Contrast introductions could slow as FDA shifts approval guidelines

Drug manufacturers and clinicians are crying foul over a recentFood and Drug Administration policy change that has thrown a monkeywrench into the marketing plans of several contrast agent developers.Reversing years of precedent, FDA officials have decided thatthe agency will use disease-specific criteria when evaluatingnew contrast agent applications.

The change voids a long-standing FDA policy of examining newcontrast agent applications on the basis of physiologic functionrather than clinical utility in targeting a particular disease.Many drug manufacturers and clinicians say the new policy is misguidedand could hamstring contrast agent development.

"It would be very damaging to the clinical practice ofdiagnostic imaging if this were to become the law of the land,"an industry observer said.

The FDA first hinted at its intention to hold contrast agentsto a higher standard at a Medical Imaging Drugs Advisory Committeehearing on May 21 for Alliance Pharmaceutical's Imagent GI, anoral MRI agent that darkens the bowel and enables clearer imagingof abdominal organs.

The San Diego contrast developer's application for Imagent,submitted in 1990, stated that when ingested, the product "willdarken the bowel image to allow its distinction from adjacenttissues."

That indication was not specific enough to comply with existingFDA drug regulations, according to Dr. Wiley Chambers, the FDA'sacting director of the Division of Medical Imaging, Surgical andDental Drug Products. Those regulations require specific indicationsfor the treatment, prevention or diagnosis of disease. Duringthe hearing Chambers proposed that the standard be applied toImagent.

The FDA, however, had for years applied the requirement onlyto therapeutic drugs and had never required manufacturers submittingcontrast agent applications to provide disease-specific information.This policy was communicated to drug manufacturers in frequentconsultations with FDA officials. In discussions with the FDAwhile Imagent was under development, agency officials suggestedthat no disease-specific information would be needed in the product'sapplication, according to an Alliance spokesperson.

Although the FDA advisory committee disagreed with Chambersand voted to recommend approval of Imagent by a unanimous vote,approval of the product's application as written remains uncertainin light of the new FDA interpretation.

An indication that the disease-specific proposal had been adoptedas policy came a month later, when Advanced Magnetics announcedthat the FDA would not accept an application as written for thecompany's gastrointestinal imaging agent Ferumoxsil.

The FDA "advised the company that the primary stated indicationfor Ferumoxsil should be the detection of a specified pathologyas opposed to the marking of the bowel," Advanced Magneticssaid.

As in the case of Alliance, the FDA's new position contradictedadvice agency officials had given Advanced Magnetics while thecompany designed research protocols and drafted language for theapplication.

FDA spokesperson Susan Cruzan confirmed that the FDA has tightenedits approval criteria for contrast agents.

"Drugs are now being evaluated more strictly to adhereto FDA regulation 201.57 that has to do with labeling," Cruzantold SCAN. "It says the indications must be supported bysubstantial evidence. In the past, companies weren't submittingapplications that included evidence for disease-specific conditions."

The policy change has exasperated manufacturers and frustratedclinicians, who believe that contrast agents are fundamentallydifferent from therapeutic drugs and should be treated as such.Requiring contrast agents to be disease-specific misses the point,according to some members of the advisory committee who discussedthe FDA's proposed new rule interpretation during the May 21 hearing.

"I have a hard time with this approach of looking foran agent to diagnose the disease," said committee consultantDr. Dominick Conca of Geisinger Medical Center in Danville, PA."If we do that, we might as well take barium sulfate andthrow it away because that doesn't diagnose any disease, and wecan take away all the iodinated contrast media because they don'tdiagnose disease."

Other clinicians see the FDA's new policy as opening up a Pandora'sbox that could increase cost and limit use of agents. An examplecan be seen in the case of nuclear medicine. The FDA requiresnew radiopharmaceutical applications to provide disease-specificcriteria, a policy nuclear medicine specialists have been attemptingto change (SCAN 9/25/91).

"With radiopharmaceuticals, we have encountered (disease-specificcriteria) for years, and it's a real problem," said Dr. CarolS. Marcus, director of the Nuclear Medicine Outpatient Clinicat Harbor-UCLA Medical Center in Torrance, CA. "On the onehand, the FDA says get it approved for one use and then you canuse it for whatever you want. But then third-party payers saythat if (an indication) is not on the package insert, they'renot going to pay for it."

The FDA has demonstrated a willingness to crack down on contrastagents in other areas besides new drug applications. In June,the FDA notified manufacturers that some companies were attemptingto make claims for contrast agents that could not be supportedby clinical data in the products' labels. The FDA warned thatall promotional materials containing unsupported claims shouldbe removed within 90 days.

Drug manufacturers are scrambling to determine how the agency'snew disease-specific policy will apply to their products. AdvancedMagnetics is reexamining completed clinical trials to see if disease-specificinformation can be gleaned from work already done. If not, newtrials could be required, according to a company spokesperson.

Alliance Pharmaceutical is also unclear on how the new policyapplies to Imagent.

The FDA has not commented on whether disease-specific criteriawill be applied to Sterling Winthrop's Omniscan and Bristol-MyersSquibb's Prohance, two other new contrast agents under reviewby the agency. Those products have been recommended for approvalby advisory committees and are awaiting final FDA action (SCAN6/3/92).

As companies and clinicians await more information on the FDA'sposition, many have expressed frustration with both the new policyand the way in which it was communicated to industry.

"The companies have done what they have been told to do,spent millions of dollars, and then they get up to the front ofthe line, and somebody says, `Oh, I'm sorry, you no longer canget in if you're two-feet-six, you have to be four-feet-eight,'"one clinician said. "I think the FDA is trying to be helpful,but the new criteria they've chosen do not fit the applications."