There is considerable variation in the characteristics of pivotal efficacy trials used by the US Food and Drug Administration to approve new medicines, raising questions about regulatory standards, post-market surveillance, comparative effectiveness and the communication of risk-benefit information to patients and physicians, a new study has found.

A team led by Nicholas Downing and Dr Joseph Ross of the Yale University School of Medicine in New Haven, US conducted a cross-sectional analysis of all novel therapeutic agents approved by the FDA between 2005 and 2012.

During that period, the researchers determined, the US agency cleared for marketing a total of 188 novel therapeutic agents for 206 indications on the basis of 448 pivotal efficacy trials. Of these agents, the FDA had granted orphan status to 31 (16.5%), while 22 (11.7%) were cleared through the accelerated-approval pathway.

The pivotal studies were then classified according to their design features – namely, randomisation, blinding, comparator and trial endpoint. The analysis also included the number of patients, trial duration and study completion rates.

Comparator use

Reporting their findings in the January 22/29 issue of JAMA, Downing et al noted that the vast majority of the pivotal trials they looked at were randomised (89%) and double-blinded (79.5%).

More than half of the studies (55%) used a placebo for comparison and 32% an active (e.g., another drug), while 13 percent did not include a comparator.

The median number of patients enrolled per indication for the 448 pivotal trials was 760. Of the 201 indications for which pivotal efficacy trials were identified, 74 (37%) were approved on the basis of a single trial, 77 (38%) based on two trials and 50 (25%) based on three trials or more. 

At least one pivotal trial with a duration of six months or more was found to have supported the approval of 68 indications.

There was also significant reliance on surrogate endpoints, defined as “any endpoint using a biomarker expected to predict clinical benefit”. Trials using surrogate endpoints as their primary outcome formed the exclusive basis of approval for 91 indications (45%) among the study sample.

Flexible standards

As Downing et al acknowledged, the variation in the quality of clinical-trial evidence used by the FDA to assess the efficacy of novel therapeutic agents “highlights the agency’s flexible standards for approval”.

This regulatory flexibility allows for a customised approach to approval, particularly with potentially effective therapies for life-threatening diseases, such as certain cancers, or for diseases where is no effective treatment exists (e.g. orphan conditions).

In these cases, “approvals can be made without requiring costly and time-consuming randomised, double-blinded, controlled trials, although these trials are regarded as the gold standard for evaluation”, the researchers commented.

Important implications

Nonetheless, they added, understanding the strength of clinical trial evidence for newly approved therapies has important implications for both patients and physicians.

As the analysis showed, comparative-effectiveness information – “which is not required as part of FDA approval” – was available for fewer than half of the indications in the sample, “consistent with prior research, but leaving uncertainty about the benefits and safety of these medications when compared with other available therapeutic agents”.

Similarly, the reliance on surrogate outcomes in many pivotal studies “leaves patients and physicians to extrapolate clinical benefits from trials, again raising questions about the certainty of the medications’ benefits in practice”.

Another finding was that the majority of pivotal trials with agents indicated for chronic treatment lasted less than one year, “raising questions about the certainty of these medications’ long-term efficacy and safety”.

Life-cycle approach

The study results underline the importance of adopting a ‘life-cycle’ approach to drug development, both with respect to product safety and for enhanced understanding of effectiveness, the authors said.

This suggests that new information on the benefits and safety of therapeutic agents should be “continually collected”. It also requires adequate and robust post-market surveillance systems that allow for re-assessments of drug efficacy and safety after launch, Downing et al noted.

Critical communication

At the same time, communicating this updated information to patients and physicians is “critical”, the researchers insisted.

They pointed to the recommendation in a recent Institute of Medicine committee report that the FDA should implement a benefit and risk assessment and management plan, whereby the agency’s evaluation of a drug’s benefit-risk profile would be summarised in a single document, to be updated continuously updated throughout the product’s commercial lifespan.

“Alternatively, or as part of this effort, the FDA could provide a summative statement, or even a grade, for each approval to signal the quality of clinical-trial evidence used to determine safety and efficacy, allowing therapeutic agents approved on the basis of more robust evidence to be distinguished from those approved on the basis of less robust evidence,” Downing et al proposed.