Trials (cid:9)
`
`VIA Central
`
`Op
`Review
`Outcome measurement in clinical trials for Ulcerative Colitis:
`towards standardisation
`Rachel M Cooney", Bryan F Warren', Douglas G Altman2, Maria T Abreu3
`and Simon PL Travis*"
`
`Address: 1Gastroenterology Unit, John Radcliffe Hospital, Oxford, OX3 9DU, UK, 2Centre for Statistics in Medicine, University of Oxford, Oxford,
`UK and 3lnflammatory Bowel Disease Center, Mount Sinai Hospital, Division of Gastroenterology, New York, New York USA
`Email: Rachel M Cooney - rachel.cooney@clinical-medicine.oxford.ac.uk; Bryan F Warren - bryan.warren@orh.nhs.uk;
`Douglas G Altman - doug.altman@cancer.org.uk; Maria T Abreu - maria.abreu@mssm.edu; Simon PL Travis* - simon.travis@ndm.ox.ac.uk
`* Corresponding author
`
`Published: 25 June 2007
`
`Trials 2007, 8:17 doi:10.1186/1745-6215-8-17
`
`Received: 2 January 2007
`Accepted: 25 June 2007
`
`This article is available from: http://www.trialsjournal.com/content/8/1/17
`
`© 2007 Cooney et al; licensee BioMed Central Ltd.
`This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)
`which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
`
`Abstract
`Clinical trials on novel drug therapies require clear criteria for patient selection and agreed
`definitions of disease remission. This principle has been successfully applied in the field of
`rheumatology where agreed disease scoring systems have allowed multi-centre collaborations and
`facilitated audit across treatment centres. Unfortunately in ulcerative colitis this consensus is
`lacking. Thirteen scoring systems have been developed but none have been properly validated.
`Most trials choose different endpoints and activity indices, making comparison of results from
`different trials extremely difficult. International consensus on endoscopic, clinical and histological
`scoring systems is essential as these are the key components used to determine entry criteria and
`outcome measurements in clinical trials on ulcerative colitis. With multiple new therapies under
`development, there is a pressing need for consensus to be reached.
`
`Background
`Clinical trials determining the efficacy of new treatments
`need internationally agreed standardised endpoints. Only
`these allow studies to be compared and, importantly,
`combined for greater statistical power and a more reliable
`estimate of the benefits and harms of an intervention.
`Agreement on endpoints has been achieved for trials in
`rheumatology (Outcome Measures in Rheumatology,
`OMERACT [1]. OMERACT's consensual approach has
`been extremely successful and we feel that this approach
`now needs to be applied to trials of inflammatory bowel
`disease.
`
`In the field of gastroenterology there are many exciting
`new drugs in development, with great prospects for the
`
`treatment of ulcerative colitis in particular. International
`consensus on the endoscopic, clinical and histological
`scoring systems is essential as these are the key compo-
`nents used to determine entry criteria and outcome meas-
`urements in clinical trials of ulcerative colitis. As the aim
`of all clinical trials is to determine whether an interven-
`tion results in clinical response and/or remission, with an
`acceptable adverse event profile, an agreed definition of
`these parameters is paramount. Whereas in rheumatology
`joint space narrowing may be measured with simple radi-
`ography, in inflammatory bowel disease direct measures
`are more difficult and often involve endoscopy. In this
`paper we discuss the systems currently available and their
`limitations. We propose potential solutions, focussing in
`
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`particular on the issue of interobserver variation in sig-
`moidoscopy.
`
`Clinical scores
`The multiplicity of clinical activity indices used for scoring
`ulcerative colitis has recently been comprehensively
`reviewed [2]. No less than seven different symptom-based
`activity scores, two composite scores, and four evaluation
`scoring systems have been used in ulcerative colitis [3-16]
`[Table 1]. The names of the indices also vary between dif-
`ferent publications which exacerbates the confusion
`[Table 2]. The scores vary in the use of objective measure-
`ments (stool frequency, temperature, pulse rate, results of
`blood tests), subjective components (physician's global
`assessment, general well being), and sigmoidoscopy,
`which is itself open to wide inter-observer variation [Table
`3].
`
`In 1955 Truelove and Witts [3] were the first to attempt to
`quantify disease activity defining mild, moderate and
`severe disease. Endoscopy was added into a continuous
`scale developed by Powell-Tuck and colleagues [4]. In the
`early 1980s the eleven components of this index were sim-
`plified in the Mayo score [5] and the Ulcerative Colitis
`Disease Activity Index (UCDAI or Sutherland Index) [6],
`which have three clinical variables and an endoscopy
`score. Later, Rachmilewitz proposed the Clinical Activity
`Index (CAI) which includes laboratory data as well as clin-
`ical and endoscopic variables [7]. Other non-invasive
`indices have been developed including the Seo index [9]
`
`Table I: Summary of activity indices used for ulcerative colitis
`
`which measures symptoms and some simple laboratory
`values (haemoglobin, erythrocyte sedimentation rate and
`albumin) and the simple clinical colitis activity index
`(SCCAI) [10] which has six clinical questions only. How-
`ever, none of these scoring systems has been validated
`with a formal evaluation of their biometric properties
`(responsiveness, reliability and validity) [17].
`
`Scoring systems for ulcerative colitis are driven by the
`need to select appropriate patients and monitor response
`in clinical trials, which is why interest waxes in time with
`drug development (steroids in the 1950s, sulfasalazine in
`the next two decades, mesalazine in the 1980s and
`ciclosporin in the 1990s). Now, in 2007, there are up to
`30 new agents being evaluated for the treatment of ulcer-
`ative colitis in phase 2 and 3 trials [18], and there has been
`a resurgence of interest in scoring systems. Yet only one
`system (Truelove and Witts' [3]) is simple and objective
`enough to use in clinical practice, as well as aiding clinical
`decision making, but this score suffers from a lack of
`responsiveness to changes in symptoms following an
`intervention. Consequently the Food and Drug Adminis-
`tration (FDA) currently favours the Mayo score, or Disease
`Activity Index (DAI) [5], for trial design in ulcerative coli-
`tis, although it is not yet completely wedded to this. This
`brings arbitrary uniformity, but fails to bring objectivity,
`because the Mayo scoring system includes the highly sub-
`jective 'physician's global assessment'. Furthermore, the
`score includes a sigmoidoscopy subscore which is itself
`subjective, contributing additional variability and lack of
`
`Index
`
`Clinical/biomedical
`Truelove &Witts'
`Powell Tuck
`Rachmilewitz
`Lichtiger
`Seo
`Walmsley
`Feagan
`
`Composite (clinical and endoscopic)
`Schroeder
`Sutherland
`
`Evaluation
`Physician's Global Evaluation
`Investigator's Global Evaluation
`Individual Symptom Score
`Patient Defined Remission
`
`Quality of life
`Inflammatory Bowel Disease Questionnaire
`Short-form 36
`
`Year
`
`Also known as
`
`References
`
`1955
`1978
`1988
`1990
`1992
`1998
`2005
`
`1 987
`1987
`
`1993
`1998
`2002
`2005
`
`St Mark's Index
`Clinical Activity Index (CAI)
`Modified Truelove &Witts' Severity Index
`Activity index (Al)
`Simple Clinical Colitis Index (SCCAI)
`Ulcerative Colitis Clinical Score (UCCS)
`
`Mayo score, Disease Activity Index (DAI)
`Ulcerative Colitis Disease Activity Index (UCDAI)
`
`PGA
`
`IBDQ
`SF36
`
`3
`4
`7
`8
`9
`10
`14
`
`5
`6
`
`I (cid:9) I
`12
`13
`19
`
`15
`39
`
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`(7j
`(3) (cid:9)
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`4- (cid:9)
`o 2
`co (cid:9)
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`a) (cid:9)
`ca.z
`a)
`co (cid:9) F,
`•-.,B.
`,..,. o
`O
`
`0
`,..
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`E
`0
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`0)
`
`Table 2: Summary of different properties measured in clinical activity indices
`
`Author and name of index
`
`Truelove &Witts [3]
`
`Powell-Tuck [4]
`
`Schroeder [5]
`
`Rachmilewitz [7]
`
`Lichtiger [8]
`
`Seo [9]
`
`Walmsley [10]
`
`Property
`
`St Mark's index
`
`Mayo score, Disease
`Activity Index (DAI)
`
`Clinical Activity Index
`(CAI)
`
`Modified Truelove &Witts'
`Severity Index (MTWSI)
`
`Activity Index
`
`Score range
`
`Mild, Moderate, Severe
`
`0-24
`
`0-12
`
`0-23
`
`0-21
`
`70-300
`
`Bowel frequency/24 hrs
`
`<4 (mild) >6 (severe)
`
`0-2 (<3 to >6)
`
`0-3 (normal to (cid:9)
`above normal)
`
`5
`
`0-3(<18 to >60/week)
`
`0-4 (cid:9)
`
`2 to (cid:9)
`
`10)
`
`add total number/24
`hr x 13
`
`Stool form
`
`Urgency
`
`Blood
`
`Abdominal Pain
`
`Abdominal tenderness
`
`General well-being
`
`Anorexia
`
`Nausea/Vomiting
`
`Extra-intestinal features
`
`Fever
`
`Tachycardia
`
`Anaemia
`
`ESR mm/hr
`
`Albumin
`
`Sigmoidoscopy
`
`Global assessment
`
`0-2
`
`0-2
`
`0-2
`
`0-4
`
`0-3
`
`0-1
`
`0—I
`
`0-3
`
`0-3
`
`0-4
`
`0-3
`
`0-3
`
`0-9
`
`Need for antidiarrhoeal
`agents
`
`Faecal incontinence 0 or I
`
`0-3
`
`0-3
`
`0-5
`
`add bloody stools/24
`hr x 60
`
`>37.5°C (severe)
`
`0 — 2 (<37.1 to >38°C)
`
`0 (<38°C) or 3 (>38°C)
`
`>90
`
`<75% of normal
`
`>30
`
`0-2
`
`0-3
`
`0-3
`
`0 or 4
`
`0-2
`
`0-12
`
`0-3
`
`subtract value x 4
`
`add value x 0.5
`
`subtract value x 15
`
`0-5
`
`Score = sum of the
`above and add 200
`
`Simple Clinical
`Colitis Index
`(SCCAI)
`
`0-20
`
`0-3(day)
`I-2(night)
`
`0-3
`
`0-3
`
`0-4
`
`0-4
`
`0-5
`
`Note: precise details of the individual components of each score are too complex to be included in a single table: refer to original article or ref [2]
`
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`Table 3: Endoscopic scores for ulcerative colitis
`
`Score [ref]
`
`0
`
`2
`
`3
`
`4
`
`Baron [ 21]
`
`Normal: matt mucosa,
`ramifying vascular
`patter clearly visible,
`no spontaneous
`bleeding, no bleeding
`to light touch
`
`Abnormal, but non-
`haemorrhagic:
`appearances between
`0 and 2
`
`Powell-Tuck [4]
`
`Non-haemorrhagic
`(no bleeding
`spontaneously or on
`light touch)
`
`Haemorrhagic
`(bleeding on light
`touch, but no
`spontaneous bleeding
`ahead of instrument)
`
`Rachmilewitz [7]
`
`Lemann [16]
`
`No granulation
`scattering light,
`normal vascular
`pattern, no mucosal
`vulnerability, no
`mucosal damage
`(mucus, fibrin,
`exudates, ulcer)
`Normal mucosa
`
`Schroeder [5]
`
`Normal or inactive
`disease
`
`Faded or disturbed
`vascular pattern
`
`Oedema and/or loss
`of mucosal vascularity,
`granularity
`
`Mild (erythema,
`decreased vascular
`pattern, mild friability)
`
`Sutherland [6]
`
`Normal
`
`Mild friability
`
`Moderately
`haemorrhagic:
`bleeding to light
`touch, but no
`spontaneous bleeding
`seen ahead of the
`instrument on initial
`inspection
`Haemorrhagic
`(spontaneous bleeding
`seen ahead of
`instrument on initial
`inspection and
`bleeding to light
`touch)
`Granulation scattering
`light, completely
`absent vascular
`pattern, contact
`bleeding, slight
`mucosal damage
`
`Friability (visible,
`induced bleeding on
`examination),
`petechiae
`Moderate (marked
`erythema, absent
`vascular pattern,
`friability, erosions)
`Moderate friability
`
`Feagan [14]
`
`Normal, smooth,
`glistening mucosa,
`with vascular pattern
`visible; not friable
`
`Granular mucosa;
`vascular pattern not
`visible; not friable;
`hyperaemia
`
`As I, with a friable
`mucosa, but not
`spontaneously
`bleeding
`
`Severely
`haemorrhagic:
`spontaneous bleeding
`seen ahead of
`instrument at initial
`inspection and bleeds
`to light touch
`
`Spontaneous
`bleeding„ pronounced
`mucosal damage
`
`Spontaneous
`haemorrhage, visible
`ulcers
`
`Severe (spontaneous
`bleeding, ulceration)
`
`Exudation,
`spontaneous
`haemorrhage
`As 2, but mucosa
`spontaneously
`bleeding
`
`As 3, but clear
`ulceration; denuded
`mucosa
`
`precision. Also, the physician's global assessment takes
`into account the sigmoidoscopy score and is therefore not
`independent of the other elements.
`
`There is in fact no reason to combine clinical, sigmoidos-
`copy, histopathology and quality of life variables into a
`single index. Indeed there is a strong argument against
`this. It is much easier to validate separate scoring systems
`for each component. Clinical trials can then be based on
`four validated scores, at least two of which (histology and
`quality of life) would usually be secondary endpoints.
`Indeed, even endoscopic mucosal healing could be a sec-
`ondary endpoint, since this represents a tiny component
`(<1%) of complete remission, compared to subjective
`clinical remission recognised by the patient [19]. These
`endpoints remain, however, important to measure
`because they may influence long term outcome measures,
`
`such as the potential link between inflammation and car-
`cinogenesis.
`
`Despite careful evaluation of the strengths and weak-
`nesses of all of these indices in the review of activity indi-
`ces by authors from the International Organisation for
`Inflammatory Bowel Disease (IOIBD) [2], there is no
`escaping the fact that there has been no validation, nor
`any determination of inter-observer variability in scoring
`between indices. This has to be done. It is otherwise
`impossible to determine which index shows greatest con-
`sistency between observers, which matters enormously
`when investigators from four continents are recruiting
`patients to the same clinical trial. A practical example of
`the dilemma that this presents was the finding in 2006
`that patients admitted from Russian centres to a clinical
`trial of a p38 MAP kinase inhibitor had significantly
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`higher remission and response rates than non-Russian
`centres [20].
`
`Endoscopic scores
`The general endoscopic grading system for ulcerative col-
`itis was defined more than forty years ago by Baron et al
`[21]. It has been used in all trials of active ulcerative colitis
`to this day, with only minor (and unvalidated) modifica-
`tion [5]. The durability of this scoring system is astonish-
`ing; especially when it is considered that it was derived
`form observations made by 3 observers in 60 patients
`using rigid sigmoidoscopy. Nevertheless, the description
`and assessment of each component (compared to the
`unvalidated terms used by other indices, Table 3) means
`that it has largely stood the test of time. Four grades are
`defined (0-3) by the Baron score according to the severity
`of macroscopic inflammation of the rectal mucosal
`appearances at rigid sigmoidoscopy [Table 3]. The score
`has not been validated using flexible sigmoidoscopy and
`higher resolution endoscopes. Seven other endoscopic
`scoring systems have since been proposed, but none has
`gained similar acceptance 121.
`
`Baron and two colleagues identified 14 visible variables
`that they scored and compared between observers [Table
`4]. There was 40% disagreement on grading appearances
`as normal, mild, moderate, or severe activity. Not surpris-
`ingly, binary variables (present or absent) were associated
`with greater inter-observer agreement than graded varia-
`bles. Unfortunately kappa scores are not available as the
`paper was written before the kappa statistic was widely
`applied to clinical medicine [22]. One variable, mucosal
`friability was pivotal in discriminating between mild and
`moderately active ulcerative colitis. This has acquired
`immediate clinical relevance now that common therapy
`has been shown to work for moderately active, but not
`mild, ulcerative colitis [23]. Friability in Baron's time was
`evaluated by wiping the mucosa with a cotton wool
`pledget on biopsy forceps or 'rocket swab' and seeing
`whether this provoked mucosal bleeding. The pressure
`needed and techniques were never defined, nor has this
`technique been validated in the era of flexible sigmoidos-
`copy when cotton wool pledges and rocket swabs are
`obsolete. Nevertheless, mucosal friability assessed at flex-
`ible sigmoidoscopy remains the pivotal discriminator not
`only for entry into clinical trials, but also for determining
`outcome. Patients who have no mucosal friability (Baron
`= 1 or 0) at outcome are deemed to have responded, as
`long as the mucosal friability (Baron = 2 or 3) was present
`at trial entry.
`
`Despite grading the severity of the appearance, the criteria
`did not claim any relation to disease severity. Baron et al
`observed that 'No attempt has been made to correlate
`these appearances with the clinical course or histological
`
`Table 4: Visible variables at sigmoidoscopy [21]
`
`Visible variable
`
`Agreement
`(3 observers)
`
`• Spontaneous bleeding (present or absent)
`• Friability = 'bleeding to light touch' (present or
`absent)
`• Moisture (normal 'dry', moist, 'oedematous)
`• Distensibility (normal, rigid/contracted)
`• Valves (normal sharp crescent folds, swollen,
`absent)
`• Large deep vessels (visible, not seen)
`• Ulcers (present or absent*)
`• Polyp (present or absent*)
`
`• Granularity (normal smoothness, granular)
`• Mucosal surface (attempt to describe the sheen on (cid:9)
`the mucosa: normal mat, dull lustreless; wet shiny)
`• Colour (red, pink, pale)
`• Mucopus (no mucus or pus, clear mucus, opaque
`pus)
`• Faeces (none, solid, liquid)
`Small superficial vessels (normal, few, patchy)
`
`>60%
`
`<60%
`
`*:100% agreement, because none seen
`
`appearances' [21]. Remarkably, after 40 years, the score
`has still not been validated against clinical symptoms or
`histopathology of biopsy specimens. Nor has it been vali-
`dated against outcome, although attempts have been
`made to correlate symptomatic (clinical) activity and
`endoscopic appearance (below). Furthermore, despite
`wide inter-observer variation and the pivotal role of
`endoscopy in clinical trials of ulcerative colitis [2,23-26],
`there has also been no attempt to determine intra-
`observer variation of scores using flexible sigmoidoscopy
`and digital imaging records viewed by the same observer
`on different occasions.
`
`Remission in ulcerative colitis
`As if controversy about measuring disease activity was not
`enough, even disease remission has been neither defined
`nor validated. Remission is the outcome that matters in
`clinical trials, so agreement on the definition of remission
`is essential. Defining remission should logically be the
`starting point of agreeing how to measure activity in ulcer-
`ative colitis.
`
`There are, however, at least three definitions of remission
`for ulcerative colitis. These may be termed clinical, regis-
`tration and complete remission [Table 5]. Clinical remis-
`sion is what is used in everyday clinical practice, meaning
`cessation of rectal bleeding and a normal stool frequency.
`This is not the same as 'registration' remission (the one
`currently, but not exclusively favoured by the FDA), which
`means cessation of rectal bleeding and a sigmoidoscopy
`score of 0 or 1 (equivalent to a normal appearance of the
`rectal mucosa, or erythema only [Table 3]). This, in turn is
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`not the same as complete remission, which implies nor-
`mal stool frequency, no rectal bleeding and a normal or
`quiescent appearances of the mucosa at sigmoidoscopy.
`The potential impact of these three definitions is consid-
`erable, but many trials simply use an arbitrary threshold
`to define the 'remission' endpoint. This is either 0, 1 or 2
`of one of the disease activity indices, or <150 in the com-
`plex Seo index [2]. This variation makes it difficult to
`know what a trial means, because obscured in these low
`scores can be symptoms (such as bleeding or increased
`stool frequency) that clinicians and their patients would
`not recognize as remission. Because most trials choose dif-
`ferent endpoints, let alone different activity indices, com-
`paring the results of different trials is exceptionally
`difficult and the conduct of systematic reviews is seriously
`impeded.
`
`The Disease Activity Index (DAI, or Mayo score) is one of
`the most widely used of the activity indices in clinical tri-
`als. The impact of different definitions of remission using
`the DAI is illustrated by one large patient cohort. The
`ASCEND studies included a total of 687 patients with
`mild to moderately active ulcerative colitis, treated with
`2.4 g or 4.8 g mesalazine [25,26]. Using these three differ-
`ent definitions of remission, the remission rate varied
`more than two-fold. When the DAI was 0, it was 22% (in
`other words, 'complete remission'); when the DAI was 1
`the remission rate was 28% (meaning no bleeding and
`normal frequency, with at least a 1 point decrease in sig-
`moidoscopy score), but when 'remission' meant a DAI
`2, it was 50% (meaning total score < 2, with no individual
`subscore >1) [26]. This last definition of 'remission' is that
`used in the ACT trials of infliximab for ulcerative colitis
`refractory to standard therapy [27]. This is an extraordi-
`nary degree of variation; it is no wonder that doctors and
`patients are confused by different activity indices of clini-
`cal trials. When inter-observer variation in sigmoidoscopy
`scoring is factored in, the confusion becomes still greater.
`
`Inter-observer variation in sigmoidoscopy assessment
`Inter-observer variation in sigmoidoscopy scoring is a cru-
`cial issue for regulatory authorities, since registration
`remission is based on just two components, sigmoidos-
`copy score and rectal bleeding. Investigators should
`expect variation between observers and expect that this
`
`Table 5: Definitions of remission in ulcerative colitis [40]
`
`variation is greatest when subjective assessments are
`made. What is required is that this variation is quantified.
`Recognition of this variation in clinical trials, further-
`more, should lead both to training of observers in agreed
`standards and at least one additional observer when sub-
`jective assessments that are pivotal in regulatory terms
`(such as endoscopy) are being made. When an independ-
`ent observer re-evaluated the sigmoidoscopy videos in a
`recent therapeutic trial of 335 patients with active ulcera-
`tive colitis, the observer disagreed with the investigators'
`sigmoidoscopy score in 12-23% of cases [28]. The impact
`on the remission rates of this variation in the sigmoidos-
`copy score was a median difference of 19% (range -10 to
`22%) for absolute clinical, registration and complete
`remission. If results were then analysed according to the
`independent observer's score, remission rates were
`reduced in absolute terms by 10-16% for registration, but
`by <3% for clinical or complete remission. It is not sur-
`prising that registration remission rates were most
`affected. The implications are substantial. Inter-observer
`variation alone has the potential to make the difference
`between a therapeutically significant outcome and no
`response, and between licensed approval and no licence.
`
`Correlation between clinical activity and endoscopic
`mucosal appearance
`It has been widely assumed that the activity of ulcerative
`colitis is related to the mucosal appearances seen at sig-
`moidoscopy. The concept is reasonable, but confidence is
`misplaced when sigmoidoscopic assessment is so subjec-
`tive and clinical activity unvalidated [29]. When 222
`observations of 10 symptoms and signs were compared
`with the sigmoidoscopic appearance, only the distinction
`between mucosa that bled spontaneously and that which
`bled on light touch or scraping was clinically meaningful
`in discriminating between moderate and severe disease
`[5]. Another study examined inter-observer agreement in
`the assessment of ulcerative colitis in 273 videotaped
`colonoscopies performed by 46 different endoscopists
`and then evaluated by two independent observers [30].
`There was agreement on mucosal friability, spontaneous
`bleeding and mucopurulent exudates, which broadly cor-
`related with clinical disease activity and histological activ-
`ity scores. However, it has to be recognised that
`sigmoidoscopy contributes very little to complete remis-
`
`Characteristic
`
`Stool frequency
`
`Rectal bleeding
`
`Sigmoidoscopy score
`
`Clinical remission
`Registration remission
`Complete remission
`
`Normal
`
`Normal
`
`Absent
`Absent
`Absent
`
`Normal or only erythema
`Normal or only erythema
`
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`sion (which includes symptomatic and endoscopic remis-
`sion), compared to patient-defined remission (normal
`stool frequency, lack of urgency and bleeding) 1191. The
`different descriptive terms illustrate the need for mini-
`mum standard terminology for describing the mucosal
`appearance at sigmoidoscopy.
`
`Histology scores
`Paradoxically the histological grading of ulcerative colitis
`has been subjected to the closest scrutiny 131-371,
`although histology is neither a criterion in any of the scor-
`ing systems, nor considered essential for the conduct of
`clinical trials by the FDA. Even so, eight separate scoring
`systems have been described for ulcerative colitis [2],
`although only three are widely used [ [11,36] and [37]].
`Inter-observer agreement has been assessed in a blinded
`fashion for 19 features. The features that provided most
`consistency (in distinguishing ulcerative colitis from
`Crohn's disease) were diffuse crypt architectural irregular-
`ity, general crypt epithelial polymorphs and reduced crypt
`numbers [35]. Binary variables (implying a 'yes' or 'no'
`answer, or ordered categorical variables) ensured the
`greatest agreement, as it was for endoscopy. Practical
`application of these variables was further tested between
`specialist gastrointestinal histopathologists, general his-
`topathologists and trainees. Specialist histopathologists
`found location of neutrophils (in the lamina propria or
`between epithelial cells), the occurrence of crypt destruc-
`tion, and the presence of erosions or ulcers to be the most
`consistent variables [36]. Once trained in identifying spe-
`cific features, inter-observer variation between general his-
`topathologists and trainees was similar (Kappa = 0.64 and
`0.53 respectively). This implies that training is valuable,
`because it can both reduce interobserver variation and
`potentially reduce the need for specialist observers
`
`Although histopathology of rectal biopsy specimens is not
`currently a trial requirement, there is a strong case for
`making it so. This is for reasons of diagnosis, safety and
`validation. Clinical trials in ulcerative colitis are recruiting
`centres in areas of the world (Eastern Europe, India, Rus-
`sia, and South America) that are not widely recognised as
`having a clinical or research background in ulcerative col-
`itis. Histopathology can corroborate the diagnosis,
`exclude infection (an important safety issue with biother-
`apy) and provide a permanent record. Trial validity is
`enhanced, because if a patient said to have active colitis
`actually has normal histology, then the diagnosis is wrong
`and the patient should not have been included in the trial.
`Furthermore, as mucosal healing emerges as a trial end-
`point [38], histology provides independent corrobora-
`tion.
`
`Unmet needs
`There is consequently a pressing need to quantify inter-
`observer variation in videoendoscopic assessment of
`
`ulcerative colitis, and to study its relation to clinical symp-
`toms and histopathology. The starting point should be to
`define the criteria for disease remission in a way that US
`and European drug regulatory authorities (FDA and
`EMEA) will recognise. Assessment of the degree of change
`in endoscopic score also needs to be quantified. Clinical
`trials have, until now, depended on unmatched scores at
`a single time point, rather than on paired assessments.
`This is because making a permanent endoscopic record
`has never been part of the procedure. Agreement on stand-
`ard outcomes for clinical trials is fundamentally impor-
`tant. Such agreement can only be achieved by common
`consent among authorative bodies of experts (such as the
`International Organisation of Inflammatory Bowel Dis-
`ease, IOIBD, or the European Crohn's and Colitis Organ-
`isation, ECCO), in conjunction with patient-perspectives.
`Such standard outcomes then have to be validated
`through clinical trials.
`
`Apart from questions that matter to drug regulatory
`authorities, there are key questions of clinical relevance,
`which also affect the conduct and outcome measurement
`of trials [Table 6]. For instance, How often is there endo-
`scopic activity when there is clinical remission? How often
`is the endoscopy normal when there is clinical disease
`activity? How often is there endoscopic activity when
`there is histological remission? and, How often is the
`endoscopy normal when there is histological activity.
`
`Potential solutions
`To answer these questions demands a substantial resource
`of information, but this too can be defined:
`
`1. Videoendoscopy of patients with active ulcerative coli-
`tis before and after treatment.
`
`Table 6: Unmet needs for outcomes of trials in ulcerative colitis
`
`(cid:226) Develop a consensus definition of remission
`For each index of disease activity:
`
`(cid:226) Quantify the inter-observer variation for disease activity
`
`Quantify the inter-observer variation for the degree of change
`between paired videos
`
`(cid:226) Evaluate the relation between endoscopic score and clinical
`symptoms
`
`>Evaluate the relation between endoscopic activity and histological
`activity
`
`(cid:226) Develop a consensus on a standard set of outcomes of disease
`activity to collect and report
`
`'Develop a consensus on a standard set of outcomes of clinical
`relevance to patients to collect and report (e.g. time to steroid-free
`remission, cumulative time off work or normal activities, hospital
`admission, colectomy)
`
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`2. Standardisation of endoscopy preparation, procedure
`and assessment of mucosal friability.
`
`3. Contemporaneous clinical scores on stool frequency
`and rectal bleeding.
`
`4. Matching mucosal biopsies from pre-determined sites.
`
`The process would necessitate a random selection of vid-
`eoendoscopies to be scored according to pre-determined
`criteria evolving from Table 2, by a group of acknowl-
`edged authorities in endoscopic and clinical practice, so
`that a kappa statistic with narrow confidence interval can
`be calculated for each component. Pre- and post-treat-
`ment videoendoscopies would be randomised to avoid
`explicit pairing and allow consistency to be evaluated, as
`well as the ability to determine the degree of change
`between videos from the same individual. The group of
`features with the least inter-observer variation would then
`be available for a validated scoring system. This need not
`be limited by the graded terms mild, moderate, or severe,
`but could simply define features such as mucosal friabil-
`ity, spontaneous bleeding or mucosal ulceration. Correla-
`tion between endoscopic appearance, clinical features and
`histology is then possible.
`
`Such a resource exists as a consequence of a recent clinical
`trial on ulcerative colitis. (EUDRACT no: 2004-004077-
`29). There are 670 videoendoscopies available for review
`(paired videos on each of 335 patients). These endoscop-
`ies were performed by experienced endoscopists who
`received specific training on the conduct of procedures for
`the study, and this training was reinforced when the inde-
`pendent observer disagreed with the investigator's sig-
`moidoscopy score during the trial. The criteria for the
`conduct of the procedure, including preparation, tech-
`nique of eliciting mucosal friability, and biopsy sites were
`pre-determined. Plans are in place to select videoendo-
`scopies for analysis by a group of experts in endoscopy
`an