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The Other End of the Bureaucracy Spectrum
In the U . S . and E . U ., national regulatory agencies keep a close watch on site investigators . In areas outside of the FDA and EMA ’ s purview , particularly in lowerand middle-income countries , though , the limited oversight of clinical research leaves patients vulnerable to exploitation . Some patients are even enrolled in trials without their knowledge because of illiteracy and other barriers to informed consent .
Theoretically , CROs could fill the need for safety monitoring in these areas ; however , recent experiences raised the question of whether CROs can be trusted to conduct these types of outsourced trials .
Investigations published in 2017 found that the Eastern European arms of the CRO-coordinated TRUE-AHF ( Trial of Ularitide Efficacy and Safety in Acute Heart Failure ) and TOPCAT ( Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist ) trials enrolled ineligible patients from Russia and Georgia . Many patients assigned to the intervention groups did not even receive the study drugs . 1 , 2 This could explain why the drugs seemed to work so well in North and South America , but not in Eastern Europe .
In 2016 , an FDA inspection of Semler Research Center ’ s facilities ( a CRO based in India ) unearthed “ significant instances of misconduct and violations of federal regulations , including the substitution and manipulation of study subject samples .” 3 The agency alerted drug makers that marketing applications containing data prepared by Semler would not be accepted due to concerns about the integrity of the data .
The World Health Organization came to similar conclusions when it examined Semler ’ s computer servers and found a file containing detailed instructions for manipulating drug samples that were used in its clients ’ clinical trials . 4 Last year , the E . U . suspended hundreds of drugs that were authorized for use based on what regulators called “ flawed ” studies conducted by GVK Biosciences , another Indian CRO . 4
While the FDA said it did not identify reports that raise serious safety concerns with the medications evaluated in these trials , the actions of these “ bad apples ” are harming the reputation of the CRO industry – and of the larger clinical trial enterprise .
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“[ CROs ] should not design trials or select investigators ,” he said . “ These [ tasks ] should be done by medical experts , not CROs with people training on the job .”
“ The potential effects of CRO use on study safety , ethical conduct , and efficiency are understudied ,” Dr . Kantarjian and coauthors wrote in a Cancer review . 3 “ Concerns raised by study personnel and occasional reports of misconduct suggest that the current CRO model is flawed and that new standards
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for CRO monitors are needed .”
Drs . Le Gouill and Rule suggested that more can be done . “ The pharmaceutical industry needs to engage properly with the regulators and stop interpreting what they believe is expected of them ,” they wrote . 7 “ Those of us who still run academic studies within the same regulatory frameworks know full well that most of what is being asked for in the name of quality and safety is not required .”
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Solutions on the Horizon ?
“ We need to be more realistic about how trials are conducted and which data are important to collect ,” said Alok Khorana , MD , from the department of hematology and medical oncology at the Cleveland Clinic in Ohio . “ These are not the responsibilities of the CROs , but rather that of the research community as a whole .”
The goal should be “ making trials more patient-friendly and real world – based , so the
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REFERENCES
1 . Hawkes N . Shortcomings in heart failure drug trial open “ can of worms .” BMJ . 2017 ; 357 : j2218 .
2 . de Denus S , O ’ Meara E , Desai AS , et al . Spironolactone metabolites in TOPCAT – new insights into regional variation . New Engl J Med 2017 ; 376:1690-2 .
3 . U . S . Food and Drug Administration . “ Notification to Pharmaceutical Companies : Clinical and Bioanalytical Studies Conducted by Semler Research Are Unacceptable ,” April 20 , 2016 . Accessed February 20 , 2018 , from www . fda . gov / Drugs / DrugSafety / ucm495778 . htm .
4 . STAT News . “ FDA and WHO warn about clinical trials run by an Indian company .” April 25 , 2016 . Accessed February 21 , 2018 , from www . statnews . com / pharmalot / 2016 / 04 / 25 / fda-warn-clinical-trials-run-indiancompany .
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52 ASH Clinical News |