories of osteoarthritis-related reasons for enrolling pa-
tients into a trial
Trial number (%)
Trial number (%)
Total trial 355
Crossover design Lower boundary of age, years
Non-crossover 332 (93.5) 20 49 (13.8)
Crossover 23 (6.5) 30 17 (4.8)
Flare design 40 103 (29.0)
Flare 32 (9.0) 50 33 (9.3)
Non-flare 323 (91.0) 60 7 (2.0)
Treatment type Unspecified 154 (43.4)
Pharmacological 261 (73.5) Upper boundary of age, years
Non-pharmacological 93 (26.2) 60 2 (0.6)
Mixed 1 (0.3) 70 17 (4.8)
Delivery routea 80 57 (16.1)
Oral 158 (45.4) 90 12 (3.4)
Invasive 100 (28.7) Unspecified 267 (75.2)
Others 90 (25.9) Gender
Female 7 (2.0)
a
Seven trials administering treatments via mixed routes were excluded Mixed 348 (98.0)
Leg treated
Single 6 (1.7)
Classification of gender-specific conditions mentioned in
Bilateral 14 (3.9)
eligibility criteria was also examined. Pregnancy (26.2 %)
Mixed 335 (94.4)
was most commonly indicated as reason for excluding pa-
Osteoarthritis type
tient from a trial, followed by lactation (16.1 %) and no
Primary 79 (22.3)
contraception (14.1 %). Meanwhile, menopause (2.8 %)
Mixed 276 (77.7)
was sometimes pointed out as a reason for enrolling patients
Localization within knee
into a trial.
Medial 24 (6.8)
Lateral 1 (0.3)
Unspecified 330 (93.0)
Discussion
Osteoarthritis severity (KellgrenLawrence scale)
1 1 (0.3)
We reviewed data on eligibility criteria from 355 randomized
12 10 (2.8)
knee osteoarthritis trials and identified several key points.
13 32 (9.0)
First, ethical considerations, such as inability to give an
14 12 (3.4)
informed consent or medical conditions potential for risks
23 62 (17.5)
Table 3 Non-osteoarthritis-related reasons for excluding patients from 24 35 (9.9)
a trial 3 4 (1.1)
34 12 (3.4)
Trial number (%)
Unspecified 187 (52.7)
Inability to give an informed consent 282 (79.4) Pain status
Medical conditions causing risks by test treatments 198 (56.0) Painful 207 (58.3)
Medical conditions difficult to participate in a trial 203 (57.2) Non-painful/unclear 148 (41.7)
Musculoskeletal conditions difficult to interpret 82 (23.1)
outcomes BMI index was excluded because of monotonous information
Previous experience of test treatment 52 (14.7)
Recent experience of other potential treatments 218 (61.4)
Difficulty in adhering to a trial 27 (7.6)
by test treatments or by participation in a trial, were the
Difficulty in completing a trial 9 (2.5)
common non-osteoarthritis-related reasons. Second, al-
Difficulty in communication 26 (7.3)
though a large number of trials did not specify age and
osteoarthritis severity, patients with 40 to 80 years in age
Participation in other trials 25 (7.0)
and grade 2 in the KellgrenLawrence scale were mostly
Clin Rheumatol (2013) 32:15691574 1573
Table 5 Categories of pain-related reasons for enrolling patients into a We also found that some factors such as age, osteoarthritis
trial
severity, and pain intensity were considered as eligibility
Trial number (%) criteria. With respect to several factors, the possibility of
applying trial results to a clinical practice may be conjectured.
Pain confirmation 207a For example, it has been reported that the prevalence of
Visual analog scale 134 (64.7) radiographic and symptomatic osteoarthritis increases sharply
WOMAC pain subscale 19 (9.2) with age [26, 27]. Besides, according to a study comparing the
Failure of previous treatment including analgesics 19 (9.2) prevalence of a Dutch village with those of different popula-
Present use of analgesics 34 (16.4) tions, only 10 % of men and women had evidence of knee
Unspecified 30 (14.5) osteoarthritis by 40 years of age [28]. This fact may justify
Lower boundary of visual analog scaleb (mm) 132 40 years of age considered as a cutoff point in knee osteoar-
020 11 (8.3) thritis trials.
2040 106 (80.3) Regarding other factors, however, it cannot be concluded
4060 14 (10.6) at present whether the generalizability of the trial results is
6080 1 (0.8) possible. This difficulty reflects limitations of our study. In
Upper boundary of visual analog scaleb (mm) 16c this study, eligibility criteria were investigated that were
6080 9 (56.3) considered as a cutoff point in the trials. Because we do not
80100 5 (31.3) know the actual rate of patients with such factors in the trials,
Lower boundary of WOMAC pain subscaleb 19 we cannot determine the possibility of the generalizability.
02 1 (5.3) Likewise, there are few studies showing reference data on
24 3 (15.8) the rate of patients with factors of interest. While there are
46 5 (26.3) numerous studies showing differences between patients with
68 8 (42.1) and without knee osteoarthritis (e.g., prevalence study [26]),
810 2 (10.5) we could not find reports presenting rates of patients with
Upper boundary of WOMAC pain subscaleb 3 specific factors.
1416 2 (66.7) This is a first report that investigated eligibility criteria in
1618 1 (33.3) knee osteoarthritis by using predetermined criteria. This
study revealed that knee osteoarthritis trials employed a
Percentage is category specific variety of items in the eligibility criteria. Whereas numerous
WOMAC Western Ontario and McMaster Universities Arthritis Index trials enrolled patients without specifying factors, other trials
a
Multiple criteria were reported by some trials focused on patients with specific factors. These varied eligi-
b
ab, >a, and b bility criteria may cause severe systematic biases, thus
c
Two trials did not specify criteria impairing the generalizability. As suggested in a previous
study [13], broad or consistent eligibility criteria may be
necessary to reduce such biases. Therefore, future studies
enrolled in other trials. Third, when trials investigating pain- should investigate the impact of such eligibility criteria. We
ful knee were considered, patients with 2040 mm in the believe that these findings will provide useful implications in
VAS and 68 in the WOMAC pain subscale were com- the design and conduct of clinical trials.
monly enrolled.
Previously, a large number of studies investigated the
generalizability of results obtained from clinical trials Disclosures None.
[513]. Although eligibility criteria were found to influence
the characteristics of patients participating in trials [13], few
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