abstract: Assumptions of Expected Benefits in Randomized Phase III Trials Evaluating Systemic Treatments for Cancer

Assumptions of Expected Benefits in Randomized Phase III Trials Evaluating Systemic Treatments for Cancer

Background In designing phase III randomized clinical trials (RCTs), the expected magnitude of the benefit of the experimental therapy (δ) determines the number of patients required and the number of person-years of follow-up. We conducted a systematic review to evaluate how reliably δ approximates the observed benefit (B) in RCTs that evaluated cancer treatment. 

Conclusions Investigators consistently make overly optimistic assumptions regarding treatment benefits when designing RCTs. Attempts to reduce the number of negative RCTs should focus on more realistic estimations of δ. Increased use of interim analyses, certain adaptive trial designs, and better biological characterization of patients are potential ways of mitigating this problem.

abstract: Assumptions of Expected Benefits in Randomized Phase III Trials Evaluating Systemic Treatments for Cancer

Blogger's Note: also reference related commentary: " Why Do Phase III Clinical Trials in Oncology Fail so Often?


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Assumptions of Expected Benefits in Randomized Phase III Trials Evaluating Systemic Treatments for Cancer

open access: Why Do Phase III Clinical Trials in Oncology Fail so Often?

Why Do Phase III Clinical Trials in Oncology Fail so Often?

 "Achieving success in the development of a cancer drug continues to be challenging. Given the increasing costs (1) and the small number of drugs that gain regulatory approval (2), it is crucial to understand these failures. In this issue of the Journal, Gan et al. (3) reviewed 235 recently published phase III randomized clinical trials (RCTs). They report that 62% of the trials did not achieve results with statistical significance. Trying to explain the high failure rate, they note the actual magnitude of benefit achieved in a clinical trial (designated B) is nearly always less than what was predicted at the time the trial was designed (designated δ) and conclude, “investigators consistently make overly-optimistic assumptions regarding treatment benefits when designing RCTs.”

But really should we be surprised that phase III trials, the venue for detecting “small” differences, so often disappoint? Almost by definition, phase III studies are designed to detect small differences (4,5). The problem is that small has given way to “marginal” as outcomes have fallen below our already modest expectations. And who or what is to blame? Are investigators really overly optimistic regarding experimental therapies and, as the authors suggest, responsible for the large number of negative studies? Although we agree that optimism regarding clinical benefit may lead to an underpowered trial, we disagree that optimistic investigators are those we should blame. We would ask, how do Gan et al. (3) define optimism? Where do they place the line between an optimistic and a realistic expectation?.........

phase 11/111 - Comparing Three Combination Chemotherapy Regimens in Treating Patients With Stage IIB, Stage IIC, Stage III, or Stage IV Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer - Full Text View - ClinicalTrials.gov

Comparing Three Combination Chemotherapy Regimens in Treating Patients With Stage IIB, Stage IIC, Stage III, or Stage IV Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer - Full Text View - ClinicalTrials.gov

Comparing Three Combination Chemotherapy Regimens in Treating Patients With Stage IIB, Stage IIC, Stage III, or Stage IV Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer

This study is currently recruiting participants.

Verified March 2012 by NCIC Clinical Trials Group

First Received on October 9, 2009.   Last Updated on March 9, 2012   History of Changes

Sponsor:	NCIC Clinical Trials Group
Collaborators:	National Cancer Institute (NCI) Grupo Español de Investigación en Cáncer de Ovario Cancer Research UK Southwestern Oncology Group (SWOG)
Information provided by (Responsible Party):	NCIC Clinical Trials Group
ClinicalTrials.gov Identifier:	NCT00993655

  Purpose

RATIONALE: Drugs used in chemotherapy, such as paclitaxel, carboplatin, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) and giving them in different ways may kill more tumor cells. It is not yet known which combination chemotherapy regimen is more effective in treating patients with ovarian epithelial cancer, primary peritoneal cancer, and fallopian tube cancer.

PURPOSE: This randomized phase II/III trial is comparing the side effects of three combination chemotherapy regimens and to see how well they work in treating patients with stage IIB, stage IIC, stage III, or stage IV ovarian epithelial cancer, primary peritoneal cancer, or fallopian tube cancer.

Condition	Intervention	Phase
Fallopian Tube Cancer Metastatic Cancer Ovarian Cancer Peritoneal Cavity Cancer	Drug: carboplatin Drug: cisplatin Drug: paclitaxel Procedure: quality-of-life assessment	Phase II Phase III

Prima BioMed Receives Regulatory Scientific Advice on CVac Phase III Trial -- SYDNEY, Feb. 18, 2011 /PRNewswire/ --

"......The trial will be conducted on 750 patients in a double blind placebo controlled study randomized 1:1 of CVac vs. Standard of Care (currently there is no approved maintenance therapy for ovarian cancer), across multiple sites in Europe, the US and Australia....."

full free access: Assessing Positive Outcomes of Phase III Trials — J. Natl. Cancer Inst.

prior abstract - new commentary: EvidenceUpdates - Phase III trial of carboplatin plus paclitaxel with or without gemcitabine in first-line treatment

Commentary:
Oncology - Gynecology - "This negative study extends the evidence base indicating that triplet chemotherapy increases toxicity without significant survival benefit in ovarian cancer patients. Further increases in survival for this group will need to come from alternate strategies."

alternate link to abstract:
Phase III trial of carboplatin plus paclitaxel with or without gemcitabine in first-line treatment of epithelial ovarian cancer

media item: Gynecologic Oncologists Advance Promising Intraperitoneal Approach - Carboplatin IP/phase 111 studies

"The present studies provide additional useful data on carboplatin and the feasibility of intraperitoneal infusion. Specifically, data relating to maximum tolerated dose and dose-limiting toxicity derived from these studies will be implemented in advanced phase-III research trials."

Analysis of Marshall Edwards, Inc.'s OVATURE Trial to Proceed Following Database Lock

"The OVATURE trial is a major multi-center international Phase III clinical trial of orally-administered investigational drug phenoxodiol in combination with carboplatin in women with advanced ovarian cancer resistant or refractory to platinum-based drugs, to determine its safety and effectiveness when used in combination with carboplatin.......The Company expects the final analysis will be performed strictly according to the protocol and now is expected to be completed in the second quarter of 2010"