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RESEARCH METHODS AND REPORTING
SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials An-Wen Chan , 1 Jennifer M Tetzlaff , 2 Peter C Gøtzsche , 3 Douglas G Altman , 4 Howard Mann , 5 Jesse A Berlin , 6 Kay Dickersin , 7 Asbjørn Hróbjartsson , 3 Kenneth F Schulz , 8 Wendy R Parulekar , 9 Karmela Krleža-Jeric , 10 Andreas Laupacis , 11 David Moher 2 10 1 Women's Col ege Research Institute at Women's Col ege High quality protocols facilitate proper mittees/institutional review boards, regulatory agencies, Hospital, Department of Medicine, medical journals, systematic reviewers, and other groups University of Toronto, Toronto, conduct, reporting, and external review of rely on protocols to appraise the conduct and reporting of clinical trials. However, the completeness 2 Ottawa Methods Centre, Clinical clinical trials. Epidemiology Program, Ottawa of trial protocols is often inadequate. To To meet the needs of these diverse stakeholders, pro- Hospital Research Institute, Ottawa, Canada help improve the content and quality tocols should adequately address key trial elements. 3 Nordic Cochrane Centre, However, protocols oft en lack information on important Rigshospitalet, Copenhagen, of protocols, an international group of concepts relating to study design and dissemination stakeholders developed the SPIRIT 2013 plans. 2 -12 Guidelines for writing protocols can help improve 4 Centre for Statistics in Medicine, University of Oxford, Oxford, UK Statement (Standard Protocol Items: their completeness, but existing guidelines vary exten- 5 Division of Medical Ethics and sively in their content and have limitations, including non- Humanities, University of Utah Recommendations for Interventional Trials). systematic methods of development, limited stakeholder School of Medicine, Salt Lake City, The SPIRIT Statement provides guidance involvement, and lack of citation of empirical evidence to USA 6 Janssen Research and in the form of a checklist of recommended support their recommendations. 13 As a result, there is also Development, Titusvil e, USA variation in the precise defi nition and scope of a trial proto- 7 Center for Clinical Trials, Johns items to include in a clinical trial protocol.
col, particularly in terms of its relation to other documents Hopkins Bloomberg School of This SPIRIT 2013 Explanation and such as procedure manuals. 14 Public Health, Baltimore, USA 8 Quantitative Sciences, FHI 360, Elaboration paper provides important Given the importance of trial protocols, an international Research Triangle Park, USA group of stakeholders launched the SPIRIT (Standard Pro- information to promote ful understanding 9 NCIC Clinical Trials Group, Cancer tocol Items: Recommendations for Interventional Trials) Research Institute, Queen's of the checklist recommendations. For each Initiative in 2007 with the primary aim of improving the University, Kingston, Canada content of trial protocols. The main outputs are the SPIRIT 10 Department of Epidemiology and checklist item, we provide a rationale and Community Medicine, University of 2013 Statement, 14 consisting of a 33 item checklist of mini- Ottawa, Ottawa, Canada detailed description; a model example from mum recommended protocol items (table 1) plus a diagram 11 Keenan Research Centre at the an actual protocol; and relevant references (fi g1); and this accompanying Explanation and Elaboration Li Ka Shing Knowledge Institute of St Michael's Hospital, Faculty of supporting its importance. We strongly (E&E) paper. Additional information and resources are also Medicine, University of Toronto, available on the SPIRIT website ( www.spirit-statement.org ). recommend that this explanatory paper The SPIRIT 2013 Statement and E&E paper refl ect the Correspondence to: A-W Chan be used in conjunction with the SPIRIT collaboration and input of 115 contributors, including [email protected] Accepted: 04 October 2012 Statement. A website of resources is also trial investigators, healthcare professionals, methodolo- Cite this as: BMJ 2013;346:e7586 gists, statisticians, trial coordinators, journal editors, as doi: 10.1136/bmj.e7586 well as representatives from research ethics committees, The SPIRIT 2013 Explanation and industry and non-industry funders, and regulatory agen- Elaboration paper, together with the cies. Details of the scope and methods have been published Statement, should help with the drafting of elsewhere. 13 -15 Briefl y, three complementary methods were specifi ed beforehand , in line with current recommenda- trial protocols. Complete documentation tions for development of reporting guidelines 16 : 1) a Delphi of key trial elements can facilitate consensus survey 15 ; 2) two systematic reviews to identify transparency and protocol review for the existing protocol guidelines and empirical evidence sup-porting the importance of specifi c checklist items; and 3) benefit of al stakeholders.
two face-to-face consensus meetings to fi nalise the SPIRIT Every clinical trial should be based on a protocol—a docu- 2013 checklist. Furthermore, the checklist was pilot tested ment that details the study rationale, proposed methods, by graduate course students, and an implementation strat- organisation, and ethical considerations. 1 Trial investiga- egy was developed at a stakeholder meeting. tors and staff use protocols to document plans for study The SPIRIT recommendations are intended as a guide conduct at all stages from participant recruitment to results for those preparing the full protocol for a clinical trial. dissemination. Funding agencies, research ethics com- A clinical trial is a prospective study in which one or more BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 1 31/01/2013 10:33:35 RESEARCH METHODS AND REPORTING
and industry sponsors. Model examples were selected to refl ect how key elements could be appropriately described in a trial protocol. Some examples illustrate a specifi c com- ponent of a checklist item, while others encompass all key recommendations for an item. Additional examples are also available on the SPIRIT website ( www.spirit-statement.org ). Eligibility screen The availability of examples for all checklist items indicates the feasibility of addressing each recommended item in the main protocol rather than in separate documents. (List other procedures) Examples are quoted verbatim from the trial protocol. Proper names of trial personnel have been abbreviated with italicised initials, and any reference numbers cited in the original quoted text are denoted by [ Reference ] to distinguish them from references cited in this E&E paper. For each checklist item we also strived to provide refer- (List other study groups) ences to empirical data supporting its relevance, which we identifi ed through a systematic review conducted to inform the content of the SPIRIT checklist. We searched MEDLINE, (List baseline variables) the Cochrane Methodology Register, and the Cochrane Data- (List outcome variables) base of Systematic Reviews (limited to methodology reviews) up to September 2009, and EMBASE up to August 2007. We (List other data variables) searched reference lists, PubMed "related articles," and cita- * List specific timepoints in this row tion searches using SCOPUS to identify additional relevant studies. We used piloted forms to screen and extract data Fig 1 Example template for the schedule of enrolment, interventions, and assessments relevant to specifi c checklist items. (recommended content can be displayed using other schematic formats). This template is Studies were included if they provided empirical data to copyrighted by the SPIRIT Group and is reproduced by BMJ with their permission.
support or refute the importance of a given protocol concept. i nt erventions are assigned to human participants in order A summary of the relevant methodological articles was pro- to assess the eff ects on health related outcomes. The recom- vided to each E&E author for use in preparing the initial draft mendations are not intended to prescribe how a trial should text for up to six checklist items; each draft was also reviewed be designed or conducted. Rather, we call for a transparent and revised by a second author. When citing empirical evi- and complete description of what is intended, regardless dence in the E&E, we aimed to reference a systematic review of the characteristics or quality of the plans. The SPIRIT when available. When no review was identifi ed, we either 2013 Statement addresses the minimum content for inter- cited all relevant individual studies, or if too numerous, a ventional trials; additional concepts may be important to representative sample of the literature. Some items had little describe in protocols for trials of specifi c designs (eg, crosso- or no identifi ed empirical evidence (eg, title) but their inclu- ver trials) or in protocols intended for submission to specifi c sion in the checklist is supported by a strong pragmatic or groups (eg, funders, research ethics committees/institu- ethical rationale. Where relevant, we also provide references tional review boards). If information for a recommended to non-empirical publications for further reading. item is not yet available when the protocol is being fi nalised Two lead authors (AWC, JMT) collated and refi ned the (eg, funding sources), this should be explicitly stated and content and format for all items, and then circulated three the protocol updated as new information is obtained. For- iterations of an overall draft to the coauthors for editing and matting conventions such as a table of contents, glossary of fi nal approval. non-standard or ambiguous terms (eg, randomisation phase or off -protocol), and list of abbreviations and references will SPIRIT 2013 Explanation and Elaboration
facilitate understanding of the protocol. Section 1: Administrative information Item 1: Descriptive title identifying the study design, Purpose and development of explanation and elaboration
population, interventions, and, if applicable, trial acronym Modelled aft er other reporting guidelines, 17  18 this E&E paper "A multi-center, investigator-blinded, randomized, 12-month, presents each checklist item with at least one model example paral el-group, non-inferiority study to compare the efficacy of 1.6 from an actual protocol, followed by a full explanation of the to 2.4 g Asacol® Therapy QD [once daily] versus divided dose (BID rationale and main issues to address. This E&E paper pro- [twice daily]) in the maintenance of remission of ulcerative colitis." 19 vides important information to facilitate full understanding of each checklist item, and is intended to be used in conjunc- tion with the SPIRIT 2013 Statement. 14 These complemen- The title provides an important means of trial identifi ca- tary tools serve to inform trial investigators about important tion. A succinct description that conveys the topic (study issues to consider in the protocol as they relate to trial design, population, interventions), acronym (if any), and basic conduct, reporting, and organisation. study design—including the method of intervention allo- To identify examples for each checklist item, we obtained cation (eg, parallel group randomised trial; single-group protocols from public websites, journals, trial investigators, trial)—will facilitate retrieval from literature or internet BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 2 31/01/2013 10:33:36 RESEARCH METHODS AND REPORTING
Table 1 SPIRIT 2013 checklist: recommended items to address in a clinical trial protocol and related documents* ItemNo Description Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym Trial registration Trial identifier and registry name. If not yet registered, name of intended registry All items from the World Health Organization Trial Registration Data Set Date and version identifier Sources and types of financial, material, and other support Roles and responsibilities Names, affiliations, and roles of protocol contributors Name and contact information for the trial sponsor Role of study sponsor and funders, if any, in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, including whether they will have ultimate authority over any of these activities Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication committee, data management team, and other individuals or groups overseeing the trial, if applicable (see Item 21a for data monitoring committee) Background and rationale Description of research question and justification for undertaking the trial, including summary of relevant studies (published and unpublished) examining benefits and harms for each intervention Explanation for choice of comparators Specific objectives or hypotheses Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group), allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory) Methods: Participants, interventions, and outcomes Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be collected. Reference to where list of study sites can be obtained Eligibility criteria Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will perform the interventions (eg, surgeons, psychotherapists) Interventions for each group with sufficient detail to allow replication, including how and when they will be administered Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose change in response to harms, participant request, or improving/worsening disease) Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence (eg, drug tablet return, laboratory tests) Relevant concomitant care and interventions that are permitted or prohibited during the trial Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy and harm outcomes is strongly recommended Participant timeline Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see fig 1) Estimated number of participants needed to achieve study objectives and how it was determined, including clinical and statistical assumptions supporting any sample size calculations Strategies for achieving adequate participant enrolment to reach target sample size Methods: Assignment of interventions (for controlled trials)Allocation:Sequence generation Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions Allocation concealment Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions Blinding (masking) Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts) and how If blinded, circumstances under which unblinding is permissible and procedure for revealing a participant's allocated intervention during the trial Methods: Data collection, management, and analysisData collection methods Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol Statistical methods Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical analysis plan can be found, if not in the protocol Methods for any additional analyses (eg, subgroup and adjusted analyses) Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation) Methods: MonitoringData monitoring Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 3 31/01/2013 10:33:37 RESEARCH METHODS AND REPORTING
ItemNo Description21b Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor Ethics and dissemination Research ethics approval Plans for seeking research ethics committee/institutional review board (REC/IRB) approval Protocol amendments Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes, analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, regulators) Consent or assent Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and how (see Item 32) Additional consent provisions for collection and use of participant data and biological specimens in ancillary studies, if applicable How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial Declaration of interests Financial and other competing interests for principal investigators for the overall trial and each study site Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that limit such access for investigators Ancillary and post-trial care Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial participation Dissemination policy Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals, the public, and other relevant groups (eg, via publication, reporting in results databases, or other data sharing arrangements), including any publication restrictions Authorship eligibility guidelines and any intended use of professional writers Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code Informed consent materials Model consent form and other related documentation given to participants and authorised surrogates Biological specimens Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in the current trial and for future use in ancillary studies, if applicable *Amendments to the protocol should be tracked and dated. The SPIRIT checklist belongs to the SPIRIT Group and is reproduced by BMJ with their permission searches and rapid judgment of relevance. 20 It can also be helpful to include the trial framework (eg, superiority, In addition to a trial registration number, the World Health non-inferiority), study objective or primary outcome, and Organization (WHO) recommends a minimum standard if relevant, the study phase (eg, phase II). list of items to be included in a trial registry in order for a trial to be considered fully registered ( www.who.int/ictrp/ Trial registration—registry
network/trds/en/index.html ). These standards are sup- Item 2a: Trial identifier and registry name. If not yet ported by ICMJE, other journal editors, and jurisdictional registered, name of intended registry legislation. 29 -31 We recommend that the WHO Trial Registra-tion Data Set be included in the protocol to serve as a brief structured summary of the trial. Its inclusion in the protocol "EudraCT: 2010-019180-10 can also signal updates for the registry when associated ClinicalTrials.gov: NCT01066572 protocol sections are amended—thereby promoting con- ISRCTN: 54540667." 21 sistency between information in the protocol and registry. Explanation There are compelling ethical and scientifi c reasons for trial Protocol version
registration. 22 -24 Documentation of a trial's existence on a Item 3: Date and version identifier publicly accessible registry can help to increase transpar- ency, 24  25 decrease unnecessary duplication of research eff ort, facilitate identifi cation of ongoing trials for prospec- "Issue date: 25 Jul 2005 tive participants, and identify selective reporting of study Protocol amendment number: 05 results. 26 -28 As mandated by the International Committee of Authors: MD, JH Medical Journal Editors (ICMJE) and jurisdictional legisla- Revision chronology: tion, 29 -31 registration of clinical trials should occur before UM . . 00, 2004-Jan-30 Original recruitment of the fi rst trial participant. UM . . 01, 2004-Feb-7 Amendment 01.: We recommend that registry names and trial identifiers Primary reason for amendment: changes in Section 7.1 regarding composition of comparator placebo assigned by the registries be prominently placed in the proto- Additional changes (these changes in and of themselves would col, such as on the cover page. If the trial is not yet registered, not justify a protocol amendment): correction of typographical the intended registry should be indicated and the protocol error in Section 3.3 . . updated upon registration. When registration in multiple reg- UM . . 05, 2005-Jul-25 Amendment No.5: istries is required (eg, to meet local regulation), each identi- At the request of US FDA statements were added to the protocol fi er should be clearly listed in the protocol and each registry. to better clarify and define the algorithm for determining clinical or microbiological failures prior to the follow-up visit." 33 Trial registration—data set
Item 2b: All items from the World Health Organization
Trial Registration Data Set Sequentially labelling and dating each protocol version Example: see table 2
helps to mitigate potential confusion over which d ocument BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 4 31/01/2013 10:33:37 RESEARCH METHODS AND REPORTING
Table 2 Example of trial registration data Primary registry and trial identifying number Date of registration in primary registry Secondary identifying numbers BNI-2009-01, 2009-017374-20, ISRCTN01005546, DRKS00000084 Source(s) of monetary or material support Bernhard Nocht Institute for Tropical Medicine Bernhard Nocht Institute for Tropical Medicine Secondary sponsor(s) German Federal Ministry of Education and Research Contact for public queries SE, MD, MPH [email address] Contact for scientific queries SE, MD, MPH Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany Probiotic Saccharomyces boulardii for the prevention of antibiotic associated diarrhoea (SacBo) S boulardii for the prevention of antibiotic associated diarrhoea—randomised, double blind, placebo controlled trial Countries of recruitment Health condition(s) or problem(s) studied Antibiotic treatment, Clostridium difficile, diarrhoeaActive comparator: S boulardii (500 mg S boulardii per day) Placebo comparator: microcristallin cellulose (matching capsules containing no active ingredients)Ages eligible for study: ≥18 years; Sexes eligible for study: both; Accepts healthy volunteers: noInclusion criteria: adult patient (≥ 18 years), patient hospitalised . . Key inclusion and exclusion criteria Exclusion criteria: allergy against yeast and/or Perenterol forte and/or placebos containing S cerevisiae HANSEN CBS 5926, lactose monohydrate, magnesium stearate, gelatine, sodium dodecyl sulfate, titan dioxide, microcrystalline celluloseInterventionalAllocation: randomized; Intervention model: parallel assignment; Masking: double blind . .
Primary purpose: prevention Phase III Date of first enrolment Target sample size Recruitment status Primary outcome(s) Cumulative incidence of any antibiotic associated diarrhoea (time frame: 2 years; not designated as safety issue) Key secondary outcomes Cumulative incidence of C difficile associated diarrhoea (time frame: 2 years; not designated as safety issue) . .
is the most recent. Explicitly listing the changes made rela- Although both industry funded and non-industry funded tive to the previous protocol version is also important (see trials are susceptible to bias, 4  35 the former are more likely Item 25). Transparent tracking of versions and amend- to report trial results and conclusions that favour their ments facilitates trial conduct, review, and oversight. own interventions. 27  36 - 39 This tendency could be due to industry trials being more likely to select eff ective inter- ventions for evaluation (Item 6a), to use less eff ective Item 4: Sources and types of financial, material, and other control interventions (Item 6b), or to selectively report outcomes (Item 12), analyses (Item 20) or full studies (Item 31). 38  40 - 43 Non-fi nancial support (eg, provision of drugs) from industry has not been shown to be associated "Tranexamic acid will be manufactured by Pharmacia (Pfizer, with biased results, although few studies have examined Sandwich, UK) and placebo by South Devon Healthcare this issue. 44  45 NHS Trust, UK. The treatment packs will be prepared by At a minimum, the protocol should identify the sources an independent clinical trial supply company (Brecon Pharmaceuticals Limited, Hereford, UK) . . of fi nancial and non-fi nancial support; the specifi c type LSHTM [London School of Hygiene and Tropical Medicine] is (eg, funds, equipment, drugs, services) and time period of funding the run-in costs for the WOMAN trial and up to 2,000 support; and any vested interest that the funder may have patients' recruitment. The main phase is funded by the UK in the trial. If a trial is not yet funded when the protocol is Department of Health and the Wellcome Trust. Funding for this fi rst written, the proposed sources of support should be trial covers meetings and central organisational costs only. listed and updated as funders are confi rmed. Pfizer, the manufacturer of tranexamic acid, have provided No clear consensus exists regarding the level of addi- the funding for the trial drug and placebo used for this trial. An tional funding details that should be provided in the trial educational grant, equipment and consumables for ROTEM [thromboelastometry procedure] analysis has been provided by protocol as opposed to trial contracts, although full dis- Tem Innovations GmbH, M.-Kollar-Str. 13-15, 81829 Munich, closure of funding information in the protocol can help to Germany for use in the WOMAN-ETAC study. An application for better identify fi nancial competing interests. Some juris- funding to support local organisational costs has been made dictional guidelines require more detailed disclosure, to University of Ibadan Senate Research Grant. The design, including monetary amounts granted from each funder, management, analysis and reporting of the study are entirely the mechanism of providing fi nancial support (eg, paid independent of the manufacturers of tranexamic acid and Tem in fi xed sum or per recruited participant), and the specifi c Innovations GmbH." 34 fund recipient (eg, trial investigator, department/insti- tute). 46 Detailed disclosure allows research ethics com- A description of the sources of fi nancial and non-fi nancial mittees/institutional review boards (REC/IRBs) to assess support provides relevant information to assess study whether the reimbursement amount is reasonable in rela- feasibility and potential competing interests (Item 28). tion to the time and expenses incurred for trial conduct. BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 5 31/01/2013 10:33:37 RESEARCH METHODS AND REPORTING
Roles and responsibilities—contributorship
Roles and responsibilities—sponsor and funder
Item 5a: Names, affiliations, and roles of protocol Item 5c: Role of study sponsor and funders, if any, in contributors study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, including " RTL [address], EJM [address], AK [address] . . whether they will have ultimate authority over any of Authors' contributions these activities RTL conceived of the study. AK , EN , SB , PR , WJ , JH , and MC initiated the study design and JK and LG helped with implementation. RTL , JK , LG , and FP are grant holders. LT and EM provided statistical expertise in clinical trial design and "This funding source had no role in the design of this study RN is conducting the primary statistical analysis. All authors and will not have any role during its execution, analyses, contributed to refinement of the study protocol and approved interpretation of the data, or decision to submit results." 54 the final manuscript." 47 There is potential for bias when the trial sponsor or Individuals who contribute substantively to protocol funder (sometimes the same entity) has competing development and draft ing should have their contribu- interests (Item 28) and substantial infl uence on the tions reported. As with authorship of journal articles, 48 planning, conduct, or reporting of a trial. Empirical listing the protocol contributors, their affi research indicates that specifi c forms of bias tend to be their roles in the protocol development process provides more prevalent in trials funded by industry compared due recognition, accountability, and transparency. Nam- to those funded by non-commercial sources. 36 -38  45  55 - 60 ing of contributors can also help to identify competing The design, analysis, interpretation, and reporting interests and reduce ghost authorship (Items 28 and of most industry-initiated trials are controlled by the 31b). 9  10 If professional medical writers are employed to sponsor; this authority is oft en enforced by contractual draft the protocol, then this should be acknowledged as agreements signed between the sponsor and trial inves- tigators (Item 29). 10  61 Naming of authors and statements of contributorship The protocol should explicitly outline the roles and are standard for protocols published in journals such as responsibilities of the sponsor and any funders in study Trials 49 but are uncommon for unpublished protocols. design, conduct, data analysis and interpretation, man- Only fi ve of 44 industry-initiated protocols approved in uscript writing, and dissemination of results. It is also 1994-95 by a Danish research ethics committee explicitly important to state whether the sponsor or funder con- identifi ed the protocol authors. 9 trols the fi nal decision regarding any of these aspects of the trial. Roles and responsibilities—sponsor contact information
Despite the importance of declaring the roles of the trial Item 5b: Name and contact information for the trial sponsor and funders, few protocols explicitly do so. Among 44 protocols for industry-initiated trials receiv-ing ethics approval in Denmark from 1994-95, none stated explicitly who had contributed to the design of "Trial Sponsor: University of Nottingham Sponsor's Reference: RIS 8024 . . Contact name: Mr PC Roles and responsibilities—committees
Address: King's Meadow Campus . . Item 5d: Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication committee, data management team, and other individuals or groups overseeing the trial, if applicable (see Item 21a for data monitoring committee) The sponsor can be defi ned as the individual, company, institution, or organisation assuming overall responsi- The protocol should outline the general membership of bility for the initiation and management of the trial, the various committees or groups involved in trial coor- and is not necessarily the main funder. 51  52 In general, dination and conduct; describe the roles and responsi- the company is the sponsor in industry initiated trials, bilities of each; and (when known) identify the chairs while the funding agency or institution of the principal and members. This information helps to ensure that investigator is oft en the sponsor for investigator initiated roles and responsibilities are clearly understood at the trials. For some investigator initiated trials, the principal trial onset, and facilitates communication from exter- inv estigator can be considered to be a "sponsor-inves- nal parties regarding the trial. It also enables readers to tigator" who assumes both sponsor and investigator understand the mandate and expertise of those respon- sible for overseeing participant safety, study design, Identifi cation of the trial sponsor provides transpar- database integrity, and study conduct. For example, ency and accountability. The protocol should identify the empirical evidence supports the pivotal role of an epide- name, contact information, and if applicable, the regula- miologist or biostatistician in designing and conducting tory agency identifying number of the sponsor. higher quality trials. 63  64 BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 6 31/01/2013 10:33:37 RESEARCH METHODS AND REPORTING
"Principal investigator and research physician Design and conduct of RITUXVAS Introduction: For people at ages 5 to 45 years, trauma is second Preparation of protocol and revisions only to HIV/AIDS as a cause of death. . Mechanisms : The haemostatic system helps to maintain the Preparation of investigators brochure (IB) and CRFs [case report forms] integrity of the circulatory system after severe vascular injury, Organising steering committee meetings whether traumatic or surgical in origin.[reference] Major Managing CTO [clinical trials office] surgery and trauma trigger similar haemostatic responses . Publication of study reports . Antifibrinolytic agents have been shown to reduce blood Members of TMC [Trial Management Committee] loss in patients with both normal and exaggerated fibrinolytic Steering committee (SC) responses to surgery, and do so without apparently increasing the risk of post-operative complications, . . (see title page for members) Existing knowledge : Systemic antifibrinolytic agents are widely Agreement of final protocol used in major surgery to prevent fibrinolysis and thus reduce All lead investigators will be steering committee members. One lead investigator per country will be surgical blood loss. A recent systematic review [reference] of nominated as national coordinator. randomised control ed trials of antifibrinolytic agents (mainly Recruitment of patients and liaising with principle [sic] investigator aprotinin or tranexamic acid) in elective surgical patients Reviewing progress of study and if necessary agreeing changes to the protocol and/or identified 89 trials including 8,580 randomised patients (74 trials investigators brochure to facilitate the smooth running of the study. in cardiac, eight in orthopaedic, four in liver, and three in vascular Trial management committee (TMC) surgery). The results showed that these treatments reduced the numbers needing transfusion by one third, reduced the volume (Principle [sic] investigator, research physician, administrator) needed per transfusion by one unit, and halved the need for further surgery to control bleeding. These differences were al Organisation of steering committee meetings highly statistical y significant. There was also a statistical y non- Provide annual risk report MHRA [Medicines and Healthcare Products Regulatory Agency] and significant reduction in the risk of death (RR=0.85: 95% CI 0.63 to ethics committee 1.14) in the antifibrinolytic treated group. SUSAR [Serious unexpected suspected adverse events] reporting to MHRA and Roche Responsible for trial master file Need for a trial : A simple and widely practicable treatment that Budget administration and contractual issues with individual centres reduces blood loss following trauma might prevent thousands of Advice for lead investigators premature trauma deaths each year and secondly could reduce exposure to the risks of blood transfusion. Blood is a scarce and Audit of 6 monthly feedback forms and decide when site visit to occur. expensive resource and major concerns remain about the risk Assistance with international review, board/independent ethics committee applications of transfusion-transmitted infection. . A large randomised trial Data verification is therefore needed of the use of a simple, inexpensive, widely practicable antifibrinolytic treatment such as tranexamic acid Organisation of central serum sample collection . . in a wide range of trauma patients who, when they reach hospital are thought to be at risk of major haemorrhage that could significantly affect their chances of survival. Maintenance of trial IT system and data entry Data verification Dose selection The systematic review of randomised controlled trials of Lead investigators antifibrinolytic agents in surgery showed that dose regimens of In each participating centre a lead investigator (senior nephrologist/rheumatologist/ immunologist) tranexamic acid vary widely.[reference] . . will be identified, to be responsible for identification, recruitment, data collection and completion In this emergency situation, administration of a fixed dose would of CRFs, along with follow up of study patients and adherence to study protocol and investigators be more practicable as determining the weight of a patient would brochure. . Lead investigators will be steering committee members, with one investigator per be impossible. Therefore a fixed dose within the dose range which country being nominated as national coordinator." 62 has been shown to inhibit fibrinolysis and provide haemostatic benefit is being used for this trial. . The planned duration of Section 2: Introduction
administration al ows for the ful effect of tranexamic acid on the immediate risk of haemorrhage without extending too far into the Background and rationale acute phase response seen after surgery and trauma." 65 Item 6a: Description of research question and justification for undertaking the trial, including summary of relevant studies (published and unpublished) examining benefits provides motivation for contributing to the trial. 68  69 It is and harms for each intervention also relevant to funders, REC/IRBs, and other stakehold- ers who evaluate the scientifi c and ethical basis for trial The value of a research question, as well as the ethical and scientifi c justifi cation for a trial, depend to a large To place the trial in the context of available evidence, degree on the uncertainty of the comparative benefi ts or it is strongly recommended that an up-to-date systematic harms of the interventions, which depends in turn on the review of relevant studies be summarised and cited in the existing body of knowledge on the topic. The background protocol. 70 Several funders request this information in section of a protocol should summarise the importance of grant applications. 71  72 Failure to review the cumulated evi- the research question, justify the need for the trial in the dence can lead to unnecessary duplication of research or context of available evidence, and present any available to trial participants being deprived of eff ective, or exposed data regarding the potential eff ects of the interventions to harmful, interventions. 73 -76 A minority of published cacy and harms). 66  67 This information is particularly trial reports cite a systematic review of pre-existing evi- important to the trial participants and personnel, as it dence, 77  78 and in one survey only half of trial investigators BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 7 31/01/2013 10:33:37 RESEARCH METHODS AND REPORTING
were aware of a relevant existing review when they had trial investigators to be eff ective despite having never designed their trial. 79 Given that about half of trials remain previously been shown to be superior to placebo. 74  97 In unpublished, 80 -82 and that published trials oft en represent a systematic review of over 100 head-to-head antibiotic a biased subset of all trials, 80  83 it is important that system- trials for mild to moderate chronic obstructive pulmo- atic reviews include a search of online resources such as nary disease, 74 cumulative meta-analysis of preceding trial registries, results databases, and regulatory agency placebo controlled trials did not show a signifi cant eff ect of antibiotics over placebo. Such studies again highlight the importance of providing a thorough background Background and rationale—choice of comparators
and rationale for a trial and the choice of comparators— Item 6b: Explanation for choice of comparators including data from an up-to-date systematic review—to enable potential participants, physicians, REC/IRBs, and funders to discern the merit of the trial. "Choice of comparator In spite of the increasing numbers of resistant strains, Objectives
chloroquine monotherapy is still recommended as standard Item 7: Specific objectives or hypotheses blood-stage therapy for patients with P [ Plasmodium ] vivax malaria in the countries in which this trial will be conducted. Its selection as comparator is therefore justified. The adult dose "1.1 Research hypothesis of chloroquine will be 620 mg for 2 days followed by 310 mg Apixaban is noninferior to warfarin for prevention of stroke on the third day and for children 10 mg/kg for the first two (hemorrhagic, ischemic or of unspecified type) or systemic days and 5 mg/kg for the third day. Total dose is in accordance embolism in subjects with atrial fibrillation (AF) and additional with the current practice in the countries where the study is risk factor(s) for stroke. conducted. The safety profile of chloroquine is well established and known. Although generally well tolerated, the following 2 STUDY OBJECTIVES side-effects of chloroquine treatment have been described: Gastro-intestinal disturbances, headache, hypotension, 2.1 Primary objective convulsions, visual disturbances, depigmentation or loss of To determine if apixaban is noninferior to warfarin (INR hair, skin reactions (rashes, pruritus) and, rarely, bone-marrow [international normalized ratio] target range 2.0-3.0) in the suppression and hypersensitivity reactions such as urticaria combined endpoint of stroke (hemorrhagic, ischemic or of and angioedema. Their occurrence during the present trial unspecified type) and systemic embolism, in subjects with AF and may however be unlikely given the short (3-day) duration of at least one additional risk factor for stroke. 2.2 Secondary objectives 2.2.1 Key secondary objectives The key secondary objectives are to determine, in subjects with AF and at least one additional risk factor for stroke, if apixaban is The choice of control interventions has important implica- superior to warfarin (INR target range 2.0 - 3.0) for, tions for trial ethics, recruitment, results, and interpre- • the combined endpoint of stroke (hemorrhagic, ischemic or of tation. In trials comparing an intervention to an active unspecified type) and systemic embolism control or usual care, a clear description of the rationale • major bleeding [International Society of Thrombosis and for the comparator intervention will facilitate under- standing of its appropriateness. 86  87 For example, a trial • al -cause death in which the control group receives an inappropriately 2.2.2 Other secondary objectives low dose of an active drug will ove restimate the relative • To compare, in subjects with AF and at least one additional risk factor for stroke, apixaban and warfarin with respect to: cacy of the study intervention in clinical practice; con- The composite endpoint of stroke (ischemic, hemorrhagic, versely, an inappropriately high dose in the control group or of unspecified type), systemic embolism and major will lead to an underestimate of the relative harms of the bleeding, in warfarin naive subjects study intervention. 87  88 The appropriateness of using placebo-only control • To assess the safety of apixaban in subjects with AF and at least groups has been the subject of extensive debate and mer- one additional risk factor for stroke." 98 its careful consideration of the existence of other eff ec-tive treatments, the potential risks to trial par ticipants, and the need for assay sensitivity—that is, ability to dis- The study objectives refl ect the scientifi c questions to be tinguish an eff ective intervention from less eff ective or answered by the trial, and defi ne its purpose and scope. ineff ective interventions. 89  90 In addition, surveys have They are closely tied to the trial design (Item 8) and a nalysis demonstrated that a potential barrier to trial participa- methods (Item 20). For example, the sample size calcula- tion is the possibility of being allocated a placebo-only tion and statistical analyses for superiority trials will diff er or active control intervention that is perceived to be less from those investigating non-inferiority. desirable than the study inter vention. 68  69  91  92 Evidence The objectives are generally phrased using neutral word- also suggests that enrolled participants perceive the eff ect ing (eg, "to compare the eff ect of treatment A versus treat- of a given intervention diff erently depending on whether ment B on outcome X") rather than in terms of a particular the control group consists of an active comparator or only direction of eff ect. 99 A hypothesis states the predicted eff ect of the interventions on the trial outcomes. For multiarm trials, Finally, studies suggest that some "active" compara- the objectives should clarify the way in which all the treat- tors in head-to-head randomised trials are presumed by ment groups will be compared (eg, A versus B; A versus C). BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 8 31/01/2013 10:33:37 RESEARCH METHODS AND REPORTING
Trial design
Item 8: Description of trial design including type of "Selection of countries trial (eg, parallel group, crossover, factorial, single . . To detect an intervention-related difference in HIV incidences group), allocation ratio, and framework (eg, superiority, with the desired power, the baseline incidences at the sites must be equivalence, non-inferiority, exploratory) sufficiently high. We chose the participating sites so that the average baseline annual incidence across al communities in the study is likely to reach at least 3%. The various sites in sub-Saharan Africa met this "The PROUD trial is designed as a randomised, controlled, criterion, but we also wanted sites in Asia to extend the generalizability observer, surgeon and patient blinded multicenter superiority of the intervention. The only location in Asia with sufficient incidence trial with two parallel groups and a primary endpoint of wound at the community level is in ethnic minority communities in Northern infection during 30 days after surgery . . randomization will be Thailand, where HIV incidence is currently in excess of 7%;[reference] performed as block randomization with a 1:1 allocation." 100 thus they were invited to participate as wel . Our final selection of sites combines rural (Tanzania, Zimbabwe, Thailand, and KwaZulu- Natal) and an urban (Soweto) location. The cultural circumstances The most common design for published randomised trials between the sub-Saharan African sites vary widely . . is the parallel group, two arm, superiority trial with 1:1 allo- Definition of community cation ratio. 101 Other trial types include crossover, cluster, Each of the three southern African sites (Harare, Zimbabwe; and factorial, split body, and n of 1 randomised trials, as well as Soweto and Vulindlela, South Africa) selected eight communities, the East African (Tanzanian) site selected 10 communities, and single group trials and non-randomised comparative trials. Thailand selected 14 communities . . They are of a population size For trials with more than one study group, the allocation of approximately 10,000 . . which fosters social familiarity and ratio refl ects the intended relative number of participants connectedness, and they are geographical y distinct. Communities in each group (eg, 1:1 or 2:1). Unequal allocation ratios are are defined primarily geographical y for operational purposes used for a variety of reasons, including potential cost sav- for the study, taking into account these dimensions of social ings, allowance for learning curves, and ethical considera- communality. The communities chosen within each country and tions when the balance of existing evidence appears to be in site are selected to be sufficiently distant from each other so that there would be little cross-contamination or little possibility that favour of one intervention over the other. 102 Evidence also individuals from a control community would benefit from the suggests a preference of some participants for enrolling in activities in the intervention community." 113 trials with an allocation ratio that favours allocation to an active treatment. 92 The framework of a trial refers to its overall objective to test A description of the environment in which a trial will be con- the superiority, non-inferiority, or equivalence of one inter- ducted provides important context in terms of the applicabil- vention with another, or in the case of exploratory pilot trials, ity of the study results; the existence and type of applicable to gather preliminary information on the intervention (eg, local regulation and ethics oversight; and the type of health- harms, pharmacokinetics) and the feasibility of conducting care and research infrastructure available. These considera- a full-scale trial. tions can vary substantially within and between countries. It is important to specify and explain the choice of study At a minimum, the countries , type of setting (eg, urban design because of its close relation to the trial objectives (Item versus rural), and the likely number of study sites should be 7) and its infl uence on the study methods, conduct, costs, 103 reported in the protocol. These factors have been associated results, 104 -106 and interpretation. For example, factorial and with recruitment success and degree of attrition for some tri- non-inferiority trials can involve more complex methods, als, 68  91  92  114 - 117 but not for others. 118  119 Trial location has also analyses, and interpretations than parallel group superior- been associated with trial outcome, 120 aspects of trial quality ity trials. 107  108 In addition, the interpretation of trial results (eg, authenticity of randomisation 121 ), and generalisability. 122 in published reports is not always consistent with the pre-specifi ed trial framework, 6  109  110 especially among reports Eligibility criteria
claiming post hoc equivalence based on a failure to demon- Item 10: Inclusion and exclusion criteria for participants. strate superiority rather than a specifi c test of equivalence. 109 If applicable, eligibility criteria for study centres and There is increasing interest in adaptive designs for clinical individuals who will perform the interventions (eg, trials, defi ned as the use of accumulating data to decide how surgeons, psychotherapists) to modify aspects of a study as it continues, without under- mining the validity and integrity of the trial. 111  112 Examples Eligibility criteria for potential trial participants defi ne the of potential adaptations include stopping the trial early, study population. They can relate to demographic informa- modifying the allocation ratio, re-estimating the sample size, tion; type or severity of the health condition; comorbidities; and changing the eligibility criteria. The most valid adaptive previous or current treatment; diagnostic procedures; preg- designs are those in which the opportunity to make adapta- nancy; or other relevant considerations. 125 In trials of operator- tions is based on prespecifi ed decision rules that are fully dependent interventions such as surgery and psychotherapy, documented in the protocol (Item 21b). it is usually important to promote consistency of intervention delivery by also defi ning the eligibility criteria for care provid- Section 3a: Methods—participants, interventions, and outcomes
ers and centres where the intervention will be administered. 126 Clear delineation of eligibility criteria serves several Item 9: Description of study settings (eg, community clinic, purposes. It enables study personnel to apply these cri- academic hospital) and list of countries where data will be teria consistently throughout the trial. 127 The choice collected. Reference to where list of study sites can be obtained of eligibility criteria can affect recruitment and attri- BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 9 31/01/2013 10:33:37 RESEARCH METHODS AND REPORTING
"Patients (or a representative) must provide written, informed consent before any study procedures "Eligible patients wil be randomised in equal proportions between occur (see Appendix 1 for sample Informed Consent Form) . . IL-1ra [interleukin-1 receptor antagonist] and placebo, receiving 5.1. Inclusion Criteria either a once daily, subcutaneous (s.c.) injection of IL-1ra (dose Patients eligible for the trial must comply with all of the following at randomization : 100 mg per 24 h) for 14 days, or a daily s.c. injection of placebo for 1. Age ≥16 years 2. Current admission under the care of the heart-failure service at the site The study drug and placebo wil be provided by Amgen Inc in its commercial y available recombinant form . . The study drug and placebo wil be relabel ed by Amgen, in col aboration with CTEU 5.2. Exclusion Criteria [Clinical Trials and Evaluation Unit] according to MHRA [Medicines 1. Acute decompensation thought by the attending heart-failure physician to require or be likely to and Healthcare Products Regulatory Agency] guidelines. require PAC [pulmonary-artery catheter] during the next 24 hours. Such patients should be entered The first dose of IL-1ra wil be given within 24 h +2 h of the positive into the PAC Registry (see below). Troponin. Injections wil be given at a standardised time (24 ± 2 h 2. Inability to undergo PAC placement within the next 12 hours after the previous dose), immediately after blood sampling. IL-1ra or placebo wil [be] administered to the patient by the research Patients enrolled in other investigational drug studies are potential candidates for ESCAPE . nurse while the patient is in hospital. During the hospital stay, As the ESCAPE protocol does not involve any investigational agents or techniques, patients would be the patient wil be taught to self-administer the injection by the eligible for dual randomization if they are on stable doses of the investigational drugs. . research nurse and on discharge wil continue at home. This has 13. Study Network, Training, and Responsibilities proven possible in other ACS [acute coronary syndrome] trials that . . To qualify, physicians responsible for PAC [pulmonary-artery catheter] placements will be required required self injection of subcutaneous heparin [reference]. Ful to show proof of insertion of ≥50 PACs in the previous year with a complication rate of <5%. Further, written guidance on self injection wil also be provided to patients. clinicians will need to show competence in the following areas to participate in the study: 1) insertion If self injection is found not to be possible in an individual patient techniques and cardiovascular anatomy; 2) oxygen dynamics; . . and 7) common PAC complications.
for unexpected reasons, an alternative method wil be sought (eg [reference] . . we will assume basic competence in these areas after satisfactory completion of the district nurse, or attending the hospital) to try and maintain ful PACEP [PAC educational programme] module." 123 compliance with scheduled study drug regimen after discharge. "Trial centre requirements Patients wil also be asked to complete a daily injection diary. Al A number of guidelines have stated thrombolysis should only be considered if the patient is admitted personnel wil be blinded to the identity of the syringe contents." 145 to a specialist centre with appropriate experience and expertise.[reference] Hospitals participating policymakers, and others to fully understand, implement, in IST-3 [third International Stroke Trial] should have an organized acute stroke service. The or evaluate the trial intervention. 148 This principle applies to components of effective stroke unit care have been identified . . In brief, the facilities (details of these all types of interventions, but is particularly true for complex requirements are specified in the separate operations manual) should include: • Written protocol for the acute assessment of patients with suspected acute stroke to include interventions (eg, health service delivery; psychotherapy), interventions to reduce time from onset to treatment. which consist of interconnected components that can vary • Immediate access to CT [computed tomographic] or MR [magnetic resonance] brain scanning between healthcare providers and settings. (preferably 24 hours a day). For drugs, biological agents, or placebos, the protocol A treatment area where thrombolysis may be administered and the patient monitored according to description should include the generic name, manufacturer, trial protocol, preferably an acute stroke unit." 124 constituent components, route of administration, and dosing schedule (including titration and run-in periods, if applica- tion, 67  114  115  117  118  128 - 130 as well as outcome event rates. 39  131 ble). 149  150 The description of non-drug interventions—such as In addition, the criteria convey key information related to devices, procedures, policies, models of care, or counselling— external validity (generalisability or applicability). 132 The is generally more complex and warrants additional details importance of transparent documentation is highlighted by about the setting (Item 9) and individuals administering the evidence that the eligibility criteria listed in publications are interventions. For example, the level of pre-trial expertise oft en diff erent from those specifi ed in the protocol. 125  133  134 (Item 10) and specifi c training of individuals administering Certain eligibility criteria warrant explicit justifi cation in these complex interventions are oft en relevant to describe the protocol, particularly when they limit the trial sample (eg, for surgeons, psychologists, physiotherapists). When to a narrow subset of the population. 132  135  136 The appro- intervention delivery is subject to variation, it is important to priateness of restrictive participant selection depends on state whether the same individuals will deliver the trial inter- the trial objectives. 137 When trial participants diff er sub- ventions in all study groups, or whether diff erent individuals stantially from the overall population to whom the inter- will manage each study group—in which case it can be dif- vention will be applied, the trial results may not refl ect the fi cult to separate the eff ect of the intervention from that of the impact in real world practice settings. 134  138 - 144 individual delivering it. Interventions that consist of "usual care" or "standard of care" require further elaboration in the Interventions
protocol, as this care can vary substantially across centres and Item 11a: Interventions for each group with sufficient patients, as well as over the duration of the trial. detail to allow replication, including how and when they will be administered Interventions—modifications
Item 11b: Criteria for discontinuing or modifying Studies of trials and systematic reviews have shown that allocated interventions for a given trial participant (eg, important elements of the interventions are not described drug dose change in response to harms, participant in half of the publications. 146  147 If such elements are also request, or improving/worsening disease) missing from the protocol, or if the protocol simply refers to other documents that are not freely accessible, then it can be For a given trial participant, the assigned study inter- impossible for healthcare providers, systematic reviewers, vention may need to be modified or discontinued by BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 10 31/01/2013 10:33:37 RESEARCH METHODS AND REPORTING
Adherence to intervention protocols refers to the degree to "Gastro-Intestinal Upset which the behaviour of trial participants corresponds to the The tablets may be taken in two equally divided doses, if necessary, to improve gastro-intestinal intervention assigned to them. 154 Distinct but related con- tolerance. Should it be necessary the daily dose may be reduced by one tablet at a time to cepts include trial retention (Item 18b) and adherence to the improve gastro-intestinal tolerance. follow-up protocol of procedures and assessments (Item 13). Renal Function Impairment On average, adherence to intervention protocols is Since sodium clodronate is excreted unchanged by the kidney its use is contra-indicated in higher in clinical trials than in non-research settings. 155 patients with moderate to severe renal impairment (serum creatinine greater than 2 times upper limit of normal range of the centre). If renal function deteriorates to this extent the trial medication Although there is no consensus on the acceptable mini- should be withdrawn from the patient. This should be reported as an adverse event. In patients mum adherence level in clinical trials, low adherence with normal renal function or mild renal impairment (serum creatinine less than 2 times upper can have a substantial eff ect on statistical power and limit of normal range of the centre) serum creatinine should be monitored during therapy. interpretation of trial results. 156 -158 Since fewer partici- Allergic Reactions pants are receiving the full intervention as intended, Allergic skin reactions have been observed in rare cases. If this is suspected withdraw the trial non-adherence can reduce the contrast between study medication from the patient. This should be reported as an adverse event. groups—leading to decreased study power and increased Biochemical Disturbances costs associated with recruiting larger sample sizes for Asymptomatic hypocalcaemia has been noted rarely. Temporary suspension of the trial evaluating superiority, or leading to potentially inap- medication until the serum calcium returns into the normal range is recommended. The trial propriate conclusions of non-inferiority or equivalence. medication can be then restarted at half the previous dose. If the situation returns withdraw the There is also the possibility of underestimating any effi trial medication from the patient. This should be reported as an adverse event . ." 151 cacy and harms of the study intervention. trial investigators for various reasons, including harms, Furthermore, if adherence is a marker for general improved health status, lack of effi cacy, and withdrawal healthy behaviour associated with better prognosis, then of participant consent. Comparability across study diff erent rates of non-adherence between study groups groups can be improved, and subjectivity in care deci- can lead to a biased estimate of an intervention's eff ect. In sions reduced, by defi ning standard criteria for interven- support of this "healthy adherer" eff ect, non-adherers to tion modifi cations and discontinuations in the protocol. placebo in clinical studies have been found to have poorer Regardless of any decision to modify or discontinue their clinical outcomes than adherers. 159 assigned intervention, study participants should be To help avoid these potential detrimental eff ects of retained in the trial whenever possible to enable follow- non-adherence, many trials implement procedures up data collection and prevent missing data (Item 18b). 152 and strategies for monitoring and improving adher-ence, 67  156 - 158 and any such plans should be described in Interventions—adherence
the protocol. 160 Among applicable drug trials published Item 11c: Strategies to improve adherence to intervention in 1997-99, 47% reported monitoring the level of adher- protocols, and any procedures for monitoring adherence ence. 161 Although each of the many types of monitoring (eg, drug tablet return; laboratory tests) methods has its limitations, 157  158 adherence data can help to inform the statistical analysis (Item 20c), trial interpretation, and choice of appropriate adherence strat- egies to implement in the trial as it progresses or in future "Adherence reminder sessions trials and clinical practice. Face-to-face adherence reminder sessions will take place at the initial product dispensing and A variety of adherence strategies exist, 156 -158 and their each study visit thereafter. This session will include: use can be tailored to the specifi c type of trial design, inter- • The importance of fol owing study guidelines for adherence to once daily study product vention, and participant population. It may be desirable to • Instructions about taking study pil s including dose timing, storage, and importance of taking pil s whole, and what to do in the event of a missed dose. select strategies that can be easily implemented in clinical • Instructions about the purpose, use, and care of the MEMS® cap [medication event monitoring practice, so that the level of adherence in the real world system] and bottle setting is comparable to that observed in the trial. 158 • Notification that there wil be a pil count at every study visit • Reinforcement that study pil s may be TDF [tenofovir disproxil fumarate] or placebo Interventions—concomitant care
• Importance of cal ing the clinic if experiencing problems possibly related to study product such as Item 11d: Relevant concomitant care and interventions symptoms, lost pil s or MEMS® cap. that are permitted or prohibited during the trial Subsequent sessions will occur at the follow-up visits. Participants will be asked about any problems they are having taking their study pills or using the MEMS® cap. There will be brief discussion of reasons for missed doses and simple strategies for enhancing adherence, eg, In a controlled trial, a key goal is to have comparable linking pill taking to meals or other daily activities. Participants will have an opportunity to ask study groups that diff er only by the intervention being questions and key messages from the initial session will be reviewed as needed . . evaluated, so that any diff erence in outcomes can be Adherence assessments attributed to eff ects of the study intervention. Cointer- To enhance validity of data, multiple methods will be used to assess medication adherence vention bias can arise when the study groups receive including pill count; an electronic medication event monitoring system (MEMS® cap) [reference]; diff erent concomitant care or interventions (in addition and ACASI [audio-computer administered interview] questionnaire items including a one month to the assigned trial interventions) that may aff ect trial visual analogue scale,[reference] reasons for non-compliance, and use of the MEMS® cap. outcomes. 162 To promote comparability of study groups, Participants will return the unused tablets and bottle at each follow-up visit. Unused tablets will be the protocol should list the relevant concomitant care and counted and recorded on the appropriate CRF [case report form]. Electronic data collected in the interventions that are allowed (including rescue interven- MEMS® cap will be downloaded into a designated, secure study computer." 153 tions), as well as any that are prohibited. BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 11 31/01/2013 10:33:37 RESEARCH METHODS AND REPORTING
The trial outcomes are fundamental to study design and " 2. Rescue Medication interpretation of results. For a given intervention, an out- For weeks 0-3 , topical mometasone furoate 0.1% cream or ointment (30 g/week) will be permitted come can generally reflect efficacy (beneficial effect) or with participants preferably using ointment. Participants will be instructed to apply the topical mometasone furoate to blisters/lesions as required (not to areas of unaffected skin). If the participant harm (adverse eff ect). The outcomes of main interest are is allergic to mometasone furoate or the hospital pharmacy does not stock it, then an alternative designated as primary outcomes, which usually appear in the topical steroid may be prescribed but this must be in the potent class. In addition, participants will be objectives (Item 7) and sample size calculation (Item 14). The advised that they can apply a light moisturiser to blisters/lesions at any time during the study. remaining outcomes constitute secondary or other outcomes. For weeks 3-6 , use of mometasone furoate (or other topical corticosteroids) is strongly discouraged For each outcome, the trial protocol should defi ne four to prevent potential systemic effects. Accidental use of mometasone furoate or other potent topical components: the specifi c measurement variable, which cor- steroid during this period will be classified as a protocol deviation. responds to the data collected directly from trial participants After week 6 , potent topical corticosteroids (up to 30 g/week) may be used to treat symptoms and localised disease if they would have normally been used as part of normal clinical care by the (eg, Beck Depression Inventory score, all cause mortality); physician in charge of that patient. This must be recorded on the trial treatment log. the participant-level analysis metric, which corresponds to However, those patients who are on a dose reducing regime for oral steroids, 30 g/week of a the format of the outcome data that will be used from each "potent" topical steroid will be allowed. trial participant for analysis (eg, change from baseline, fi nal 3. Prohibited Concomitant Medications value, time to event); the method of aggregation, which refers The administration of live virus vaccines is not permitted for all participants during weeks 0-6 as the to the summary measure format for each study group (eg, investigator is blinded to treatment allocation, and must therefore warn all participants to refrain for mean, proportion with score > 2); and the specifi c measure- [sic] having a live virus vaccine. However, after week 6, once the investigator knows which medication ment time point of interest for analysis. 163 the participant is on, only those taking prednisolone will not be allowed live virus vaccines. Participants should continue to take medications for other conditions as normal. However, if it is It is also important to explain the rationale for the choice of anticipated that the participant will need a live virus vaccine during the intervention phase, they will trial outcomes. An ideal outcome is valid, reproducible, rel- be ineligible for entry into the study . ." 50 evant to the target population (eg, patients), and responsive to changes in the health condition being studied. 67 The use of Outcomes
a continuous versus dichotomous method of aggregation can Item 12: Primary, secondary, and other outcomes, aff ect study power and estimates of treatment eff ect, 164  165 and including the specific measurement variable (eg, systolic subjective outcomes are more prone to bias from inadequate blood pressure), analysis metric (eg, change from baseline, blinding (ascertainment bias) and allocation concealment final value, time to event), method of aggregation (eg, (selection bias) than objective outcomes. 166  167 Although median, proportion), and time point for each outcome. composite outcomes increase event rates and statistical Explanation of the clinical relevance of chosen efficacy and power, their relevance and interpretation can be unclear if harm outcomes is strongly recommended the individual component outcomes vary greatly in event rates, importance to patients, or amount of missing data. 168 -171 The number of primary outcomes should be as small as "1. Primary Outcome Measures possible. Although up to 38% of trials defi ne multiple pri- • Difference between the two treatment arms in the proportion of participants classed as treatment mary outcomes, 4  35  163 this practice can introduce problems success at 6 weeks. Treatment success is defined as 3 or less significant blisters present on with multiplicity, selective reporting, and interpretation when examination at 6 weeks. Significant blisters are defined as intact blisters containing fluid which are at there are inconsistent results across outcomes. Problems also least 5 mm in diameter. However, if the participant has popped a blister, or the blister is at a site that makes it susceptible to bursting such as the sole of the foot, it can be considered part of the blister arise when trial protocols do not designate any primary out- count, providing there is a flexible (but not dry) roof present over a moist base. Mucosal blisters wil comes, as seen in half (28/59) of protocols for a sample of tri- be excluded from the count. als published from 2002-2008, 12 and in 25% of randomised A survey of the UK DCTN [Dermatology Clinical Trials Network] membership showed that a point estimate trial protocols that received ethics approval in Denmark in of 25% inferiority in effectiveness would be acceptable assuming a gain in the safety profile of at least 10%. 1994-95. 4 Furthermore, major discrepancies in the primary • This measure of success was selected as it was considered to be more clinical y relevant than a outcomes designated in protocols/registries/regulatory sub- continuous measure of blister count. It would be less clinical y relevant to perform an absolute blister missions versus fi nal trial publications are common; favour count and report a percentage reduction. Instead, to state that treatment is considered a success if the reporting of statistically signifi cant primary outcomes remission is achieved (ie the presence of three or less blisters on physical examination at 6 weeks) more closely reflects clinical practice. In addition, it is far less burdensome on investigators than over non-signifi cant ones; and are oft en not acknowledged including a ful blister count, which would mean counting in the region of 50-60 blisters in many in fi nal publications. 172 -176 Such bias can only be identifi ed cases. This outcome measure wil be performed as a single blind assessment. and deterred if trial outcomes are clearly defi ned beforehand • Difference between the two treatment arms in the proportion of participants reporting grade 3, 4 in the protocol and if protocol information is made public. 177 and 5 (mortality) adverse events which are possibly, probably or definitely related to BP [bul ous Where possible, the development and adoption of a com- pemphigoid] medication in the 52 weeks fol owing randomisation. A modified version of The mon set of key trial outcomes within a specialty can help to Common Terminology Criteria for Adverse Events (CTCAE v3.0) wil be used to grade adverse events. deter selective reporting of outcomes and to facilitate compari- At each study visit, participants wil be questioned about adverse events they have experienced since the last study visit (using a standard list of known side effects of the two study drugs). sons and pooling of results across trials in a meta-analysis. 178 -180 The COMET (Core Outcome Measures in Eff ectiveness Trials) 2. Secondary Outcome Measures Initiative aims to facilitate the development and application of For the secondary and tertiary endpoints a participant wil be classed as a treatment success if they have 3 or less significant blisters present on examination and have not had their treatment modified (changed or such standardised sets of core outcomes for clinical trials of spe- dose increased) on account of a poor response. cifi c conditions ( www.comet-initiative.org ). Trial investigators • Difference in the proportion of participants who are classed as a treatment success at 6 weeks. are encouraged to ascertain whether there is a core outcome • Difference in the proportion of participants in each treatment arm who are classed as treatment set relevant to their trial and, if so, to include those outcomes in success at 6 weeks and are alive at 52 weeks. This measure wil provide a good overal comparison of their trial. Existence of a common set of outcomes does not pre- the two treatment arms." 50 clude inclusion of additional relevant outcomes for a given trial. BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 12 31/01/2013 10:33:37 RESEARCH METHODS AND REPORTING
Participant timeline
Item 13: Time schedule of enrolment, interventions A clear and concise timeline of the study visits, enrolment (including any run-ins and washouts), assessments, process, interventions, and assessments performed on and visits for participants. A schematic diagram is highly participants can help to guide trial conduct and enable recommended (see fig 1 ) external review of participant burden and feasibility. These factors can also aff ect the decision of potential investigators and participants to join the trial (Item 15). 91 "The main outcomes of interest are the drug and sex-related HIV and HCV [hepatitis C virus] risk A schematic diagram is highly recommended to effi behaviors . . Clients will be assessed using the full battery of instruments from the Common present the overall schedule and time commitment for trial Assessment Battery (CAB), along with the Self-Efficacy and Stages of Change questionnaires and participants in each study group. Though various presenta- a Urine Drug Screen after consenting . . questionnaires will take place for all participants 14-30 tion formats exist, key information to convey includes the days after randomization during which they will be given the Stages of Change and Self-Efficacy timing of each visit, starting from initial eligibility screen- questionnaires, the Timeline Follow-Back, and a UA [urine analysis]. Follow-up interviews, using ing through to study close-out; time periods during which the full battery (CAB and questionnaires), will be collected at 2 months (56 days), 4 months (112 trial interventions will be administered; and the procedures days) and 6 months (168 days) after the randomization date. A 14 day window, defined as 7 days before and 7 days after the due date, will be available to complete the 2 and 4 month follow-up and assessments performed at each visit (with reference to interviews and a 28 day window, defined as 7 days before and 21 days after the due date, will be specifi c data collection forms, if relevant) (fi g 1). available to complete the 6 month follow up interview . . 7.1.1 Common Assessment Battery (CAB) Sample size
A Demographic Questionnaire . . Item 14: Estimated number of participants needed to The Composite International Diagnostic Interview Version 2.1 . . achieve study objectives and how it was determined, The Addiction Severity Index-Lite (ASI-Lite) . . including clinical and statistical assumptions supporting The Risk Behavior Survey (RBS), . . any sample size calculations Explanation 7.1.2 Additional Interviews/Questionnaires To assess drug use, urinalysis for morphine, cocaine, amphetamine, and methamphetamine will The planned number of trial participants is a key aspect of be performed at the 2-Week Interim Visit, and the 2-, 4-, and 6-month Follow-up visits . . study design, budgeting, and feasibility that is usually deter- Stage of change for quitting drug use will be measured using a modification of the mined using a formal sample size calculation. If the planned Motivation Scales [table 3] . ." 181 sample size is not derived statistically, then this should be "The trial consists of a 12-week intervention treatment phase with a 40-week follow-up phase. explicitly stated along with a rationale for the intended sam- The total trial period will be 12 months. As shown . . measurements will be undertaken at four ple size (eg, exploratory nature of pilot studies; pragmatic time-points in each group: at baseline, directly after completing the 12-week internet program, considerations for trials in rare diseases). 17  184 and at six and 12-month follow-up [see fig 2]."182 For trials that involve a formal sample size calculation, the guiding principle is that the planned sample size should be large enough to have a high probability (power) of detect-ing a true eff ect of a given magnitude, should it exist. Sam-ple size calculations are generally based on one primary outcome; however, it may also be worthwhile to plan for adequate study power or report the power that will be avail-able (given the proposed sample size) for other important outcomes or analyses because trials are oft en underpowered to detect harms or subgroup eff ects. 185  186 Among randomised trial protocols that describe a sample size calculation, 4-40% do not state all components of the calculation. 6  11 The protocol should generally include the following: the outcome (Item 12); the values assumed for the outcome in each study group (eg, proportion with event, or mean and standard deviation) (table 4); the statistical test (Item 20a); alpha (type 1 error) level; power; and the calcu-lated sample size per group—both assuming no loss of data and, if relevant, aft er any infl ation for anticipated missing data (Item 20c). Trial investigators are also encouraged Table 4 Outcome values to report in sample size calculation Type of summary outcome Assumed result for Proportion (%) Mean and Note: Although the sample size calculation uses the expected outcome value for each group, the corresponding contrast between groups (estimated effect) should also be reported. Fig 2: Flow of participants 182 BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 13 31/01/2013 10:33:37 RESEARCH METHODS AND REPORTING
Table 3 HIV/HCV risk reduction protocol schedule of forms and procedures (adapted from original table 181 ) Study visit 2 and/or 2 Follow-up Follow-up Follow-up Activity/ assessment complete (min) consent Prescreening consent Study coordinator Study coordinator Consent form/quiz Study coordinator Inclusion/ exclusion form Study coordinator Study coordinator Addiction severity index (ASI) lite Composite international diagnostic interview)HIV risk behaviour survey Timeline follow back Study coordinator Voluntary blood sample Counselling Study phlebotomist and education intervention (treatment group)All groups, optional blood sample at Study phlebotomist study closeTermination form Study coordinator Serious adverse event form Study coordinator As needed throughout protocol Communication log Every phone or in-person contact outside of a regular visit "The sample size was calculated on the basis of the would require 120 patients in each arm of the trial. To rates and decision boundaries for the interim and the primary hypothesis. In the exploratory study,[reference] al ow for 30% drop out, 170 wil be recruited per arm, ie, final analysis are specified: those referred to PEPS [psychoeducation with problem 340 in total." 183 • Overal one-sided type I error rate: 0.025 solving] had a greater improvement in social functioning "Superficial and deep incisional surgical site infection • Boundary for the one-sided p-value of the first stage at 6 month fol ow-up equivalent to 1.05 points on the rates for patients in the PDS II® [polydioxanone suture] for accepting the nul -hypothesis within the interim SFQ [Social Functioning Questionnaire]. However, a group are estimated to occur at a rate of 0.12.[reference] analysis: α =0.5 number of people received PEPS who were not included The trials by [reference] have shown a reduction of SSI • One-sided local type I error rate for testing the nul - in the trial (eg, the wait-list control) and, for this larger [surgical site infections] of more than 50% (from 10.8% hypothesis within the interim analysis: α =0.0102 sample (N=93), the mean pre-post- treatment difference to 4.9% and from 9.2% to 4.3% respectively). Therefore, • Boundary for the product of the one-sided p-values of was 1.79 (pre-treatment mean=13.85, SD=4.21; we estimate a rate of 0.06 for PDS Plus® [triclosan- both stages for the rejection of the nul -hypothesis in the post-treatment mean=12.06, SD=4.21). (Note: a lower coated continuous polydioxanone suture]. final analysis: cα=0.0038 SFQ score is more desirable). This difference of almost For a fixed sample size design, the sample size If the trial wil be continued with a second stage after 2 points accords with other evidence that this is a required to achieve a power of 1-β=0.80 for the the interim analysis (this is possible if for the one-sided clinical y significant and important difference.[reference] one-sided chi-square test at level α=0.025 under p-value p of the interim analysis p A reduction of 2 points or more on the SFQ at 1 year these assumptions amounts to 2×356=712 (nQuery 1∈]0.0102,0.5[ [ie 0.5≥P ≥0.0102] holds true, the results of the interim fol ow-up in an RCT of cognitive behaviour therapy in Advisor®, version 7.0). It can be expected that including analysis can be taken into account for a recalculation of health anxiety was associated with a halving of secondary covariates of prognostic importance in the logistic the required sample size. If the sample size recalculation care appointments (1.24.vs 0.65), a clinical y significant regression model as defined for the confirmatory leads to the conclusion that more than 1200 patients reduction in the Hospital Anxiety and Depression Scale analysis wil increase the power as compared to the are required, the study is stopped, because the related (HADS[reference]) Anxiety score of 2.5 (9.9 vs 7.45) chi-square test. As the individual results for the primary treatment group difference is judged to be of minor and a reduction in health anxiety (the main outcome) endpoint are available within 30 days after surgery, the clinical importance. of 5.6 points (17.8 vs 12.2) (11 is a normal population drop-out rate is expected to be smal . Nevertheless, score and 18 is pathological).[reference] These findings a potential dilution of the treatment effect due to The actual y achieved sample size is then not fixed but suggest that improvements in social functioning may drop-outs is taken into account (eg no photographs random, and a variety of scenarios can be considered. accrue over 1 year, hence we expect to find a greater available, loss to fol ow up); it is assumed that this If the sample size is calculated under the same magnitude of response at the 72 week fol ow-up than we can be compensated by additional 5% of patients to assumptions with respect to the SSI rates for the two did in the exploratory trial. Therefore, we have powered be randomized, and therefore the total sample size groups, applying the same the overal significance level this trial to be able to detect a difference in SFQ score of 2 required for a fixed sample size design amounts to of α=0.025 (one-sided) but employing additional y points. SFQ standard deviations vary between treatment, n=712+38=750 patients. the defined stopping boundaries and recalculating the control, and the wait-list samples, ranging from 3.78 to sample size for the second stage at a conditional power 4.53. We have based our sample size estimate on the An adaptive interim analysis [reference] will be of 80% on the basis of the SSI rates observed in the most conservative (ie, largest) SD [standard deviation]. performed after availability of the results for the interim analysis results in an average total sample size To detect a mean difference in SFQ score of 2 point (SD = primary endpoint for a total of 375 randomized of n=766 patients; the overal power of the study is then 4.53) at 72 weeks with a two-sided significance level of patients (ie, 50% of the number of patients required in 90% (ADDPLAN®, version 5.0)." 100 1% and power of 80% with equal al ocation to two arms a fixed sample size design). The following type I error BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 14 31/01/2013 10:33:38 RESEARCH METHODS AND REPORTING
to provide a rationale or reference for the outcome values assumed for each study group. 187 The values of certain pre- "Each center wil screen subjects to achieve screening percentages specifi ed variables tend to be inappropriately infl ated (eg, of 50% women and 33% minority; screening wil continue until clinically important treatment eff ect size) 188  189 or underes- the target population is achieved (12 subjects/site). We recognize timated (eg, standard deviation for continuous outcomes), 190 that, because of exclusion by genotype and genotypic variation leading to trials having less power in the end than what was among diverse populations,[reference], the enrol ed cohort may originally calculated. Finally, when uncertainty of a sam- not reflect the screened population. The enrol ment period wil ple size estimate is acknowledged, methods exist for re- extend over 12 months. estimating sample size. 191 The intended use of such an adap- Recruitment Strategy tive design approach should be stated in the protocol. Each clinical center involved in the ACRN [Asthma Clinical Research For designs and frameworks other than parallel group Network] was chosen based on documentation for patient availability, among other things. It is, however, worthy to note the superiority trials, additional elements are required in the specific plans of each center.
sample size calculation. For example, an estimate of the . . The Asthma Clinical Research Center at the Brigham & Women's standard deviation of within-person changes from baseline Hospital utilizes three primary resources for identifying and should be included for crossover trials 192 ; the intracluster recruiting potential subjects as described below.
correlation coeffi cient for cluster randomised trials 193 ; and 1. Research Patient Database the equivalence or non-inferiority margin for equivalence The Asthma Clinical Research Center at the Brigham and Women's or non-inferiority trials respectively. 108  194 Such elements Hospital has a database of over 1,500 asthmatics . .
2. Asthma Patient Lists . .
are oft en not described in fi nal trial reports, 110  195 - 198 and 3. Advertisements . .
it is unclear how oft en they are specifi ed in the protocol. . . the Madison ACRN site has utilized some additional approaches Complete description of sample size calculations in the to target minority recruitment. We have utilized a marketing expert protocol enables an assessment of whether the trial will be to coordinate and oversee our overal efforts in recruiting and adequately powered to detect a clinically important diff er- retaining minorities. . As a result of his efforts, we have advertised ence. 189  199 - 206 It also promotes transparency and discour- widely in newspapers and other publications that target ethnic ages inappropriate post hoc revision that is intended to minorities, established contacts with various ethnic community, support a favourable interpretation of results or portray con- university, church, and business groups, and conducted community-based asthma programs . . For example, student sistency between planned and achieved sample sizes. 6  207 groups such as AHANA (a pre-health careers organization focusing on minority concerns) wil be contacted. . In addition, we wil Recruitment
utilize published examples of successful retention strategies such Item 15: Strategies for achieving adequate participant as frequent payment of subject honoraria as study landmarks are enrolment to reach target sample size achieved and study participant group social events. Study visits wil be careful y planned and scheduled to avoid exam-time and The main goal of recruitment is to meet the target sam- university calendar breaks . .
ple size (Item 14). However, recruitment diffi The Harlem Hospital Center Emergency Department (ED) sees an average of eight adult patients per day for asthma. Through the commonly encountered in clinical trials. 209 -213 For exam- REACH (Reducing Emergency Asthma Care in Harlem) project, we ple, reviews of government funded trials in the US and have . . successful y recruited and interviewed 380 patients from UK found that two thirds did not reach their recruitment targets. 214  215 Low enrolment will reduce statistical power Responses to inquiries about participation in research studies and can lead to early trial stoppage or to extensions with are answered by a dedicated phone line that is manned during delayed results and greater costs. business hours and answered by voicemail at al other times. A Strategies to promote adequate enrolment are thus impor- research assistant responds to each inquiry immediately, using a tant to consider during trial planning. Recruitment strate- screening instrument . .
Patients are recruited for clinical trials at the Jefferson Center through gies can vary depending on the trial topic, context, and site. two primary mechanisms: (1) local advertising; and (2) identification Diff erent recruitment methods can substantially aff ect the in the asthma patient registry (database). Local advertising takes number and type of trial participants recruited 128  209  216 - 220 advantage of the printed as wel as the audio-visual media. Printed and can incur diff erent costs. 221 -223 Design issues such as the media include . . Al advertising in the printed and audio-visual number and stringency of eligibility criteria will also directly media has prior approval of the Institutional Review Board.
aff ect the number of eligible trial participants. The Jefferson patient registry (database) has been maintained Protocol descriptions of where participants will be since 1992 and currently contains 3,100 patients . . It is estimated that 300-400 new asthmatic patients are seen each year, while recruited (eg, primary care clinic, community), by whom a smal er number become inactive due to relocation, change of (eg, surgeon), when (eg, time aft er diagnosis), and how (eg, health care provider, etc. Once identified in the database, patients advertisements, review of health records) can be helpful potential y eligible for a specific study are contacted by the nurse for assessing the feasibility of achieving the target sample coordinator who explains the study and ascertains the patient's size and the applicability of the trial results in practice. interest. If interested, the patient is seen in the clinical research Other relevant information to explicitly provide in the laboratories where more detailed evaluations are made . .
protocol includes expected recruitment rates, duration of Each subject wil receive financial compensation within FDA the recruitment period, plans to monitor recruitment dur- [Food and Drug Administration] guidelines for participation in an amount determined by the local center. For subjects who drop out, ing the trial, and any fi nancial or non-fi nancial incentives payments wil be pro-rated for the length of time they stayed in the provided to trial investigators or participants for enrolment study, but payment wil not be made until the study would have (Item 4). If strategies diff er by site in m ulticentre trials, been completed had the subject not dropped out."208 these should be detailed to the extent possible. BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 15 31/01/2013 10:33:38 RESEARCH METHODS AND REPORTING
Section 3b: Methods—assignment of interventions (for
Box 1 Key elements of random sequence to specify in trial controlled trials)
Allocation—sequence generation • Method of sequence generation (eg, random number table or Item 16a: Method of generating the allocation sequence computerised random number generator) (eg, computer-generated random numbers) and list of any • Al ocation ratio (Item 8) (eg, whether participants are al ocated factors for stratification. To reduce predictability of a random with equal or unequal probabilities to interventions) sequence, details of any planned restriction (eg, blocking) • Type of randomisation (box 2): simple versus restricted; fixed should be provided in a separate document that is unavailable versus adaptive (eg, minimisation); and, where relevant, the reasons for such choices to those who enrol participants or assign interventions • If applicable, the factors (eg, recruitment site, sex, disease stage) to be used for stratification (box 2), including categories and relevant cut-off boundaries "Participants will be randomly assigned to either control or experimental group with a 1:1 allocation as per a computer generated randomisation schedule stratified by site and the as these terms have been used inappropriately to describe baseline score of the Action Arm Research Test (ARAT; <=21 non-random, deterministic allocation methods such as versus >21) using permuted blocks of random sizes. The block sizes will not be disclosed, to ensure concealment." 224 alternation or allocation by date of birth. 121 In general, these non-random allocation methods introduce selec- tion bias and biased estimates of an intervention's eff ect Participants in a randomised trial should be assigned to size, 17  167  228  229 mainly due to the lack of allocation con- study groups using a random (chance) process character- cealment (Item 16b). If non-random allocation is planned, ised by unpredictability of assignments. Randomisation then the specifi c method and rationale should be stated. decreases selection bias in allocation; helps to facilitate Box 1 outlines the key elements of the random sequence blinding/masking aft er allocation; and enables the use of that should be detailed in the protocol. Three quarters of probability theory to test whether any diff erence in out- randomised trial protocols approved by a research ethics come between intervention groups refl ects chance. 17  225 - 227 committee in Denmark (1994-95) or conducted by a US Use of terms such as "randomisation" without further elab- cooperative cancer research group (1968-2006) did not oration is not suffi cient to describe the allocation process, describe the method of sequence generation. 2  11 Box 2 Randomisation and minimisation (adapted from CONSORT 2010 Explanation and Elaboration) 17  230  231 Simple randomisation Stratified randomisation Randomisation based solely on a single, constant allocation Stratification is used to ensure good balance of participant ratio is known as simple randomisation. Simple randomisation characteristics in each group. Without stratification, study groups with a 1:1 allocation ratio is analogous to a coin toss, although may not be wel matched for baseline characteristics, such as age tossing a coin is not recommended for sequence generation. and stage of disease, especial y in smal trials. Such imbalances can No other allocation approach, regardless of its real or be avoided without sacrificing the advantages of randomisation. supposed sophistication, surpasses the bias prevention and Stratified randomisation is achieved by performing a separate unpredictability of simple randomisation. 231 randomisation procedure within each of two or more strata of Restricted randomisation participants (eg, categories of age or baseline disease severity), Any randomised approach that is not simple randomisation is ensuring that the numbers of participants receiving each intervention restricted. Blocked randomisation is the most common form. are closely balanced within each stratum. Stratification requires some Other forms, used much less frequently, are methods such as form of restriction (eg, blocking within strata) in order to be effective. replacement randomisation, biased coin, and urn randomisation. 231 The number of strata should be limited to avoid over-stratification. 234 Stratification by centre is common in multicentre trials. Blocked randomisation Blocked randomisation (also cal ed permuted block randomisation) Minimisation assures similar distribution of selected participant assures that study groups of approximately the same size wil be factors between study groups. 230  235 Randomisation lists are not set generated when an al ocation ratio of 1:1 is used. Blocking can up in advance. The first participant is truly randomly al ocated; for also ensure close balance of the numbers in each group at any time each subsequent participant, the treatment al ocation that minimises during the trial. After every block of eight participants, for example, the imbalance on the selected factors between groups at that time is four would have been al ocated to each trial group. 232 Improved identified. That al ocation may then be used, or a choice may be made balance comes at the cost of reducing the unpredictability of the at random with a heavy weighting in favour of the intervention that sequence. Although the order of interventions varies randomly would minimise imbalance (for example, with a probability of 0.8). The within each block, a person running the trial could deduce some of use of a random component is general y preferable. 236 Minimisation the next treatment al ocations if they discovered the block size. 233 has the advantage of making smal groups closely similar in terms of Blinding the interventions, using larger block sizes, and randomly participant characteristics at al stages of the trial. varying the block size wil help to avoid this problem. Minimisation offers the only acceptable alternative to Biased coin and urn randomisation randomisation, and some have argued that it is superior. 237 On the Biased coin designs attain the similar objective as blocked designs other hand, minimisation lacks the theoretical basis for eliminating without forcing strict equality. They therefore preserve much of the bias on al known and unknown factors. Nevertheless, in general, trials unpredictability associated with simple randomisation. Biased-coin that use minimisation are considered methodological y equivalent to designs alter the al ocation ratio during the course of the trial to rectify randomised trials, even when a random element is not incorporated. imbalances that might be occurring. 231 Adaptive biased-coin designs, For SPIRIT, minimisation is considered a restricted randomisation such as the urn design, vary al ocation ratios based on the magnitude approach without any judgment as to whether it is superior or inferior of the imbalance. However, these approaches are used infrequently. compared to other restricted randomisation approaches. BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 16 31/01/2013 10:33:38 RESEARCH METHODS AND REPORTING
Box 3 Need for a separate document to describe restricted randomisation Table 5 Differences between allocation concealment and If some type of restricted randomisation approach is to be used, in particular blocked randomisation blinding (masking) for trials with individual randomisation or minimisation, then the knowledge of the specific details could lead to bias. 238  239 For example, if the trial protocol for a two arm, parallel group trial with a 1:1 allocation ratio states that blocked randomisation will be used and the block size will be six, then trial implementers know that the Unawareness of the Unawareness of the intervention assignments will balance every six participants. Thus, if intervention assignments next study group study group to which trial become known after assignment, knowing the block size will allow trial implementers to predict assignment in the participants have already allocation sequence when equality of the sample sizes will arise. A sequence can be discerned from the pattern of past Prevent selection bias Prevent ascertainment, assignments and then some future assignments could be accurately predicted. For example, if part of by facilitating enrolment performance, and attrition a sequence contained two "As" and three "Bs," trial implementers would know the last assignment in biases by facilitating the sequence would be an "A." If the first three assignments in a sequence contained three "As," trial participants in each comparable concomitant care implementers would know the last three assignments in that sequence would be three "Bs." Selection (aside from trial interventions) bias could result, regardless of the effectiveness of allocation concealment (Item 16b). and evaluation of participants Of course, this is mainly a problem in open label trials, where everyone becomes aware of the in each study group intervention after assignment. It can also be a problem in trials where everyone is supposedly blinded Before study group Upon study group assignment and beyond (masked), but the blinding is ineffective or the intervention harms provide clues such that treatments Trial participants and One or more of the individuals enrolling following: trial participants, We recommend that trial investigators do not provide full details of a restricted randomisation investigators, care providers, scheme (including minimisation) in the trial protocol. Knowledge of these details might undermine outcome assessors. randomisation by facilitating deciphering of the allocation sequence. Instead, this specific Other groups: endpoint information should be provided in a separate document with restricted access. However, simple adjudication committee, randomisation procedures could be reported in detail in the protocol, because simple randomisation data handlers, data analysts is totally unpredictable. Always possible to Yes Box 2 defi nes the various types of randomisation, includ- to provide informed consent, or a recruiter's decision to ing minimisation. When restricted randomisation is used, enrol a participant, is not infl uenced by knowledge of the certain details should not appear in the protocol in order group to which they will be allocated if they join the trial. 242 to reduce predictability of the random sequence (box 3). Allocation concealment should not be confused with blind- The details should instead be described in a separate docu- ing (masking) (Item 17) (table 5). 243 ment that is unavailable to trial implementers. For blocked Without adequate allocation concealment, even ran- randomisation, this information would include details on dom, unpredictable assignment sequences can be sub- how the blocks will be generated (eg, permuted blocks by verted. 233  241 For example, a common practice is to enclose a computer random number generator), the block size(s), assignments in sequentially numbered, sealed envelopes. and whether the block size will be fi xed or randomly var- However, if the envelopes are not opaque and contents are ied. Specific block size was provided in 14/102 (14%) visible when held up to a light source, or if the envelopes randomised trial protocols approved by a Danish research can be unsealed and resealed, then this method of alloca- ethics committee in 1994-95, potentially compromising tion concealment can be corrupted. allocation concealment. 2 For trials using minimisation, it Protocols should describe the planned allocation is also important to state the details in a separate document, concealment mechanism in sufficient detail to enable including whether random elements will be used. assessment of its adequacy. In one study of randomised trial protocols in Denmark, over half did not adequately Allocation—concealment mechanism
describe allocation concealment methods. 2 In contrast, Item 16b: Mechanism of implementing the allocation central randomisation was stated as the allocation con- sequence (eg, central telephone; sequentially numbered, cealment method in all phase III trial protocols initiated opaque, sealed envelopes), describing any steps to in 1968-2003 by a cooperative cancer research group that conceal the sequence until interventions are assigned used extensive protocol review processes. 11 Like sequence generation, inadequate reporting of allocation conceal-ment in trial publications is common and has been asso- ciated with infl ated eff ect size estimates. 167  244  245 "Participants wil be randomised using TENALEA, which is an online, central randomisation service . . Al ocation concealment wil be ensured, as the service wil not release the randomisation Allocation—implementation
code until the patient has been recruited into the trial, which takes Item 16c: Who will generate the allocation sequence, who place after al baseline measurements have been completed." 240 will enrol participants, and who will assign participants to interventions Successful randomisation in practice depends on two Based on the risk of bias associated with some methods interrelated aspects: 1) generation of an unpredictable of sequence generation and inadequate allocation con- allocation sequence (Item 16a) and 2) concealment of cealment, trial investigators should strive for complete that sequence until assignment irreversibly occurs. 233  241 separation of the individuals involved in the steps before The allocation concealment mechanism aims to prevent enrolment (sequence generation process and allocation participants and recruiters from knowing the study group concealment mechanism) from those involved in the imple- to which the next participant will be assigned. Allocation mentation of study group assignments. When this separa- concealment helps to ensure that a participant's decision tion is not possible, it is important for the investigators to BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 17 31/01/2013 10:33:38 RESEARCH METHODS AND REPORTING
tees (Item 5d), data analysts, 253 and manuscript writers. Blinding of data monitoring committees is generally dis- couraged. 254  255 All patients who give consent for participation and who fulfil the inclusion criteria will be randomized. When blinding of trial participants and care providers Randomisation will be requested by the staff member responsible for recruitment and clinical is not possible because of obvious diff erences between the interviews from CenTrial [Coordination Centre of Clinical Trials]. interventions, 256  257 blinding of the outcome assessors can In return, CenTrial wil send an answer form to the study therapist who is not involved in assessing outcome of the study. This form wil include a randomisation number. In every centre closed envelopes oft en still be implemented. 17 It may also be possible to blind with printed randomisation numbers on it are available. For every randomisation number the participants or trial personnel to the study hypothesis in corresponding code for the therapy group of the randomisation list wil be found inside the envelopes. terms of which intervention is considered active. For exam- The therapist wil open the envelope and wil find the treatment condition to be conducted in this patient. ple, in a trial evaluating light therapy for depression, par- The therapist then gives the information about treatment al ocation to the patient. Staff responsible for ticipants were informed that the study involved testing two recruitment and symptom ratings is not al owed to receive information about the group al ocation. diff erent forms of light therapy, whereas the true hypothesis was that bright blue light was considered potentially eff ec- The al ocation sequence wil be generated by the Institute for Medical Biometry (IMB) applying a tive and that dim red light was considered placebo. 258 permuted block design with random blocks stratified by study centre and medication compliance (favourable vs. unfavourable). . The block size wil be concealed until the primary endpoint wil be Despite its importance, blinding is often poorly analysed. Throughout the study, the randomisation wil be conducted by CenTrial in order to keep the described in trial protocols. 3 The protocol should explicitly data management and the statistician blind against the study condition as long as the data bank is open. state who will be blinded to intervention groups—at a mini- The randomisation list remains with CenTrial for the whole duration of the study. Thus, randomisation mum, the blinding status of trial participants, care provid- wil be conducted without any influence of the principal investigators, raters or therapists." 246 ers, and outcome assessors. Such a description is much preferred over the use of ambiguous terminology such as ensure that the assignment schedule is unpredictable and "single blind" or "double blind." 259  260 Protocols should locked away from even the person who generated it. The also describe the comparability of blinded interventions protocol should specify who will implement the various (Item 11a) 150 —for example, similarities in appearance, use stages of the randomisation process, how and where the of specifi c fl avours to mask a distinctive taste—and the tim- allocation list will be stored, and mechanisms employed to ing of fi nal unblinding of all trial participants (eg, aft er the minimise the possibility that those enrolling and assigning creation of a locked analysis data set). 3 participants will obtain access to the list. Furthermore, any strategies to reduce the potential for unblinding should be described in the protocol, such as pre- Blinding (masking)
trial testing of blinding procedures. 261 The use of a fi xed code Item 17a: Who will be blinded after assignment to (versus a unique code for each participant) to denote each interventions (eg, trial participants, care providers, study group assignment (eg, A=Group 1; B=Group 2) can be outcome assessors, data analysts) and how problematic, as the unblinding of one participant will result in the inadvertent loss of blinding for all trial participants. Some have suggested that the success of blinding be for- "Assessments regarding clinical recovery will be conducted mally tested by asking key trial persons to guess the study by an assessor blind to treatment allocation. The assessor will group assignment and comparing these responses to what go through a profound assessment training program . . Due would be expected by chance. 262 However, it is unclear how to the nature of the intervention neither participants nor staff can be blinded to allocation, but are strongly inculcated not to best to interpret the results of such tests. 263  264 If done, the disclose the allocation status of the participant at the follow planned testing methods should be described in the trial up assessments. An employee outside the research team will feed data into the computer in separate datasheets so that the researchers can analyse data without having access to Blinding (masking)—emergency unblinding
information about the allocation." 247 Item 17b: If blinded, circumstances under which unblinding is permissible and procedure for revealing a Blinding or masking (the process of keeping the study group participant's allocated intervention during the trial assignment hidden aft er allocation) is commonly used to reduce the risk of bias in clinical trials with two or more study Among 58 blinded Danish trials approved in 1994-95, groups. 166  248 Awareness of the intervention assigned to par- three quarters of protocols described emergency unblind- ticipants can introduce ascertainment bias in the measure- ing procedures. 3 Such procedures to reveal the assigned ment of outcomes, particularly subjective ones (eg, quality intervention in certain circumstances are intended to of life) 166  167 ; performance bias in the decision to discontinue increase the safety of trial participants by informing the or modify study interventions (eg, dosing changes) (Item clinical management of harms or other relevant conditions 11b), concomitant interventions, or other aspects of care that arise. A clear protocol description of the conditions (Item 11d) 229 ; and exclusion/attrition bias in the decision and procedures for emergency unblinding helps to pre- to withdraw from the trial or to exclude a participant from vent unnecessary unblinding; facilitates implementation the analysis. 249  250 We have elected to use the term "blind- by trial personnel when indicated; and enables evalua- ing" but acknowledge that others prefer the term "masking" tion of the appropriateness of the planned procedures. In because "blind" also relates to an ophthalmological condi- some cases (eg, minor, reversible harms), stopping and tion and health outcome. 251  252 then cautiously reintroducing the assigned intervention Many groups can be blinded: trial participants, care in the aff ected participant can avoid both unblinding and providers, data collectors, outcome assessors or commit- BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 18 31/01/2013 10:33:38 RESEARCH METHODS AND REPORTING
reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol "To maintain the overall quality and legitimacy of the clinical trial, code breaks should occur only in exceptional circumstances when knowledge of the actual treatment is absolutely essential for further The validity and reliability of trial data depend on the quality management of the patient. Investigators are encouraged to discuss with the Medical Advisor or PHRI [Population Health Research Institute] physician if he/she believes that unblinding is necessary. of the data collection methods. The processes of acquiring If unblinding is deemed to be necessary, the investigator should use the system for emergency and recording data oft en benefi t from attention to training of unblinding through the PHRI toll-free help line as the main system or through the local emergency study personnel and use of standardised, pilot tested meth- number as the back-up system. ods. These should be identical for all study groups, unless The Investigator is encouraged to maintain the blind as far as possible. The actual allocation precluded by the nature of the intervention. must NOT be disclosed to the patient and/or other study personnel including other site personnel, The choice of methods for outcome assessment can aff ect monitors, corporate sponsors or project office staff; nor should there be any written or verbal study conduct and results. 268 - 273 Substantially differ- disclosure of the code in any of the corresponding patient documents. The Investigator must report all code breaks (with reason) as they occur on the corresponding CRF ent responses can be obtained for certain outcomes (eg, [case report form] page. harms) depending on who answers the questions (eg, the Unblinding should not necessarily be a reason for study drug discontinuation." 265 participant or investigator) and how the questions are pre-sented (eg, discrete options or open ended). 269  274 - 276 Also, Section 3c: Methods—data collection, management, and
when compared to paper based data collection, the use of analysis
electronic handheld devices and internet websites has the Data collection methods potential to improve protocol adherence, data accuracy, user Item 18a: Plans for assessment and collection of outcome, acceptability, and timeliness of receiving data. 268  270  271  277 baseline, and other trial data, including any related processes The quality of data also depends on the reliability, valid- to promote data quality (eg, duplicate measurements, ity, and responsiveness of data collection instruments training of assessors) and a description of study instruments such as questionnaires 278 or laboratory instruments. (eg, questionnaires, laboratory tests) along with their Instruments with low inter-rater reliability will reduce "Primary outcome Secondary outcomes required information wil be discussed in detail on an Delirium recognition : In accordance with national The study will collect demographic and baseline item by item basis. Coordinators wil learn how to code guidelines [reference], the study will identify delirium functional information from the patient ' s legally medications using the WHODrug software and how to by using the RASS [Richmond Agitation-Sedation authorized representative and/or caregivers. code symptoms using the MedDRA software. Entering Scale] and the CAM-ICU [Confusion Assessment Cognitive function status will be obtained by data forms, responding to data discrepancy queries and Method for the intensive care unit] on all patients interviewing the patient ' s legally authorized general information about obtaining research quality who are admitted directly from the emergency representative using the Informant Questionnaire on data wil also be covered during the training session. room or transferred from other services to the Cognitive Decline in the Elderly (IQCODE). IQCODE is ICU. Such assessment will be performed after a questionnaire that can be completed by a relative 13.7. Quality Control of the Core Lab 24 hours of ICU admission and twice daily until or other caregiver to determine whether that person Data from the Core Lab will be securely transmitted in discharge from the hospital . . RASS has excellent has declined in cognitive functioning. The IQCODE batches and quality controlled in the same manner inter-rater reliability among adult medical and lists 26 everyday situations . . Each situation is as Core Coordinating Center data; ie data will be surgical ICU patients and has excellent validity rated by the informant for amount of change over the entered and verified in the database on the Cleveland when compared to a visual analogue scale and previous 10 years, using a Likert scale ranging from Clinic Foundation SUN with a subset later selected for other selected sedation scales[reference] . . The 1-much improved to 5-much worse. The IQCODE has additional quality control. Appropriate edit checks will CAM-ICU was chosen because of its practical use a sensitivity between 69% to 100% and specificity of be in place at the key entry (database) level. in the ICU wards, its acceptable psychometric 80% to 96% for dementia.[reference] The Core Lab is to have an internal quality control properties, and based on the recommendation Utilizing the electronic medical record system system established prior to analyzing any FSGS [focal of national guidelines[reference] . . The CAM-ICU (RMRS), we will collect several data points of interest segmental glomerulosclerosis] samples. This system diagnosis of delirium was validated against the at baseline and throughout the study period . will be outlined in the Manual of Operations for the DSM-III-R [Diagnostic and Statistical Manual of . We have previously defined hospital-related Core Lab(s) which is prepared and submitted by the Mental Disorders, Third Edition—Revised] delirium consequences to include: the number of patients Core Lab to the DCC [data coordinating centre] prior to criteria determined by a psychiatrist and found to with documented falls, use of physical restraints initiating of the study. have a sensitivity of 97% and a specificity of 92%.
. . These will be assessed using the RMRS, direct At a minimum this system must include: [reference] The CAM-ICU has been developed, daily observation, and retrospective review of the 1) The inclusion of at least two known quality control validated and applied into ICU settings and multiple electronic medical record. This definition of delirium samples; the reported measurements of the quality investigators have used the same method to identify related hospital complications has been previously control samples must fall within specified ranges in patients with delirium.[reference] used and published.[reference]" 266 order to be certified as acceptable. Delirium severity : Since the CAM-ICU does not "Training and certification plans 2) Calibration at FDA approved manufacturers' evaluate delirium severity, we selected the Delirium . . Each center's personnel will be trained centrally in recommended schedules. Rating Scale revised-1998 (DRS-R-98)[reference] . . the study requirements, standardized measurement 13.8. Quality Control of the Biopsy Committee The DRS-R-98 was designed to evaluate the breadth of height, weight, and blood pressure, requirements The chair of the pathology committee will circulate to of delirium symptoms for phenomenological studies for laboratory specimen collection including morning all of the study pathologists . . samples [sic] biopsy in addition to measuring symptom severity with urine samples, counseling for adherence and the specimens for evaluation after criteria to establish high sensitivity and specificity . . The DRS-R-98 is a eliciting of information from study participants in a diagnosis of FSGS has been agreed. This internal 16-item clinician-rated scale with anchored items uniform reproducible manner. review process will serve to ensure common criteria descriptions . . The DRS-R-98 has excellent inter-rater . . The data to be col ected and the procedures to and assessment of biopsy specimens for confirmation reliability (intra-class correlation 0.97) and internal be conducted at each visit wil be reviewed in detail. of diagnosis of FSGS." 267 consistency (Cronbach 's alpha 0.94).[reference] Each of the data col ection forms and the nature of the BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 19 31/01/2013 10:33:38 RESEARCH METHODS AND REPORTING
statistical power, 272 while those with low validity will not accurately measure the intended outcome variable. One Trial investigators must oft en seek a balance between achiev- study found that only 35% (47/133) of randomised trials ciently long follow-up for clinically relevant out- in acute stroke used a measure with established reliability come measurement, 122  288 and a suffi ciently short follow-up or validity. 279 Modifi ed versions of validated measurement to decrease attrition and maximise completeness of data col- tools may no longer be considered validated, and use of lection. Non-retention refers to instances where participants unpublished measurement scales can introduce bias and are prematurely "off -study" (ie, consent withdrawn or lost to infl ate treatment eff ect sizes. 280 follow-up) and thus outcome data cannot be obtained from Standard processes should be implemented by local them. The majority of trials will have some degree of non- study personnel to enhance data quality and reduce bias retention, and the number of these "off -study" participants by detecting and reducing the amount of missing or incom- usually increases with the length of follow-up. 116 plete data, inaccuracies, and excessive variability in meas- It is desirable to plan ahead for how retention will be pro- urements. 281 -285 Examples include standardised training moted in order to prevent missing data and avoid the associ- and testing of outcome assessors to promote consistency; ated complexities in both the study analysis (Item 20c) and tests of the validity or reliability of study instruments; and interpretation. Certain methods can improve participant reten- duplicate data measurements. tion, 67  152  289 - 292 such as fi nancial reimbursement; systematic A clear protocol description of the data collection proc- methods and reminders for contacting patients, scheduling ess—including the personnel, methods, instruments, and appointments, and monitoring retention; and limiting par- measures to promote data quality—can facilitate imple- ticipant burden related to follow-up visits and procedures mentation and helps protocol reviewers to assess their (Item 13). A participant who withdraws consent for follow-up appropriateness. Inclusion of data collection forms in the assessment of one outcome may be willing to continue with protocol (ie, as appendices) is highly recommended, as the assessments for other outcomes, if given the option. way in which data are obtained can substantially aff ect the Non-retention should be distinguished from non-adher- results. If not included in the protocol, then a reference ence. 293 Non-adherence refers to deviation from intervention to where the forms can be found should be provided. If protocols (Item 11c) or from the follow-up schedule of assess- performed, pilot testing and assessment of reliability and ments (Item 13), but does not mean that the participant is validity of the forms should also be described. "off -study" and no longer in the trial. Because missing data can be a major threat to trial validity and statistical power, Data collection methods—retention
non-adherence should not be an automatic reason for ceas- Item 18b: Plans to promote participant retention and ing to collect data from the trial participant prior to study complete follow-up, including list of any outcome data to completion. In particular for randomised trials, it is widely be collected for participants who discontinue or deviate recommended that all participants be included in an inten- from intervention protocols tion to treat analysis, regardless of adherence (Item 20c). "5.2.2 Retention • Provide periodic incentives for school staff and have the following clinical and laboratory evaluations . . As with recruitment, retention addresses all levels performed, if possible: • Provide monetary incentives for the schools that At the parent and student level, study investigators increase with each year of the study [table 6]. ." 286 5.5 Participant Retention "5.4 Infant Evaluations in the Case of Treatment Once an infant is enrolled or randomized, the study site • Provide written feedback to al parents of participating Discontinuation or Study Withdrawal will make every reasonable effort to follow the infant for students about the results of the "health screenings" . . All randomized infants completing the 18-month the entire study period . . It is projected that the rate of • Maintain interest in the study through materials and evaluation schedule will have fulfilled the infant loss-to-follow-up on an annual basis will be at most 5% clinical and laboratory evaluation requirements for . . Study site staff are responsible for developing and • Send letters to parents and students prior to the final implementing local standard operating procedures to data col ection, reminding them of the upcoming data All randomized infants who are prematurely achieve this level of follow-up. col ection and the incentives the students wil receive. discontinued from study drug will be considered At the school level, study investigators and staff: off study drug/on study and will follow the same 5.6 Participant Withdrawal • Provide periodic communications via newsletters schedule of events as those infants who continue Participants may withdraw from the study for any and presentations to inform the school officials/ study treatment except adherence assessment. All of reason at any time. The investigator also may withdraw staff, students, and parents about type 2 diabetes, these infants will be followed through 18 months as participants from the study in order to protect their the current status of the study, and plans for the next safety and/or if they are unwilling or unable to comply phase, as wel as to acknowledge their support. Randomized infants prematurely discontinued with required study procedures after consultation with from the study before the 6-month evaluation will the Protocol Chair, National Institutes of Health (NIH) • Become a presence in the intervention schools to have the following clinical and laboratory evaluations Medical Officers, Statistical and Data Management monitor and maintain consistency in implementation, performed, if possible: . . Center (SDMC) Protocol Statistician, and Coordinating . . be as flexible as possible with study schedule and • Roche Amplicor HIV-1 DNA PCR [polymerase chain and Operations Center (CORE) Protocol Specialist. proactive in resolving conflicts with schools. reaction] and cell pellet storage Participants also may be withdrawn if the study • Provide school administration and faculty with the • Plasma for storage (for NVP [nevirapine] resistance, sponsor or government or regulatory authorities schedule or grid showing how the intervention fits HIV-1 RNA PCR and NVP concentration) terminate the study prior to its planned end date. into the school calendar . . Note: Early discontinuation of study product for • Solicit support from parents, school officials/staff, Randomized infants prematurely discontinued from any reason is not a reason for withdrawal from the and teachers . . the study at any time after the 6-month evaluation will BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 20 31/01/2013 10:33:38 RESEARCH METHODS AND REPORTING
Table 6 Excerpts from table showing compensation provided in study 286 Intervention school School program enhancement $2000 in year 1, $3000 in year 2, $4000 in year 3 Physical education class equipment required to implement intervention $15 000 over 3 years Food service department to defray costs of nutrition intervention School program enhancement $2000 in year 1, $4000 in year 2, $6000 in year 3 Return consent form (signed or not) Gift item worth $5 Participation in health screening data collection measures and forms $50 baseline (6th grade), $10 interim (7th grade), $60 end of study (8th grade) Focus groups to provide input about family outreach events and activities $35/year per parent, up to two focus groups per field center, 6-10 participants per focus group Protocols should describe any retention strategies and values). Reference to where details of data management defi ne which outcome data will be recorded from protocol procedures can be found, if not in the protocol non-adherers. 152 Protocols should also detail any plans to record the reasons for non-adherence (eg, discontinuation Careful planning of data management with appropriate of intervention due to harms versus lack of effi personnel can help to prevent flaws that compromise retention (ie, consent withdrawn; lost to follow-up), as this data validity. The protocol should provide a full descrip- information can infl uence the handling of missing data and tion of the data entry and coding processes, along with interpretation of results. 152  294  295 measures to promote their quality, or provide key elements and a reference to where full information can be found. Data management
These details are particularly important for the primary Item 19: Plans for data entry, coding, security, and outcome data. The protocol should also document data storage, including any related processes to promote data security measures to prevent unauthorised access to or quality (eg, double data entry; range checks for data loss of participant data, as well as plans for data storage "13.9.2. Data Forms and Data Entry 13.9.4. Data Discrepancy Inquiries and Reports to wil be performed twice a month. These tapes wil be In the FSGS-CT [focal segmental glomerulosclerosis— Core Coordinating Centers stored off-site in a climate-control ed facility and wil clinical trial], all data will be entered electronically. Additional errors wil be detected by programs designed be retained indefinitely. Incremental data back-ups This may be done at a Core Coordinating Center or to detect missing data or specific errors in the data. wil be performed on a daily basis. These tapes wil at the participating site where the data originated. These errors wil be summarized along with detailed be retained for at least one week on-site. Back-ups of Original study forms will be entered and kept on file descriptions for each specific problem in Data Query periodic data analysis files wil also be kept. These tapes at the participating site. A subset will be requested Reports, which wil be sent to the Data Managers at the wil be retained at the off-site location until the Study is later for quality control; when a form is selected, Core Coordinating Centers . . completed and the database is on file with NIH [National the participating site staff will pull that form, copy it, The Data Manager who receives the inquiry wil Institutes of Health]. In addition to the system back- and sent [sic] the copy to the DCC [data coordinating respond by checking the original forms for inconsistency, ups, additional measures wil be taken to back-up and center] for re-entry. checking other sources to determine the correction, export the database on a regular basis at the database . . Participant files are to be stored in numerical modifying the original (paper) form entering a response management level. . order and stored in a secure and accessible place and to the query. Note that it wil be necessary for Data 13.9.6. Study status reports manner. Participant files will be maintained in storage Managers to respond to each inquiry received in order to The DCC wil send weekly email reports with information for a period of 3 years after completion of the study. obtain closure on the queried item. on missing data, missing forms, and missing visits. 13.9.3. Data Transmission and Editing The Core Coordinating Center and participating site Personnel at the Core Coordinating Center and the The data entry screens will resemble the paper forms personnel wil be responsible for making appropriate Participating Sites should review these reports for approved by the steering committee. Data integrity corrections to the original paper forms whenever any accuracy and report any discrepancies to the DCC. will be enforced through a variety of mechanisms. data item is changed . . Written documentation of Referential data rules, valid values, range checks, and changes wil be available via electronic logs and audit 13.9.8. Description of Hardware at DCC consistency checks against data already stored in the A SUN Workstation environment is maintained in the database (ie, longitudinal checks) will be supported. department with a SUN SPARCstation 10 model 41 as The option to chose [sic] a value from a list of valid Biopsy and biochemistry reports wil be sent via e-mail the server . . Primary access to the departments [sic] codes and a description of what each code means will when data are received from the Core Lab. computing facilities wil be through the Internet . . For be available where applicable. Checks will be applied maximum programming efficiency, the Oracle database at the time of data entry into a specific field and/or 13.9.5. Security and Back-Up of Data management system and the SAS and BMDP statistical before the data is written (committed) to the database. . . Al forms, diskettes and tapes related to study data analysis systems wil be employed for this study. . Modifications to data written to the database will be wil be kept in locked cabinets. Access to the study Oracle facilitates sophisticated integrity checks through documented through either the data change system data wil be restricted. In addition, Core Coordinating a variety of mechanisms including stored procedures, or an inquiry system. Data entered into the database Centers wil only have access to their own center's data. stored triggers, and declarative database integrity—for will be retrievable for viewing through the data entry A password system wil be utilized to control access . . between table verifications. Oracle al ows data checks applications. The type of activity that an individual These passwords wil be changed on a regular basis. Al to be programmed once in the database rather than user may undertake is regulated by the privileges reports prepared by the DCC wil be prepared such that repeating the same checks among many applications associated with his/her user identification code and no individual subject can be identified. . . Security is enforced through passwords and may be A complete back up of the primary DCC database assigned at different levels to groups and individuals." 267 BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 21 31/01/2013 10:33:38 RESEARCH METHODS AND REPORTING
(including timeframe) during and aft er the trial. This infor- mation facilitates an assessment of adherence to applica- "The intervention arm (SMS [short message system (text ble standards and regulations. message)]) will be compared against the control (SOC [standard Diff erences in data entry methods can aff ect the trial in of care]) for all primary analysis. We will use chi-squared test terms of data accuracy, 268 cost, and effi ciency. 271 For exam- for binary outcomes, and T-test for continuous outcomes. ple, when compared with paper case report forms, elec- For subgroup analyses, we will use regression methods with tronic data capture can reduce the time required for data appropriate interaction terms (respective subgroup×treatment entry, query resolution, and database release by combining group). Multivariable analyses will be based on logistic regression . . for binary outcomes and linear regression for continuous data entry with data collection (Item 18a). 271  277 When data outcomes. We will examine the residual to assess model are collected on paper forms, data entry can be performed assumptions and goodness-of-fit. For timed endpoints such as locally or at a central site. Local data entry can enable fast mortality we will use the Kaplan-Meier survival analysis followed correction of missing or inaccurate data, while central data by multivariable Cox proportional hazards model for adjusting entry facilitates blinding (masking), standardisation, and for baseline variables. We will calculate Relative Risk (RR) and RR training of a core group of data entry personnel. Reductions (RRR) with corresponding 95% confidence intervals Raw, non-numeric data are usually coded for ease of data to compare dichotomous variables, and difference in means will storage, review, tabulation, and analysis. It is important be used for additional analysis of continuous variables. P-values will be reported to four decimal places with p-values less than to defi ne standard coding practices to reduce errors and 0.001 reported as p < 0.001. Up-to-date versions of SAS (Cary, observer variation. When data entry and coding are per- NC) and SPSS (Chicago, IL) will be used to conduct analyses. For formed by diff erent individuals, it is particularly impor- all tests, we will use 2-sided p-values with alpha≤0.05 level of tant that the personnel use unambiguous, standardised significance. We will use the Bonferroni method to appropriately terminology and abbreviations to avoid misinterpretation. adjust the overall level of significance for multiple primary As with data collection (Item 18a), standard processes are outcomes, and secondary outcomes. oft en implemented to improve the accuracy of data entry To assess the impact of potential clustering for patients cared and coding. 281  284 Common examples include double data by the same clinic, we will use generalized estimating equations [GEE] assuming an exchangeable correlation structure. Table [7] entry 296 ; verifi cation that the data are in the proper format provides a summary of methods of analysis for each variable. (eg, integer) or within an expected range of values; and Professional academic statisticians (LT, RN) blinded to study independent source document verifi cation of a random groups will conduct all analyses." 47 subset of data to identify missing or apparently errone-ous values. Though widely performed to detect data entry errors, the time and costs of independent double data entry Results for the primary outcome can be substantially from paper forms need to be weighed against the magni- aff ected by the choice of analysis methods. When investiga- tude of reduction in error rates compared to single-data tors apply more than one analysis strategy for a specifi c pri- mary outcome, there is potential for inappropriate selective reporting of the most interesting result. 6 The protocol should Statistical methods
prespecify the main ("primary") analysis of the primary out- The planned methods of statistical analysis should be come (Item 12), including the analysis methods to be used fully described in the protocol. If certain aspects of the for statistical comparisons (Items 20a and 20b); precisely analysis plan cannot be prespecifi ed (eg, the method of which trial participants will be included (Item 20c); and how handling missing data is contingent on examining pat- missing data will be handled (Item 20c). Additionally, it is terns of "missingness" before study unblinding), then helpful to indicate the eff ect measure (eg, relative risk) and the planned approach to making the fi nal methodological signifi cance level that will be used, as well as the intended choices should be outlined. Some trials have a separate use of confi dence intervals when presenting results. document—commonly called a statistical analysis plan The same considerations will oft en apply equally to pre- (SAP)—that fully details the planned analyses. Any SAP specifi ed secondary and exploratory outcomes. In some should be described in the protocol, including its key ele- instances, descriptive approaches to evaluating rare out- ments and where it can be found. As with the protocol, the comes such as adverse events—might be preferred over SAP should be dated, amendments noted and dated, and formal analysis given the lack of power. 300 Adequately the SAP authors provided. powered analyses may require preplanned meta-analyses with results from other studies. Statistical methods—outcomes
Most trials are aff ected to some extent by multiplicity Item 20a: Statistical methods for analysing primary and issues. 301  302 When multiple statistical comparisons are secondary outcomes. Reference to where other details performed (eg, multiple study groups, outcomes, interim of the statistical analysis plan can be found, if not in the analyses), the risk of false positive (type 1) error is infl ated protocol and there is increased potential for selective reporting of favourable comparisons in the fi nal trial report. For trials The protocol should indicate explicitly each intended with more than two study groups, it is important to specify analysis comparing study groups. An unambiguous, com- in the protocol which comparisons (of two or more study plete, and transparent description of statistical methods groups) will be performed and, if relevant, which will be facilitates execution, replication, critical appraisal, and the the main comparison of interest. The same principle of ability to track any changes from the original pre-specifi ed specifying the main comparison also applies when there is more than one outcome, including when the same variable BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 22 31/01/2013 10:33:38 RESEARCH METHODS AND REPORTING
Table 7 Variables, measures, and methods of analysis (reproduced from original table 47 ) Methods of analysis Intervention improved outcome from baseline to 6 months a) Adherence at 12 months Percent adherence in previous 30 days >95% [binary] b) Suppression of HIV viral load at 12 months Viral load ≤400 copies/ml [binary] improvement occurred Adherence % (>95%) [binary] Adherence percentage at 12 monthsHIV viral load at 12 months improvement occurred Viral load (copies) Immune reconstitution (change in CD4 T cell count from improvement occurred CD4 T-cells/mm 3 (continuous) baseline)Time to virological failure improvement occurred Virological failure after successful suppression Kaplan-Meier survival analysis Weight gain [lbs] and BMI improvement occurred Change in weight (lbs) and BMI [continuous] Occurrence of opportunistic infections (OIs) improvement occurred Presence of AIDS defining opportunistic infection [binary] Time to reporting of adverse drug events (ADEs) improvement occurred Presence of drug-related adverse event [time to event] Kaplan-Meier survival analysis Deaths (all cause) improvement occurred All-cause mortality [binary] Chi-squared test and Kaplan-Meier survival analysis SF-12 [short form 12 adapted for regional application in improvement occurred Quality pf [sic] life questionnaire [continuous] Kiswahili]Satisfaction with care provided improvement occurred Level of disclosure of HIV status improvement occurred Disclosed to a family member [binary] Impression of stigma improvement occurred Family dyamics [sic] improvement occurred Employment attendance improvement occurred Household member school attendance improvement occurred Cell phones lost/stolen improvement occurred Presence of cellphone [binary] Poisson regression Stopped taking HAART [highly active antiretroviral therapy] improvement occurred Self-report [binary] Required active tracing for 12 month follow-up improvement occurred Field officers [binary] 3) Subgroup Analyses: Regression methods with appropriate interaction term Distance affects adherence Sex affects adherence Phone ownership (owned vs. shared) Ownership affects adherence Level of education Low education affects adherence 4) Sensitivity Analyses: improvement occurred a) Per protocol analysis a) Chi-squared/T-test b) Adjusting for baseline covariates b) Multivariable regression c) clustering among individuals within a clinic IMPORTANT REMARKS: • The GEE [generalised estimating equations] [reference] is a technique that allows to specify the correlation structure between patients within a hospital and this approach produces unbiased estimates under the assumption that missing observations will be missing at random. An amended approach of weighted GEE will be employed if missingness is found not to be at random [reference]. • In all analyses results will be expressed as coefficient, standard errors, corresponding 95% and associated p-values. • Goodness-of-fit will be assessed by examining the residuals for model assumptions and chi-squared test of goodness-of-fit. • Bonferroni method will be used to adjust the overall level of significance for multiple secondary outcomes. is measured at several time points (Item 12). Any statistical However, subgroup analyses are problematic if they are approaches to account for multiple comparisons and time inappropriately conducted or selectively reported. Sub- points should also be described. group analyses described in protocols or grant applications Finally, diff erent trial designs dictate the most appropri- do not match those reported in subsequent publications ate analysis plan and any additional relevant information for more than two thirds of randomised trials, suggesting that should be included in the protocol. For example, clus- that subgroup analyses are oft en selectively reported or not ter, factorial, crossover, and within-person randomised tri- prespecifi ed. 6  7  305 Post hoc (data driven) analyses have a als require specifi c statistical considerations, such as how high risk of spurious fi ndings and are discouraged. 306 Con- clustering will be handled in a cluster randomised trial. ducting a large number of subgroup comparisons leads to issues of multiplicity, even when all of the comparisons Statistical methods—additional analyses
have been pre-specifi ed. Furthermore, when subgroups Item 20b: Methods for any additional analyses (eg, are based on variables measured aft er randomisation, the subgroup and adjusted analyses) analyses are particularly susceptible to bias. 307 Preplanned subgroup analyses should be clearly speci- Subgroup analysis fi ed in the protocol with respect to the precise baseline Subgroup analyses explore whether estimated treatment variables to be examined, the defi nition of the subgroup eff ects vary signifi cantly between subcategories of trial par- categories (including cut-off boundaries for continuous or ticipants. As these data can help tailor healthcare decisions ordinal variables), the statistical method to be used, and to individual patients, a modest number of prespecifi ed the hypothesised direction of the subgroup eff ect based subgroup analyses can be sensible. on plausibility. 308  309 BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 23 31/01/2013 10:33:38 RESEARCH METHODS AND REPORTING
"We plan to conduct two subgroup analyses, both with strong biological rationale and possible "Nevertheless, we propose to test non-inferiority using two interaction effects. The first will compare hazard ratios of re-operation based upon the degree of analysis sets; the intention-to-treat set, considering al patients as soft tissue injury (Gustilo-Anderson Type I/II open fractures vs. Gustilo-Anderson Type IIIA/B open randomized regardless of whether they received the randomized fractures). The second will compare hazard ratios of re-operation between fractures of the upper treatment, and the "per protocol" analysis set. Criteria for and lower extremity. We will test if the treatment effects differ with fracture types and extremities by determining the "per protocol" group assignment would be putting their main effect and interaction terms in the Cox regression. For the comparison of pressure, established by the Steering Committee and approved by the we anticipate that the low/gravity flow will be more effective in the Type IIIA-B open fracture than in PSMB [performance and safety monitoring board] before the trial the Type I/II open fracture, and be more effective in the upper extremity than the lower extremity. For begins. Given our expectation that very few patients wil crossover the comparison of solution, we anticipate that soap will do better in the Type IIIA-B open fracture than or be lost to fol ow-up, these analyses should agree very closely. in the Type I/II open fracture, and better in the upper extremity than the lower extremity." 303 We propose declaring medical management non-inferior to "A secondary analysis of the primary endpoint will adjust for those pre-randomization variables which interventional therapy, only if shown to be non-inferior using both might reasonably be expected to be predictive of favorable outcomes. Generalized linear models the "intention to treat" and "per protocol" analysis sets. will be used to model the proportion of subjects with neurologically intact (MRS ≤ 3 [Modified Rankin Score]) survival to hospital discharge by ITD [impedance threshold device]/sham device group 10.4.7 Imputation Procedure for Missing Data adjusted for site (dummy variables modeling the 11 ROC [Resuscitation Outcomes Consortium] While the analysis of the primary endpoint (death or stroke) will sites), patient sex, patient age (continuous variable), witness status (dummy variables modeling the be based on a log-rank test and, therefore, not affected by patient three categories of unwitnessed arrest, non-EMS [emergency medical services] witnessed arrest, and withdrawals (as they will be censored) provided that dropping EMS witnessed arrest), location of arrest (public versus non-public), time or response (continuous out is unrelated to prognosis; other outcomes, such as the variable modeling minutes between call to 911 and arrival of EMS providers on scene), presenting Rankin Score at five years post-randomization, could be missing rhythm (dummy variables modeling asystole, PEA [pulseless electrical activity], VT/VF [ventricular for patients who withdraw from the trial. We will report reasons tachycardia/fibrillation], or unknown), and treatment assignment in the Analyze Late vs. Analyze for withdrawal for each randomization group and compare Early intervention. The test statistic used to assess any benefit of the ITD relative to the sham device the reasons qualitatively . . The effect that any missing data will be computed as the generalized linear model regression coefficient divided by the estimated might have on results will be assessed via sensitivity analysis of "robust" standard error based on the Huber- White sandwich estimator[reference] in order to account augmented data sets. Dropouts (essentially, participants who for within group variability which might depart from the classical assumptions. Statistical inference withdraw consent for continued follow-up) will be included in the will be based on one-sided P values and 95% confidence intervals which adjust for the stopping rule analysis by modern imputation methods for missing data. used for the primary analysis." 304 The main feature of the approach is the creation of a set of clinically reasonable imputations for the respective outcome for each dropout. This will be accomplished using a set of repeated Adjusted analysis imputations created by predictive models based on the majority Some trials prespecify adjusted analyses to account for of participants with complete data. The imputation models imbalances between study groups (eg, chance imbalance will reflect uncertainty in the modeling process and inherent across study groups in small trials), improve power, or variability in patient outcomes, as reflected in the complete data. account for a known prognostic variable. Adjustment is After the imputations are completed, all of the data (complete oft en recommended for any variables used in the allocation and imputed) will be combined and the analysis performed process (eg, in stratifi ed randomisation), on the principle for each imputed-and-completed dataset. Rubin's method of multiple (ie, repeated) imputation will be used to estimate that the analysis strategy should match the design. 310 Most treatment effect. We propose to use 15 datasets (an odd number trial protocols and publications do not adequately address to allow use of one of the datasets to represent the median issues of adjustment, particularly the description of vari- analytic result). These methods are preferable to simple mean imputation, or It is important that trial investigators indicate in the pro- simple "best-worst" or "worst-worst" imputation, because the tocol if there is an intention to perform or consider adjusted categorization of patients into clinically meaningful subgroups, analyses, explicitly specifying any variables for adjustment and the imputation of their missing data by appropriately and how continuous variables will be handled. When both different models, accords well with best clinical judgment concerning the likely outcomes of the dropouts, and therefore unadjusted and adjusted analyses are intended, the main will enhance the trial's results." 313 analysis should be identifi ed (Item 20a). It may not always be clear, in advance, which variables will be important for adjustment. In such situations, the objective criteria to be come data obtained from all participants are included in used to select variables should be prespecifi ed. As with the data analysis, regardless of protocol adherence (Items subgroup analyses, adjustment variables based on post- 11c and 18b). 249  250 These two conditions (ie, all partici- randomisation data rather than baseline data can intro- pants, as randomised) defi ne an "intention to treat" analy- duce bias. 311  312 sis, which is widely recommended as the preferred analysis strategy. 17 Statistical methods—analysis population and missing data
Some trialists use other types of data analyses (com- Item 20c: Definition of analysis population relating to monly labelled as "modifi ed intention to treat" or "per pro- protocol non-adherence (eg, as randomised analysis), tocol") that exclude data from certain participants—such and any statistical methods to handle missing data (eg, as those who are found to be ineligible aft er randomisation multiple imputation) or who deviate from the intervention or follow-up proto- cols. This exclusion of data from protocol non-adherers In order to preserve the unique benefi t of randomisation as can introduce bias, particularly if the frequency of and a mechanism to avoid selection bias, an "as randomised" the reasons for non-adherence vary between the study analysis retains participants in the group to which they groups. 314  315 In some trials, the participants to be included were originally allocated. To prevent attrition bias, out- in the analysis will vary by outcome—for example, analysis BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 24 31/01/2013 10:33:39 RESEARCH METHODS AND REPORTING
of harms (adverse events) is sometimes restricted to par- ticipants who received the intervention, so that absence or occurrence of harm is not attributed to a treatment that "Appendix 3. Charter and responsibilities of the Data Monitoring Committee was never received. A Data Monitoring Committee (DMC) has been established. The Protocols should explicitly describe which participants DMC is independent of the study organisers. During the period will be included in the main analyses (eg, all randomised of recruitment to the study, interim analyses will be supplied, in participants, regardless of protocol adherence) and defi ne strict confidence, to the DMC, together with any other analyses the study group in which they will be analysed (eg, as ran- that the committee may request. This may include analyses of domised). In one cohort of randomised trials approved in data from other comparable trials. In the light of these interim 1994-5, this information was missing in half of the proto- analyses, the DMC will advise the TSC [trial steering committee] cols. 6 The ambiguous use of labels such as "intention to if, in its view: a) the active intervention has been proved, beyond reasonable treat" or "per protocol" should be avoided unless they are doubt*, to be different from the control (standard management) fully defi ned in the protocol. 6  314 Most analyses labelled as for all or some types of participants, and "intention to treat" do not actually adhere to its defi nition b) the evidence on the economic outcomes is sufficient because of missing data or exclusion of participants who to guide a decision from health care providers regarding do not meet certain post-randomisation criteria (eg, spe- recommendation of early lens extraction for PACG [primary angle cifi c level of adherence to intervention). 6  316 Other ambigu- closure glaucoma]. ous labels such as "modifi ed intention to treat" are also The TSC can then decide whether or not to modify intake to the trial. Unless this happens, however, the TSC, PMG [project variably defi ned from one trial to another. 314 management group], clinical collaborators and study office staff In addition to defi ning the analysis population, it is nec- (except those who supply the confidential analyses) will remain essary to address the problem of missing data in the pro- ignorant of the interim results. tocol. Most trials have some degree of missing data, 317  318 The frequency of interim analyses will depend on the which can introduce bias depending on the pattern of judgement of the Chair of the DMC, in consultation with the "missingness" (eg, not missing at random). Strategies to TSC. However, we anticipate that there might be three interim maximise follow-up and prevent missing data, as well as analyses and one final analysis. the recording of reasons for missing data, are thus impor- The Chair is Mr D.G.-H. , with Dr D.C. , and Professor B.D. Terms of reference for the DMC are available on request from the EAGLE tant to develop and document (Item 18b). 152 [Effectiveness in Angle Closure Glaucoma of Lens Extraction] The protocol should also state how missing data will be handled in the analysis and detail any planned methods to *Appropriate criteria for proof beyond reasonable doubt cannot be specified impute (estimate) missing outcome data, including which precisely. A difference of at least three standard deviation [sic] in the interim variables will be used in the imputation process (if applica- analysis of a major endpoint may be needed to justify halting, or modifying, such a study prematurely.[reference]" 325 ble). 152 Diff erent statistical approaches can lead to diff erent results and conclusions, 317  319 but one study found that the accumulated data have suffi ciently disturbed the clini- only 23% of trial protocols specifi ed the planned statistical cal equipoise that justifi ed the initiation of the trial. Data methods to account for missing data. 6 monitoring can also inform aspects of trial conduct, such Imputation of missing data allows the analysis to con- as recruitment, and identify the need to make adjustments. form to intention to treat analysis but requires strong The decision to have a data monitoring committee (DMC) assumptions that are untestable and may be hard to will be infl uenced by local standards. While certain trials justify. 152  318  320  321 Methods of multiple imputation are warrant some form of data monitoring, many do not need more complex but are widely preferred to single imputa- a formal committee, 326 such as trials with a short duration tion methods (eg, last observation carried forward; base- or known minimal risks. A DMC was described in 65% line observation carried forward), as the latter introduce (98/150) of cancer trial protocols with time-to-event out- greater bias and produce confi dence intervals that are too comes in Italy in 2000-5, 327 and in 17% (12/70) of pro- narrow. 152  320 - 322 Specifi c issues arise when outcome data tocols for Danish randomised trials approved in 1994-5. 6 are missing for crossover or cluster randomised trials. 323 About 40% of clinical trials registered on ClinicalTrials.gov Finally, sensitivity analyses are highly recommended to from 2007-2010 reported having a DMC. 328 The protocol assess the robustness of trial results under diff erent meth- should either state that there will be a DMC and provide ods of handling missing data. 152  324 further details, as discussed below, or indicate that there will not be a DMC, preferably with reasons. Section 3d: Methods—monitoring
When formal data monitoring is performed, it is oft en Data monitoring—formal committee done by a DMC consisting of members from a variety of dis- Item 21a: Composition of data monitoring committee ciplines. 254  329 The primary role of a DMC is to periodically (DMC); summary of its role and reporting structure; review the accumulating data and determine if a trial should statement of whether it is independent from the sponsor be modifi ed or discontinued. The DMC does not usually have and competing interests; and reference to where further executive power; rather, it communicates the outcome of its details about its charter can be found, if not in the protocol. deliberations to the trial steering committee or sponsor. Alternatively, an explanation of why a DMC is not needed Independence, in particular from the sponsor and trial investigators, is a key characteristic of the DMC and can For some trials, there are important reasons for periodic be broadly defi ned as the committee comprising members inspection of the accumulating outcome data by study group. who are "completely uninvolved in the running of the trial In principle, a trial should be modifi ed or discontinued when and who cannot be unfairly infl uenced (either directly BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 25 31/01/2013 10:33:39 RESEARCH METHODS AND REPORTING
or indirectly) by people, or institutions, involved in the the risk of a false positive (type I) error, and various sta- trial." 254 DMC members are usually required to declare any tistical strategies have been developed to compensate for competing interests (Item 28). Among the 12 trial proto- this infl ated risk. 254  333 - 335 Aside from informing stopping cols that described a DMC and were approved in Denmark guidelines, prespecifi ed interim analyses can be used for in 1994-5, 6 four explicitly stated that the DMC was inde- other trial adaptations such as sample size re-estimation, pendent from the sponsor and investigators; three had alteration to the proportion of participants allocated to non-independent DMCs; and independence was unclear each study group, and changes to eligibility criteria. 111 for the remaining fi ve protocols. A complete description of any interim analysis plan, The protocol should name the chair and members of the even if it is only to be performed at the request of an over- DMC. If the members are not yet known, the protocol can sight body (eg, DMC), should be provided in the proto- indicate the intended size and characteristics of the mem- col—including the statistical methods, who will perform bership until further details are available. The protocol the analyses, and when they will be conducted (timing and should also indicate the DMC's roles and responsibilities, indications). If applicable, details should also be provided planned method of functioning, and degree of independ- about the decision criteria—statistical or other—that will be ence from those conducting, sponsoring, or funding the adopted to judge the interim results as part of a guideline trial. 254  330  331 A charter is recommended for detailing this for early stopping or other adaptations. Among 86 proto- information 331 ; if this charter is not appended to the proto- cols for randomised trials with a time-to-event cancer out- col, the protocol should indicate whether a charter exists come that proposed effi cacy interim analyses, all stated the or will be developed, and if so, where it can be accessed. planned timing of the analyses, 91% specifi ed the overall reason to be used for stopping (eg, superiority, futility), and Data monitoring—interim analysis
94% detailed the statistical approach. 327 Item 21b: Description of any interim analyses and In addition, it is important to state who will see the out- stopping guidelines, including who will have access come data while the trial is ongoing, whether these indi- to these interim results and make the final decision to viduals will remain blinded (masked) to study groups, and terminate the trial how the integrity of the trial implementation will be pro-tected (eg, maintaining blinding) when any adaptations to the trial are made. A third of protocols for industry initiated "Premature termination of the study randomised trials receiving Danish ethics approval in 1994- An interim-analysis is performed on the primary endpoint when 95 stated that the sponsor had access to accumulating trial 50% of patients have been randomised and have completed data, which can introduce potential bias due to competing the 6 months follow-up. The interim-analysis is performed by an interests. 10 Finally, the protocol should specify who has independent statistician, blinded for the treatment allocation. The statistician will report to the independent DSMC [data and safety the ultimate authority to stop or modify the trial—eg, the monitoring committee]. The DSMC will have unblinded access principal investigator, trial steering committee, or sponsor. to all data and will discuss the results of the interim-analysis with the steering committee in a joint meeting. The steering committee decides on the continuation of the trial and will report Item 22: Plans for collecting, assessing, reporting, and to the central ethics committee. The Peto approach is used: the managing solicited and spontaneously reported adverse trial will be ended using symmetric stopping boundaries at P < events and other unintended effects of trial interventions 0.001 [reference]. The trial will not be stopped in case of futility, or trial conduct unless the DSMC during the course of safety monitoring advices [sic] otherwise. In this case DSMC will discuss potential stopping for futility with the trial steering committee." 332 Evaluation of harms has a key role in monitoring the condi-tion of participants during a trial and in enabling appropri- ate management of adverse events. Documentation of trial Interim analyses can be conducted as part of an adaptive related adverse events also informs clinical practice and trial design to formally monitor the accumulating data in the conduct of ongoing and future studies. We use the term clinical trials. They are generally performed in trials that "harms" instead of "safety" to better refl ect the negative have a DMC, longer duration of recruitment, and poten- eff ects of interventions. 300 An adverse event refers to an tially serious outcomes. Interim analyses were described in untoward occurrence during the trial, which may or may 71% (106/150) of cancer trial protocols with time-to-event not be causally related to the intervention or other aspects outcomes in Italy in 2000-5, 327 and in 19% (13/70) of pro- of trial participation. 300  336 This defi nition includes unfa- tocols for Danish randomised trials approved in 1994-5. 6 vourable changes in symptoms, signs, laboratory values, The results of these analyses, along with non-statistical cri- or health conditions. In the context of clinical trials, it can teria, can be part of a stopping guideline that helps inform cult to attribute causation for a given adverse event. whether the trial should be continued, modifi ed, or halted An adverse eff ect is a type of adverse event that can be earlier than intended for benefi t, harm, or futility. Criteria attributed to the intervention. for stopping for harm are oft en diff erent from those for ben- Harms can be specifi ed as primary or secondary outcomes efi t and might not employ a formal statistical criterion. 333 (Item 12) or can be assessed as part of routine monitoring. Stopping for futility occurs in instances where, if the study To the extent possible, distinctions should be made between were to continue, it is unlikely that an important eff ect adverse events that are anticipated versus unanticipated, and would be seen (ie, low chance of rejecting null hypoth- solicited versus unsolicited, because expectation can infl u- esis). Multiple analyses of the accumulating data increase ence the number and perceived severity of recorded events. BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 26 31/01/2013 10:33:39 RESEARCH METHODS AND REPORTING
" Secondary outcomes "11.4 Data Monitoring and Quality Assurance . . In our study an adverse event will be defined as any untoward medical occurrence in a subject Through the combination of our web-based, instantaneous without regard to the possibility of a causal relationship. Adverse events will be collected after the electronic validation, the DCC's [data coordinating centre] daily subject has provided consent and enrolled in the study. If a subject experiences an adverse event visual cross-validation of the data for complex errors, and regular after the informed consent document is signed (entry) but the subject has not started to receive study on-site monitoring, the quality and completeness of the data will intervention, the event will be reported as not related to study drug. All adverse events occurring be reflective of the state of the art in clinical trials. after entry into the study and until hospital discharge will be recorded. An adverse event that meets Both the European and US DCCs will conduct monitoring of the criteria for a serious adverse event (SAE) between study enrollment and hospital discharge will source documents via fax at all enrolling ARUBA [A Randomised be reported to the local IRB [institutional review board] as an SAE. If haloperidol is discontinued as trial of Unruptured Brain Arteriovenous malformations] sites and a result of an adverse event, study personnel will document the circumstances and data leading will conduct at least one on-site monitoring visit per year over the to discontinuation of treatment. A serious adverse event for this study is any untoward medical course of the study at 100% of clinical sites (with repeat visits to occurrence that is believed by the investigators to be causally related to study-drug and results in any sites where performance is a concern). Monitoring of European of the following: Life-threatening condition (that is, immediate risk of death); severe or permanent study sites will be assured by the European Coordinating Center disability, prolonged hospitalization, or a significant hazard as determined by the data safety (Paris). The primary objectives of the DCC during the on-site visits monitoring board. Serious adverse events occurring after a subject is discontinued from the study will are to educate, support and solve problems. The monitors will NOT be reported unless the investigators feels that the event may have been caused by the study drug discuss the protocol in detail and identify and clarify any areas or a protocol procedure. Investigators will determine relatedness of an event to study drug based on of weakness. At the start of the trial, the monitors will conduct a a temporal relationship to the study drug, as well as whether the event is unexpected or unexplained tutorial on the web-based data entry system. The coordinators given the subject's clinical course, previous medical conditions, and concomitant medications. will practice entering data so that the monitors can confirm . . The study will monitor for the following movement-related adverse effects daily through patient that the coordinators are proficient in all aspects of data entry, examination and chart review: dystonia, akathisia, pseudoparkinsonism, akinesia, and neuroleptic query response, and communication with the DCC. They will malignant syndrome. Study personnel will use the Simpson-Angus [reference] and Barnes Akathisia audit the overall quality and completeness of the data, examine [reference] scales to monitor movement-related effects. source documents, interview investigators and coordinators, and confirm that the clinical center has complied with the For secondary outcomes, binary measures, eg mortality and complications, logistic regression will be requirements of the protocol. The monitors will verify that all used to test the intervention effect, controlling for covariates when appropriate . ." 266 adverse events were documented in the correct format, and are consistent with protocol definition. The monitors will review the source documents as needed, to For example, providing statements in the informed consent determine whether the data reported in the Web-based system process about the possibility of a particular adverse eff ect or are complete and accurate. Source documents are defined as using structured, as opposed to open ended, questionnaires medical charts, associated reports and records including initial for data collection, can increase the reporting of specifi c hospital admission report . . events ("priming"). 269  337 - 339 The timeframe for recording The monitors will confirm that the regulatory binder is complete adverse events can also aff ect the type of data obtained. 340  341 and that all associated documents are up to date. The regulatory The protocol should describe the procedures for and binder should include the protocol and informed consent (all frequency of harms data collection, the overall surveil- revisions), IRB [institutional review board] approvals for all of the above documents, IRB correspondence, case report forms, lance timeframe, any instruments to be used, and their investigator's agreements . . validity and reliability, if known. Substantial discrepan- Scheduling monitoring visits will be a function of patient cies have been observed between protocol specifi ed plans enrollment, site status and other commitments. The DCC will for adverse event collection and reporting, and what is notify the site in writing at least three weeks prior to a scheduled described in fi nal publications. 5 Although trials are oft en visit. The investigators must be available to meet with the not powered to detect important diff erences in rates of monitors. Although notification of the visits will include the list of uncommon adverse events, it is also important to describe patients scheduled to be reviewed, the monitors reserve the right plans for data analysis, including formal hypothesis testing to review additional ARUBA patients. If a problem is identified during the visit (ie, poor or descriptive statistics. 300  342 communication with the DCC, inadequate or insufficient staff to Finally, the protocol should address the reporting of conduct the study, missing study documents) the monitor will harms to relevant groups (eg, sponsor, research ethics com- assist the site in resolving the issues. Some issues may require mittee/institutional review board, data monitoring com- input from the Operations Committee, Steering Committee or one mittee, regulatory agency), which is an important process of the principal investigators. that is subject to local regulation. 343 Key considerations The focus of the visit/electronic monitoring will be on source include the severity of the adverse event, determination document review and confirmation of adverse events. The monitor will verify the following variables for all patients: initials, of potential causality, and whether it represents an unex- date of birth, sex, signed informed consent, eligibility criteria, pected or anticipated event. For multicentre studies, proce- date of randomization, treatment assignment, adverse events, dures and timing should be outlined for central collection, and endpoints . ." 313 evaluation, and reporting of pooled harms data. Auditing
day-to-day measures to promote data quality (Items 18a Item 23: Frequency and procedures for auditing and 19). Auditing is intended to preserve the integrity trial conduct, if any, and whether the process will be of the trial by independently verifying a variety of proc- independent from investigators and the sponsor esses and prompting corrective action if necessary. The processes reviewed can relate to participant enrolment, Auditing involves periodic independent review of core consent, eligibility, and allocation to study groups; trial processes and documents. It is distinct from routine adherence to trial interventions and policies to protect BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 27 31/01/2013 10:33:39 RESEARCH METHODS AND REPORTING
participants, including reporting of harms (Item 22); Protocol amendments
and completeness, accuracy, and timeliness of data col- Item 25: Plans for communicating important lection. In addition, an audit can verify adherence to protocol modifications (eg, changes to eligibility applicable policies such as the International Conference criteria, outcomes, analyses) to relevant parties (eg, on Harmonisation Good Clinical Practice and regulatory investigators, REC/IRBs, trial participants, trial registries, agency guidelines. 160 journals, regulators) In multicentre trials, auditing is usually considered both overall and for each recruiting centre. Audits can be done by exploring the trial dataset or performing site visits. "13.10 Modification of the Protocol Audits might be initially conducted across all sites, and Any modifications to the protocol which may impact on the conduct of the study, potential benefit of the patient or may subsequently conducted using a risk based approach that affect patient safety, including changes of study objectives, study focuses, for example, on sites that have the highest enrol- design, patient population, sample sizes, study procedures, ment rates, large numbers of withdrawals, or atypical (low or significant administrative aspects will require a formal or high) numbers of reported adverse events. amendment to the protocol. Such amendment will be agreed If auditing is planned, the procedures and anticipated upon by BCIRG [Breast Cancer International Research Group] and frequency should be outlined in the protocol, including Aventis, and approved by the Ethics Committee/IRB [institutional a description of the personnel involved and their degree review board] prior to implementation and notified to the health of independence from the trial investigators and sponsor. authorities in accordance with local regulations. Administrative changes of the protocol are minor corrections If procedures are further detailed elsewhere (eg, audit and/or clarifications that have no effect on the way the study is manual), then the protocol should reference where the to be conducted. These administrative changes will be agreed full details can be obtained. upon by BCIRG and Aventis, and will be documented in a memorandum. The Ethics Committee/IRB may be notified of Section 4: Ethics and dissemination
administrative changes at the discretion of BCIRG." 345 Research ethics approval Item 24: Plans for seeking research ethics committee/ institutional review board (REC/IRB) approval Aft er initial ethics approval, about half of trials have sub-sequent protocol amendments submitted to the REC/ IRB. 125  346  347 While some amendments may be unavoid- "This protocol and the template informed consent forms able, a study of pharmaceutical industry trials found that contained in Appendix II will be reviewed and approved by according to the sponsors, a third of amendments could the sponsor and the applicable IRBs/ECs [institutional review have been prevented with greater attention to key issues boards/ethical committees] with respect to scientific content during protocol development. 346 Substantive amendments and compliance with applicable research and human subjects can generate challenges to data analysis and interpreta- tion if they occur part way through the trial (eg, changes in The protocol, site-specific informed consent forms (local language and English versions), participant education and eligibility criteria), 348 and can introduce bias if the changes recruitment materials, and other requested documents—and are made based on the trial data. 173 -176 The implementation any subsequent modifications — also will be reviewed and and communication of amendments are also burdensome approved by the ethical review bodies. . and potentially costly. 346 Subsequent to initial review and approval, the responsible Numerous studies have revealed substantive changes local Institutional Review Boards/Ethical Committees (IRBs/ between prespecifi ed methods (eg, as stated in approved ECs) will review the protocol at least annually. The Investigator protocols, registries, or regulatory agency submissions) will make safety and progress reports to the IRBs/ECs at least and those described in trial publications, including annually and within three months of study termination or completion at his/her site. These reports will include the total changes to primary outcomes, 12  172 - 176 sample size calcu- number of participants enrolled . . and summaries of each lations, 6 eligibility criteria, 125  133  134 as well as methods DSMB [data safety and monitoring board] review of safety and/ of allocation concealment, 2 blinding, 3 and statistical or efficacy." 287 analysis. 6 -8  174 These substantive modifi cations are rarely acknowledged in the fi nal trial reports, providing an inac- curate impression of trial integrity. A universal requirement for the ethical conduct of clinical It is important that substantive protocol amendments be research is the review and approval of the research proto- reviewed by an independent party, such as the REC/IRB, col by qualifi ed individuals who are not associated with and transparently described in trial reports. The notion the research team and have no disqualifying competing of "substantive" is variably defi ned by authorities, but in interests as reviewers. 1 The review is typically conducted general refers to a protocol amendment that can aff ect the by a formal REC/IRB in accordance with jurisdictional safety of trial participants or the scientifi c validity, scope, policy. Despite the importance of ethics review, approval or ethical rigour of the trial. 349  350 To refl ect the degree of by a REC/IRB is not always obtained. Among 767 trials oversight for the trial and adherence to applicable regu- published in leading general medical journals from 1993- lation, the protocol should describe the process for mak- 95, 37 authors (5%) disclosed that such approval had not ing amendments, including who will be responsible for been sought for their trials. 344 The protocol should docu- the decision to amend the protocol and how substantive ment where approval has been obtained, or outline plans changes will be communicated to relevant stakeholders to seek such approval. (eg, REC/IRBs, trial registries, regulatory agencies). Version BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 28 31/01/2013 10:33:39 RESEARCH METHODS AND REPORTING
control using protocol identifi ers and dates (Item 3), as well will be secured should they regain decisional capacity. For as a list of amendments, can help to track the history of certain trials, such as cluster randomised trials, it may not amendments and identify the most recent protocol version. be possible to acquire individual informed consent from participants before randomisation, and the consent proc- Consent or assent
ess may be modifi ed or waived. An explanation should be Item 26a: Who will obtain informed consent or assent provided in the protocol in these instances. 357 from potential trial participants or authorised surrogates, and how (see Item 32) Consent or assent—ancillary studies
Item 26b: Additional consent provisions for collection
and use of participant data and biological specimens in " . . Trained Research Nurses will introduce the trial to patients ancillary studies, if applicable who will be shown a video regarding the main aspects of the trial. Patients will also receive information sheets. Research Nurses will discuss the trial with patients in light of the information provided in the video and information sheets. Patients will then be able to "6.4.1. Samples for Biorepositories have an informed discussion with the participating consultant. Additional biological samples will be obtained to be stored Research Nurses will obtain written consent from patients willing for use in future studies of the pathobiology of FSGS [focal to participate in the trial. Information sheets and consent forms segmental glomerulosclerosis]. A materials consent will be are provided for all parents involved in the trial however these obtained to specifically address the collection of these . . urine, have been amended accordingly in order to provide separate serum and plasma specimens . . information sheets and consent form [sic] which are suitable for 14.3.4. Instructions for Preparation of Requests for an children and teenagers. All information sheets, consent forms and the video transcript have been translated into Bengali, . . A signed consent must be obtained from every participant in Punjabi, Gujarati, and Urdu. There are also separate information the ancillary study, if the data collection/request is not covered in sheets and consent forms for the cohort group." 351 the original informed consent process for the main FSGS Clinical Trial. The notion of acquiring informed consent involves the A copy of the IRB [institutional review board] letter for the ancillary presentation of comprehensible information about the study should be sent to the DCC [data coordinating centre]. If a separate consent form is required for the ancillary study, a copy of research to potential participants, confi rmation that they the signed ancillary study consent form for each study participant understand the research, and assurance that their agree- must be included in the FSGS-CT [clinical trial] record. A data file ment to participate is voluntary. The process typically tracking all signed ancillary consent forms must be maintained involves discussion between the potential participant by the ancillary study and an electronic copy of that file must be and an individual knowledgeable about the research; the delivered to the FSGS-CT DCC." 267 presentation of written material (eg, information leafl et or consent document); and the opportunity for potential participants to ask questions. Surveys of trial investigators Ancillary studies involve the collection or derivation of reveal that appropriate informed consent is not always data for purposes that are separate from the main trial. obtained. 344  352 The acquisition and storage of data and biological speci- The content, quantity, and mode of delivery of consent mens for ancillary studies is increasingly common in information can aff ect trial recruitment, participant com- the context of clinical trials (Item 33). Specimens may prehension, anxiety, retention rates, and recruitment cos be used for a specifi ed subset of studies or for submis- ts. 68  114  218  292  353 - 355 We recommend that a model consent sion to biorepositories for future specifi ed or unspecifi ed or assent form be provided as a protocol appendix (Item 32). Assent represents a minor's affi rmative agreement to Ancillary studies have additional processes and con- participate in the trial, which typically involves signing a siderations relating to consent, which should be detailed document that provides age appropriate information about in the protocol. Guidance for the creation of a simplifi ed informed consent document for biobanking is available. 358 The protocol should include details of the consent proc- Participants can be given several options to consider with ess as well as the status, experience, and training (if appli- respect to their participation in ancillary research: con- cable) of the research team members who will conduct it. sent for the use of their data and specimens in specifi ed In paediatric research, regulations may stipulate obtaining protocols; consent for use in future research unrelated to rmative assent for participation from children above a the clinical condition under study; consent for submis- certain age. 356 The protocol should then describe how perti- sion to an unrelated biorepository; and consent to be con- nent information will be provided to potential participants tacted by trial investigators for further informational and and how their understanding and assent will be ascer- consent-related purposes. This is commonly referred to as tained. When potential participants lack decisional capac- tiered consent. Participants should also be informed about ity for reasons other than young age (eg, mental status), whether their withdrawal from the ancillary research is and proxy consent can be obtained from a legally-author- possible (eg, the data and specimens are coded and iden- ised representative, the protocol should describe who will tifi able); what withdrawal means in this context (eg, used determine an individual's decisional capacity, whether a specimens and data derived from them cannot be with- formal capacity instrument will be utilised, and how the drawn); and what information derived from the specimen individual's informed agreement to continue participation related research will be provided to them, if any. BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 29 31/01/2013 10:33:39 RESEARCH METHODS AND REPORTING
Confidentiality
Item 27: How personal information about potential and enrolled participants will be collected, shared, and 1. Was the Principal Investigator of the second International maintained in order to protect confidentiality before, Stroke Trial (IST-2) to evaluate a neuroprotective compound during, and after the trial (619c89). . 2. Has received lecture fees and travel expenses from Bayer and from Boehringer Ingelheim for lectures given at international "8.5 Confidentiality All study-related information will be stored securely at the study 3. He serves on the Independent Data Monitoring and Safety site. All participant information will be stored in locked file Board of the RELY trial, funded by Boehringer Ingelheim and cabinets in areas with limited access. All laboratory specimens, receives attendance fees and travel expenses for attending reports, data collection, process, and administrative forms will be identified by a coded ID [identification] number only to maintain 4. He does not have any paid consultancies with participant confidentiality. All records that contain names or other pharmaceutical companies, and is not a member of the personal identifiers, such as locator forms and informed consent Speaker's Panel of any company. forms, will be stored separately from study records identified by code number. All local databases will be secured with password- Received an honorarium for a lecture from Boehringer protected access systems. Forms, lists, logbooks, appointment Ingelheim and had costs for participating in scientific meetings books, and any other listings that link participant ID numbers to reimbursed. ." 124 other identifying information will be stored in a separate, locked file in an area with limited access. All HIV test results will be kept strictly confidential, all Competing interests, or confl icts of interest, exist when counseling and blood draws will be conducted in private rooms, there is potential for divergence between an individual's and study staff will be required to sign agreements to preserve the confidentiality of all participants. Study staff will never inform or institution's private interests and their responsibilities network members of the serostatus of other members of their to scientifi c and publishing activities. 360 More positive group, but counselors will provide general messages about outcomes, larger treatment eff ect sizes, and more favour- the prevalence of HIV in the study population in the interests of able interpretation of results have been found in clinical emphasizing harm reduction. trials with pharmaceutical industry sponsorship (Item Participants' study information will not be released outside 4) 27  36 - 38  42 and investigators who have declared compet- of the study without the written permission of the participant, ing interests, 57  60 compared to those without such interests. except as necessary for monitoring by NIAID [National Institute Although competing interests are most oft en associated of Allergy and Infectious Diseases] and/or its contractors . . representatives of the HPTN CORE [HIV Prevention Trials Network with drug and device industries, they may exist with sup- Coordinating and Operations Center] . . and US or in-country port from or affi liation with government agencies, chari- government and regulatory authorities." 359 ties, not for profi t organisations, and professional and civic organisations. Competing interests do not in themselves imply wrong- doing. Their disclosure and regular updating enables Personal information about participants is acquired during appropriate management plans to be developed and the process of trial recruitment, eligibility screening, and implemented, and facilitates transparent assessment of data collection. Much of this information consists of private the potential for bias. details over which people customarily wish to maintain Many trials and non-industry sponsors have a confl ict control, such as their health status, personal genotype, and of interest policy for their investigators, and checklists are social and family history. available to guide potential interests that should be dis- The protocol should describe the means whereby per- closed and regularly updated by trial investigators. 361  362 sonal information is collected, kept secure, and main- Types of fi nancial ties include salary support or grants; tained. In general, this involves: 1) the creation of coded, ownership of stock or options; honorariums (eg, for advice, depersonalised data where the participant's identifying authorship, or public speaking); paid consultancy or serv- information is replaced by an unrelated sequence of char- ice on advisory boards and medical education companies; acters; 2) secure maintenance of the data and the linking and receipt of patents or patents pending. Non-fi nancial code in separate locations using encrypted digital fi les competing interests include academic commitments; per- within password protected folders and storage media; and sonal or professional relationships; and political, religious, 3) limiting access to the minimum number of individuals liations with special interests or advocacy posi- necessary for quality control, audit, and analysis. The protocol should also describe how the confi dentiality of data will be preserved when the data are transmitted to Access to data
sponsors and coinvestigators (eg, virtual private network Item 29: Statement of who will have access to the final internet transmission). trial dataset, and disclosure of contractual agreements that limit such access for investigators Declaration of interests
Item 28: Financial and other competing interests for The validity of results from interventional trials can be principal investigators for the overall trial and each study verifi ed only by individuals who have full access to the complete fi nal dataset. For some multicentre trials, only BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 30 31/01/2013 10:33:39 RESEARCH METHODS AND REPORTING
"12.10.1 Intra-Study Data Sharing "Patients that are enrolled into the study are covered by The Data Management Coordinating Center will oversee the indemnity for negligent harm through the standard NHS intra-study data sharing process, with input from the Data [National Health Service] Indemnity arrangements. The Management Subcommittee. University of Sheffield has insurance to cover for non-negligent All Principal Investigators (both US and host country) will be given harm associated with the protocol . . This will include cover access to the cleaned data sets. Project data sets will be housed for additional health care, compensation or damages whether on the Project Accept Web site and/or the file transfer protocol awarded voluntarily by the Sponsor, or by claims pursued through site created for the study, and all data sets will be password the courts. Incidences judged to arise from negligence (including protected. Project Principal Investigators will have direct access those due to major protocol violations) will not be covered by to their own site's data sets, and will have access to other sites study insurance policies. The liability of the manufacturer of data by request. To ensure confidentiality, data dispersed IL1RA (Amgen Corporation) is strictly limited to those claims to project team members will be blinded of any identifying arising from faulty manufacturing of the commercial product and participant information." 113 not to any aspects of the conduct of the study." 145 "13.6 Access to Effective Products the steering group has access to the full trial dataset in Should this study provide evidence of the effectiveness of TDF order to ensure that the overall results are not disclosed [tenofovir disoproxil fumarate], FTC [emtricitabine]/TDF and/or by an individual study site prior to the main publication. tenofovir 1% gel in preventing HIV infection, it will be critical to Many of these trials will allow site investigators to access provide access to the effective product(s) to study participants, their communities, and the worldwide population at risk for the full dataset if a formal request describing their plans is HIV infection in a timely manner. In preparation for this study, approved by the steering group. The World Medical Asso- discussions have begun with Gilead Sciences, Inc. and CONRAD ciation supports the principle that trial investigators retain [Contraceptive Research and Development Organization] to the right to access data. 363 However, among protocols of ensure such access. Considerations under discussion include industry initiated randomised trials published in 2008-9 in licensing agreements and preferred pricing arrangements for the the Lancet or approved in 2004 by a Danish ethics commit- study communities and other resource-poor settings. tee, 30-39% stated that the sponsor owned the data while While this study is ongoing, the MTN [Microbicide Trials Network] 0-3% stated that principal investigators had access to all will continue these discussions. In addition, discussions will be initiated with other public and private funding sources such trial data. 10  364 Similar constraints were found in Danish as the WHO, UNAIDS, Gates Foundation, and appropriate site trial protocols from 1994-5. 10 government agencies that may be able to purchase product The protocol should identify the individuals involved supplies in bulk and offer them at low or no cost to the study in the trial who will have access to the full dataset. Any communities and other resource-poor communities most in need restrictions in access for trial investigators should also be of the product(s). Operations and marketing research also may explicitly described. be conducted to determine how best to package and distribute the products, and maximize their acceptability and use, in at-risk Ancillary and post-trial care
populations." 365 Item 30: Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from study participants to interventions identified as ben- trial participation efi cial in the study or access to other appropriate care or benefi ts." 1 This principle is particularly applicable—and The provision of ancillary care refers to the provision of controversial—when research enabling the development care beyond that immediately required for the proper and and regulatory approval of interventions is performed in safe conduct of the trial, and the treatment of immediate countries where subsequent access to the interventions is adverse events related to trial procedures. It is generally limited by cost or lack of availability. 368 agreed that trial sponsors and investigators should plan to The protocol should describe any plans to provide or pay provide care for participants' healthcare needs that arise as for ancillary care during the trial and identify any interven- a direct consequence of trial participation (eg, intervention tions, benefi ts, or other care that the sponsor will continue related harms). It is also important to consider whether to provide to participants and host communities aft er the care should be provided for certain ancillary needs that trial is completed. 369 Any plans to compensate participants may otherwise arise during trial participation. Provision for trial related harms should also be outlined. of care for ancillary needs refl ects the fact that participants implicitly, but unavoidably, entrust certain aspects of their Dissemination policy—trial results
health to the research team. The scope of entrustment Item 31a: Plans for investigators and sponsor to will vary depending on the nature of the trial (eg, setting, communicate trial results to participants, healthcare health condition under study, investigations performed). 366 professionals, the public, and other relevant groups (eg, Additional factors that infl uence the strength of the claim via publication, reporting in results databases, or other to ancillary care include participants' vulnerabilities; data sharing arrangements), including any publication uncompensated burdens and harms; the intensity and restrictions duration of the participant-researcher relationship; and the degree to which participants are uniquely dependent A fundamental ethical principle in clinical trials is that on the research team for health care. 367 the potential risks incurred by study participants should The Declaration of Helsinki states that "the protocol be balanced by the benefi t of contributing to publicly should describe arrangements for post-study access by available knowledge. 371 Unfortunately, about half of BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 31 31/01/2013 10:33:39 RESEARCH METHODS AND REPORTING
Furthermore, any conditions relating to the investiga- tors' right to publish or present trial results should be "XII. Publication Policy explicitly described. Publication restrictions have been The Publications subcommittee will review all publications following the guidelines given below and imposed by various groups, including industry sponsors report its recommendations to the Steering Committee. or the trial steering group (eg, to maintain the integrity A. Data analysis and release of results of the overall dataset). 10  380 These restrictions are some- The scientific integrity of the project requires that the data from all BEST [Beta-Blocker Evaluation of times not described in the protocol but rather in separate Survival Trial] sites be analyzed study-wide and reported as such. Thus, an individual center is not publication agreements. 10 However, as they can interfere expected to report the data collected from its center alone . . all presentations and publications are expected to protect the integrity of the major objective(s) of the study; data that break the blind with the ethical responsibility of investigators and spon- will not be presented prior to the release of mainline results. Recommendations as to the timing of sors to disseminate trial results in an unbiased and timely presentation of such endpoint data and the meetings at which they might be presented will be given manner, 38  381 - 384 any restrictions should be disclosed in by the Steering Committee. the protocol for review by REC/IRBs, funders, and other B. Review process stakeholders. A review of industry initiated randomised Each paper or abstract, as described below, must be submitted to the appropriate Subcommittee trial protocols approved in Denmark in 1994-95 revealed for review of its appropriateness and scientific merit prior to submission. The Subcommittee may that 91% had publication restrictions imposed by spon- recommend changes to the authors and will finally submit its recommendations to the Steering sors; similar constraints were noted for protocols approved Committee for approval. C. Primary outcome papers The primary outcome papers of BEST are papers that present outcome data . . The determination Dissemination policy—authorship
of whether or not a particular analysis represents a primary outcome will be made by the Steering Item 31b: Authorship eligibility guidelines and any Committee on the recommendation of the Publications Subcommittee . . intended use of professional writers D. Other study papers, abstracts and presentations All studies other than those designated as "Primary Outcome" fall within this category . . All papers and abstracts must be approved by the Publications Committee before they are submitted. It is possible that in certain instances BEST may be asked to contribute papers to workshops, "17.4. Assignment of Writing Committees symposia, volumes, etc. The individuals to work on such requests should be appointed by the Topics suggested for presentation or publication will be Executive Committee, but where time permits, a proposal will be circulated soliciting other circulated to the PIs [principal investigators] of the CCCs [core participants as in the case of other study papers as described in the Application Review Process. coordinating centers], the DCC [data coordinating centre], Core XIII. Close-out Procedures Lab and the NIH [National Institutes of Health]. These groups BEST may terminate at the planned target of 1.5 years after the last participant has been are requested to suggest and justify names for authors to be randomized, or at an earlier or later date if the circumstances warrant . . Regardless of the timing and reviewed by the PC [publications committee]. . If a topic is circumstances of the end of the study, close-out will proceed in two stages: suggested by a participant of the FSGS-CT [focal segmental • Interim period for analysis and documentation of study results. glomerulosclerosis—clinical trial], the writing committee will • Debriefing of participants and dissemination of study results. be formed as just described except that the person making the suggestion may be considered as the lead author. The PI of an Every attempt will be made to reduce to an absolute minimum the interval between the completion of ancillary study should be considered for lead author of material data collection and the release of the study results. We expect to take about 3 to 4 months to compile derived from this study. Disputes regarding authorship will be the final results paper for an appropriate journal. settled by the Study Chair after consultation with the Chair of the B. Reporting of study results The study results will be released to the participating physicians, referring physicians, patients and 17.5. Reports of the FSGS-CT: Classes of Reports the general medical community." 370 There are three classes of reports of the FSGS-CT: A. Reports of the major outcomes of the Study. clinical trials remain unpublished. 80  83 Trials with statisti- B. Reports addressing in detail one aspect of the FSGS-CT, but in cally non-signifi cant results or industry funding are more which the data are derived from the entire study. prone to non-publication, 36  38  80 - 83 although government C. Reports of data derived from a subset of centers by members funded trials are also susceptible. 81 When published, of the FSGS-CT, (eg, sub-studies or ancillary studies), or reports of investigations initiated outside of the FSGS-CT, but using trials with non-signifi cant results oft en have a longer data or samples collected by the FSGS-CT. . delay to publication. 80  83 Overall, the medical literature represents a biased subset of existing data, potentially 17.6. Authorship Policy The authors of FSGS publications will be listed as detailed below. leading to overestimation of benefi ts, underestimation Type A publications: of harms, and a detrimental impact on patient care and abstracts: from the FSGS Clinical Trial Group x , presented by research. 80  372 - 377 Although peer reviewers can be biased in favour of papers: from the FSGS Clinical Trial Group x , prepared by XXXX. positive fi ndings, 378 lack of publication appears to be x The FSGS participant box, detailed below, must be included primarily due to trial investigators or sponsors failing in these papers. If a journal's publication policy does not allow to submit negative or null results, rather than journals authorship by a group, the authors will be listed first as in Type B rejecting them. 80  379 A plan to disseminate trial results to key stakeholders should be outlined in the protocol, Type B publications: including a process and timeframe for approving and submitting reports for dissemination (eg, via journal 17.7. Authorship: Professional Participants Listing in the publication, trial registry, trial website), and an explicit FSGS Participant Box The FSGS participant box will list all professionals that have statement that the results will be disseminated regardless participated in the FSGS-CT for a minimum of one year." 267 of the magnitude or direction of eff ect. BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 32 31/01/2013 10:33:39 RESEARCH METHODS AND REPORTING
Avenues for providing access to full protocols include Substantive contributions to the design, conduct, inter- journals, 407  408 trial websites, and trial registries. 163 Several pretation, and reporting of a clinical trial are recognised journals and funders support the sharing of participant through the granting of authorship on the fi nal trial report. level data, 405  409 - 411 while others routinely publish a state- Authorship guidelines in the protocol are intended to help ment regarding sharing of protocols, statistical codes, and enhance transparency and avoid disputes or misunder- datasets for all of their published research articles. 412  413 standing aft er trial completion. These guidelines should The protocol should indicate whether the trial protocol, defi ne criteria for individually named authors or group full study report, anonymised participant level dataset, and statistical code for generating the results will be made Individuals who fulfi l authorship criteria should not publicly available; and if so, describe the timeframe and remain hidden (ghost authorship) and should have fi nal any other conditions for access. authority over manuscript content. 9  386  387 Similarly, those who do not fulfi l such criteria should not be granted Section 5: Appendices
authorship (guest authorship). 386  388 The International Informed consent materials Committee of Medical Journal Editors has defi ned author- Item 32: Model consent form and other related ship criteria for manuscripts submitted for publication, 389 documentation given to participants and authorised although these criteria have reportedly been open to surrogates abuse. 390 If some protocol authors are not named authors of subsequent publications, their role in protocol design "APPENDIX 7 SAMPLE PATIENT INFORMED CONSENT should at least be acknowledged in the published report. Note: . . Each Ethics Committee or Institutional Review Among 44 protocols of industry initiated trials, 75% had Board will revise and adapt according to their own institution's evidence of ghost authorship when compared with corre- sponding journal publications. 9 MULTICENTER PHASE III RANDOMIZED TRIAL COMPARING Professional medical writers are sometimes hired to DOXORUBICIN AND CYCLOPHOSPHAMIDE . . improve clarity and structure in a trial report, and guide- Study number: BCIRG 006 (TAX GMA 302) lines for ethical collaborative writing have been devel- Investigator name: Address: oped. 391  392 Because the draft ing of text can infl uence how the study results and conclusions are portrayed, plans for This consent form is part of the informed consent process. It the employment of writers and their funding source should is designed to give you an idea of what this research study is be acknowledged in both protocols and trial reports. about and what will happen to you if you choose to be in the study. ." 345 Dissemination policy—reproducible research
Item 31c: Plans, if any, for granting public access to the
full protocol, participant-level dataset, and statistical The Declaration of Helsinki states that each potential trial participant must normally, at a minimum, be adequately informed about the purpose of the trial; potential ben- efi ts and risks; their right to refuse participation or to " Data sharing statement No later than 3 years after the withdraw consent at any time; institutional affi collection of the 1-year postrandomisation interviews, we will and potential competing interests of the researcher; and deliver a completely deidentified data set to an appropriate data sources of trial funding. 1 There are rare exceptions where archive for sharing purposes." 393 deferred consent can be acceptable, such as trials involv-ing unconscious patients in emergency situations. Special attention is required to ensure that relevant Given the central role of protocols in enhancing transpar- information is provided and appropriate modes of deliv- ency, reproducibility, and interpretation of trial results, ery are used during the consent process (Item 26). 414 Con- there is a strong ethical and scientifi c imperative to ensure sent and participant information forms are oft en written that full protocols are made publicly available. 24  394  395 at a much higher reading level than is acceptable for the High quality protocols contain relevant details on study general population. 415 Depending on the nature of the design and conduct that are generally not available in jour- trial, several diff erent consent documents may be needed. nal publications or trial registries. 84  396 It is also important For example, a paediatric trial may involve both parental to make available the full study report, such as the "clinical permission and participant assent documents. For mul- study report" submitted to regulatory agencies by industry ticentre trials, a model or sample document is typically sponsors. 377  396 - 400 This detailed report provides the most draft ed for distribution to local investigators, who may comprehensive description of trial methods (including the then revise the document to comply with local require- full protocol) and all published and unpublished analyses. In addition, there have increasingly been calls to improve the availability of participant-level datasets and statisti- Biological specimens
cal code aft er journal publication to enable verifi cation Item 33: Plans for collection, laboratory evaluation, and and replication of analyses, facilitate pooling with other storage of biological specimens for genetic or molecular studies, and accelerate research through open knowledge analysis in the current trial and for future use in ancillary sharing. 372  401 - 406 studies, if applicable BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 33 31/01/2013 10:33:39 RESEARCH METHODS AND REPORTING
Discussion
It is critical that every clinical trial has a complete and "White Blood Cell and Plasma Collection Procedures transparent protocol, which can then facilitate trial con- duct and appraisal by communicating relevant infor- 1.1 To provide a resource for studies of early markers, etiology, and genetic risk factors for prostate mation to key stakeholders. In response to observed cancer and other diseases. defi ciencies in protocol content, the SPIRIT Initiative has 2.0 Background The Prostate Cancer Prevention Trial (PCPT) is a randomized double blind chemoprevention trial . . produced recommendations for minimum relevant proto- Initial blood collection was specifically for the analysis of PSA [prostate specific antigen] and storage col items to include in a protocol, published in the form of serum . . an additional blood collection will be carried out using anticoagulant so that plasma and of the SPIRIT 2013 Statement and this Explanation and white blood cells can be isolated. Plasma will allow the analysis of additional biomarkers . . This DNA Elaboration (E&E) paper. 14 The strengths that distinguish will be used (among other possible uses) for studies to investigate polymorphisms in genes which SPIRIT from other protocol guidance documents include may influence prostate cancer risk . . its systematic and transparent development methods; The PCPT WBC [white blood cell] sample will be available to PCPT investigators as well as outside participation of a wide range of key stakeholders; use of researchers who have important, timely hypotheses to test. Because the sample bank is a limited empirical evidence to support its recommendations; and resource, proposals to use it will be evaluated in terms of scientific relevance, significance, and validity as well as the potential impact of the proposed study. The amount and type of material availability of detailed guidance including model examples needed will also be considered and the efficient use of material will be required. Strict confidentiality will be exercised and the information provided to investigators will not contain personal identifiers. The overall aim of SPIRIT is to improve the completeness When specific uses of the WBC samples are approved, the SWOG-9217 protocol will be amended. and transparency of trial protocols. The SPIRIT documents Participation in this research is not required for continued participation in the PCPT. can serve as a practical resource for trial investigators and personnel to draft and understand the key elements of a 3.1 Because the original model consent form did not specifically address genetic studies, participants protocol. In doing so, our vision is that the SPIRIT 2013 will be asked to sign an additional consent form to document their consent to the collection and Statement and E&E paper will also facilitate and expedite submission of additional blood samples for storage and future testing (including genetic analysis). the review of protocols by research ethics committees/ 3.2 Institutions will be asked to submit additional materials from participants who consent to the institutional review boards, scientifi c review groups, and additional blood collection. The blood is to be collected, processed and shipped as described in the PCPT Study Manual. funders—for example, by reducing the number of avoid- 3.3 NCI-Frederick Cancer Research Development Center (FCRDC) in Frederick, Maryland will serve as able queries to trial investigators regarding missing or the processing, aliquotting and storage facility. unclear protocol information during the review process. 3.4 Upon arrival at FCRDC the blood will be pooled and centrifuged. Plasma will be separated into 5 Furthermore, improved protocol content would help facili- x 1.8 ml aliquots and frozen . . tate the critical appraisal of fi nal trial reports and results. 3.5 All samples will be logged in and aliquots will be bar coded with a unique storage ID. These data Finally, several SPIRIT items correspond to items on the will be electronically transmitted to the Statistical Center for verification. CONSORT 2010 checklist (Consolidated Standards of 3.6 The scientists who will carry out analyses on these materials will not have access to personal identifiers and will not be able to link the results of these tests to personal identifier information. No Reporting Trials), 417 which should facilitate the transition individual results will be presented in publications or other reports. . from the protocol to the fi nal study report. 3.7 Participants will not be informed on an individual basis of any results from these studies . . The next steps for the SPIRIT Initiative include an imple- 4.0 Sample analysis mentation strategy to encourage uptake of the SPIRIT 2013 4.1 Investigators planning to submit NIH [National Institutes of Health] grant applications must obtain Statement. The SPIRIT website ( www.spirit-statement.org ) approval for their study and specimen access from the PCPT Serum and Tissue Utilization Committee will provide the latest resources and information on the ini- before submission of a grant proposal. Potential investigators will be required to submit a brief tiative, including a list of supporters. We invite stakehold- abstract and 1-4 page outline . . This proposal will be circulated for review to members of the PCPT ers to assist in the evaluation of the SPIRIT Statement and Serum and Tissue Utilization Committee and two ad hoc members having relevant expertise . . E&E paper by using the documents and providing feedback 4.2 It is anticipated that proposals will be reviewed once a year . . Approval by this group as well as to inform future revisions. Through widespread uptake and appropriate Institutional Review Board approval from the investigator's institution will be required before release of samples." 416 support, the potential to improve the completeness and quality of trial protocols, as well as the effi ciency of their review, can be fully realised. We thank Raymond Daniel for his help with reference management and Biological specimens (eg, biopsy tissue; blood for DNA Jessica Kitchen for her work with manuscript formatting and identifi cation extraction) obtained during the conduct of clinical tri- of protocol examples. We also acknowledge GlaxoSmithKline for providing als can be stored in repositories—often designated as a sample of their trial protocols to serve as potential examples. biobanks—for the current trial and future research. This Competing interests: All authors have completed the ICJME unifi ed declaration form at www.icmje.org/coi_disclosure.pdf (available on process is usually governed by local regulation and has request from the corresponding author) and declare: JAB is employed by particular ethical considerations (Item 26b). the Janssen Pharmaceutical Companies of Johnson & Johnson; KKJ was If the trial involves genetic or molecular analysis of formerly employed by CIHR (Knowledge Translation Branch), and WRP is affi liated with the NCIC Clinical Trials Group. Trish Groves is deputy editor biological specimens derived from humans, or if any of BMJ and a member of the SPIRIT group but did not take part in the peer specimens will be stored for future use (specified or review and decision making process about this publication. unspecifi ed), the protocol should describe details about Contributors: AWC, JT, and DM conceived of the paper. All authors contributed to the draft ing and revision of the manuscript, and approve the specimen collection, storage, and evaluation, including the fi nal version. AWC is the guarantor for the article. location of repositories. In addition, the protocol should Funding: The SPIRIT meetings were funded by the Canadian Institutes of state whether collected samples and associated participant Health Research (CIHR grant DET - 106068); National Cancer Institute of Canada (now Canadian Cancer Society Research Institute); and Canadian related data will be de-identifi ed or coded to protect partici- Agency for Drugs and Technologies in Health. CIHR has also funded pant confi dentiality. If a repository is overseen by a named ongoing dissemination activities (grant MET-117434). KKJ was formerly research ethics committee/institutional review board, then employed by CIHR (Knowledge Translation Branch), and WRP is affi liated with the NCIC Clinical Trials Group. The funders had no input into the this information should also be provided. BMJ RESEARCH METHODS AND REPORTING chaa006386.indd 34 31/01/2013 10:33:39 RESEARCH METHODS AND REPORTING
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