FDA panel rejects Ampligen application for use in Chronic Fatigue Syndrome | US press reports | 20 December 2012

December 21, 2012

ADDED ON 31 December 2012: We have been asked to post a link to an epetition called FDA should give CFS patients access to Ampligen! The target is to obtain 20,000 signatures by the time of the FDA meeting on 3 February.

From the Wall Street Journal, business section, 20 December 2012 (story by Jennifer Corbett Doreen).

A federal advisory panel on Thursday said a proposed medicine from Hemispherx Biopharma Inc. to treat chronic fatigue syndrome isn't ready for approval, dealing another setback to the drug maker.

Hemispherx Biopharma is seeking approval from the U.S. Food and Drug Administration for the drug, Ampligen. The product, which been in development for more than two decades, was reviewed Thursday by the agency's arthritis-drugs advisory panel, which is made up of non-FDA medical experts. In an 8-to-5 vote, the panel said the company didn't provide sufficient data to support the approval of Ampligen. The vote amounts to a recommendation that that FDA not approve the drug.

Several panel members said they struggled with their decisions because it appears the drug works in certain patients even if it wasn't strongly shown in the clinical data presented to the panel.

“I think the advisory panel in general hopes there will be an effective drug and hopes this might be the drug” for chronic fatigue syndrome, said Lenore Buckley, the panel's chairwoman and a professor at Yale School of Medicine. “We are interested in seeing more data.” A decision by the FDA on whether to approve Ampligen is expected by early February.

Almost three dozen patients or family members testified in person or via video before panel, urging them to approve Ampligen. Anita Kathryn Patton, who's had chronic fatigue syndrome for more than 20 years, was first given Ampligen in 1997.

“It was like rising from the dead,” Ms. Patton said of her disease improvement. She and some other patients are receiving Ampligen through a special access program at a cost of about $25,000 a year.

At issue is whether Ampligen, which is the drug's proposed brand name, is effective and safe. The FDA said there was missing data in clinical studies that made it hard to tell whether the drug is safe. Potential safety concerns include infections and liver problems. FDA medical reviewers questioned whether the data meet drug-approval requirements demonstrating “substantial evidence” of safety and efficacy, or effectiveness.

Theresa Michele, an FDA team leader, said the agency believes that chronic fatigue syndrome is a serious disease that needs treatments, but said clinical studies submitted in support of products have to meet federal drug approval standards showing “substantial” safety and effectiveness. “We have to be certain a drug works and we clearly know what the risks are,” Dr. Michele said.

The FDA and the company differed on whether one of the main clinical studies reached a goal showing a statistically significant test showing patients receiving the drug were able to walk on a treadmill for a longer period than patients receiving placebo injections.

The company said on average there was an improvement of about one minute while the FDA said the difference appeared to be about 20 seconds.

“Regardless of the [measurement] approach there's a consistent pattern of benefit in the data, which favor Ampligen,” said William Carter, Hemispherx chief executive. At a minimum, Dr. Carter said, the drug “prevents further disease progression.” After the meeting, Dr. Carter said he had no comment.

Chronic fatigue syndrome, also known as myalgic encephalomyelitis, is believed to affect more than one million Americans, according to the Centers for Disease Control and Prevention. The condition is marked by severe fatigue, muscle pain and memory and concentration problems. It isn't known what causes the condition and there are currently no specific treatments.

Ampligen, an injectable drug, is believed to boost the body's immune system and fight viruses.

And this has been published by MedPage Today (story filed by David Pattman, Washington Correspondent):

SILVER SPRING, Md. — An FDA advisory panel voted 8-5 against recommending approval for the drug rintatolimod (Ampligen) for use in chronic fatigue syndrome (CFS), citing questionable clinical trial results that were based on a small number of patients.

Rintatolimod only met its primary endpoint in a confirmatory study after a post-hoc analysis of patients who had CFS for less than 10 years. Excluding 37 patients from the 234-patient trial significantly improved patient outcomes in exercise tolerance testing but also caused the P-value to slip outside the range showing clinical significance.

Members of the agency's Arthritis Advisory Committee voiced confidence that rintatolimod may work in a small group of CFS patients, but that wasn't shown clearly by its manufacturer, Philadelphia-based Hemispherx.

“There's probably a subgroup where this works,” Gailen Marshall, MD, PhD, medical professor at the University of Mississippi Medical Center, said. “It's just not for everyone.”

Some panelists questioned — as the FDA did in briefing documents released before the meeting — differing results from two phase III trials. In one, a double-blinded, placebo controlled, randomized trial of 92 patients demonstrated a slight benefit, but that benefit was only shown after data was transformed by a logarithmic scale.

Patients in that trial receiving rintatolimod over placebo showed an average 10-point change in the Karnofsky Performance Scale (KPS), a scale of 0 to 100 that assesses functional impairment (P=0.02).

“What we need is two studies that have adequate sample size and the same endpoint,” said Irwin Russell, MD, PhD, director of fibromyalgia research at the Arthritis & Osteoporosis Center of South Texas in San Antonio.

CFS is defined as 6 or more consecutive months of profound fatigue that is not improved by bed rest and is worsened by mental or physical activity. Treatment options are limited and there are no approved therapies, the FDA said. It afflicts one in 4 million people, according to the CDC.

Many panelists including chairperson Lenore Buckley, MD, professor of internal medicine at the Yale School of Medicine, questioned the lack of long-term studies for a drug that could be given to patients for the rest of their life.

The FDA also said a few patients account for all the treatment difference.

The FDA also questioned the single dose — 400 mg — studied in the drug. “It does limit our ability to interpret much of the data that you see,” Theresa Michele, MD, clinical team leader of the FDA's pulmonology products division, said.

Rintatolimod is a twice-weekly intravenous infusion.

Panel members were heavily swayed by nearly 2 hours of compelling patient testimony from patients during the meeting's public hearing portion. Even panelists who voted no said they didn't want to keep the drug from patients who might be helped, although it might be just a small group.

The FDA's analysis also found discrepancies in the drug's safety data — so much so that FDA officials called what Hemispherx submitted unreliable.

“As we reviewed the sponsor's data, we found multiple areas of discrepancies,” Michele said. “Every time, we see that it raises our eyebrows a little bit and makes us question whatever else is in the packet.”

The agency noted that patients taking the drug may be at increased risk for thrombosis, major cardiac events, malignancy, liver function, and abdominal pain.

Hemispherx officials said they believe the safety issues the FDA raised — for the first time in nearly 20 years of development — are unfounded and could be resolved by a more thorough review of its data.

“We would be pleased to sit down with the FDA reviewers to discuss these issues,” Hemispherx Chief Executive William Carter said Thursday.

For example, Hemispherx said the FDA counted single adverse events as multiple ones, and also counted benign tumors and malignancies. The drugmaker also said there was no increased risk of death or suicide from the drug. The FDA noted three deaths, two of them suicides.

One patient had a lupus flare, which the FDA counted as an adverse event. The drugmaker said the patient had lupus before the trial started, but having that condition should have disqualified the patient from participating.

The FDA is expected to render its decision on the drug by Feb. 3. The agency isn't required to follow the advice of its advisory committees, but usually does.

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