CCR-12-3722 1..11Trial Designs for Personalizing Cancer Care: A Systematic Review and Classification
Parvin Tajik1,2, Aleiko H. Zwinderman1, Ben W. Mol2, and Patrick M. Bossuyt1
Abstract There is an increasing interest in the evaluation of prognostic and predictive biomarkers for personalizing
cancer care. The literature on the trial designs for evaluation of these markers is diverse and there is no
consensus in the classification or nomenclature. We set this study to review the literature systematically, to
identify the proposed trial designs, and todevelop a classification scheme.We searchedMEDLINE, EMBASE,
Cochrane Methodology Register, and MathSciNet up to January 2013 for articles describing these trial
designs. In each eligible article, we identified the trial designs presented and extracted the term used for
labeling the design, components of patient flow (marker status of eligible participants, intervention, and
comparator), study questions, and analysis plan. Our search strategy resulted in 88 eligible articles, wherein
315 labels had been used by authors in presenting trial designs; 134 of these were unique. By analyzing
patient flow components, we could classify the 134 unique design labels into four basic patient flow
categories, which we labeled with the most frequently used term: single-arm, enrichment, randomize-all,
and biomarker-strategy designs. A fifth category consists of combinations of the other four patient flow
categories. Our review showed that a considerable number of labels has been proposed for trial designs
evaluating prognostic and predictive biomarkers which, based on patient flow elements, can be classified
into five basic categories. The classification system proposed here could help clinicians and researchers in
designing and interpreting trials evaluating predictive biomarkers, and could reduce confusion in labeling
and reporting. Clin Cancer Res; 19(17); 1–11. 2013 AACR.
Introduction Recent progress in understanding the molecular basis of
cancer has redefined the landscape for achieving stratified and personalized medicine for patients with cancer. Ongo- ing efforts concentrate on the translation of thesemolecular insights into biomarkers that can reliably guide application of existing and new cancer treatments. Biomarkers that are informative for selecting treatment
can be broadly classified as prognostic or predictive bio- markers. Prognostic biomarkers classify patients treated with standard therapies—including no treatment, if that is standard practice—into subgroups with distinct expected clinical outcomes. Predictive biomarkers identify patients whose tumors are likely to be sensitive or resistant to a specific agent (1). Valid and definitive evidence showing
the clinical use of these biomarkers can be obtained by conducting well-designed clinical trials with adequate sam- ple size (1–3). These clinical trials are planned to evaluate biomarker-based treatment strategies. Their design often differs from the more conventional comparative clinical trials of interventions. Following the recent dramatic devel- opments in the technologies for identifying potential novel biomarkers and the huge increase in the number of claimed biomarkers, there has also been a great expansion in the number of trial designs proposed for validation of biomar- kers for treatment selection purposes.
A rapid review of the biomarker trial designs in the oncology literature suggests substantial variability in the designs, as well as in the terms proposed by authors for labeling them. This makes retrieval, interpretation, com- parison, and critical appraisal of these types of studies complicated for consumers of trial results, who can be practicing physicians, researchers, or policymakers. The variability in labeling is a phenomenon typical for many rapidly developing areas of science. However, now that the field is maturing, and experts in other fields of medicine, such as cardiovascular diseases and infectious diseases, have started to apply the methodologic achievements of the oncology biomarker trials, it is time for harmonizing the terminologies in use and framing a classification of the designs. A harmonized terminology for describing bio- marker clinical trials and a simple classification scheme may help in speeding up the translation process of the
Authors' Affiliations: Departments of 1Clinical Epidemiology, Biostatistics and Bioinformatics and 2Obstetrics and Gynaecology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
Corresponding Author: Parvin Tajik, Department Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Room J1b-210, PO Box 22700, 1100 DE Amsterdam, the Netherlands. Phone: 31-20-56-66-877; Fax: 31-20-69-12-683; E-mail: P.Tajik@amc.uva.nl
doi: 10.1158/1078-0432.CCR-12-3722
Clinical Cancer
Published OnlineFirst June 20, 2013; DOI: 10.1158/1078-0432.CCR-12-3722
biomarker findings and could assist in paving the way for making personalized medicine a reality.
Here, we report on a systematic review of literature on trial designs for evaluating biomarkers for treatment selec- tion. The review is based on a comprehensive and system- atic search in multiple databases. We propose a classifica- tion scheme based on the flowof patients in these trials. The classification system is presented using recent biomarker clinical trials in oncology as examples, along with the main questions each category of designs can answer.
Materials and Methods Literature search
We searched MEDLINE, EMBASE, Cochrane Methodol- ogy Register, and MathSciNet up to 15 January 2013, and hand searched references and cited articles of all included studies using theWeb of Science database. The search filters that we developed and used in collaboration with a clinical librarian are presented in the Supplementary Materials and Methods. Eligible for inclusion were methodologic articles that described one or more trial designs for identification and/or validationof prognostic or predictive biomarkers for treatment selection. The searchwas not limited to oncology. No language restrictions were applied.
One author (P. Tajik) independently identified poten- tially eligible articles by reading titles and abstracts, whereas a second author (P.M. Bossuyt) independently screened a random sample of 400 abstracts to ensure that no abstracts weremissed. Therewas a 99%agreement on the selection of abstracts and disagreements were resolved in consensus discussions. Thereafter, full text copies of all potentially eligible articles were obtained and read in full. Articles were included if they satisfied the inclusion criteria.
Data extraction From all included articles and for each proposed trial
design, we extracted detailed data on the proposed design label, trial objectives, patient flow elements, and the analysis plan. Our definition of patient flow is composed of the bio- markerstatusofparticipantsdeemedeligible for thestudy, the intervention participants are assigned to (whether or not biomarker status is used for assigning study participants to the experimental treatment) and the comparator (standard treatment or both standard and experimental treatments).
Analysis We started our analysis by developing the list of study
labels from all included studies. For each label in the list, we explored the participant–intervention–comparator compo- nents of patient flow.We then clustered all study labels with identical components into disjoint categories. The most commonly used label for describing designs of each cate- gory was selected for labeling the corresponding category.
Results Search results
Our initial search yielded 2,506 abstracts, of which 136 were deemed eligible based on title and abstract. After
assessing the full texts of these 136 articles, 71 were included. Seventeen other articles were added by hand searching references and citing articles, resulting in a total of 88 articles in the final analysis (Supplementary Table S1). A summary of the search process is outlined in Fig. 1.
Trial design labels From the included articles, we could extract 315 design
labels. The identified labels and the definitions as pre- sented in the studies are listed in the Supplementary Table S2. By analyzing the extracted labels along with their patient flow components, we found 134 unique combinations of label and patient flow elements. There were many trial designs with the very same patient flow elements, which had received different labels. There were also a few labels used for describing designs with completely different patient flows. The 134 unique label and patient flow combinations are presented in Table 1. By comparing the patterns of all the included designs, we could distinguish four basic and distinct patient flow categories, as well as a fifth category, consisting of combinations of two or more of the four basic patient flow elements (Table 1). In a later section, we discuss these categories in more detail.
CCR Reviews
Databases searched using keywords
2,056 Abstracts identified 1680 PubMed
1313 EMBASE
Did they present a trial design for evaluating
markers for treatment selection?
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Trial design categories To ease the presentation, we present the flow elements for
two treatment options, labeled as experimental (Exp) and control (Ctrl), in the presence of a single, binary biomarker (Fig. 2). However, the flow diagrams are generalizable to conditions with more than two treatment options and in which the biomarker hasmore than two levels, or is numer- ic. For sake of simplicity and consistency, we define bio- marker positivity as the biomarker status that is associated with a better outcome on the experimental treatment. Therefore, in cases where overexpression of the biomarker is associated with a worse response to treatment, we con- sider the normal expression as biomarker-positive and overexpression as biomarker-negative. Single-arm. In single-arm trials, all patients, irrespective
of their biomarker status, are included in the trial and all undergo the experimental treatment (Fig. 2A; refs. 4–8). This trial has no control group, and no random assignment. Enrichment. With an enrichment design, all potentially
eligible patients are first tested for the biomarker and only biomarker-positives are randomly assigned to the experi- mental or control treatment. Other patients are in principle excluded from further investigation in the study (Fig. 2B). We found12 labels for describing this design,whichwere all interchangeable and referred to the main feature of the design: biomarker status performs as a key trial eligibility criterion (Table 1). The pivotal trial for trastuzumab is a well-known example
of an enrichment design (9). Patients with HER2-positive breast adenocarcinoma were enrolled and randomly allo- cated to chemotherapy with or without trastuzumab. This study provided strong evidence that trastuzumab combined with chemotherapy improves outcomes among women with HER2-positive breast cancer. Randomize-all. In designs in the randomize-all catego-
ry, all patients meeting the trial eligibility criteria, irrespec- tive of their biomarker status, are randomly allocated to either experimental or control treatment. Thereafter, asso- ciations between biomarker status and treatment response are evaluated (Fig. 2C). Because its eligibility criteria is not restricted by biomark-
er status, it has commonly been labeled as "randomize-all" (2, 10–13), "all-comers" (14–18), or "untargeted" (19–22). The design is also called "traditional" (23–25) or "conven- tional" (1, 26) because it has the samepatient flow elements as routine randomized controlled trials (RCT) for evaluat- ing treatment options. It is possible that researchers evaluate a biomarker retrospectively, using data and stored biospeci- mens collected in previously completed RCTs. In such scenarios, trials are commonly labeled as "biomarker anal- ysis within an existing RCT" (18) or "prospective/retrospec- tive" (27). All these label variations mainly refer to the timing of introducing the biomarker question to the trial. The type of randomization is another source of variability
in labeling of randomize-all trials. In cases where a simple 1:1 randomization procedure is applied to all patients, trials are labeled as "simple randomization" (28). However, in cases where the biomarker under evaluation is binary or
categorical with few categories, randomization can be done separately for each biomarker category through stratified randomization. Labels such as "biomarker-stratified" (29, 30), "stratified randomized" (31), "non-targeted RCT (strat- ified by marker)" (32), "stratified analysis" (25), "stratifi- cation" (33, 34), and "separate randomization" (35) all refer to this type of randomization. A special case of strat- ified randomization is when randomization is conducted bymeans of a Bayesian response-adaptive procedure, rather than a standard equal randomization procedure. The "Bayesian adaptive randomization design" by Zhou and colleagues is an example (36). It has also been called "outcome-based adaptive randomization" (5, 37).
The next source of variability in labeling the trials in the randomize-all category is the trial’s statistical analysis plan. In many cases, authors have coined a design label for referring to a randomize-all design when analyzed on the basis of their novel analysis plan. Examples of such labels are "biomarker analysis" (38), "sequential testing" (39), "prospective subset" (2), "adaptive threshold" (40), "adap- tive biomarker" (33), "adaptive signature" (41), "cross- validated adaptive signature" (42), and "generalized adap- tive signature" (33). All these designs have a randomize-all patient flow structure, but they differ in their analysis plan.
The Sequential Tarceva in unresectable non–small cell lung cancer (NSCLC) trial (SATURN; ref. 43) has been labeled as "prospective-subset design" (2). In the SATURN trial, all eligible patients were randomly allocated to erlo- tinib or placebo plus standard supportive care. The trial had two primary objectives: evaluating the effectiveness of erlo- tinib separately in all patients and in patients with EGF receptor (EGFR) immunohistochemistry-positive tumors. To address the multiple comparisons issue, authors used an a splitting technique; the a level of 5%was split between the two primary objectives: 3% for all patients and 2% for patients with EGFR immunohistochemistry-positive tumors.
There are five "adaptive" designs in this category, which are labeled after adaptive elements in their analysis plan. Each of these adaptive plans evaluates the efficacy of experimental treatment in all patients and, if not signifi- cant, tries to define a biomarker-defined subset that is responsive to the experimental treatment. In settings where a single continuous candidate biomarker is available but its positivity threshold is not predefined, adaptive thresh- old plans try to find such a threshold (40). Adaptive biomarker designs have been proposed to evaluate mul- tiple binary biomarkers defined in advance (33). Adaptive signature (41) and cross-validated adaptive signature (42) designs develop a predictive combination of biomarkers in a training set of the trial and consequently evaluate it in a test set. The proposed "generalized adaptive signature design" uses a training set of the trial to select among several candidate biomarkers and optimize cutoff points, and thereafter evaluates the selected biomarkers in a test set (33).
Biomarker-strategy. The distinguishing feature of designs in the biomarker-strategy category is the inclusion of a new
Trial Designs for Personalizing Cancer Care
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management strategy. This strategy is not the standard or experimental treatment, but a prespecified maker-based treatment strategy. For example, biomarker-positive patients would receive experimental therapy, whereas all biomarker- negative patients get standard of care. Eligible patients are randomized to this biomarker-based treatment strategy or to control treatment. In our review, we could identify three subtypes of this category.
Biomarker-strategy, with biomarker assessment in the control arm. Biomarker status is assessed in all patients enrolled in the trial, who are then randomly allocated to either the biomarker-strategy arm or to standard treatment (ref. 1; Fig. 2D). Some other labels for this design type were biomarker- strategy (15, 38, 44), "marker-based strategy I" (45), "cus-
tomized strategy" (12), "direct predictive biomarker-based" (46), and "biomarker-guided" (47). There were also other labels in use, such as "random disclosure" (48), "classifier randomization" (49), or "parallel controlled phrmacoge- netic study" (50).
Biomarker-strategy, without biomarker measurement in the control arm. In settings where it is not feasible or ethical to evaluate the biomarker in all patients, biomarker status is only acquired in patients allocated to the biomarker- strategy arm (Fig. 2E). This design is also labeled as "biomarker-strategy with standard control" (2), "direct predictive biomarker-based" (46), "RCT of testing" (48), "test-treatment" (51), or "parallel controlled pharmaco- genetic diagnostic study" (50).
Biomarker-strategy, with treatment randomization in the control arm. Sargent and Allegra (52) have proposed a modification of the biomarker-strategy design, wherein a second randomization between experimental versus con- trol therapy replaces the control arm (Fig. 2F). They called it "modified marker-based strategy" design (53). Some other authors referred to the design as "marker-based strategy design II" (45), "augmented strategy" (13), or simply "marker-strategy" (28).
Combination of patient flows. A final, fifth category consists of trial designs in which two or more of the aforementioned basic patient flow structures are combined to form a new design. Combination of designs is usually required when the trial aims at evaluating multiple hypoth- eses,multiple biomarkers,multiple treatments, or when the trial has several stages. Freidlin and colleagues have simi- larly proposed a category called "combination of biomarker trial designs" in a comparable review of study designs (1).
The simplest combination is when in enrichment trials biomarker-negative patients are not excluded from the study but assigned to control treatment(s) for which the outcomes are assessed. Here, an enrichment flow is com- bined in parallel with a single-arm trial of standard therapy in biomarker-negative patients. Most authors have referred to this flow as "hybrid" design. An example of a hybrid design is the Trial Assigning Individualized Options for Treatment (TAILORx). The study was designed to evaluate Oncotype Dx, a 21-gene recurrence score, in tamoxifen- treated patients with breast cancer. In this trial, patients are divided into three subgroups of low, intermediate, and high risk based on their OncotypeDx recurrence score. Low- risk patients receive hormonal therapy, high-risk patients receive both hormonal and chemotherapy, whereas pati- ents at intermediate risk are randomized to hormonal therapy or chemotherapy plus hormonal therapy. This trial is a parallel combination of enrichment trial in intermedi- ate-risk group and two single-arm trials in the low- and high-risk groups. Other labels used for this design are "intermediate risk randomized" (2) or "two-way stratified" (49) design.
The Microarray In Node-negative Disease may Avoid ChemoTherapy (MINDACT) trial also has an enrichment element in its patient flow. Here, patients with discordant risk estimations by tumor’s clinicopathologic features and a
CCR Reviews
Exp
Exp
Ctrl
A
Figure 2. The main types of patients' flow in RCTs for evaluation of prognostic and prediction biomarkers: (A) single-arm; (B) enrichment; (C) randomize-all; (D) biomarker-strategywith biomarkermeasurement in the control arm; (E) biomarker-strategy without biomarker measurement in the control arm; (F) biomarker-strategywith treatment randomization in the control arm [Marker (M), biomarker under evaluation].
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70-gene signature (MammaPrint) are eligible for random- ization. Patients with concordant risk estimations receive control treatment. Consenting discordant patients are ran- domized to treatment determined on the basis of the clinocopathologic risk category versus MammaPrint risk category. This way, theMINDACT is a trial combining three flow types: enrichment, single-arm, andbiomarker-strategy. This combination has been described in the literature as "discrepant case randomization" (31), "discordant risk randomization" (2), and "discordant test results RCT" (48). Simon refers to this trial as a modified marker-based strategy (33), as only patients for whom the treatment assignment is influenced by biomarker results are randomized. Staged trial designs are also, in essence, a combination of
basic patient flows. For instance, the proposed "two-stage sample-enrichment" design by Liu and colleagues (54) startswith accruing only biomarker-positive patients during the initial stage of the trial. At the end of the first stage, an interimanalysis is conducted comparing the outcomeof the experimental versus control treatment in biomarker-posi- tives. If the results are not promising for the new treatment,
accrual stops and no treatment benefit is claimed. Other- wise, accrual continues with recruiting unselected popula- tion. This design is a combination of an enrichment and a traditional flow, conditional on the result of the interim analysis.
Contrariwise, in "adaptive patient enrichment" design (55)—also labeled as "adaptive accrual" (18, 37)—the trial begins with a biomarker-stratified first stage in which it accrues both biomarker-positive and -negative patients. If the results of an interim analysis comparing the outcome of the experimental versus control treatment in biomarker- negatives are not promising, accrual to biomarker-negative subgroup is terminated and the second stage continues as an enrichment trial in biomarker-positive patients until the planned total sample size is reached.
Effects assessed by each category of designs There are four types of effects we are commonly interested
in when designing a biomarker trial: the treatment effect, the biomarker effect, the biomarker by treatment effect, and the strategy effect. These are presented with 8 study ques- tions in Table 2. The treatment effect (experimental vs.
Table 2. List of effects that canbeassessedandquestions that canbeansweredby the trials of eachdesign category
Biomarker-strategy
Questions trial can answer Single-arm Enrichment Randomize-all
With biomarker measurement in the control arm
Without biomarker measurement in the control arm
With treatment randomization in the control arm
Treatment effects Q1. How does the experimental treatment compare with the control treatment in biomarker-positives?
— H H H H Indirect H
Q2. How does the experimental treatment compare with the control treatment in biomarker-negatives?
— — H — — H
Q3. How does the experimental treatment compare with the control treatment in overall study population?
— — H — — H
Biomarker effects Q4. Is the biomarker status associated with theoutcome in the standardof care group? (Is the biomarker prognostic?)
— — H H H Indirect H
Q5. Is the biomarker status associated with the outcome in the experimental treatment group?
H — H H H H
Biomarker by treatment effect Q6. Is the biomarker status associated with a benefit of experimental treatment? (Is the biomarker is predictive?)
— — H — — H
Strategy effects Q7. How does the biomarker-based treatment strategy compare with the control treatment in the overall study population?
— — H Indirect H H H
Q8. How does the biomarker-based treatment strategy compare with the experimental treatment in the overall study population?
— — H Indirect — — H
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control) can be estimated separately for biomarker-positive patients (Q1), for biomarker-negative patients (Q2), and in the overall population (Q3). Single-arm trials do not answer any of these questions, as they lack a control arm to allow comparisons. Enrichment trials recruit biomarker- positive patients and allocate them to experimental or control treatment, thus letting us evaluate the effect of treatment, but only in biomarker-positive patients (Q1; ref. 1). Randomize-all trials recruit patients from the whole spectrum of the biomarker values and allocate them ran- domly to either of the two treatment options. Therefore, they allow estimation of the treatment effect in biomarker- positives, -negatives, and in the overall population (Q1–3).
To evaluate if a biomarker is prognostic (Q4), one needs to compare the outcome of biomarker-positive and -nega- tive patients on control treatment, a comparison which is possible in randomize-all study designs but not in single- arm or enrichment trials (1, 28). The only effect one can estimate in the single-arm trials is the biomarker effect in the experimental arm, whether biomarker status is associ- ated with the outcome of experimental treatment (Q5).
To assess the predictive capacity of a biomarker (Q6)— the biomarker by treatment effect—one needs to have the outcome of biomarker-positive and -negative patients separately after experimental and control treatments. Ran- domize-all trials allow such an assessment by providing estimates for all four aforementioned outcomes (1).
In the biomarker-strategy trials, patients are randomized to treatment strategies, instead of treatments. This feature permits direct comparison of the outcomes of a biomarker- based strategy versus those in a strategy of control treatment for all (Q7). Addition of a randomization to the control arm of a biomarker-strategy trial allows direct comparison with a strategy of experimental treatment for all (Q8; ref. 56). With a randomize-all trial, one cannot estimate these effects using randomization properties. By combining marker-positivity rate, outcome of experimental treatment in biomarker-positives and outcome of control treatment in biomarker-negatives, an indirect estimate of strategy effects, can be obtained (57), though it might be biased considering confounding effects of other prognostic factors and it may miss the additional effects of testing, apart from treatment selection (58). In biomarker-strategy de- signs, there are biomarker-positive and -negative patients who are treatedwith the control treatment, soone can assess prognostic capacity of the biomarker in all three subtypes. However, the evaluation of biomarker-predictive capacity is only possible when treatment is randomized in the control arm allowing estimation of experimental treatment effect in biomarker-negative patients (1).
Discussion This systematic review documented a substantial vari-
ability in the labeling of clinical trial designs for evaluating biomarkers for treatment selection in individual patients. We identified more than 300 labels, half of which were unique. In evaluating the heterogeneity in design labels, we
used a classification scheme based on patient flow compo- nents of the corresponding trial designs. Under each of the four basic patient flow categories, several labels could be categorized, where some labels are completely interchange- able terms. Other designs, while having the same patient flow elements, carried specific objectives or had diverging analysis plans, which authors have labeled differently, to emphasize these distinctive aspects.
Using our patient flow scheme, one would be able to classify biomarker trial designs into a small set of basic categories. This could be useful for identifying similarities between novel designs and existing ones, or to evaluate proposed modifications of existing designs. It could also be helpful in reducing the confusion around the design of biomarker trials and help with standardizing the reporting ofbiomarker clinical trials. Because the classification isbased on patient flow, it is directly connected to the possible comparisons that canbemade in the trial and, consequently, the questions that could be potentially answered by the trial.
By comparing the designs in Table 2, a biomarker-strategy design with treatment randomization in the control arm seems a very attractive option, allowing for direct estimation of all biomarker-related effects, yet this feature might come at the cost of a large sample size. Nevertheless, in situations where the biomarker-strategy is complex—having a large number of treatment options or biomarker categories—or when the trial is planned primarily for confirmatory assess- ment of a specific biomarker-based strategy, a biomarker- strategy trial can be the design of choice. A limitation of biomarker-strategy trials is that assessments are restricted to a prespecified biomarker-treatment combination strategy and they cannot be used for further identification or vali- dation of other biomarkers.
Randomize-all trials alsoallowassessmentof all biomark- er-related effects, but provide indirect estimates of strategy effects. An attractive aspect of randomize-all trials is that they allow identification and evaluation of biomarkers that were not specified in the design phase of the trial. Single or multiple biomarkers can be studied and multimarker mod- els can be developed and tested in trials of randomize-all category. If one collects and stores biologic specimens from participants of a randomize-all trial in biobanks, the trial data can be used later to identify or evaluate single or multiple biomarkers, possibly not even known at the time of trial design (59). However, as all analyses that emerge after designing the trial are considered post hoc and explor- atory, cross-validation and/or independent validation approaches are required to establish the use of biomarkers.
Enrichment design can be selected when there is a strong prior biologic evidence that the experimental treatment has no effect in biomarker-negative patients (3, 20). Yet, a positive trial does not prove the use of the biomarker because there may exist a positive treatment effect in the unevaluated biomarker-negative patients (1, 3).
Biomarker trials have predominantly been proposed and discussed in the setting of phase III trials in oncology. All categories identified in this review apply when designing a phase III biomarker trial, though some designs have been
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suggested primarily for a phase II setting. These include randomize-all designs with adaptive randomization, such as the outcome-based trials with Bayesian adaptive ran- domization (5, 36), as well as some of the designs in the combined category, such as tandem two-step phase II predictor marker evaluation (60), which aim at finding a promising treatment/biomarker pair that can be moved forward to a phase III evaluation. To our knowledge, this review is the first systematic
review of trial designs for evaluation of prognostic and predictive biomarkers. Several other narrative reviews are available, most often written by experts (1, 2, 33, 35, 53), who commonly have discussed a selected series of biomark- er trial designs and used their personally preferred design labels. Yet our review was also not without limitation, which was the shortcoming of our search strategy in the electronic databases. The retrieval of methodologic articles is challenging because no specific keywords are available to distinguish articles that have described or presented a method from those which have just applied that method. Most of the search terms we could use were nonspecific. Even the terms "prognostic" and "predictive" are common- ly used by authors in other situations. To compensate for these challenges, we designed our search strategy to be broad and sensitive. We also looked for relevant articles by checking the references and citations of the selected retrieved articles. Biomarkers are changing the way doctors handle many
cancers, but there is still a long way to go before biomarkers reach their full potential in cancer management. With the advent of rapidly growing technologies for measuring new
biomarkers, there is a parallel need for validating the clinical use of using such biomarkers for selection treatment of individual patients. Well-designed and properly conducted trials may support the timely introduction of new biomar- kers in clinical management, to the benefit of cancer patients.
Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed.
Authors' Contributions Conception and design: P. Tajik, P.M. Bossuyt Development ofmethodology: P. Tajik, A.H. Zwinderman, B.W.Mol, P.M. Bossuyt Acquisitionofdata (provided animals, acquired andmanagedpatients, provided facilities, etc.): P. Tajik, B.W. Mol, P.M. Bossuyt Analysis and interpretation of data (e.g., statistical analysis, biosta- tistics, computational analysis): P. Tajik, A.H. Zwinderman, B.W. Mol, P.M. Bossuyt Writing, review, and/or revision of the manuscript: P. Tajik, A.H. Zwinderman, B.W. Mol, P.M. Bossuyt Administrative, technical, or material support (i.e., reporting or orga- nizing data, constructing databases): P. Tajik Study supervision: P.M. Bossuyt
Acknowledgments The authors thank Ms. Faridi van Etten-Jamaludin for her help with
developing the search strategy and searching the databases.
Grant Support Funding for this research was provided by The Netherlands Organization
for Health Research and Development (ZonMw), the Hague, the Nether- lands (grant number 152002026).
Received December 3, 2012; revised May 24, 2013; accepted June 9, 2013; published OnlineFirst June 20, 2013.
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