More broadly, the FDA, concerned that the number of innovative new drugs is declining, is moving beyond its traditional role of scrutinizing drug applications to trying to speed and smooth the development of medicines. The FDA is looking particularly at diseases where there are few treatment options and drug development is challenging.

As with lupus, the agency now wants to provide drug companies with markers and other techniques that can show more clearly when their new drugs are working. "If the lack of tools to evaluate a drug is a roadblock, we see it as part of our mission to address that," says Janet Woodcock, an acting deputy FDA commissioner and a rheumatologist, who worked closely on the lupus effort.

Key to Approval

In more common diseases, a clear consensus about proxy markers has been a key to approval of big-selling drugs. Statin drugs, for example, such as Bristol-Myers Squibb Co.'s Pravachol, reduce LDL, or "bad" cholesterol, indicating that they reduce the risk of heart disease. Hypertension drugs such as Pfizer Inc.'s Norvasc are approved because they lower blood pressure, which ultimately reduces the risk of stroke and some cardiovascular problems. AIDS drugs such as DDC, approved originally for Hoffmann-La Roche Inc., got the FDA nod because patients who took them saw an increase in CD4 cells, the immune sentries depleted by the virus. That improvement, in turn, was expected to reflect more practical benefits such as longer survival.

Lupus and some other diseases still lack this consensus. With ovarian cancer, for instance, it is difficult to detect tumors and measure if they are shrinking in response to a drug. But there is some evidence that ovarian-cancer patients' blood has a unique combination of proteins. Researchers are trying to figure out whether a drug's impact on those proteins could be used as a marker indicating a drug's effects on a tumor. That would help drug companies, which want more ways to prove the efficacy of new cancer treatments to avoid depending on long, costly studies showing the drugs prolong patients' lives.

The FDA generally avoids boxing itself in with detailed lists of what it's looking for. The agency tends to hold off issuing guidelines until it gets a consensus of experts, a challenge with diseases such as lupus, where specialists often disagree. The agency considers each drug individually and shies away from offering guarantees about what will lead to approval.

Matter of Economics

The FDA also can't change the fundamental economics of the industry. Big drug makers aim to develop blockbuster treatments for common conditions such as impotence. They aren't as eager to invest in relatively rare diseases, particularly when they're not sure how to get approval. Lupus was a loser on both counts.

Every major potential lupus drug over the last decade had run into problems in clinical trials. Much of the difficulty stemmed from how hard it was to design studies that would show that the drugs were working, largely because symptoms vary widely among patients.

Lupus, the result of the immune system attacking the victim's own healthy tissue, is difficult to diagnose and treat. Symptoms range from rashes to arthritis and kidney disorders. Ultimately it can be crippling and even fatal. Estimates of lupus cases in the U.S. range from about 250,000 to more than a million, including less serious forms of the disease. Young women are among the most common victims.

Karl Note:  Medical "main stream science" is NOT looking for free radical causation, so cannot find the cause for Lupus, nor the cure, since the cure will NOT be some drug which can be patented.

Sometimes, patients don't know if their symptoms are from disease or treatment because of the drugs' serious side effects. Japel Filiaci, a New York attorney, spoke at the conference in 2002 of blisters that left her clothes bloody and pain that made her scream. She was diagnosed at age 26. As the disease worsened, she suffered joint and muscle pain. Because blisters on her feet were so bad, she sometimes wore bathroom slippers to court. Her hair fell out -- perhaps because of the drugs. Steroids helped, but her doctor limited her intake because of such risks as weight gain and bone thinning.

Dr. Simon, a rheumatologist, had treated one woman who was diagnosed with lupus at the age of 17. By 25, her organs were failing. He stood by her bedside as a surgeon amputated a leg after gangrene set in. She died about six weeks later. He stayed in touch with her parents for years afterward.

Before he arrived at the FDA in November 2001, Dr. Simon, then a 50-year-old Harvard professor and administrator with a sometimes forceful style, had done some consulting for drug companies. When industry officials heard he was going to the agency, they began coming to him with complaints about the lack of FDA guidance on lupus. "Clarity in the regulatory pathway" has been a "missing link," says David Stump, executive vice president at Human Genome Sciences Inc. "You get the clarity by seeing how the FDA handles the review and approval of other products, and there haven't been any."

Genelabs Technologies Inc.'s efforts to get a lupus drug approved, for example, were hurt after the company sought to adjust some aspects of the ground rules for its clinical trials after they began. The FDA rejected its drug in 2001. Biogen Inc. stopped trials on a promising treatment after some patients developed blood clots. La Jolla Pharmaceutical Co. lost a partnership with Abbott Laboratories after an initial trial failed to show their drug was achieving its target.

Because symptoms vary among patients and tend to flare up intermittently, it's difficult to show that a drug is working for a large number of patients. Lupus patients typically mix different medicines, making it even harder to pinpoint the effects of any single new drug.

Drug makers complain that one widely used drug adds further hurdles to getting new treatments approved. That's a result of an FDA policy that lupus researchers criticize. The FDA hasn't approved the drug, cyclophosphamide, for treating lupus and doesn't recognize it as meeting agency standards for effectiveness, even though doctors prescribe it. So, any new drug must work better than cyclophosphamide, a chemotherapy drug. By contrast, if the FDA has already approved a drug for a disease, a new drug simply has to match its effectiveness.

Dr. Simon researched the details of a 1992 regulation that allows the FDA to more quickly approve a drug by using factors it deems "reasonably likely" to predict clinical benefit. The markers that can be proxies for bigger effects on patients can be one factor. As a condition of approval, the drug's sponsor must agree to do a follow-up study. It would be a bold effort to push the approach for lupus because scientists didn't agree on any clear proxy markers as they did with heart disease and AIDS.

When Dr. Simon tried to organize a conference about biological markers, he had to first win over lupus advocates. The four lupus support organizations rarely worked together. The groups tended to support their own research and educational agendas, with separate and sometimes competing fund-raising operations. They didn't even promote a common lapel pin. One group pushed an orange oval-shaped pin with the slogan "Get into the loop." It didn't catch on.

Eventually, Dr. Simon persuaded the four lupus groups and a number of prominent lupus experts to support the conference. They mailed out a joint fund-raising appeal with all the groups' logos. Dr. Simon insisted the meeting be near Washington to make it easier for FDA officials to attend.

Afterward, National Institutes of Health officials, working with advocacy groups and researchers, helped launch a continuing series of meetings on biological markers for lupus. Companies and academics are continuing to target several possible markers. One that could be a shortcut is the behavior of a certain type of immune cell called B-cells, which can act differently in lupus patients. If a drug could make such cells work more like healthy people's B-cells, that could signal that the lupus patient's out-of-whack immune system is improving.

Dr. Simon and other FDA staffers began writing what they called a lupus "concept paper," an early draft of guidelines for drug companies with lupus drugs to test. It endorsed the notion of proxy markers for lupus but not any specific one.

Broad Measures

The document also grappled with how to measure the effects of drugs on different lupus patients. Researchers had devised indexes to give broad measures of people's conditions. They assigned different point values to various manifestations of the disease, such as rashes or seizures. Doctors could add them up to get an overall assessment of a patient's status. The sums could also be used in clinical trials for drugs.

But researchers often disagree over which index would work best. The Systemic Lupus Erythematosus Disease Activity Index and the British Isles Lupus Assessment Group, for instance, differ in what they measure and how they assign points.

In September 2003, Dr. Simon convened an FDA advisory committee that made some headway. It agreed that drug companies should be able to use indexes of lupus symptoms to measure results, though it didn't endorse a particular index. It agreed that drugs could be approved if they helped improve problems in a particular organ, as long as the overall disease didn't get worse.

When Dr. Simon finished his stint at FDA last November, returning to Harvard at the end of his maximum two-year leave, his staff gave him a T-shirt with a picture of Grumpy the dwarf that read: "I'm right. You're wrong. Any questions?"

Lupus specialists and industry officials say that the FDA's support -- along with increased research funding, new scientific developments and growing collaboration among lupus specialists -- have had an impact. Human Genome Sciences, Genentech Inc. and Aspreva Pharmaceuticals Corp. are developing or testing lupus treatments.

"We wouldn't maintain our interest in lupus if we didn't think the agency was willing to work with us and other companies," says Akshay Vaishnaw, senior director of medical research at Biogen Idec Inc., the result of Biogen's merger with Idec Pharmaceuticals Corp. last year.

Industry officials still want more details about how the FDA will measure patient improvement from their drugs. Dr. Simon is waiting for the FDA to finalize the guidelines, release them to drug makers, and begin to use them.

"It's our goal to give clear guidance for what type of trial, how long and what type of result would be adequate to get a claim," says Jeffrey Siegel, a team leader in the FDA's drug center who is working on the lupus-guidance effort. "We are trying to be as specific as we can."

Even without finalized guidelines, some companies are moving forward. Genelabs, whose drug was rejected in 2001, is planning a new submission based on a more limited goal of preventing bone thinning in lupus patients.

La Jolla Pharmaceutical is hoping to get FDA approval for a drug based largely on a proxy marker. It is looking at the quantity of a particular antibody that attacks a certain type of DNA in lupus patients. Lowering the number of such antibodies is potentially a sign that a drug is easing the immune system's attack on the patient's tissue.

Write to Anna Wilde Mathews at anna.mathews@wsj.com³