Newsletter
Issue 13 Summer 2008

A clinical trial is like an air journey. You first prepare a flight plan (the trial protocol) which must be approved by air traffic control (the regulators). Before taking off (enrolling the first patient), the captain (the lead collaborator at each site) must ensure that all the relevant documents have been seen and approved (ethics approvals). 

It takes a huge amount of energy (effort) to get a plane (a trial) off the ground but eventually it reaches the correct cruising altitude (monthly recruitment rate). The CRASH-2 trial is now recruiting around 450 patients per month and is getting close to its cruising altitude of 550 patients per month. We have covered a lot of ground (11,000 patients recruited) and hope to arrive at our destination (20,000 patients recruited) on schedule (December 2009).

Just like air travel, safety is our primary concern. In the CRASH-2 trial patient safety is inspected regularly by an expert independent data monitoring committee. This newsletter shows their latest report. You will be reassured that there are no safety concerns and that the committee strongly encourages us to keep recruiting so that we reach our destination on time.

The data monitoring committee checks the accumulating trial data and to do its job properly it is vital that the trial data are accurate and complete. In this newsletter the trial Data Manager Lin Barnetson explains what data checking involves and why obtaining complete data on every randomised patient is essential.

At this stage it is tempting to say "so sit back and enjoy your flight" but this is a newsletter for captains (collaborators) rather than passengers (patients)! The message for captains is "full throttle, safety is the primary concern and keep in touch with the ground staff"!

On target recruitment keeps us airborne – good quality data and completeness of follow-up ensures a safe and happy landing.

MONITORING THE ACCURACY AND QUALITY OF THE CRASH-2 TRIAL DATA

WHY IS THIS IMPORTANT?

The integrity of the CRASH-2 Trial data must be verified to ensure the results of the trial are valid and the safety of future patients is protected.

HOW DO WE MONITOR DATA QUALITY?

INDEPENDENT OVERVIEW

In CRASH-2 we have an independent Data Monitoring and Ethics Committee (DMEC) who review our unblinded data on a regular basis. This review was last carried out on 2 June 2008 on 9,210 patients – see the latest feedback from DMEC in this newsletter.

In addition to reviewing the unblinded data to ensure the trial remains safe for patients, the DMEC also look at our rate of recruitment, how we ensure the security of the blinding of the trial and the quality of data we receive. The quality review includes the number of protocol violators, the number of packs used out of sequence and percentage of missing data. We also provide the DMEC with information on our quality assurance procedures.

TCC MONITORING PROCEDURE

The following are some of the procedures we carry out here at the TCC. Checks are made within each collaborating centre and across the trial as a whole.

Daily computerised validity and consistency checks on both entry and outcome data. These can give rise to queries which we resolve directly with the investigators at each site.

The data are also subjected to monthly statistical checks for irregularities (International Society for Clinical Biostatistics Subcommittee on Fraud, Statist Med 1999;18:3435-51) such as:

• too little or too great variance
  
• no outliers
  
• abnormally flat distribution

By comparing means, standard deviations and coefficient of variance, sites showing any of the anomalies listed above are identified. These checks are only carried out on sites with an adequate sample size for analysis. Figure 1 shows the results for systolic BP where 3 sites fall out with the normal distribution.

All measures are subjected to regular checks for relative frequencies and these are compared across the trial. Figure 2 shows the output for one of the standard checks carried out to examine the primary outcome (mortality) for the trial. The figure indicates the number of sites with mortality rates that fall below or are above the expected range.

Validation checks are also carried out between baseline measures and outcome event rates, e.g. severity of capillary refill time v mortality.
Any centre that has provided data that fail these checks are immediately brought to the attention of the Trial Management Group for discussion and are subject to full source data verification/audit.

Site visits and source data verification of between 5-100% is also routinely carried out depending on specific rates of recruitment. This involves a member of the TCC staff / National Co-ordinator visiting your hospital. Monitoring visits should also be regarded as an opportunity to ask questions and consolidate knowledge of the trial processes and progress. Many of you have experienced our audits and we hope you have found them useful.

ARE WE RECRUITING THE CORRECT PATIENTS?
Our statistical checks look at the baseline characteristics of patients being randomised at all trial sites. The graph below shows that 3 hospitals were outside the expected normal distribution for systolic BP measures within the trial. In these cases, we review all the data we have received, query any anomalies, re-educate site staff about the eligibility criteria and conduct a site visit/source data verification/audit.

Figure 1. Mean v standard deviation for systolic BP

ARE WE ACHIEVING THE EXPECTED OUTCOME EVENTS RATE?
Our checks are carried out on all outcome measures. This chart shows the number of sites where mortality rates are below, or above, the expected range. The statistical checking program automatically outputs the list of site names of those with mortality rates below 10% and above 30%. These sites are contacted to ensure the eligibility criteria are fully understood and are being applied correctly. This ensures that patients whose condition may be too mild or too severe are not being included.

Figure 2. Primary outcome check

COLOMBIA: Fundacion Clinica Valle del Lili; Hospital San Felix ESE; Hospital Universitario Del Caribe; Hospital Universitario San Jose De Popayan; Hospital Universitario San Vicente de Paul

CUBA: Hospital Abel Santamaria Cuadrado; Hospital Clí­nico-Quirúrgico Docente "Saturnino Lora“; Hospital Provincial Docente "Manuel Ascunce Domenech“

ECUADOR: Hospital Luis Vernaza

EGYPT: Mataria Teaching Hospital; Suez Canal University

GEORGIA: Tbilisi City Hospital #1; Tbilisi First Hospital, University Clinic, Neurosurgery Center; Tbilisi State Medical University, ER Department; Tbilisi State University Clinical Hospital 'I Javakhishvili‘

INDIA: Aditya Neuroscience Centre; Apollo Health City; Bhattacharya Orthopaedic and Related Research Centre; Calicut Medical College Hospital; Care Hospital; Christian Medical College Hospital Vellore; Government Medical College and Associated Hospitals Jammu; Government Rajaji Hospital; Goyal Hospital Jalna; KLE Hospital & Medical Research Centre; Krishnamai Medical & Research Foundation's NIKOP Hospital; LTM Medical College and General Hospital; Medical Trust Hospital Kochi; MKCG Medical College; NKP Salve Institute of Medical Sciences and Lata Mangeshkar Hospital; North Bengal Neuro Research Centre; Sanjeevani Hospital; Sanjivani Hospital; Sheth VS General Hospital & NHL Municipal College

INDONESIA: Saiful Anwar General Hospital; Sanglah General Hospital

MALAYSIA: Hospital University Science Malaysia

MEXICO: Hospital General Regional 25; Hospital Gustavo Rovirosa

NIGERIA: Baptist Medical Centre, National Hospital Abuja; National Orthopaedic Hospital Enugu; University of Benin Teaching Hospital; University of Uyo Teaching Hospital

PERU: Hospital Nacional Hipólito Unanue; Hospital Regional Docente de Trujillo

SRI LANKA: National Hospital of Sri Lanka

THAILAND: Khon Kaen Regional Hospital; Pattani Hospital; Suratthani Hospital

high achievers – CONGRATULATIONS!

100

• Suresh David, Christian Medical College Hospital Vellore, India
• Anil P Lal, Aditya Neuroscience Centre, India
• Edward Komolafe, Obafemi Awolowo University Teaching Hospitals, Nigeria

50

• Rakesh Sharaf, Government Medical College & Associated Hospitals Jammu, India
  
• Ashok Pangi, KLE Hospital & Medical Research Centre, India
  
• Sushil Mankar, NKP Salve Inst & Lata Mangeshkar Hosp, India
  
• Jose Caballero Alvarado, Hospital Regional Docente de Trujillo, Peru
  
• Sakchai Tangchitvittaya, Suratthani Hospital, Thailand

CAMEROON

• Ernest Francis Jangwa, Bali District Hospital
  
• Jules Djokam-Liapoe, Bamenda Provincial Hospital
  
• Ninying Fuh Fointama, Fundong District Hospital
  
• Nguemo J Pascal, St John of God Medical Centre
  
• Nguemo J Pascal, Tombel District Hospital
  

ECUADOR

• Johnny Jerez, Hospital Universitario Guayaquil
  

GHANA

• Ballu Sibiri, Methodist Hospital Wenchi
  
• Emmanuel Kasu, Nkwanta District Hospital
  

INDIA

• Gopal Sharma, Apex Neurotrauma & Superspeciality Hospital
  
• Satish Devadoss, Devadoss Multispeciality Hospital
  
• Sanjay Gupta, Government Medical College Chandigarh
  
• Praveendra Kumar Sachan, Himalayan Institute of Medical Sciences
  
• Raju Subodh, Kamineni Hospital
  
• Jalindar Pol, Krishnamai Medical & Research Foundation's NIKOP Hospital
  
• Vinod Kumar Tewari, Neuro Center, Gola Ghat
  
• Akhilesh Mohan Lahari, Niramay Hospital
  
• Rakesh Kumar Gupta, PGIMS, Rohtak
  
• Sushil Chandra, Presidency Hospital, Gorakhpur
  
• Sujoy Kumar Bhattacharjee, QRG Central Hospital&Research Centre
  
• Gajendra Kant Tripathi, Rajeev Gandhi Memorial Hospital & Research Centre
  
• RP Gupta, Shanti Mukand Hospital
  
• Vinod Kumar Jain, Shri KM Memorial Jain Heart & General Hospital

KENYA

• Vincent Mutiso, Kenyatta National Hospital
  

NIGERIA

• Kenneth Ozoilo, Dalhatu Araf Specialist Hospital
  

THAILAND

• Kamol Wattanakrai, Bhumibol Adulyadej Hospital
  
• Surasak Meephant, Lampang Hospital

• Christian Dellera, Hospital "4 de Junio" Dr Ramon Carrillo, Argentina
  
• Lawrence C E Mbuagbaw, Bafut District Hospital, Cameroon
  
• Ernest Francis Jangwa, Bali District Hospital, Cameroon
  
• Johnny Jerez, Hospital Naval Guayaquil, Ecuador
  
• Nino Kajaia, Institute of Critical Care Medicine, Georgia
  
• Ballu Sibiri, Methodist Hospital Wenchi, Ghana
  
• Mubarak Moideen, Al Shafi Hospital, India
  
• Deepak Vangani, Fortis Escorts Hospital, India
  
• Anil P Lal, GM Hospital, India
  
• Kabul Chandra Saikia, Gauhati Medical College and Hospital, India
  
• Prakash Gokaldas Modha, Gokul Hospital & Trauma Centre, India
  
• Sanjay Gupta, Government Medical College Chandigarh, India
  
• Chawngrolien Chonzik, International Hospital Assam, India
  
• Raju Subodh, Kamineni Hospital, India
  
• M Saleem, KIOT Hospital, India
  
• Jalindar Pol, Krishnamai Medical & Res Foundation's NIKOP Hospital, India
  
• Vinod Kumar Tewari, Neuro Center Gola Ghat, India
  
• Ashok Oberai, Oberai Hospital, India
  
• Rakesh Kumar Gupta, PGIMS Rohtak, India
  
• Sanjay Vhora, Ruby Hall Clinic, India
  
• Anil P Lal, Sanjivani Hospital, India
  
• Julio Cesar Casasola-Vargas, Hospital General de Ecatepec "Dr José María Rodríguez", Mexico
  
• John Chukwuemeka Eze, Univ of Nigeria Teaching Hospital Enugu, Nigeria
  
• Maite Misis, Hospital Universitario Germans Trias i Pujol, Spain
  
• Maria de los Angeles Muñoz, Hospital Universitario Virgen del Rocio, Spain
  
• Kamol Wattanakrai, Bhumibol Adulyadej Hospital, Thailand
  
• Rusta Salaeh, Pattani Hospital, Thailand
  
• Ramzi Freij, Queens Medical Centre, University Hospitals Nottingham, UK
  

Team from Hospital Regional Docente de Trujillo in Peru, with PI Jose Caballero Alvarado

Bhumibol Adulyadej Hospital team in Thailand, with PI Kamol Wattanakrai

Christian Medical College, Vellore, India, with PI Suresh David