Back in the 1970s and 1980s, the US Food and Drug Administration (FDA) made clear that at least two adequate and well-controlled studies were necessary to establish a new drug’s effectiveness, except in only the rarest of circumstances.
Then in 1997, the Food and Drug Administration Modernization Act
was passed, and Congress clarified that FDA may consider “data from one adequate and well-controlled clinical investigation and confirmatory evidence” to approve a new drug.
But in guidance from 1998
, FDA says that its reliance on only a single study “will generally be limited to situations in which a trial has demonstrated a clinically meaningful effect on mortality, irreversible morbidity, or prevention of a disease with potentially serious outcome and confirmation of the result in a second trial would be practically or ethically impossible.”
The agency also explains the persuasiveness of using two studies versus one.
“Whether to rely on a single adequate and well-controlled study is inevitably a matter of judgment. A conclusion based on two persuasive studies will always be more secure than a conclusion based on a single, comparably persuasive study,” the guidance notes.
Aaron Kesselheim, professor of medicine
at Harvard Medical School, told Focus
: “Historically, FDA guidance seemed to indicate a preference for two adequate and well-controlled trials since any single trial may be subject to unanticipated or undetected systematic biases. Of course, in some cases, the clinical need is high enough or the drug’s efficacy is powerful enough that a single trial should be sufficient at least for initial FDA approval.
“But reliance on a single trial—particularly if that trial is single-arm, unblinded, or evaluates unvalidated surrogate measures as the endpoint—increases the risk to patients that the drug may not work as well as expected (or, separately, may have safety issues that outweigh its benefits). It would be useful to clearly inform patients when a new drug is approved on the basis of a single pivotal trial and follow those drugs more closely after approval, with the idea of formally revisiting their benefit-risk balance in the future. But studies unfortunately show that postmarket requirements are often not followed up completely or in a timely fashion,” Kesselheim added.
Approvals Based on a Single Trial
According to a 2014 JAMA study
, between 2005 and 2012, FDA approved 188 novel therapeutic agents for 206 indications, and 74 indications (36.8%) were approved on the basis of a single pivotal trial.
Most recently, IQVIA released a report
finding that 25 of 59 (42%) novel drugs approved in 2018 were approved on the basis of only one trial. And one out of eight approvals relied only on Phase 1 or 2 trials, with no Phase 3 trials. But as in previous years, a large portion of the drugs relying on only one trial were new orphan and cancer drugs.
For instance, AstraZeneca’s orphan drug Lumoxiti (moxetumomab pasudotox-tdfk) was approved in September 2018
based on one trial of less than 100 patients with a rare, slow-growing blood cancer. Stemline Therapeutics also won approval
in December 2018 for Elzonris (tagraxofusp-erzx) to treat a rare, rapidly progressing cancer of the bone marrow and blood after conducting one trial of 94 patients in the US.
Other cancer drugs, meanwhile, won approval after larger single trials.
Pfizer’s Vizimpro (dacomitinib), for example, was approved in September 2018
on the basis of one clinical trial of 452 patients with advanced non-small cell lung cancer in Asia. Array Biopharma’s Braftovi (encorafenib) was approved, in combination with Mektovi (binimetinib) in June 2018
on evidence from one clinical trial of 383 patients with BRAF V600 mutation-positive melanoma that was advanced or could not be removed by surgery. The trial was conducted at 162 sites in Europe, North America and elsewhere.
And Advanced Accelerator Applications’ Lutathera (lutetium 177 dotate) was approved
based on one trial of 229 patients with a specific type of rare tumor at 41 sites in Belgium, France, Germany, Italy, Portugal, Spain, UK and the US.
But not all the new drugs approved in 2018 based on one clinical trial were cancer treatments. For instance, Achaogen’s Zemdri (plazomicin) was approved in June 2018
as a complicated urinary tract infection treatment based on one trial of 604 patients in Europe, the US and Mexico.
Paratek Pharmaceuticals also won approval
for its antibacterial medicine Nuzyra (omadacycline) in October 2018 on the basis of a single trial of 774 patients with community acquired bacterial pneumonia at 86 sites in Asia, Europe, Israel, Latin America, South Africa and the US.
But Kesselheim said he does not think this is a recent shift to the use of one pivotal trial, and he did not know if the 42% figure from 2018 “is a sign that the number is creeping higher or just normal year to year fluctuation.”
The IQVIA report also reports a slight uptick in the number of pivotal trials in 2018 being randomized controlled trials compared to previous years and that active control arms were more common in 2018 than recent past years.
The Changing Landscape of Research and Development