The FDA will soon issue a final guidance distinguishing between adverse events and unanticipated problems in clinical trials, clarifying when the former have to be reported to an institutional review board (IRB). It is the sponsor’s responsibility to report serious and unexpected adverse events to the FDA. While clinical investigators are not required to report adverse events that do not fall into this category to the IRB, they must record all adverse events on case report forms and submit them to the FDA in annual reports. The regulations on devices stipulate that clinical investigators must report unanticipated adverse device effects within 10 working days to the sponsor and the IRB. In federally funded trials, even a serious adverse event might not have to be reported to HHS’ Office for Human Research Protections if it were anticipated, but it still would have to be reported to the FDA. The FDA’s draft guidance can be viewed at

For more information about our expertise in Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.

Most breast cancers contain estrogen 1) ___, which enable them to grow in the presence of the hormone estrogen. The presence of receptors can determine whether tumors will respond to the estrogen-blocking drug 2) ___. A tiny modification called methylation on estrogen receptors prolongs the life of these growth-driving molecules in breast cancer cells. The finding may help researchers sort out how mutations change the estrogen receptor’s function and allow some breast cancers to resist tamoxifen. The problem is that a significant fraction of estrogen receptor positive 3) ___ don’t respond to tamoxifen. Development of new drugs that interfere with the methylation of the 4) ___ receptor may be an alternative way to treat those tumors. Until recently, scientists thought methylation enzymes acted only on DNA molecules or on histones, 5) ___ that bundle DNA into spool-like packages. Methylation enzymes add tags called methyl groups to other 6) ___, influencing their ability to turn genes on or off. The scientists found that one of the modification enzymes, called SET7, methylates a flexible part of the estrogen receptor. When they created breast cancer cells with reduced levels of SET7, the estrogen receptor molecules lasted only half as long and were less effective in turning on genes. The research team showed that a mutation in the estrogen receptor found in more aggressive breast tumors interferes with methylation in cells. Also, the methylation appears in exactly the same spot where another protein called BRCA1 adds a different kind of regulatory marking, and may block BRCA1’s restrictive effects on the estrogen receptor. Women who inherit a 7) ___ in the gene that encodes BRCA1 have up to an 80% lifetime risk of developing breast cancer, several times the risk of those who don’t have it. BRCA1 mutations are estimated to account for about a third of all inherited breast cancers and roughly 2-3% of all breast cancers. Scientists are beginning to look for drugs that could 8) ___ methylation enzymes. Methylation probably affects several other proteins similar to the estrogen receptor. This may be just the tip of the iceberg. Methylation may be just as common as other protein modifications, and even more complicated. The results are published in the May 9, 2008 issue of the journal Molecular Cell.

ANSWERS: 1) receptors; 2) tamoxifen; 3) tumors; 4) estrogen; 5) proteins; 6) molecules; 7) mutation; 8) modulate

Dr. Jules Mitchel, President of Target Health Inc., will moderate a panel at the annual meeting of the 2008 Life Sciences Industry Summit. The panel is entitled: “Pre-Clinical Regulatory Strategies: Advancing Into Clinical Trials.” The meeting will be held on Thursday, June 5, 2008 from 8am-6pm at the Hilton Long Island,. Let us know if you will be attending. The panelists include:

* Don Cilla, PharmD, President and CEO, DCPS
* Colleen Dragula Johnson, M.S., D.A.B.T, Independent Toxicology Consultant
* Glen Park, PharmD, Senior Director Clinical and Regulatory Affairs, Target Health Inc.
* Mary Shatzoff, MS, Senior Manager of Regulatory Affairs, Target Health Inc.

For more information about Target Health or any of our software tools for clinical research, please contact Dr. Jules T. Mitchel or Ms. Joyce Hays