User login
New research has revealed shortcomings of post-approval studies for drugs granted accelerated approval in the US.
Researchers found that, for drugs granted accelerated approval from 2009 to 2013, both pre-approval and post-approval trials had limitations in their design and the endpoints used.
“One might expect accelerated approval confirmatory trials to be much more rigorous than the pre-approval trials,” said study author Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“But we found that there were few differences in these key design features of the trials conducted before or after approval.”
Dr Kesselheim and his colleagues reported these findings in JAMA.
The researchers examined pre- and post-approval clinical trials of drugs granted accelerated approval by the US Food and Drug Administration (FDA) between 2009 and 2013.
During that time, the FDA granted 22 drugs accelerated approval for 24 indications (15 of them for hematologic disorders).
Fourteen of the indications were approved on the basis of single-intervention-group studies that enrolled a median of 132 patients.
The FDA ordered 38 post-approval studies to confirm the safety and efficacy of the drugs.
Three years after the last drug’s approval, half of those studies (n=19) were not complete. Eight (42%) of the incomplete studies were either terminated or delayed by more than 1 year.
For 14 of the 24 indications (58%), results from the post-approval studies were not available after a median of 5 years of follow-up.
Study comparison
Published reports were available for 18 of the 19 completed post-approval studies. The characteristics of these studies did not differ much from the 30 pre-approval studies.
There were no statistically significant differences with regard to median patient enrollment (P=0.17), the use of randomized (P=0.31) or double-blind trials (P=0.17), the use of placebo as a comparator (P=0.17), or the lack of a comparator (P=0.21).
However, there was a significant difference in the use of an active comparator (P=0.02), with more post-approval studies using an active comparator.
The researchers also found that 17 of the 18 post-approval trials still used surrogate measures of effect as primary endpoints.
There was no significant difference between pre- and post-approval trials when it came to the use of disease response (P=0.17) or most other surrogate measures (P=0.21) as the trials’ primary endpoint.
The same was true for overall survival (P=0.20), although significantly more post-approval studies used progression-free survival (P=0.001) as a primary endpoint.
“It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes—or even make them worse,” Dr Kesselheim said.
To address these issues and improve the quality of confirmatory studies, Dr Kesselheim suggested the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies.
He also suggested the agency work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug. 
New research has revealed shortcomings of post-approval studies for drugs granted accelerated approval in the US.
Researchers found that, for drugs granted accelerated approval from 2009 to 2013, both pre-approval and post-approval trials had limitations in their design and the endpoints used.
“One might expect accelerated approval confirmatory trials to be much more rigorous than the pre-approval trials,” said study author Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“But we found that there were few differences in these key design features of the trials conducted before or after approval.”
Dr Kesselheim and his colleagues reported these findings in JAMA.
The researchers examined pre- and post-approval clinical trials of drugs granted accelerated approval by the US Food and Drug Administration (FDA) between 2009 and 2013.
During that time, the FDA granted 22 drugs accelerated approval for 24 indications (15 of them for hematologic disorders).
Fourteen of the indications were approved on the basis of single-intervention-group studies that enrolled a median of 132 patients.
The FDA ordered 38 post-approval studies to confirm the safety and efficacy of the drugs.
Three years after the last drug’s approval, half of those studies (n=19) were not complete. Eight (42%) of the incomplete studies were either terminated or delayed by more than 1 year.
For 14 of the 24 indications (58%), results from the post-approval studies were not available after a median of 5 years of follow-up.
Study comparison
Published reports were available for 18 of the 19 completed post-approval studies. The characteristics of these studies did not differ much from the 30 pre-approval studies.
There were no statistically significant differences with regard to median patient enrollment (P=0.17), the use of randomized (P=0.31) or double-blind trials (P=0.17), the use of placebo as a comparator (P=0.17), or the lack of a comparator (P=0.21).
However, there was a significant difference in the use of an active comparator (P=0.02), with more post-approval studies using an active comparator.
The researchers also found that 17 of the 18 post-approval trials still used surrogate measures of effect as primary endpoints.
There was no significant difference between pre- and post-approval trials when it came to the use of disease response (P=0.17) or most other surrogate measures (P=0.21) as the trials’ primary endpoint.
The same was true for overall survival (P=0.20), although significantly more post-approval studies used progression-free survival (P=0.001) as a primary endpoint.
“It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes—or even make them worse,” Dr Kesselheim said.
To address these issues and improve the quality of confirmatory studies, Dr Kesselheim suggested the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies.
He also suggested the agency work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug.
New research has revealed shortcomings of post-approval studies for drugs granted accelerated approval in the US.
Researchers found that, for drugs granted accelerated approval from 2009 to 2013, both pre-approval and post-approval trials had limitations in their design and the endpoints used.
“One might expect accelerated approval confirmatory trials to be much more rigorous than the pre-approval trials,” said study author Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“But we found that there were few differences in these key design features of the trials conducted before or after approval.”
Dr Kesselheim and his colleagues reported these findings in JAMA.
The researchers examined pre- and post-approval clinical trials of drugs granted accelerated approval by the US Food and Drug Administration (FDA) between 2009 and 2013.
During that time, the FDA granted 22 drugs accelerated approval for 24 indications (15 of them for hematologic disorders).
Fourteen of the indications were approved on the basis of single-intervention-group studies that enrolled a median of 132 patients.
The FDA ordered 38 post-approval studies to confirm the safety and efficacy of the drugs.
Three years after the last drug’s approval, half of those studies (n=19) were not complete. Eight (42%) of the incomplete studies were either terminated or delayed by more than 1 year.
For 14 of the 24 indications (58%), results from the post-approval studies were not available after a median of 5 years of follow-up.
Study comparison
Published reports were available for 18 of the 19 completed post-approval studies. The characteristics of these studies did not differ much from the 30 pre-approval studies.
There were no statistically significant differences with regard to median patient enrollment (P=0.17), the use of randomized (P=0.31) or double-blind trials (P=0.17), the use of placebo as a comparator (P=0.17), or the lack of a comparator (P=0.21).
However, there was a significant difference in the use of an active comparator (P=0.02), with more post-approval studies using an active comparator.
The researchers also found that 17 of the 18 post-approval trials still used surrogate measures of effect as primary endpoints.
There was no significant difference between pre- and post-approval trials when it came to the use of disease response (P=0.17) or most other surrogate measures (P=0.21) as the trials’ primary endpoint.
The same was true for overall survival (P=0.20), although significantly more post-approval studies used progression-free survival (P=0.001) as a primary endpoint.
“It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes—or even make them worse,” Dr Kesselheim said.
To address these issues and improve the quality of confirmatory studies, Dr Kesselheim suggested the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies.
He also suggested the agency work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug.