Last week, Sanofi-Aventis (SNY) announced disappointing results from a phase III trial evaluating iniparib in breast cancer. The drug failed to improve survival and progression-free survival (PFS) in breast cancer patients and although actual data were not published, approval is unlikely even for a subset of patients. Failed phase III trials are quite common in oncology, a field with one of the highest attrition rates in the pharmaceutical industry. Nevertheless, iniparib's failure is particularly disturbing, as the phase III was supported by compelling results from a randomized controlled phase II trial as well as strong scientific rationale. Importantly, this trial could have broader implications as it raises questions regarding the role of randomized phase II trials as a go/no go decision point for pivotal trials.
The weakest link
Randomized phase II trials have become all the rage, hailed as the cure to the frustratingly low success rate in phase III cancer trials. Traditionally, oncology drugs have been evaluated in three phases. Phase I studies were typically dose escalation studies for evaluating safety and initial signs of efficacy in 20-30 patients. Phase II studies were intended for fine tuning the dosing regimen and obtaining a clear efficacy signal. These single arm trials usually included 40-70 patients, all of whom received the drug. If the phase II data looked promising compared to historic controls, then a phase III trial would be initiated. Phase III trials typically accrue 400-800 patients (depending on the indication and statistical assumptions) and included a control arm on top of the active arm. The control arm can be an approved treatment or placebo.
As the number of approved treatments and the efficacy bar for obtaining regulatory approval got higher, it became harder and harder to generate positive results in phase III studies. It also became apparent that single arm phase II trials often overstate the drug's efficacy, as drugs performed poorly in phase III trials compared to the phase II results. This was partially attributed to bias in patient selection as patients with favorable prognosis were often picked. In addition, the control arm in phase III trials often achieved better results than past trials, making it harder to beat. Thus, the industry identified single arm phase II trials as the weakest link, as they simply did not deliver in terms of predicting phase III outcome.
In the early 00's, a new model was gaining momentum: randomized controlled phase II trials. The idea was to make phase II more difficult to cross by adding a control arm and increasing the number of patients to 80-150. Patients were to be randomized to receive either the investigational agent combined with standard of care or standard of care alone. This design was hoped to eliminate the patient selection bias as well as provide a real life reliable control arm. In other words, oncology phase II's turned into mini phase III trials. Of course, the cost doubled or tripled, but the ability of distinguishing promising drugs from those that are doomed to fail seemed to more than compensate.
Although it is too early to reach a verdict regarding randomized phase II trials in oncology, so far they haven't panned out as expected in terms of predicting phase III outcomes.