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| Brookings January Conference Update |
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Richard Schilsky, MD, University of
Janet Woodcock, MD, Food and Drug Administration
Gwen Fyfe, MD, Genentech
Robert Irwin, Marti Nelson Cancer Foundation
Recommendations:
Effort should be made to ensure that data are useful and collected consistently and accurately. Building on the proposals in the Panel 1 issue brief, researchers should use data from completed trials to develop a decision tree that would help sponsors design optimal data collection protocols.
Current Status:
A follow-up meeting was held in November between FDA and the NCI Cooperative Group Leaders. At the meeting it was stressed by all participants that any consideration of optimizing the scope of data collection was only being discussed in the case of supplemental applications. Several examples of past trials that led to expanded indications were reviewed in order explore the question “when in the course of data collection is a full data set unnecessary because sufficient data and safety profile exists?” Participants noted that this would depend on extent of data, known pharmacology of the agent, similarities with other supplemental indications, and take the setting into consideration (i.e. more data may need to be collected for expansion into the adjuvant setting).
In order to help develop an outline of optimal data standards for different situations, additional clinical trial data for supplemental applications will be analyzed. This will be done in a similar manner to the data presented by Genentech at the September meeting. To date, it has been agreed upon that data sets will be provided and analyzed by Eli Lilly, GlaxoSmithKline, Novartis, and CALGB.
ASCO is planning a meeting this spring to review the status of all the study re-analyses and determine if enough data has been collected for a public meeting later this summer.
Raymond DuBois, MD,
Donald Berry, PhD,
Jim Doroshow, MD, FACP, National Cancer Institute
Paolo Paoletti, MD, Glaxo SmithKline
Richard Pazdur, MD, Food and Drug Administration
Nancy Roach, C3: Colorectal Cancer Coalition
Recommendations:
Researchers should perform simulations on data from a series of completed PFS trials involving blinded independent centralized review (BICR), to quantify the potential for bias. This analysis should yield evidence-based recommendations for when BICR will meaningfully reduce bias, and on what percentage of cases should be reviewed. The approach to improving auditing procedures for PFS suggests a method for increasing the quality of data produced in clinical trials utilizing other auxiliary endpoints: researchers should strive to make auxiliary endpoints standardized and quantifiable. Studies, analogous to those needed for PFS, should be carried out to validate other auxiliary endpoints.
Current Status:
A PhRMA PFS working group has been established and has the goal of understanding and promoting the use of PFS as a primary endpoint in cancer clinical trails. One focus of the group is to develop an auditing procedure for PFS to rule out the presence of systematic bias in the estimation of the treatment effect in the investigator’s assessment of progression thereby eliminating the need for the full review of the radiological scans by an independent review facility thereby greatly reducing the cost of conducting clinical trials.
The next step of the working group is to utilize existing datasets to evaluate various measures of discordance based on random samples of different sizes. This is being done in conjunction with the NCI. Results of this retrospective analysis will then be confirmed through trial simulation and use in on-going clinical studies. Through this process, criteria will be developed to determine a sufficient percentage of radiologic scans that will be required to undergo blinded independent centralized review to confirm study results.
Daniel Hayes, MD,
Steven Gutman, MD, MBA, Food and Drug Administration
Richard Frank, MD, PhD, GE Healthcare
Nancy Roach, C3: Colorectal Cancer Coalition
Richard Simon, DSc, National Cancer Institute
Ray Woosley, MD, PhD, Critical Path Institute
Recommendations:
The FDA, relevant FDA advisory panels, and professional societies should begin to discuss ways to clarify the development pathway for cancer diagnostics in general and those co-developed with targeted therapies in particular. This discussion should address methods for generating reliable evidence to show that diagnostics influence treatment decisions and impact health outcomes. Such evidence can influence how diagnostic tests are reimbursed.
An ODAC-like committee should be established to begin work on improving consistency and intra-FDA coordination in tumor marker clearance and approval. An initial item of business for this committee and FDA staff should be to define a conditional form of approval for diagnostic tests that seem to have demonstrated clinical utility.
Current Status:
On December 16, 2008 FDA held an ODAC meeting to discuss the biologic license application (BLA) for Erbitux (cetuximab) and Vectibix (panitumumab) in the context of K-ras as a predictive and/or prognostic biomarker in oncology drug development.
The ODAC meeting was not held to decide whether the labels of the two products should be updated, but rather to discuss the kinds of evidence the FDA should require from sponsors in order to redefine the patient population for a drug based on a genetic test developed after the product came to market.
Committee members generally agreed that when considering retrospective data on genetically targeted treatments, the FDA should validate the assay used to define the subpopulation; ensure that tumor samples used in the study represent the disease state of the patients in the trial; and require sponsors to replicate retrospective findings in a prospective trial.
FDA agreed to accept the data under the following conditions: the trials must be adequate and well-controlled; the sample size must be sufficiently large to ensure randomization; tumor tissue must be obtained in more than 95 percent of registered study participants and an evaluable result must be available for greater than 90 percent of study subjects; the assay must be reviewed and validated by the FDA; genetic analyses must be performed according to a qualified assay methods by blinded investigators; and that sponsors and the FDA must create an analytical plan to test hypotheses for updating labels and making promotional claims.
This discussion could help better define what would be required for diagnostic/therapeutic co-development. FDA is planning a formal guidance document to follow-up its 2005 whitepaper on the topic. It was announced in November 2008 that FDA will convene a multi-center and multi-disciplinary working group to advance the guidance document. Though no formal timeline has been set, it is hoped to be released mid to late 2009.
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