Last September, people from various walks of life came together in a meeting room in Rockville, Md., to testify, some in deeply emotional terms, about a chemical from the benzothiazole family called riluzole.

The occasion was a meeting of the Peripheral and Central Nervous System Drugs Advisory Committee, called by the U.S. Food and Drug Administration (FDA) to discuss and evaluate riluzole, a drug developed under the trade name Rilutek by the global pharmaceutical company Rhone-Poulenc Rorer (RPR).

In clinical trials, Rilutek extended survival in people with ALS for about three months, although it wasn't shown to improve symptoms or slow muscle deterioration. Company representatives from RPR appeared before the panel to present data and argue that Rilutek should be recommended for approval by the FDA - a necessary step before any drug can be marketed.

Also speaking before the panel was Dr. Robert G. Miller, director of the Forbes Norris MDA/ALS Research Center at California Pacific Medical Center in San Francisco. Miller, whose MDA center took part in clinical trials of Rilutek, testified as a key investigator and ALS clinician and brought a message from the World Federation of Neurology Subcommittee on Neuromuscular Diseases.

"The chairman of that committee, Dr. Theodore Munsat, urged me to convey to this group that, although we see a modest clinical benefit here, we think it's a definite one, and we think that it has altered the course of this disease, and we urge approval from that perspective."

In a public portion of the hearing, people affected by ALS as well as family members gave compelling, heartfelt testimony in favor of approving any drug that had any effect, no matter how limited, on ALS (see "Facing the Committee," below). The committee had to weigh these emotional pleas against dispassionate consideration of scientific data before deciding what to tell the FDA. A committee's recommendation carries much weight with the FDA, although the FDA itself has the last word on approval.

The families listened and waited tensely for the decision, which would help determine if Rilutek was to hit the market soon or if more clinical study would be necessary. Rilutek was at a crossroads, but as with other drugs that companies wish to bring to market, the journey had begun years before - in the laboratory.

THE JOURNEY BEGINS

The FDA is a regulatory agency overseen by the Public Health Service and the Department of Health and Human Services. Through its Center for Drug Evaluation and Research, the FDA provides guidelines to manufacturers seeking to develop drugs. Eventually it rules on whether a company has met FDA standards and produced a drug that can be lawfully sold over the counter or prescribed by physicians. The burden rests on the drug company to prove to the FDA that its product is safe and effective.

Recently, the FDA approved drugs for conditions ranging from hypertension and migraines to AIDS, from depression to heartburn and even alcoholism. Rilutek is the first drug brought before the FDA for approval as a treatment for ALS.

The earliest stages of drug development involve researchers looking at substances in the lab, performing test tube experiments and using computers to determine whether these substances might have a beneficial effect on the human body. Once a substance is singled out as potentially therapeutic, it's tested in animals for negative side effects.

The next step is testing in humans, and this is where the FDA's involvement begins. The company sponsoring the drug must submit an Investigational New Drug Application (IND), detailing the drug's chemical properties and its effects in animal studies. FDA staff, including scientists and physicians, review the application. Usually it takes about 30 days for them to render a decision on whether the drug appears safe enough to test in humans.

If they say yes, controlled clinical trials of the drug may begin, but not before another safety checkpoint is passed. At research institutions or hospitals where clinical trials take place, committees of experts and laymen called Institutional Review Boards (IRBs) ensure that the rights and welfare of participants are respected. In particular, they look for "informed consent," which guarantees that anyone taking part in a trial is doing so voluntarily and is informed about the nature of the trial. The FDA periodically inspects the records of IRBs, in addition to conducting on-site inspections of clinical trial centers and drug manufacturing sites.

Drawing upon MDA-funded re-search showing that a buildup of a central nervous system chemical called glutamate may be involved in the death of motor neurons in ALS, RPR began developing a glutamate-blocking agent known generically as riluzole under the trade name Rilutek.

CLINICAL TRIALS: THREE PHASES

In phase one clinical trials, the drug is tested in healthy human subjects to find out how the body uses it and whether there are unacceptable side effects.

Phase two trials are larger in scale but may still involve a relatively small number of centers and patients. For the first time, volunteers who have the targeted disease get the drug.

The results of Rilutek's phase two trials, conducted in Europe, showed for the first time the drug's ability to prolong survival in ALS. Now a wider study was needed. Rob Partridge, senior manager of product communications at RPR, says: "The number of patients and the length of the trial really didn't give us the statistical significance to say what we wanted to say before we approached the FDA, and confirming trials are generally needed."

Phase three trials for Rilutek involving 959 patients were conducted in seven countries at 31 centers, including five in the United States, all MDA clinics. The five are at Baylor College of Medicine in Houston, Johns Hopkins University in Baltimore, Northwestern University in Chicago, California Pacific Medical Center in San Francisco and Tufts-New England Medical Center in Boston. Patients taking a placebo - an inactive substance such as a sugar pill - were compared with patients taking 50-, 100- or 200-milligram doses of Rilutek.

The results of the trial confirmed phase two's findings, that Rilutek had an effect on prolonging life in ALS. The drug has side effects such as nausea, fatigue and elevated liver enzymes, but was generally well tolerated. RPR felt it had enough ammunition to proceed to the next step.

FILING THE NEW DRUG APPLICATION

On June 29, 1995, RPR submitted its New Drug Application (NDA), an event Partridge calls "the real benchmark, the real milestone...which means we have enough data, we believe, to substantiate that this drug is safe and effective and that we'd like the FDA to render a decision on the application."

What is an NDA? It's a detailed package chronicling the entire history of the drug dating back to laboratory and animal studies, outlining its chemical makeup with full documentation and analysis of all human clinical trials, and providing information about the proposed packaging and dosage. Its purpose is to show that the drug is effective for its intended use, and that the benefit the drug offers outweighs the side effects or risks. A wide range of FDA experts - from chemists and pharmacologists to physicians and statisticians - evaluate the drug company's data.

A QUESTION OF REFORM

Recently, some members of Congress and the pharmaceutical and biotechnology industries have set their sites on lessening the federal government's control over such areas as new drug development and gene therapy (see "Regulating Gene Therapy - Or Not?" page 16). A major complaint aimed at the FDA is that it takes too long to evaluate a new drug following an NDA submission.

FDA Commissioner David A. Kessler says that internal reform efforts at the agency have cut the average NDA review period in half during the last five years. But critics feel the process is still taking too long and want to overhaul the agency and the drug approval system completely. They say the agency should rely more on outside experts in making decisions, and that the FDA has let its attention wander from core issues to ones that critics deem peripheral, such as the FDA's controversial efforts to regulate nicotine as a drug.

In the case of Rilutek, many who are close to the approval process feel that the FDA is doing its job well. Abbey S. Meyers, president of the National Organization for Rare Disorders (NORD), credits the FDA with having recognized during the 1980s the need to give special "accelerated" status to drugs for serious and life-threatening conditions such as ALS. The FDA made changes that now reduce the time between NDA submission and final approval for drugs like Rilutek.

In addition, drugs for conditions that affect fewer than 200,000 people in the United States, such as ALS, are eligible for "orphan" status. This allows the FDA to provide incentives such as tax credits and marketing exclusivity - as has been done with RPR and Rilutek - to encourage manufacturers to invest in diseases that affect comparatively small numbers of individuals.

RPR's Partridge says: "We believe the FDA has done a very good job in handling this with great speed, to this point."

Dr. Miller acknowledges frustration with FDA bureaucracy in the past, but now praises the agency for sticking to a fast track on Rilutek. When it comes to ALS clinical trials, he says he senses "a growing sophistication, interest and commitment on the part of the FDA."

EARLY ACCESS

An area in which the FDA has shown an awareness of the needs of ALS patients is in the early access program for Rilutek. In June, the FDA approved a Treatment Investigational New Drug Application, or Treatment IND, for Rilutek, allowing the drug to be administered on an experimental basis prior to formal approval.

NORD coordinated the early access program for RPR, and MDA assisted by allowing the use of more than 55 MDA clinics across the country as sites where people with ALS could get the experimental drug. "MDA has been extremely helpful in getting the early access program up and running," Partridge says. More than 3,000 Americans with ALS were named through a random selection process to receive the drug at no charge.

In October, another company, Cephalon, applied to the FDA for a Treatment IND for IGF-1, trade name Myotrophin, another drug being developed for ALS. Both Cephalon and Amgen/Regeneron, maker of BDNF, yet another ALS drug, hope to attain the stage RPR and Rilutek have reached with the FDA in the near future.

OUTSIDE ADVICE

To help determine whether an NDA should be approved or not, and to make certain the decision is balanced and impartial, the FDA convenes advisory hearings of outside scientific experts and consumer representatives.

"Their real responsibility is to advise the FDA as to whether or not they're comfortable with what they see in terms of effectiveness or in terms of safety," Partridge says.

Which brings us back to the Sept. 18 meeting in Maryland and the deliberations on Rilutek. The nine committee members cast separate votes on safety and effectiveness. They voted unanimously in favor of the FDA approving Rilutek on safety grounds.

The issue of effectiveness was tougher. The main controversy concerned the phase three data comparing patients taking various doses of Rilutek with those taking placebo, both in Europe and the United States. Effectiveness was clearly shown in the European studies, but in the American studies there was little or no difference between patients taking the drug and those taking placebo.

Partridge questions the validity of focusing on one portion of the data. "When you do," he says, "you run the risk of seeing an effect that is purely chance. Statistical significance was reached when you included data from all 959 patients." Nevertheless, some committee members balked at approving a drug for the American market if it had been shown to be effective in Europeans but not in Americans.

The question was complicated because the U.S. patients were fewer in number and taking the drug for a shorter time, and also because the placebo patients fared much better in the U.S. "We could talk for an hour about this issue," Miller says. "But the bottom line is that that wasn't the question. The question was 'Does the evidence from these trials show an effect of the drug on ALS?' and the answer was 'Yes, it does.'"

Miller recalls that another point of debate had to do with the fact that the effect of the drug is modest. "Advisory committee members were asking whether they should approve a drug that has a small effect or hold out for a drug that has a bigger effect," he said. "The FDA administrator again rightly reminded them that their charge was not to assess the size of the effect. The charge was to decide whether the evidence was convincing that there was an effect."

CLOSE CALL

Finally, to the relief of the ALS families that had stayed through the long hours of deliberations, the committee voted 5-4 that Rilutek be favorably recommended to the FDA on grounds of effectiveness.

Rilutek had passed the committee, but the positive recommendation was no guarantee of swift approval by the FDA. "These decisions frequently lead the FDA to ask additional questions or to ask for clarifications about areas that were not made clear during the advisory hearing," Partridge says.

On Dec. 12, 1995, RPR announced that it had received approval from the FDA to market Rilutek. In one sense, Rilutek's journey had reached an end, but for the people at RPR, the journey was just beginning. At a news conference on Jan. 10, RPR announced that Rilutek was now available in drug stores nationwide. (Rilutek comes in the form of a 50-milligram tablet to be taken twice daily. It can be ground up or dissolved for people who have difficulty swallowing.) RPR officials said the company will offer help in getting financial assistance for those who can't afford the several hundred dollars per month that Rilutek costs.

The consumer information line at the FDA is (301) 443-3170. RPR has established several information lines. For general information about Rilutek, call (800) RX-TRIAL. With questions about obtaining the drug or about financial assistance, call (800) 790-RTEC. For information about the Rilutek Early Access Phase-Out Program, call (800) 459-7599.

FACING THE COMMITTEE

"There wasn't a dry eye in the place, including my own," says MDA-funded clinician and researcher Dr. Robert G. Miller about the FDA advisory hearing on Rilutek and the heart-wrenching testimony by members of the ALS community.

Those with the disease and their families spoke about the realities of living with ALS and about their willingness to accept any drug, even one like Rilutek that has limited treatment potential. "It was extremely moving because people spoke articulately, convincingly and from the heart," Miller says.

Patricia Lake told the committee: "I can accept the fact that my husband died well before his time. I can accept the fact that our children will grow up without their father... What I will never accept is the way he died, the abominable nature of this disease, and the fact that there is no cure." Emphasizing the precious nature of time, she said: "Had he lived one month longer, he could have seen his oldest child receive first Holy Communion. Had he lived two months longer, we would have celebrated our 10-year wedding anniversary together."

Stacey Henninger, 31, used a voice-assisted device to tell the committee that she had always been a tomboy who was active in sports. "Today, things are very different, for today I have ALS," she said. "Whereas I used to run, I now struggle to walk... I have learned how precious and fragile life is. I realize how many things I took for granted. I realize how badly I want to live."

Terry McCullough's husband, Wayne, who has ALS and uses a ventilator and a feeding tube, wasn't able to attend the hearing but his wife testified for him. "My husband has a goal," she said. "Our daughter is getting married next June. The goal is to escort her down the aisle."

Joe Martin, a man with ALS who was wearing a Yankees baseball cap, said: "Everyone said that Lou Gehrig's record could never be broken, but (Cal) Ripken broke it, and he did it by getting up every day and going to the ball park and trying to do his very best. That is also the challenge for those of us with ALS and to those who care for us: Get up every day, go to the ball park, try to do our very best."

Of Rilutek, he said: "Suddenly, there are clues as to how to treat this disease. Suddenly, there is some hope of winning the game. And suddenly, the bases are loaded. Please bring this runner home and move the game along."

People cheered when the committee announced its decision to recommend that Rilutek be approved. Abbey Meyers, president of the National Organization for Rare Disorders, says: "It was a way to empower the people... They can step up to the microphone and they can express their opinion and they can have an impact."

"It was very emotionally charged," recalls Linda McKnight, who told the committee that she lost her best friend when her sister died of ALS. "I truly believe that this would not have passed without the testimony of those in the ALS community."