FDA's cardiotoxicity biomarker working group is preparing a position paper recommending the use of cardiac troponins as a biomarker of cardiac injury.

The paper will state that "a treatment-associated increase in circulating troponin should be considered an indication of treatment-related myocardial cell injury," the group said Nov. 13. It hopes to submit the troponin paper for publication in the first half of 2002.

In addition, group members are working on designing a "definitive experiment" to determine whether there is a correlation between the magnitude of circulating troponin and the extent of cardiac histopathology, group Chair Kendall Wallace, PhD, University of Minnesota, told a meeting of the Nonclinical Studies Subcommittee of FDA's Advisory Committee for Pharmaceutical Science.

The expert group on biomarkers of cardiac damage is one of the working groups established under the direction of the subcommittee; a second group is focusing on biomarkers for vascular injury. The groups, which held their first meeting in May, include representatives from industry, government and academia (¹ Also see "FDA Toxicity Biomarker Working Groups Voice Data Sharing Concerns" - Pink Sheet, 21 May, 2001., p. 31).

The subcommittee met to review the working groups' progress and discuss the subcommittee's future direction, including oversight and reporting.

Unlike biomarkers for cardiotoxicity, biomarkers for vascular injury/vasculitis are not yet known, working group members noted. "What the real difficulty is the findings...in animals," FDA Supervisory Pharmacologist Thomas Papoian, PhD, said. "How do we find if there are such effects in humans?"

The collection of vascular injury information is one area where intercompany collaboration, along with large-scale postmarketing monitoring, would be especially useful, FDA suggested.

If a research facility has tools to look at a biomarker in a certain population, "they can do that, instead of five different labs trying to develop the pathology," FDA Office of Pharmaceutical Science Division of Applied Pharmacology Research Director Frank Sistare, PhD, said. "Can we get other sponsors who are wrestling with this issue to the table?" he asked.

"Maybe we can somehow open it up and get them involved," Sistare suggested, and "if they're not willing to share their compounds, maybe they could dose animals and then they could share samples."

An issue revisited by the subcommittee was the need to use proprietary data and experimental compounds to aid in biomarker development. "[We] very likely would be coming back to NCSS...for them to help us gain that access to proprietary data," Wallace said.

For example, he noted, data on the correlation of troponin levels to drug-induced clinical cardiotoxicity "might be the type of data where we could actually mine it from some of the sponsor companies. They may have that data from their clinical trials...that isn't necessarily available in the public literature."

Acting Office of Pharmaceutical Science Director Helen Winkle said the agency plans to form a policy regarding proprietary data and ownership of working group publications.

"I think as far as proprietary data, publications, etc., we need to put some information together and be able to address these issues, and [we] are not ready to address them right now....Some of them are just coming up for the first time, so I think they're definitely very good issues," Winkle said.

Pharmaceutical companies participating in the vasculitis working group "may fund selected collaborative projects between FDA, academia and industry," Papoian noted. Companies represented in the group include GlaxoSmithKline, Pfizer, Boehringer-Ingelheim and Schering-Plough.

Other potential sources of funding for both working groups include The International Life Sciences Institute and the National Institute for Environmental Health Sciences.

The vascular injury group's work will supplement a planned FDA guidance on drug-induced vasculitis. The guidance, which will address the evaluation and interpretation of preclinical vasculitis findings in terms of their potential relevance to humans, has been in the works for several years, and will likely take at least another year to complete, the agency said.

Winkle said that FDA has not yet decided whether to move the nonclinical studies subcommittee (and its working groups) to oversight by the National Center for Toxicological Research science board. Winkle advocated the change, pointing to funding as one advantage.

"NCTR really has the scientific expertise to help support these projects and help direct these projects," Winkle said. "I feel that NCTR, because of its focus on toxicology, is in a better situation to do that than CDER."

Winkle said the primary concern in transferring the subcommittee is retaining the connection with regulators. "Unless the results of those projects...are used in the review process, the committee, or the decisions that are made by the committee, are really not going to be viable," she said.

One way to ensure the connection to CDER, she suggested, is continuing to have pharmaceutical science committee members concurrently serve as members of the subcommittee, and retaining center liaisons in the working groups. Another possibility is to hold joint meetings of the NCTR and pharmaceutical science committees.

FDA's Sistare expressed concern that the link to drug development could not be adequately maintained. CDER "is very closely intertwined with the drug development process, NCTR is not," he noted. "These questions are problems because they are [important to ensure] progress to the developmental pipeline" by communicating safety issues to sponsors.

Office of Review Management Pharmacology & Toxicology Associate Director Joe DeGeorge, PhD, maintained that moving the subcommittee to NCTR should not impact CDER's involvement in its activities.

"I think our center would continue to...identify the issues that are of concern...and [FDA's pharmacology/ toxicology coordinating committee] will make recommendations that we think need to be pursued in terms of developing approaches to address those problems," he said. DeGeorge is chair of the coordinating committee.

FDA Cardiotoxicity Group Paper To Suggest Use Of Troponins As Biomarkers

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