3 Overview of Policy Implementation, Screening and Consent Procedures Vipul Jairath, Ana Mora, Sian Davies11:30 – 12:15
4 Overview of trial recruitment processes Participant admitted to hospital with suspected AUGIBAlgorithm is followed for all patients except those where the clinician feels immediate transfusion is needed when the patient presents, regardless of or prior to obtaining the Hb result, due to severity of bleedingFollow the hospital’s allocated transfusion policy – Restrictive or LiberalScreen and Complete Screening Log DailyIf participant declines consent for data use and follow-up, the algorithm is still followedApproach Eligible Patients to seek ConsentComplete CRFs for Consenting PatientsCollect data – discharge/death/D28Telephone follow-up at Day 28
5 The Screening LogEach site should develop their own methods of case-ascertainmentLog should be completed daily Monday – FridayShould record all new admissions with Acute Upper Gastrointestinal Bleeding (AUGIB) defined by:- Haematemesis: vomiting of blood, blood clots or witnessed coffee grounds- Melaena: passage of dark tarry stools either on clinical history witnessed by medical or nursing staff, or discovered on rectal examination
6 The Screening LogScreening Log (a): complete for ALL admission with AUGIBScreening Log (b): only complete for patients considered ‘Ineligible due to severity of bleeding’See Screening Log forms (a) and (b) and Study Handbook pages 10 – 11Send log through every Monday to CSU
7 Consent – for what? Randomisation – from the cluster Intervention – from the clusterData collection – from the participantFollow-up – from the participant
8 Consent – what is capacity? Mental Capacity Act 2005, Section 2‘... a person lacks capacity if at the material time he is unable to make a decision for himself in relation to the matter because an impairment of, or disturbance in, the functioning of the mind or brain’The following factors have to considered when assessing if someone has capacity to make a decision, section 3 (1):- whether they are able to understand the information- whether they are able to retain the information related to the decision to be made- whether they are able to use or weigh that information as part of the process of making the decision- whether they are able to communicate that decision – by any means
9 Consent proceduresSpectrum of illnessAnticipate that most patients will be able to provide consent for themselvesPatients who may lack capacity include:- elderly patients with pre-existing cognitive impairmentPatients who may have fluctuating capacity include:- elderly patients with acute confusional state- decompensated liver disease- alcohol withdrawal – especially Delerium Tremens
10 When and How to approach patients Suggested timeframe to approach eligible patients/delegate:- on the same day for those who present in normal hours- the following day for those who present overnight- Monday for those who present over the weekend... provided this is appropriate to their clinical conditionPlease use the suggested script as a guide which may help explain the transfusion policy – page 15 of Study HandbookRemember – you cannot complete any paperwork other than the anonymised screening log until you have written patient consent
11 Definitions - England Personal Consultee Nominated Consultee - ‘... someone whom the person who lacks capacity would trust with important decisions about their welfare, but who is not acting in a professional or paid capacity, e.g you could consult a family member or close friend of the prospective trial participant, but not a paid carer or other professional such as social worker. Remuneration does not cover family members receiving some of the person’s pension or other benefits as a payment towards their share of the household expenses’Nominated Consultee- ‘... Someone who is prepared to be consulted by the researcher, but has no connection with the research study, e.g this could be the consultant responsible for the patient’s care, provided they are not a named local PI, and should be of consultant (or equivalent) status. They must have received information about the research and a PIS is considered appropriate’
12 Definitions - Scotland Relative/Welfare Attorney- ‘... Someone who has been appointed by a court to make decisions on behalf of those lacking capacity’
13 Consent Procedures – England (p.13 SH) CRF Form 1b Does the patient have mental capacity in relation to the study?YesApproach patient and use information sheet and consent form for participants with capacityNoDoes a personal consultee exist who can be approached in person?YesNoApproach nominated consultee. Use clinician agreement formApproach personal consultee. Use personal consultee information sheet and declaration formDoes the patient regain mental capacity in relation to the study?Use declaration provided by personal consulteeNoYesUse information sheet & consent form for participants regaining capacity and data preservation form
14 Consent Procedures – Scotland (p.14 SH) CRF Form 1b Does the patient have mental capacity in relation to the study?YesApproach patient and use information sheet and consent form for participants with capacityNoDoes a relative/welfare attorney exist who can be approached in person?YesNoPatient is not enrolled into studyApproach relative/WA. Use relative/WA information sheet and declaration formDoes the patient regain mental capacity in relation to the study?Use consent provided by relative/WANoYesUse information sheet & consent form for participants regaining capacity and data preservation form
15 When is a Data Preservation form needed? All patients who lacked capacity, and proxy consent (consultee/relative/welfare guardian) was obtained, must be approached once they regain capacityUse Data Preservation form (DPF) if:- a patient who regains capacity (and was enrolled on the basis of proxy consent) then declines to take part further in the study. Use of a Data Preservation Form will allow use of data up to that point, provided the patient agrees to this- a proxy initially provides consent and then decides to with draw this. Use of a Data Preservation Form will allow use of data up to that point, provided the proxy agrees to this
16 Special Considerations - Scotland Any participant with a pre-existing condition which would render them unable to provide consent would preclude them from participating in the study, e.g dementiaNeither patients nor relatives/welfare guardians should be approached in this circumstance
17 Patients discharged prior to consent Some centres are more pro-active at discharging lower risk patients from the EDThose will need to attempt to identify those patients and indicate this option on the weekly screening logIn Scotland- post a cover letter and PIS/Consent Form plus stamped return envelopeIn Englandsame approach applies but you will require R&D approval before you can implement this and these are pending at this time
18 Patients who die prior to consent We anticipate this in very few circumstancesCurrently no approval process in place at this time and under REC reviewEngland – anticipate writing to relative >1 month after the event; this is under review and will not be in place for the start of the trialScotland – under review
19 Trial Participant Checklist (p.8 SH) Screening LogConsent – document in notes and 3 copiesInsert algorithm into medical and nursing notes and adjacent to blood prescription chartInform member of the clinical team of enrolmentInform Blood Bank if you have a flagging systemRecord preferred contact number(s)Post GP letterStart completing CRFs 1 – 10b, 15 – 17Contact GP surgery to check survival status – D28Administer telephone follow-up (Forms 11a – 13f)Complete End of Study form (Form 14)
21 Special considerations when consenting patients with AUGIB: A first hand nursing perspective Sian Davies – RN11:30 – 12:15
22 Characteristics of patients who may present with AUGIB Older patientsPatients with liver cirrhosis/alcoholic liver diseasePatients with gastrointestinal malignancy (oesophageal/gastric/pancreatic)Patients taking Antiplatelets/NSAIDS
23 Patients with liver cirrhosis After a GI bleed, patient’s with cirrhosis can decompensate and develop encephalopathy. This often resolves over hours once treatment commencedIn some situations encephalopathy is chronic, resulting in persistent fluctuating levels of confusion. Direct consent in this situation is often not achievable
24 Patients withdrawing from alcohol Some patients (may or may not have cirrhosis) may be withdrawing from alcoholIf withdrawal symptoms are adequately controlled, gaining consent should be straightforwardIf withdrawal symptoms are severe, e.g Delerium Tremens, consent would need to be initially sought from a personal consultee/relative/welfare guardianDay 3-5 of admission is often the most challenging. It should be possible to re-approach the patient after this time
25 Patients with malignancy Under these circumstances there may be no issues with consenting the patient from a capacity perspectivePatients may be taking high doses of Opioid medication which could effect their ability to consentCaution around time of approach would be advised after discussion with medical/nursing team
26 Patients taking Antiplatelets/NSAIDS Antiplatelets – likely to be older patient with co-morbidity. In this case they could suffer with an acute confusional state. Consent would need to be sought from a personal consultee/relative/welfare guardian until confusion resolvesNSAIDS – combination of younger and older patients. Most should be capable of consenting
27 Review of Case Report Forms Vipul Jairath & Ana Mora12:15 – 13:15
28 Review of CRFsTour through each CRF other than follow-up questionnaire (11a – 13f) and SAE forms (16a&b & 17) which will be reviewed later in the dayOpen CRFs and Completion Guidance pages 16 – 42 of Study HandbookAll CRFs are the same apart from the front page, page headers and the consent form 1b
29 Forms 1a&b, 2, 3 & 4 – ‘Batch 1’These should be submitted together as the first batchForm 1a – EligibilityForm 1b – Consent England and ScotlandForm 2 – Presenting Signs and SymptomsForm 3 – First recorded Laboratory DataForm 4 – Pre-existing Co-morbidities and Medication
30 Forms 5a – 10b, 15 – ‘Batch 2’These should be submitted together as the second batchForm 5a&b – Medication administered in HospitalForm 6a&b – Hb Measurements and RBC TransfusionForm 7 – Protocol Deviation FormForm 8a&b – Endoscopy RecordForm 9 – Acute Transfusion ReactionsForm 10a&b – Clinical Outcomes during Hospital AdmissionForm 15 – Additional Resource Use
31 Forms 11a – 14, 18 – ‘Batch 3’These should be submitted together as the third batchForms 11a – 13f – Follow-up QuestionnaireForm 14 – End of Study FormForm 18 – Investigator Declaration Form
32 Transmittal of CRFs Order of transmittal - Forms 1a – 4 at trial entry - Forms 5a – 10b, 15 at Hospital Discharge- Forms 11a – 14, 18 at end of studySAE transmittal forms- 16a, 16b & 17 as they occur
35 Investigator responsibilities and Safety reportingAlison DearyClinical Operations ManagerNHSBT13:45-14:15
36 Investigator Responsibilities These are divided into several areas:Qualifications and agreementsResourcesResponsibilities to the ParticipantEthics and GovernanceRecord KeepingSafety Reporting
37 Qualifications and Agreements GCP states that the investigator should be qualified by education, training and experience to assume responsibility for the proper conduct of the trial..CV/GCP training certificateFamiliar with the protocol and the appropriate use of the investigational productDelegation of trial-related duties
38 Qualifications and Agreements Should be aware of, and comply with GCP and applicable regulatory requirementsShould permit monitoring and audit by the sponsor and inspection by regulatory authorityShould maintain a list of appropriately qualified persons to whom trial related duties are delegated
39 ResourcesBe able to demonstrate the potential to recruit the required number of suitable participants within the agreed recruitment periodHave sufficient timeHave adequate number of qualified staff and adequate facilitiesEnsure all staff are adequately informed
40 Responsibilities to the Participant Medical care of the participants – make all trial related medical decisionsEnsure adequate care for adverse eventsMake a reasonable effort to ascertain reasons for withdrawal from the trialEnsure participant confidentiality respected at all timesEnsure participant’s medical records reflects their participationInform GP
41 Ethics and GovernanceEnsure have ethical and trust approval to conduct the studyConduct study according to current version of the protocolDocument and explain any deviation from the protocolNot to implement any deviation from study without permission from sponsor (and REC) unless immediate safety concern
42 Ethics and Governance Obtain informed consent Ensure using current version of information and consent formsUntil consent obtained, no trial-related activity may commenceEnsure a copy of information and consent form are provided to participant/representativeFollow randomised trial treatment policy
43 Record keeping Obtain informed consent and document this Ensure data collected are consistent with source documentsCollect, record and report all study data accurately , completely, legibly and in a timely mannerTo sign the completed CRFsTo ensure all trial documentation is maintained appropriatelyTo ensure essential documents are archivedTo ensure annual reports are made to the R&D department
45 Adverse Event Definitions An adverse event is defined as “Any untoward occurrence in a subject receiving treatment according to the protocol, including occurrences which are not necessarily caused by or related to administration of the research procedures”
46 Serious Adverse Events (SAE) Defined as any adverse event thatResults in deathIs life-threateningResults in hospitalisation or prolongation of existing hospitalisationResults in persistent disability or incapacityDo not confuse serious with severe
47 Expected or Unexpected? Section 9 of the protocol contains a list of “expected” SAEsOnly unexpected SAEs – i.e. not on the list of “expected” SAEs - are subject to expedited notification to the CSUAn unexpected related SAE is one that is judged to be possibly, probably or definitely related to the transfusion policy
48 Definitions of Imputability RelationshipDescriptionPossibleThere is some evidence to suggest a causal relationship, however the influence of other factors may have contributed to the eventProbableThe evidence is clearly in favour of attributing the SAE to the transfusion policyDefiniteThere is conclusive evidence beyond reasonable doubt attributing the SAE to the transfusion policye.g. Because the event occurs within a reasonable timeframe after the transfusion or with-holding of the transfusione.g. patients clinical condition or concomitant treatments
49 Expected SAEs which are clinical outcome measures DeathFurther bleedingNeed for surgery or radiological intervention to control bleedingAny element of the composite endpoint of thromboembolic and ischaemic events (MI, stroke, PE, DVT, acute kidney injury)Acute transfusion reaction
50 Other expected SAEs Multi-organ failure Congestive Cardiac Failure Respiratory complicationsTransient ischaemic attackDecompensated liver diseaseNeed for paracentesis to drain ascitesGut infarction
51 Other expected SAEs Rise in serum Troponin I or E GI perforation or obstructionPost-operative complicationNeed for repeat endoscopy for any reasonNon-acute transfusion reaction
52 Notification within one working day Any unexpected SAEDeathFurther bleedingAny element of the composite endpoint of thromboembolic and ischaemic events (MI, stoke, PE, DVT, acute kidney injury)
53 Reporting to IDMCWhen received at the CSU, the reports of the events listed will be sent to the IDMC and the CIBe prepared to answer any queries in a timely mannerThe IDMC will know which treatment regimen the site has been randomised to
54 When to collect SAEsCollect on all participants from enrolment to Study Day 28Include any that occur following discharge if before Day 28, in particular infection, further bleeding and thromboembolic/ischaemic events
55 Responsibilities -PIEnsure notification of all SAEs in the appropriate timeframeSAE forms must be completed by the PI, or, if a designate, counter-signed by the PIInitial report must contain at least patient identifier, name of event, date of occurrence and causalityFurther more detailed information can be provided later
56 Responsibilities - Sponsor The CI will review all reported SAEs and Clinical Outcomes.Any disagreement with regard to imputability will be recorded but the PI opinion cannot be over-ruled.Unexpected related SAEs will be reported to REC within 15 days
57 Form CompletionReview of Forms 16a&b, 17SAE transmittal
59 Case-Study 168 year old female admitted with UGIB and found to have a large ulcer at endoscopy which is treated. Has further bleeding 72 hours later and a repeat endoscopy and therapy. Discharged home 5 days later uneventfully.How many SAEs in this scenario?Are they expected or unexpected?Within what timeframe should they be notified to the CSU?
60 Case-Study 1 Answer68 year old female admitted with UGIB and found to have a large ulcer at endoscopy which is treated. Has further bleeding 72 hours later and a repeat endoscopy and therapy. Discharged home 5 days later uneventfully.How many SAEs in this scenario? - OneAre they expected or unexpected? ExpectedWithin what timeframe should they be notified to the CSU? Within 1 working day
61 Case-Study 245 year old female with alcoholic liver disease admitted with a variceal bleed. Varices successfully banded at endoscopy but she was combative during the procedure and it was prolonged. She then developed an aspiration pneumonia requiring antibiotics. She was discharged without further complicationsHow many SAE’s are there in this scenario?Are they expected or unexpected?Within what timeframe should they be notified to the CSU?
62 Case-Study 2 Answer45 year old female with alcoholic liver disease admitted with a variceal bleed. Varices successfully banded at endoscopy but she was combative during the procedure and it was prolonged. She then developed an aspiration pneumonia requiring antibiotics. She was discharged without further complicationsHow many SAE’s are there in this scenario? OneAre they expected or unexpected? ExpectedWithin what timeframe should they be notified to the CSU? Within one week
63 Case-Study 354 year old male has a successfully treated duodenal ulcer at endoscopy. He has further bleeding and then goes straight to radiological embolisation. He has further bleeding and then has surgery. He is due for discharge 10 days later but develops a wound infection and is kept in for a further 4 days for antibiotics.How many SAE’s are there in this scenario?Are they expected or unexpected?Within what timeframe should they be notified to the CSU?
64 Case-Study 3 Answer54 year old male has a successfully treated duodenal ulcer at endoscopy. He has further bleeding and then goes straight to radiological embolisation. He has further bleeding and then has surgery. He is due for discharge 10 days later but develops a wound infection and is kept in for a further 4 days for antibiotics.How many SAE’s are there in this scenario? FourAre they expected or unexpected? All expectedWithin what timeframe should they be notified to the CSU? Further bleeding within one working day; Embolisation/surgery/wound infection within one week
65 Case-Study 478 year old man previous heart attacks and “mini-strokes” taking life-long aspirin and dypiridamole. Found to have a gastric cancer at endoscopy. Anti-platelets are withheld and he develops a stroke with a dense right hemi-paresis.How many SAE’s are there in this scenario?Are they expected or unexpected?Within what timeframe should they be notified to the CSU?
66 Case-Study 4 Answer78 year old man previous heart attacks and “mini-strokes” taking life-long aspirin and dypiridamole. Found to have a gastric cancer at endoscopy. Anti-platelets are withheld and he develops a stroke with a dense right hemi-paresis.How many SAE’s are there in this scenario? OneAre they expected or unexpected? ExpectedWithin what timeframe should they be notified to the CSU? Within one working day
67 Case-Study 5A 32 year old alcoholic went on a binge and was vomiting for 24 hours. He was found to have a Mallory-Weiss tear at endoscopy. His alcohol withdrawal symptoms were severe and he fell on the ward whilst mobilising to the toilet, banged his head and required 4 stitches.How many SAE’s are there in this scenario?Are they expected or unexpected?Within what timeframe should they be notified to the CSU?
68 Case-Study 5 AnswerA 32 year old alcoholic went on a binge and was vomiting for 24 hours. He was found to have a Mallory-Weiss tear et endoscopy. His alcohol withdrawal symptoms were severe and he fell on the ward whilst mobilising to the toilet, banged his head and required 4 stitches.How many SAE’s are there in this scenario? None!This is an adverse event, not a serious adverse event. Adverse events do not need reporting.
69 Health Economics Research Centre-University of Oxford Health Economics Evaluations: What are they and what will we do in TRIGGERElizabeth StokesResearcherHealth Economics Research Centre-University of Oxford14:15-14:40
70 Overview of session Introduction to health economic evaluation Rationale for itWhat it isHow it is conducted and results interpretedHealth economics in TRIGGERData collection forms in TRIGGERIntroduce economic evaluation and why it is important70
71 What is health economic evaluation? Premise: scarce (health care) resourcesAim: to maximise health gain with the resources availableMethod: compare costs and outcomes of two or more interventionsDefinition: “The comparative analysis of alternative courses of action in terms of both their costs and their consequences” (Drummond et al. 2005)Explicit way of making choicesEconomics looks at what mechanisms we can use to allocate scarce resources.Sometimes known as the gloomy or dismal science as the idea that we can’t have everything that we want is at the basis of all our work.Resources are scarce, and we have to make choices about how to allocate these scarce resources.Resources – basic inputs to production – land, labour, capital.Scarcity – not enough resources to satisfy all demands/wants – 2 sides: infinite nature of human wants, finite nature of resources.NHS has a finite budget, and what we spend on 1 thing, we will not have to spend on something else.Methods - Costs and effectiveness of new interventions must be compared with existing interventions. Comparative.So economic evaluation is about costs and effects, inputs and outputsExplicit - it allows us to quantify the change in costs and the change in effects as we move from one treatment or intervention to another, and it provides a means of identifying which is the most cost-effective treatment or intervention, in other words the one which represents value for money.71
72 Types of health economic evaluation CostsOutcomesCost-effectiveness analysisMonetary unitsNatural units e.g. cases detected, life years gained, episode-free dayCost-utility analysisQuality Adjusted Life Years (QALYs)Cost-benefit analysisAll three forms of evaluation are the same in that they measure costs in monetary units, it being on the outcome side that they differ.CEA: outcomes or effects are measured in natural units, specific to what is being evaluated.E.g. studies comparing different diagnostic strategies for DVT have used cases detected as their outcome measure, studies comparing various treatments for prolonging life after renal failure have used life years gained, and studies comparing treatments for asthma have used episode-free days.CEA is perhaps most useful at a local level when an individual decision maker working with a budget is considering a range of treatments or interventions within a particular specialty or for a particular condition. It is not so useful for assessing the cost-effectiveness of interventions across specialties or conditions, because of the lack of a common outcome measure, for example one couldn’t directly compare an intervention where outcomes are measured using cases detected, with one where outcomes were measured as symptom free days. In this case, we need some generic or common measure of outcome, and we get this with CUA, where outcomes are measured using QALYs.The QALY is a composite measure of health outcome combining two things, firstly the impact that an intervention has on quantity of life or years of survival and secondly the impact it has on quality of life experienced through out those years of survival. The rationale behind the QALY is we give health care treatments and interventions either to improve patients’ survival prospects, to improve their HRQoL (so to make people feel better), or both, and therefore in theory the QALY can be used to capture the impact of any health care intervention. It is a generic measure of health outcome and this makes it attractive in that it can be used to measure and compare the effectiveness and cost-effectiveness of health care programmes across different specialties, from say, blood transfusion to hip replacement to cardiac surgery to cancer screening. It is because of these advantages, and the recent drive towards the need to demonstrate the cost-effectiveness of new health care interventions against those already funded, that cost-utility analysis is the most frequently conducted type of economic evaluation, and is the approach that we shall take in TRIGGER. I’ll talk more about QALYs on the next slide.Finally we have cost-benefit analysis, in which both costs and outcomes are valued in monetary units. The idea behind CBA is that it goes one step further than CUA, in that because the outcome is not specific to health, this form of analysis could be used to compare the value for money not just of competing health care interventions, but also of programmes or policies across other sectors of the economy for example in education, transport and so on. In theory therefore it could enable resources to be allocated efficiently across all sectors of the economy. In practice however, CBA is rarely conducted because of the difficulties that arise when attempting to place monetary values on health outcomes. For this reason, we shall set CBA aside, and say that what follows refers to CEA and CUA only.72
73 Quality Adjusted Life Years (QALYs) Composite endpoint combining:Quantity of life (survival)Health related quality of life (HRQoL) measured on a 0 (dead) to 1 (full health) scaleHealth related quality of life1Survival time (years)188.8.131.52.8Patient 1 = = 1.4 QALYsPatient 2 = = 0.55 QALYsQALY difference = 0.85 QALYsA bit more on QALYs. QALYS are increasingly used as the measure of outcome in CEA and are a composite measure of health outcome which combine 2 different things: firstly we look at the quantity of life - survival or years of life lived by individuals, and then secondly, we adjust for the level of HRQoL at which those years of life are lived, and we measure HRQoL on a scale from 0 to 1 where 0 is considered equivalent to death and 1 to perfect health.Using this graph here, I would like to illustrate to you what we call a QALY profile and how we go about calculating QALYs. On the vertical axis we are measuring HRQoL on our 0 to 1 scale, and on the horizontal axis, survival time in years. Lets assume we have a patient who we know survives for 2 years following some new intervention or treatment. We have measured the patient’s QoL and know that in the first year he is at a level of 0.8 whereas in the second year his QoL falls to The QALYs experienced by this patient are estimated simply by taking the area under the curve, so we have 0.8 * 1 = 0.8 QALYs in the first year, and 0.6*1, 0.6 QALYs in the second year, giving a total of 1.4 QALYs experienced over the two years survival period. Suppose now we have a second patient who received the comparator intervention or treatment. This patient survives for only 1.5 years, and has a much lower quality of life throughout, accruing just 0.55 QALYs, 0.4 QALYs in year 1, and then 0.15 QALYs thereafter. The QALY difference is therefore 0.85, and this is the area between the two QALY profile curves, and so takes into account the differences in quality of life and length of life.73
74 Cost-effectiveness framework Intervention 1Intervention 2Cost 1Cost 2Effectiveness 1Effectiveness 2As I have mentioned previously, the approach to determining whether an intervention is cost-effective when carrying out an economic evaluation necessitates the measurement of costs and effects on two or more competing interventions. Intervention 1 is normally some new treatment or policy and intervention 2 is what we call the comparator intervention, it is the treatment or policy that we wish to compare our new intervention against. In most evaluations, the comparator intervention will be that which is being already carried out in routine practice.The key thing to emphasise is that we are interested in the differences between these two interventions, so what is the difference in cost and the difference in outcomes if we were to replace intervention 2, with intervention 1? In certain situations we also often relate the difference in costs to the difference in effects using something called the incremental cost-effectiveness ratio which is estimated by dividing the difference in costs by the difference in effects. To give you a published example…….Incremental cost-effectiveness ratio (ICER) =Cost 1 - Cost 2Effect 1 – Effect 274
75 Incremental Costs and Outcomes: Example – chronic low back pain Surgery£7,8301.004 QALYsRehabilitation£4,5260.936 QALYs£7,830 - £4,526These are the cost and effect results from a study comparing surgical stabilisation of the spine with rehabilitation for patients with chronic low back pain. The study was a RCT and patients were followed up for 2 years; data was collected as part of the trial which would enable the costs and effects of each intervention to be estimated.The cost in the surgery arm was on average £7,830 per patient and surgery was associated with QALYs over the two years. Rehabilitation cost on average £4526 per patient and was associated with QALYs.Surgery therefore was on average more costly than rehabilitation but also more effective – a common situation which often prevails in cost-effectiveness analyses. Concluding that the intervention costs around £3,300 more and generates an additional QALYs is perhaps not so useful and so we kind of standardise the results using the incremental cost-effectiveness ratio. By dividing the difference in costs by the difference in effects, we can determine what the additional costs would be to generate 1 whole additional unit of outcome. In this case, close to £50,000 per additional QALY. As you will see in just a moment, it is this ICER which is key when determining whether an intervention is cost-effective.=£48,588 per QALY1.004 QALY QALYRivero-Arias et al. BMJ 2005; 330(7502): 123975
76 Health Economics in TRIGGER Feasibility trialFeasibility of gathering data required in a cost-effectiveness analysis to inform data collection for the phase III trialPilot resource use data collection formsAssess feasibility of collecting inpatient data from routine hospital information systems, post-discharge data from patients by telephone, and HRQoL data using the EQ-5DFeasibility of using these data within a cost-effectiveness model to identify parameters with the potential to be key drivers of cost-effectivenessThese will require detailed measurement in phase III trialFeasibility of using EQ-5D in this patient group – good response rate? Responses intuitive and complete?Feasibility of collecting data to allow us to estimate and compare the costs and effects of a restrictive versus a liberal transfusion policy in AUGIB patients. On the cost side, we are interested in what is the net cost impact of moving from a liberal to a restrictive transfusion policy. It is challenging a priori to determine what this might be.On the outcome side, we are interested in the net impact of a restrictive transfusion policy upon both length and quality of life. In particular we would hypothesise that patients for whom death is averted will likely survive into the future and continue to enjoy additional years of life that might otherwise have been lost. Taking into account the quality of life at which years of life are lived is also of interest.76
77 Costs IPerspective of National Health Service, patients / their carers, and employersData will be collected from each trial patient on inpatient health care resource use, including:RBCs and other blood products transfusedEndoscopiesTime spent in ICU, HDU, general wardsAdverse eventsDischarge / transfer to another hospital / facilityData collection integrated into the CRFsFocussing in on the costing side of the study, the perspective we have decided to adopt is that of the National Health Service, patients, and employers. When we talk about perspective or viewpoint, we are basically talking about whose costs we are going to include and measure. In the past, the majority of cost-effectiveness studies adopted quite a narrow perspective and focussed only on direct health care costs. Nowadays though, economists are encouraged to include a wider range of costs especially if there is reason to believe they might vary between the interventions being evaluated.Inpatient resources ...., hopefully all of the main in-hospital cost drivers.77
78 Costs IIPrimary and secondary health care resource use post discharge will be captured via a telephone contact with patients at 28 daysAlso in this questionnaire patients will be asked aboutany unpaid care received from relatives or friends and any costs they have incurredand about return to paid employmentUnit costs from a variety of sources will be used to cost this resource use data.Additionally, to capture health care costs after hospital discharge, we shall use a telephone contact with the patient at day 28 to ask about their contacts with the primary and secondary health care sectors since discharge.Ask about hospital readmissions, outpatient visits, community care, GP visitsUnpaid informal care / employment – determine if these are important to capture in the phase III trialFinally, once measured, we shall cost all of this resource use data using unit costs from a variety of sources including NHS Reference Costs, Personal and Social Services Research Unit.78
79 Effects I Measured using Quality Adjusted Life Years (QALYs) EuroQol EQ-5D questionnaire used to classify a person’s health state by telephone at day 28EQ-5D asks respondents whether they have no problems, some problems or extreme problems withResponses are converted into a single index value on the scale 0 to 1, dead to perfect health, using an accompanying scoring tariff- Mobility- Self-care- Usual activities- Pain / discomfort- Anxiety / depressionThe effectiveness or outcomes associated with a restrictive versus a liberal transfusion policy in AUGIB patients will be measured using QALYs.We have selected the QALY as the outcome measure for a number of reasons. Firstly, the potential exists for the use of a restrictive transfusion policy in AUGIB patients to both reduce patient mortality and possibly have a positive impact upon HRQoL, effects which would both be captured by the QALY. Secondly, the QALY is a generic measure of health outcome and therefore it becomes possible to assess the value for money offered by health care interventions across different specialties, from say, blood transfusion to hip replacement to cardiac surgery to cancer screening. It also explains why in England and Wales, when assessing the value for money of new interventions and making recommendations on adoption to the NHS, NICE specifically requires that for cost-effectiveness analyses, the value of health effects should be expressed in terms of QALYs.HRQoL captured by the EQ-5D.For patients still in hospital at day 28, the EQ-5D will be completed in hospital.79
80 Effects II Survival data available for each trial patient to 28 days HRQoL assessed at 28 days using the EQ-5D questionnaireNo baseline values due to unplanned nature of the conditionQuality and quantity of life combined and used as inputs into decision modelTo facilitate the calculations of QALYs, we shall collect survival data for each trial patient at 28 days, and assess patient HRQoL at 28 days using the EuroQol EQ-5D questionnaire.No baseline HRQoL data, so we will likely have to make some assumption about levels of QoL at this time and test these assumptions in some kind of sensitivity analysis.Final step is to generate a QALY profile for each patient to 28 days and estimate the number of QALYs accrued by each patient.80
81 Key drivers of cost-effectiveness Trial data will allow exploration of mean costs and QALYs per patient for each trial arm to 28 daysFeasibility trial, so the time horizon is shortModel acute upper GI bleeding (AUGIB) patient pathway & associated costs and outcomes beyond 28 days to identify parameters with the potential to be key drivers of cost-effectivenessUse trial data, and other sources such as audit of AUGIBThe same model will be used to model costs/ effects beyond 28 days to identify key cost drivers as part of the feasibility trial, as will be used to extrapolate costs and effects beyond the end of the trial time horizon in the phase III trial. But, models being used in different ways.Feasibility – lots of sensitivity analysis as lot of uncertainty about parameter estimates given v short follow up, and also to test the influence and effects of various parameters.Phase III trial – model used to draw cost-effectiveness conclusions and assess uncertainty around findings.20 year time horizon.81
82 Summary This feasibility trial will allow us to Determine workable data collection methods for resource use, unit costs and outcomes (quality of life) for the phase III trialIdentify key parameters for focussed measurement in the phase III trial82
83 Data Collection Forms in TRIGGER All data collection is integrated into the CRFsForm 15 - length of stay around various departments and wards of hospitalFollow up telephone contact at day 28Form 12a – EQ-5DForms 13a-f – resource useGP verification of patient reported eventsE.g. Form 5 captures medications, Form 8 endoscopies, Form 10b – # lab tests, # other blood products.Form 1a and 14 capture where patients were admitted from and discharged to.Forms particularly for health economics:Form 15 – length of stay around various depts and wards of hospital – clearly an important cost driverTelephone follow up83
84 The Do’s and Dont’s of CRF Completion Tania ReedClinical Data ManagerNHSBT14:40-14:55
85 (Principle 11 - Records, WHO Good Clinical Research Practice) All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification.(Principle Records, WHO Good Clinical Research Practice)Preparation and maintenance of clinical trial documents that leaves an audit trail throughout the conduct of the clinical trial.
86 The Importance of Data Quality and Integrity in Clinical Trials Data quality refers to the extent to which data is accurate, legible, complete, original, and attributable to the person generating itData integrity refers to the extent to which data is credible, consistent and verifiableIt is important that we maximise data quality and integrity when recording information on CRFs and resolving data queries, in the TRIGGER trialData quality and integrity both important when recording information on CRFs or resolving data queries.
87 Objectives of Clinical Data Management To ensure the quality and integrity of clinical trial dataTo ensure that trial data is collected in accordance with the clinical trial protocolTo provide a data set that is of sufficient quality for statistical analysis, interpretation and reportingTo work in accordance with ICH-GCP principlesInternational Conference on Harmonisation Good clinical practice principles
88 Things to remember when recording information on CRFs: Write in black inkIf you make an error put a make sure your original entry is visible, write your correction alongside, sign and dateDo not scribble over your original entryDo not change numbers by writing over themDo not use correction fluidDo not destroy CRFs if you make an error(s)
89 Things to remember when recording information on CRFs: If you make an error effecting the whole CRF page, put a line across the page, write ‘In error’, sign and date. Make sure the original entry is visible. Keep the copy in the patients fileWrite clearly, make sure it is legibleMake sure that your writing is readable on fax or scanned copies
90 Things to remember when recording information on CRFs: If data is unknown or not recorded write ‘UNK’ or ‘NR’ in boxes or write ‘UNKNOWN’ or ‘NOT RECORDED', alongside, sign and dateWhen transcribing from source documents e.g. patient records, laboratory records, double check what you have writtenInclude leading zeros e.g. write 8.23 as 08.23Complete decimal places if boxes are provided for them, if no decimal place enter zero e.g. 4 should be 4.0
91 Things to remember when recording information on CRFs: Use dd-mm-yyyy format for dates, if there are no boxes providedUse hh:mm format for timesDouble check your calculations before recording on CRF e.g. Blatchford score, Rockall scoreIf you add any additional comments to CRFs remember to sign and date each oneIf sending any additional pages or documents with CRFs - include the patient’s trial no, date of birth and initials on each page
92 Sending CRFs to the CSU: Check that all questions on the CRF have been completedCheck that the patient’s trial no, initials and date of birth are correct and the same on all CRF pagesCheck that you have printed your name, signed and dated at the bottom of all CRF pagesDo not write any patient identifiable information on any documents to be sent to the CSU
93 Sending CRFs to the CSU: Always use a CRF transmittal formSend copies of the Screening Log every MondaySend CRFs in 3 batches for each patient(1) Trial entry (Forms 1a – 4)(2) Discharge or Day 28 (Forms 5a – 10b)(3) End of study/Follow up (Forms 11a – 14 & 18)Always complete a safety event transmittal form when sending Serious Adverse Events and Serious Transfusion Related Adverse Event CRFs
94 Sending CRFs to the CSU: The preferred method of sending the CRFs is by scanning and ing or by postor fax SAE formsAt the CSU the Trial data manager will send an to confirm that the CRF pages or Screening log pages have been received
95 Resolving Data Queries: Data Queries are usually raised due to:-Missing dataMissing CRF pagesData anomaliesThe Trial Data Manager will send an to site staff, with details of the query
96 Resolving Data Queries: Data clarification forms are generated by the database during data entry, and will be attached to the query as a pdfData clarification form specifies the site, patient, form, question and the actual query textSite staff should clarify the discrepancy, provide missing data or missing CRF(s)Record the amended or missing data on the CRFWrite the requested information in the ‘Answer’ section below the query textShow e.g. of data clarification form
97 Resolving Data Queries: If no data clarification form send an back responding to the query and attach or send a copy of the amended CRFPrint your name, sign and date each data clarification formSend a copy of the amended CRF and/or missing CRF pages to CSUKeep the original amended CRF(s), and data clarification form in the site fileData query
98 SummaryDiscussed best practice when completing CRFs and resolving data queriesThe aim of following this best practice is to maximise data quality and integrity during the TRIGGER trialReduce the number of data queries sent to you - thereby reducing your workload!
99 Exercise in pairsHow many discrepancies can you find on this CRF - Haemoglobin Measurements and RBC Transfusion Record – Form 6a?We have completed Form 6a including quite a lot of errors ... We want you to try to find as many as you can...Work in pairs circle each error that you find... Once all finished run through the errors and give a sheet with how it should be completed...Give example of a data clarification form!!
108 Investigator Site File An Investigator Site File (ISF) contains essential documents on the trial and forms/documents used by the individual site• The responsibility to hold and maintain an up to date ISF, including all superseded documents, is with the Principal Investigator at each participating siteWhen new or amended trial documents become available (e.g. protocols, PIS, reports, etc), it is the responsibility of the Trial coordinating team to provide copies to the Investigator Site together with relevant Ethics approvals
113 Site Initiation/Activation Before enrolling patients each site must ensure they have: An Investigator Site file Written permission from the site R&D A signed study site agreementA signed delegation log.
114 Vipul Jairath, Ana Mora, Elizabeth Stokes, Tania Reed, Alison Deary Open Forum for Q’s&A’sVipul Jairath, Ana Mora, Elizabeth Stokes, Tania Reed, Alison Deary15:20-16:20
115 Lower Gastrointestinal Bleeding Pragmatic study – patient will have been included on the basis of a suspected UGIB which later turns out to be a LGIB.Stop completing any further CRFs and proceed to end of study form (Form 14) and indicate the patient did NOT complete the study as planned with the reason.Do not complete Day 28 follow up questionnaireDo return all completed CRFs and end of study form
116 Co-Enrolment Guidelines The only competing study we are currently aware of is the early TIPSS study in Edinburgh and Glasgow.Patients can be co-enrolled to this study.Any future competing studies will be considered on a case by case level after discussion with each trial steering committee.
117 Trial Website and Close Vipul Jairath & Ana Mora16:20-16:30