Review of Selected Presentations, Cardiovascular Clinical Trials in Emerging Countries 2010
Compiled by K. Roumeliotou, May 20, 2010
Cardiovascular Monitoring in Malaria Studies; Issues, Solutions and Quality Control
Dr. Robert Miller (UK) - Chief Medical Officer, Fulcrum Pharma
A Phase I through III Clinical Study Programme for Malaria was developed in Africa and Asia between 2003 and 2009, with the participation of 4,200 patients adults and children, 23 sites, 17 countries.
Getting quality ECG information from multinational multi-centre studies in emerging countries presents several challenges. The Common Errors were limb lead reversal, inconsistent chest lead placement, lead detachment, possible shivering, voltage amplitude & paper speed.
Modern ECG equipment was provided to sites. This was capable of providing an assessment of the ECG with heart rate, measures of key intervals, assessment of wave forms and rhythm & a putative diagnosis made on the basis of the tracing. However, an over-reliance on this printout may give rise to a false positive finding of cardiological abnormalities, especially if the investigators are not cardiologists and have little access to specialist review.
Summary of Malaria Clinical Study Programme results:
- Central review of ECGs (all or as part of a QC process) reduces the risk of over-reporting of ECG and QT abnormalities
- The quality of ECGs from developing countries is as good as those from the developed world and more than 98% of scheduled ECGs were performed
- Especially in young, otherwise fit individuals, changes from the disease to the non-disease state can lead to reporting of bradycardia as an adverse event
- The use of the automated printout is useful and can act as an indicator, but closer examination of the ECGs may be necessary
- Rarely when the ECG was reported as normal or the QTc <450 ms, was there disagreement with this from the central review. But the presence of an automated printout reading can unduly influence a non cardiologist. On the other hand, the automated printout can be useful for the central review, reducing the time required to assess ECGs by providing a possible signal that can then be confirmed or refuted
- Malaria is a very serious disease, with a high mortality, and there is a need for more effective drugs that can provide a quick and inexpensive cure
- Overestimation of ECG abnormalities can delay or prevent registration of such drugs with very severe consequences
- Reporting of normal findings in a young population as a result of a change from baseline coloured by the signs and symptoms of malaria to the normal state may be reported as an adverse event and further distort the safety profile of the drug(s)
- It is imperative that ECG monitoring is monitored carefully and all abnormalities double checked
Preparing for and Surviving a Regulatory Inspection
Dr Andrew Waddell (Scotland, UK) - Director, TMQA and Chairman of the British Association for Research Quality Assurance - BARQA
As Defined in ISO 19011, an Inspection is an audit performed by the regulatory authorities that means a systematic and independent examination that determines if:
- there is a quality system
- it can meet the required quality standards
- the activities and results are in compliance with this system
The Inspectors' expectations regarding Regulations are that the Investigative site is aware of them & up to date, their systems are capable of meeting the requirements and the site is following these systems.
Warning negative signs would be multiple personnel changes - in the company or in the project, multiple deviations/non-compliances, multiple late changes to SOPs (just before the inspection date), evasive behaviour or delaying tactics for inspection as well as "too good to be true" data! Preparation is everything! Personnel of each site should make practical preparation (Knowledge of Regulations, inspection process, Knowledge of site's standards and systems, of the trial under inspection and—very important—knowledge of SOP on handling regulatory inspections. The "People Factor" is very important as "People can make or break inspections". The site has to identify those who can contribute most to the inspection, ensure that they have the necessary skills and knowledge, attitudes and behaviours. The siteshould also prepare the documents that the Inspector is likely to need, prepare the working areas for the Inspectors and for those supporting the inspection in the "back office".
In case of Adverse findings, their handling should be based on CCAPA (Correction - Corrective action - Preventive Action):
- Correction: Action to eliminate a detected nonconformity
- Corrective action: Action to eliminate the cause of a detected non-conformity
- Preventive action: Action to eliminate the cause of a potential non-conformity or other undesirable potential situation
Conducting Cardiovascular Trials in CEE Countries and Central Asia. What Have Been the Results, Problems and Solutions?
CSO: Alexander Siebel, MD
Taking the example of a Phase II Study in Atrial Fibrillation, the approval process, site selection, recruitment strategy & common pitfalls were presented.
China, India & Russia are the most attractive locations to perform Clinical Trials outside of the United States. However, various strategies have to be taken into consideration in order to avoid delays in recruitment, especially developing a realistic scenario for recruitment strategy at the beginning, selection of high recruiting centers by pre-study evaluation services & selection of a CRO specialised in the region & the indication. Finally, very important factors for the success of the trial & the interpretation of the results are the Placebo Effect, the Dropout Effect, local Social Factors & Traditional Practices.
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