Assessing positive outcomes of phase III trials

December 03, 2010

Randomized phase III studies should be designed to find out whether a new drug or treatment makes a meaningful difference in patients' survival or quality of life, according to a commentary published online December 3rd in The Journal of the National Cancer Institute. Instead, most trials now are designed to detect a statistically significant difference between treatment and control groups, which may not be clinically meaningful, write Alberto Ocana, M.D., Ph.D. and Ian F. Tannock, M.D., Ph.D., of Princess Margaret Hospital in Toronto.

Regulatory agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) approve drugs usually based on statistically significant results of randomized phase III trials comparing a new, investigational drug with standard treatment. Ocana and Tannock note that pharmaceutical companies have typically sponsored clinical trials that are large enough to detect statistically significant differences in survival. But these differences are often trivial, they say. For instance, the trial that led to approval of erlotinib (Tarceva) for pancreatic cancer found that patients who took the drug had a median survival just 10 days longer than patients in the control group. However, the difference was statistically significant, and the drug was approved.

The authors write that pharmaceutical companies look for a difference in survival outcome between two groups of a trial that is "not usually the minimal difference in overall survival or progression-free survival that is clinically important, but more likely the minimal difference that is feasible to detect, considering the limits on the sample size and hence the cost of the trial."

The authors argue for another approach: "Ideally, trials should be designed [to detect] the minimum clinically important difference, taking into account the tolerability and toxicity of the new treatment, that would persuade oncologists to adopt the news treatment in place of the standard treatment" and investigators should try to reach at least a clinically important difference that was specified in the protocol.

They also suggest that the FDA and EMEA "should define what constitute a positive trial based on the concept of establishing a meaningful clinical benefit for patients similar to those included in any given trial."

In an accompanying editorial, J. Jack Lee, Ph.D., of the M.D. Anderson Cancer Center, writes that this "excellent commentary" calls for a new drug approval paradigm and challenges both the medical and statistical communities to find a better way to assessing whether a drug really works.

Lee goes on to argue for the adoption of the Bayesian approach in contrast to the more conventional frequentist approach. "Statistics in medicine has passed through its infancy and childhood. As it moves into its adolescence, the growing pains of reconciling frequentist and Bayesian views continue," he writes. In his view, though, the "roadblocks" of the Bayesian approach, namely the notion of subjectivity and computation difficulty, have been overcome.

"The Bayesian approach is complementary to and can provide a superior alternative to the frequentist paradigm," Lee writes. "I encourage medical researchers to have an open mind, learn more about Bayesian methods, and apply them to provide a more accurate statistical assessment of the results in clinical trials."
-end-
Contact:

Article: Jane Finlayson, Senior Public Affairs Advisor, Princess Margaret Hospital, 416-946-2846, jane.finlayson@uhn.on.ca

Editorial: Jack Lee, 713-794-4158 jjlee@mdanderson.org

Journal of the National Cancer Institute

Related Clinical Trials Articles from Brightsurf:

Nearly 1 in 5 cancer patients less likely to enroll in clinical trials during pandemic
A significant portion of cancer patients may be less likely to enroll in a clinical trial due to the ongoing coronavirus pandemic.

COVID-19 clinical trials lack diversity
Despite disproportionately higher rates of COVID-19 infection, hospitalization and death among people of color, minority groups are significantly underrepresented in COVID-19 clinical trials.

Why we should trust registered clinical trials
In a time when we have to rely on clinical trials for COVID-19 drugs and vaccines, a new study brings good news about the credibility of registered clinical trials.

Inclusion of children in clinical trials of treatments for COVID-19
This Viewpoint discusses the exclusion of children from coronavirus disease 2019 (COVID-19) clinical trials and why that could harm treatment options for children.

Review evaluates how AI could boost the success of clinical trials
In a review publishing July 17, 2019 in the journal Trends in Pharmacological Sciences, researchers examined how artificial intelligence (AI) could affect drug development in the coming decade.

Kidney patients are neglected in clinical trials
The exclusion of patients with kidney diseases from clinical trials remains an unsolved problem that hinders optimal care of these patients.

Clinical trials beginning for possible preeclampsia treatment
For over 20 years, a team of researchers at Lund University has worked on developing a drug against preeclampsia -- a serious disorder which annually affects around 9 million pregnant women worldwide and is one of the main causes of death in both mothers and unborn babies.

Underenrollment in clinical trials: Patients not the problem
The authors of the study published this month in the Journal of Clinical Oncology investigated why many cancer clinical trials fail to enroll enough patients.

When designing clinical trials for huntington's disease, first ask the experts
Progress in understanding the genetic mutation responsible for Huntington's disease (HD) and at least some molecular underpinnings of the disease has resulted in a new era of clinical testing of potential treatments.

New ALS therapy in clinical trials
New research led by Washington University School of Medicine in St.

Read More: Clinical Trials News and Clinical Trials Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.