The completion of a two-year co-operative research and development agreement (CRADA) between the Food and Drug Administration (FDA) and US-based Novartis affiliate Novartis Pharmaceuticals Corporation has yielded a process for defining and qualifying safety biomarkers as well as real-world data to support regulatory decision-making on renal safety.

The project was one of the first to be taken up under the FDA’s Critical Path initiative, launched in March 2004 with the aim of modernising and streamlining medical product development from discovery or ‘proof of concept’ to the marketplace, Novartis notes.

The US agency has made biomarkers central to the Critical Path programme. It sees a role for the next generation of predictive biomarkers in providing surrogate endpoints for efficacy; identifying safety problems at an early stage of clinical development; evaluating dose ranges; tracking disease progression; facilitating the emergence of novel and more effective clinical trial designs; and supplying new diagnostics that can measure responsiveness to targeted therapies.

There were two main objectives to the FDA-Novartis CRADA: defining a process for qualifying preclinical safety biomarkers to be used in regulatory decision-making; and testing this pilot process by submitting kidney-related safety biomarkers, identified and characterised through preclinical studies, to the FDA for qualification.

The first of these steps resulted in the publication, in the journal Pharmacogenomics (2006:7(5); 773-782), of the first pilot framework for a preclinical regulatory biomarker qualification process. This will have “a broad impact on the understanding of the qualification of safety biomarkers far beyond this partnership”, Novartis says.

Moreover, the preclinical data generated so far under the CRADA have “demonstrated evidence for the superiority of new renal biomarkers over the current standards used to assess renal injury in drug testing, namely serum creatinine and blood urea nitrogen (BUN)”, the company adds. Further efforts in this area will focus on extended clinical qualification of the renal biomarkers, with the aim of enabling clinicians to detect kidney injury in patients earlier than current practice allows.

Predictive safety consortium
The relevant safety biomarker data produced by Novartis under the CRADA have been shared with the Critical Path Institute’s Predictive Safety Testing Consortium (PSTC). This is a broader public/private partnership between industry, academia and regulators, intended as a neutral body for co-ordinating activities related to biomarker qualification in drug development.

The PSTC was set up by the non-profit Critical Path Institute two years ago, with the FDA serving in an advisory capacity, A consortium of eight leading pharmaceutical companies, including Novartis, took the unprecedented step of agreeing to share preclinical laboratory data in order to improve the testing of medicines before they reached human clinical trials.

The CRADA data, together with data generated by other partners in the PSTC, have been filed with the FDA and the European Medicines Agency (EMEA) as part of a Voluntary Exploratory Data Submission (VXDS). The agencies are now considering whether to approve the use of these biomarker data to support particular aspects of regulatory decision making, Novartis says.

The joint evaluation of additional data under the auspices of the PSTC is expected to lead to further submissions of peripheral biomarkers representing other renal pathologies, the company notes. For its part, Novartis will continue to leverage the data generated through its co-operative efforts with the FDA. The company plans to submit additional data on genomic- and proteomic-based renal safety biomarkers to the US agency and the EMEA this summer.

Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, described the biomarker CRADA with Novartis as “a significant step in bridging the gap between basic scientific research and the medical product development process”.