The Learning Portal will be under maintenance Monday, 6 December between 6 AM and 5 PM EST. Portal functionality will be unavailable during this window.
We apologize for any inconvenience caused during this time.

Regulatory Focus™ > News Articles > Nearly Half of Recent EU Approvals Based on a Single Pivotal Study

Nearly Half of Recent EU Approvals Based on a Single Pivotal Study

Posted 10 November 2017 | By Michael Mezher 

Nearly Half of Recent EU Approvals Based on a Single Pivotal Study

A recent study found that 45% of marketing authorizations granted in the EU from 2012 to 2016 were based on evidence from a single pivotal trial.

The authors of the study, Anne Vinther Morant and Henrik Tang Vestergaard, both employees of Danish drugmaker Lundbeck, say they found the figure to be "surprisingly high," but in line with findings from a recent study of US Food and Drug Administration (FDA) approvals from 2005-2012.

Despite the high overall figure, the authors found that approvals based on a single pivotal study were mostly limited to life threatening conditions and areas of high unmet need, such as cancer or rare diseases.

For the study, the authors identified 163 new active substances (NAS) authorized from 2012-2016 for a total of 180 indications, a quarter of which were granted orphan designation. Of those, 20 were authorized conditionally and five were authorized under exceptional circumstances.

When broken up by pathway, indications with standard marketing authorization were mostly supported by two or more pivotal trials (61%), while expedited applications were mostly authorized based on a single pivotal trial.

Similarly, indications with orphan designation were much more likely to be approved based on a single pivotal trial (79%) compared to non-orphan indications (33%).

The authors also found that authorizations based on a single pivotal trial varied significantly by therapeutic area.

Using the World Health Organization anatomical therapeutic chemical (ATC) classification system to distinguish between drugs, the authors found that 74% of antineoplastic and immunomodulating agents were supported by a single pivotal trial, while only 11% of respiratory system drugs and no nervous system drugs were.

However, when excluding orphan indications and antineoplastic and immunomodulating agents, most other indications (80/101) were supported by two or more pivotal studies.

Similarly, the authors found that the characteristics of the single pivotal trials varied largely by therapeutic area. "In most therapeutic areas, the vast majority of the single pivotal clinical trials were randomized, controlled, and double blinded," the authors write.

But cancer drugs, especially ones with orphan designation, were much more likely to be supported by non-randomized, uncontrolled and open label studies.

Regulatory Flexibility

The authors say these findings show that both EMA and FDA can be flexible when approving new drugs, even outside of oncology and rare diseases.

"Sponsors could consider making a case for [marketing authorization] applications based on a single pivotal clinical trial also for other and more common diseases, especially when solid confirmatory evidence can be generated from non-pivotal clinical trials or from related indications," the authors write.

While both the US and EU studies found central nervous system (CNS) drugs to be the most likely to be supported by two or more pivotal studies, FDA recently approved indications for several CNS drugs based on a single pivotal trial.

  • Nuplazid (pimavanserin) to treat hallucinations and delusions associated with Parkinson's disease in 2016;
  • Ingrezza (valbenazine) to treat tardive dyskinesia in 2017; and
  • Ocrevus (ocrelizumab) to treat primary progressive multiple sclerosis in 2017, though Ocrevus was also approved to treat relapsing multiple sclerosis based on data from two separate pivotal studies.
  • So far Nuplazid and Ingrezza have not been submitted to EMA for review, though the agency announced today that it is recommending Ocrevus for approval for both indications.

The authors also point to a 2014 survey of EMA scientific advice procedures on adaptive clinical trial designs that found that EMA endorsed most sponsor proposals for a single pivotal trial, though in most of those cases the drugs in question were for cancer or rare diseases.



© 2021 Regulatory Affairs Professionals Society.

Regulatory Focus newsletters

All the biggest regulatory news and happenings.