Promises to Keep

In the early 1990s, the Food and Drug Administration responded to the AIDS crisis by allowing accelerated approval of new drugs for serious or life-threatening illnesses. Under accelerated approval, experimental drugs are rushed to market based on trials involving a relatively small number of patients. In many cases, the proof they work rests on a diagnostic test that provides only the most tentative evidence that the patient will in fact get better with the drug.

There’s a quid pro quo for these rapid approvals, of course. The drug company promises to conduct a post-approval trial to determine whether the claims made for what is known as a surrogate marker in fact panned out.

Late last week, the FDA reported that the drug industry hasn't even started two-thirds of the more than 1,200 promised post-approval trials. Deputy Commissioner Scott Gottlieb said the agency would take a year to study the problem, prompting Vanderbilt medical school asssociate dean Alastair Wood to tell the New York Times: "Who would turn in their homework if they didn't have to?"

Drug companies pursuing new oncology drugs have been enthusiastic supporters of the accelerated approval, often using surrogate markers like tumor shrinkage to show efficacy for new drugs. But they're no better than the rest in carrying out the promised post-approval trials.

There have been 25 cancer drugs for 29 indications given accelerated approval status since 1995. Yet only a third have so far submitted data confirming their efficacy. Moreover, at least six of the drugs entered the market before 2002 – giving the companies plenty of time to conduct the trials.

What happened? At an FDA Oncology Drugs Advisory Committee (ODAC) held last fall, the companies behind the six drugs discussed their reasons for not meeting the requirements. Johnson & Johnson, whose Doxil received accelerated approval for AIDS-related Kaposi’s Sarcoma, said the success of highly active anti-retroviral therapy (HAART) meant there are no longer enough patients around to conduct a valid trial. Curiously, the company then produced a physician who begged the FDA not to repeal its approval since she still saw plenty of patients with the syndrome who needed the drug.

Good data for Genzyme’s Campath, a monoclonal antibody for treating chronic lymphocytic leukemia, was hard to come by because of FDA incompetence, the company suggested. When the company designed its post-approval trial in 2000, the FDA insisted on comparing it to chlorambucil, then the only approved treatment. But within a few years, almost no one in the U.S. was using chlorambucil and the FDA wasn’t flexible enough to change the protocol. The company had to go to Eastern Europe to conduct the trial. Results are expected later this year.

And so it went for all six companies. Each had their excuses. The FDA’s expert advisers fumbled for a solution. Dr. Bruce Cheson of Georgetown University Hospital decried the “crappy study design” and the fact that “the bar is set way too low” for accelerated approval of many drugs.

The FDA clearly needs to drive a harder bargain with companies seeking accelerated approval. First, it should change the name to Conditional Approval, which was suggested by one member of the ODAC. The accelerated approval tag creates an unfortunate image for patients and physicians that the drug is someone better than what’s out there, when it fact it may be worse.

Second, the agency should forbid the off-label use of any drug given Conditional Approval unless the patients are enrolled in an active clinical trial.

Finally, the FDA should create a publicly accessible registry where physicians must record the results of every clinical use of a conditionally approved drug. Given the cost of new cancer drugs, a small surcharge to reimburse oncologists for providing this data will appear as a pittance on insurers’ bills. Yet it will provide epidemiological data that, while it won’t have the rigor of a controlled clinical trial, should provide clinicians with crucial information about the actual value of the conditionally approved drugs.

Posted by gooznews at March 6, 2006 08:41 PM