FDA action on monoclonals will ignite industry

January 29, 1992

Cytogen received an advisory committee recommendation this monthfor Food and Drug Administration approval of its indium-111-labeledmonoclonal antibody agent for colorectal and ovarian cancer imaging. Following shortly after a November panel

Cytogen received an advisory committee recommendation this monthfor Food and Drug Administration approval of its indium-111-labeledmonoclonal antibody agent for colorectal and ovarian cancer imaging.

Following shortly after a November panel recommendation forapproval of Centocor's monoclonal cardiac imaging agent (SCAN12/25/91), the Cytogen recommendation sets the stage for commercializationof these targeted nuclear medicine agents.

"The committee action was very positive for the industryas a whole," said Paul G. Abrams, president and CEO of NeoRx,a monoclonal imaging agent developer with applications beforethe FDA for both small-cell lung cancer and melanoma imaging.

Although Centocor's Myoscint and Cytogen's OncoScint have receivednational approvals in Europe, this long-awaited action by theFDA will supply a stronger boost to the monoclonal imaging fieldworldwide. Many U.S. developers have not applied for Europeanapprovals, while Japanese authorities seem to be awaiting thelead of the FDA, said Lonnie Bookbinder, director of in vivo productsfor Immunomedics, another monoclonal firm with an applicationpending in the U.S.

"The Japanese have been waiting for the FDA to make astrong recommendation for a monoclonal antibody that is made inmice. They have been a little concerned that the FDA may neverapprove these things," Bookbinder said.

Agents that use mouse monoclonals cause patients to producehuman anti-mouse antibodies (HAMA). There is evidence that HAMAcan reduce the effectiveness of subsequent doses. This was oneof the main concerns raised at the Cytogen panel meeting, saidDr. Carol S. Marcus, director of the nuclear medicine outpatientclinic of Harbor UCLA Medical Center.

Marcus was a guest panelist for the FDA's biological responsemodifiers advisory committee during its discussion of OncoScint.

"The problem is that if you maintain (HAMA), a secondscan could possibly be of no value or decreased value. The circulatingantibodies will react with the radiopharmaceutical and the complexwill go to the liver," she said. "If you have enoughcirculating HAMA, you end up with a liver scan and not a usefulantibody scan."

Researchers are also concerned that HAMA produced by a monoclonalimaging agent may rule out patients as candidates for monoclonalantibody therapy agents, Marcus said.

"There probably will be ways to handle many of these problems.It is just that we have never faced them before, so people areconcerned," she said.

Ways to circumvent problems such as HAMA will not be developeduntil there is a sufficiently large number of patients in whomthe monoclonal imaging agents have been used, Marcus said. Thatis one reason she recommended nonrestrictive labeling of OncoScint.

"I have encouraged the FDA to have a very broad indication.They should put down all of their caveats to warn physicians butnot artificially restrict them. If you do (restrict indications),HCFA (Medicare's Health Care Financing Administration) will notreimburse, and no one is going to use it," Marcus said.

The FDA's Center for Biologics Evaluation and Research hasgiven careful consideration to the monoclonal imaging agents becausethey are fundamentally a new category of drug. CBER now appearsanxious, however, to begin approval of these products, she said.

A positive signal of the FDA's higher level of comfort andits desire to move on monoclonals came in December, when the agencygave its advisory committee criteria for approval of monoclonalimaging agents. Those criteria were similar to the basis for approvalof other imaging agents, Abrams said.

Responsibility for approval of monoclonal antibody imagingand therapy agents was transferred several years ago to CBER fromthe Center for Drug Evaluation and Research. This was the biologicsunit's first experience with imaging agents, so the pace was slowinitially. CBER has, however, taken a cooperative stance concerningthe new technology, Marcus said.

"I have never seen a group at FDA work so hard with amanufacturer, with such enthusiasm, intelligence and a sense ofnational caring to get this out." she said.

Bureaucratic obstacles for the monoclonal agents remain, however.The Nuclear Regulatory Commission wrote regulations in 1987 stipulatingthat only products possessing investigational new drug (IND) ornew drug application (NDA) certificates could be used by NRC-licensedphysicians. The NRC did not change its rules to reflect the newterminology when authority for monoclonals was shifted from CDERto CBER, which issues product license applications (PLAs), Marcusnoted.

Marcus authored a petition to the NRC by the Society of NuclearMedicine and the American College of Nuclear Physicians in 1989that included a reminder of the need to change this rule.

NRC has not responded to the request, but may be pushed intoaction when the first monoclonals receive FDA approval. Abouthalf of all licensed nuclear physicians should be free to usethe agents anyway, because state boards of pharmacies will allowfor the use of FDA-approved drugs, she said.

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