FDA Panel Recommends Against Ampligen Approval

Setting the Stage

On Dec. 20, 2012, an advisory committee convened by the Food and Drug Administration (FDA) heard presentations and public testimony and discussed the evidence for the safety and efficacy of rintatolimod (Ampligen) for treating CFS. Background on the drug, its long route leading to this public meeting and the issues to be considered by the advisory committee and FDA before marketing approval is given are covered here in a post titled, “FDA Set to Review Ampligen Application.” Background materials posted by the agency for FDA and the drug’s manufacturer, Hemispherx Biopharma, were described and linked from this post.

The public session was the first such FDA advisory committee meeting to consider a specific treatment for CFS and the tightly structured format was new to most participants and observers from outside the agency. Seated at the front of the large room at FDA’s White Oak campus at a U-shaped table were members of the Arthritis Advisory Committee, including three regular voting members, 11 temporary voting members, one non-voting industry representative, five non-voting FDA participants and the designated federal official, an FDA employee. The temporary voting member of the panel appointed as the patient representative was Alaine M. Perry, MPH. Ms. Perry is known to the CFS community as the federal representative to the Department of Health and Human Services CFS Advisory Committee (CFSAC) from the Centers for Medicare and Medicaid Services. In her introduction, Ms. Perry made her first public disclosure that she has had CFS for more than 20 years and that she represented only herself on the panel and not the agency she represents at CFSAC meetings. To the left of the center table were two rows of representatives from Hemispherx Biopharma, the manufacturer of Ampligen. On the right, FDA staff. Members of the public were separated from these three groups by a red rope. There were about 100 people in attendance and the full session was broadcast live over the web by FDA. The meeting recording, minutes and a transcript will be archived by the FDA, along with slide presentations shown by the manufacturer and the FDA.Great-Room-view

The morning session began with an overview by Dr. Theresa Michele of the FDA’s Center for Drug Evaluation and Research. She emphasized FDA’s recognition of CFS as a serious disease with no approved therapies and acknowledged the strong public interest in the day’s topic as evidenced by written testimony submitted to the record by more than 700 people. She reviewed the agenda and four questions that the committee would be voting on during the afternoon session. Dr. Michele noted the first question about drug safety was somewhat unusual and that it originated with agency’s concern about the reliability of the safety data submitted by Hemispherx.

Presentations and Discussion

Dr. William Carter, chairman and CEO of Hemispherx Biopharma, led the series of presentations that outlined the two controlled and seven open studies of Ampligen initiated by the company. He committed to “complete clarity and transparency” in presenting data about the safe and effective use of Ampligen by 589 unique persons with CFS. Dr. Carter’s information was supplemented by other speakers on behalf of Hemispherx, including Dr. Lucinda Bateman, a physician who participated in the “AMP 516″ controlled study of Ampligen and who administers the drug to selected CFS patients in her Salt Lake City clinic through a compassionate use program approved by FDA called AMP 511. Robert Miller, a well-known patient advocate who has had CFS since 1982, also presented information on behalf of the company, reporting the positive response to the drug that he experienced during two courses of treatment. The panel of speakers emphasized the safe use of a similar compound as an adjuvant in the human papillomavirus vaccine, the unmet medical need represented by CFS, the FDA’s transfer of the Ampligen application to five divisions over the 22-year development period and data showing Ampligen led to improved time on a treadmill test and reduced use of other medications compared to placebo. Questions from the committee to Hemispherx representatives followed; Dr. Carter was forceful in his responses that the company had met the burden of proof. [Note: Hemispherx’s slide presentation can be viewed here: http://1.usa.gov/WAeOSJ]

Two members of the FDA’s internal review team then reviewed the agency’s analysis of the Ampligen clinical program. Their presentations drew attention to several areas in which the agency’s interpretation of data differed from the company’s. FDA speakers traced the regulatory review process beginning with the company’s first request to study the drug in 1990. They focused on missing or conflicting data submitted by the manufacturer, data analyses planned by Hemispherx (but not conducted) that reduced the differences between the group treated with Ampligen and those who received placebo, and concerns raised by study conduct issues documented at various time points. Again, committee members’ questions followed the FDA presentations. [Note: FDA’s slide deck presentation can be viewed here: http://1.usa.gov/SMTU4J]

After a short lunch break, the committee heard compelling testimony from 30 members of the public, many of whom had received substantial benefit from Ampligen treatment or had family members who responded to the therapy. Others spoke to the desire among patients to get access to the drug in the absence of other primary therapies. Testimony was limited to three minutes per witness and time limits were strictly observed. Three videotaped testimonies were permitted for individuals unable to travel to the meeting. Only one witness, Dr. Sidney Wolfe of the Public Citizen Health Research Group, specifically requested that FDA decline the application for drug approval. The Solve ME/CFS Initiative’s testimony, which I delivered, focused on the unmet need for safe and effective treatment, the burden of illness imposed on the individual and the community and personal risk and benefit assessment made by every CFS patient every day in the absence of specific treatment.

Before committee discussion and votes, Dr. Michele reviewed the committee’s charge and the regulatory process. She again conveyed the agency’s understanding of the “life-destroying” nature of CFS and reiterated the readiness to engage with drug developers to foster safe and effective treatments for CFS. In response to questions from the committee, she described the meaning of “safe” and “effective” in regulatory terms as well as accelerated approval mechanisms that helped to frame the committee’s response to six topics defined by the FDA, four of which would be subject to a vote. She emphasized that the approval standard was “adequate well-controlled studies,” not individual accounts. She noted that approvals of immunomodulatory drugs are generally based on studies that involve thousands of participants, rather than hundreds.

Votes Cast

The discussion about the evidence presented to evaluate safety and efficacy centered on the company’s presentation of data analyses other than those planned as part of the study, exercise testing protocols used to measure improvement and side effects of treatment based on case reports and adverse events summaries filed by the company. Votes revealed ambivalence about the strength of the data and the conclusions that could be confidently drawn. The member-by-member voting tally is presented below. In all, the majority of committee members recommended that another larger study be conducted before approving the drug. Individual committee members suggested various enhancements to future study design to help clarify the drug’s effect, such as:

  • Define “adverse events” and “serious adverse events” at the outset of the study so that differences can be detected between those treated with the drug and those receiving placebo, as well as the characteristic symptoms of the disease itself.
  • Identify subgroups of responders to the drug and focus on them using “enrichment” study protocols.
  • Select a different endpoint than time on treadmill in light of difficulties these studies had establishing a tolerable exercise testing protocol and which cutoffs were clinically meaningful.
  • Choose a different endpoint than Karnofsky Performance Score. The 10-point improvement shown in only one of the two pivotal studies may be substantial to individual patients, but is a challenging statistical measure.
  • Gain a better understanding of the effect of placebo in this population, a group of people that suffers isolation and medical neglect — being enrolled in a study and receiving regular medical attention as part of the study may have a therapeutic effect in itself that made the drug’s effect harder to demonstrate.
  • Focus on securing approval for severely affected individuals, rather than the wider population that meets CFS criteria

The vote on the final question, “Has the applicant provided sufficient efficacy and safety data to support marketing of Ampligen for the treatment of CFS?” ended with five votes “yes” and eight votes “no.” Comments that followed the vote reflected struggle with the decision by most panel members. Those voting against the measure voiced concern about the weak data showing the drug to be effective and the lapses in data submitted to show safety. Members who supported approval indicated that post-marketing studies could be required to resolve outstanding concerns. After all the votes were tallied, the non-voting industry representative, Brian Kotzin, M.D., of Amgen, offered his perspective that the inadequacies of trial design and irregularities in the data didn’t measure up to the industry standard for showing safety and efficacy and that he hoped a subset of patients would be studied further. Dr. Michele was the last to speak before adjournment. She summarized the “very difficult” decision ahead of the agency and commended the panel and the public for their input which would be strongly considered in the final assessment of whether or not to approve Ampligen as the first treatment for CFS. She took the final opportunity to emphasize the agency’s active interest in working with sponsors to make safe and effective drugs available to CFS patients.

Potential Outcomes

FDA will render a decision on Hemispherx’s request for marketing approval on or around Feb. 2, 2013, six months from the date the manufacturer’s application was accepted by FDA. FDA is not bound to act in accordance with the advisory committee’s recommendation, although it is unusual for the agency to depart from advisory committee guidance. The presentations by Hemispherx representatives and public testimony seemed to make a strong case for the patient community’s willingness to tolerate risks of side effects that mimicked the disease symptoms themselves, but the committee did not seem persuaded that the trials demonstrated clear and sufficient benefit across large enough numbers of patients to warrant approval for at least one million CFS patients and other patient groups that might try to gain off-label access for other conditions.

If the FDA follows the advisory committee’s recommendation and does not approve the drug for marketing, the next move will be Hemipsherx’s. The company can try to raise capital to conduct a third controlled study, shaping its study design to address concerns expressed by FDA in the briefing documents and by committee members through their votes and discussion. In a press release issued the day after the meeting, Hemispherx stated that it “will seek to do everything necessary to confirm in a scientifically rigorous manner that Ampligen® is a safe and effective treatment for CFS.” Regardless of the FDA’s decision on this application, hopefully access to the drug will be provided by the company to those who have benefitted from it.

Media Coverage

In the days leading up to the public meeting and vote, news stories focused on the stock value and prospects for investors to gain or lose based on the critical assessment of data reflected in the FDA’s pre-briefing materials.

After the meeting, news stories focused on the vote and the mixed data on efficacy that failed to win the committee’s endorsement for effectiveness and overall approval.

(Note: The article posted to Medscape Today provides a good overview of the issues raised at the meeting and the outcome. Free registration may be required to access it.)

[Update: In the weeks since the advisory committee meeting, interested individuals have launched a petition seeking approval of Ampligen and are conducting other activities to influence the final outcome. Press releases and financial and legal sector media outlets have reported that some Hemispherx stockholders are considering or have taken legal action against the company.]

Member-by-Member Vote
(R = regular voting member of the Arthritis Advisory Committee; T = Temporary voting member of the Arthritis Advisory Committee)

Vote 1

Vote 2

Vote 3

Vote 4

Member Is there substantial evidence of   efficacy? Has safety been adequately assessed? Is the safety profile adequate for   approval? Do the safety and efficacy data support approval?
Lisa Gualtieri, PhD, ScM (R) No No No No
Robert Lahita, MD, PhD (R) Left early; did not vote
I Jon Russell, MD, PhD (R) No Yes Yes No
Larry Borish, MD (T) Yes No Yes Yes
Lenore Buckley, MD, PhD (T) No No No No
Ralph D’Agostino, Sr., PhD (T) No No No No
Jacqueline Gardner, MPH, PhD (T) No No Yes No
Sean Hennessy, PharmD, PhD (T) No No Yes Yes
Anthony Komaroff, MD, MA (T) No No No No
Gailen Marshall, Jr., MD, PhD (T) Yes Yes Yes Yes
Alaine Perry, MPH (T) Yes Yes Yes Yes
Matthew Rudorfer, MD (T) Yes Yes Yes Yes
Elizabeth Unger, PhD, MD (T) No No Yes No
James Ware, PhD (T) No No No No
Yes: 4
Did not vote: 1
No: 9
Yes: 4
Did not vote: 1
No: 5
Yes: 8
Did not vote: 1
No: 8
Yes: 5
Did not vote: 1


 K. Kimberly McCleary was the Solve ME/CFS Initiative ’s chief staff executive from 1991-2013.

This article was updated most recently on Jan. 25, 2013.

December 27, 2012