In a issued at 7:35 p.m. on Feb. 4, 2013, Hemispherx Biopharma announced that the U.S. Food and Drug Administration (FDA) has declined the company”s application to market rintatolimod (Ampligen) for the treatment of CFS. Weighing the evidence submitted by Hemispherx, the votes of an FDA advisory committee that met on Dec. 20, 2012, and other regulatory issues (like manufacturing inspections), Hemispherx reports that FDA has recommended that the company “conduct at least one additional clinical trial, complete various nonclinical studies and perform a number of data analyses.” On Feb. 5, 2013, FDA posted a public response to emails it received about the decision and answered some frequently asked questions about the review process for the drug and the agency”s efforts to foster drug development for CFS and ME.
The decision is deeply disappointing to many in the CFS community, especially patients who have benefitted from the drug. This is the first potential therapy for CFS to make it through the , designed to ensure that only “safe and effective” drugs are marketed for specific conditions after thorough testing. This FDA decision is disheartening but it should not be viewed as the end. The company”s commitment to developing this drug for CFS has raised visibility for the illness within the agency and has brought a number of important issues to the fore that smooth the way forward. Valuable information was gained that helps bridge gaps. Working together across the stakeholder community, we can leverage the size and ignite the passion of this community to light the path to a world without CFS. The CFIDS Association of America is steadfastly committed to achieving that vision, with you and for you.
Outlined below are some of the issues that have been raised in recent days and weeks, especially as this decision neared. We hope this information will help to build understanding around the complicated history so that we can work productively toward the shared goal of more and better treatment options for people living with CFS.
Ampligen”s history is long and rugged. Testing of the drug in CFS began in 1990 with the AMP501 study, enrolling 10 patients. Three placebo-controlled studies involved 346 patients, half of whom received the drug. Open label studies and expanded access programs enrolled a total of 911 participants, 737 of whom received the drug. Some individuals participated in more than one study, so the number of “unique” individuals receiving Ampligen over the past 23 years is 565, according to in advance of the FDA advisory committee meeting. Drug approvals are typically based on multiple studies that involve thousands of patients.
The most recent controlled study of Ampligen, AMP516, began in 1998 and was completed in 2004. It enrolled 234 patients at 12 clinical sites in the U.S. Data from that study was published in PLoS ONE on March 14, 2012. This study used time on an exercise treadmill test as its primary measure of effectiveness. As a group, patients who received Ampligen for 40 weeks were able to perform 81 seconds longer on treadmill tests than the patients who received placebo over the same amount of time. Analyses of this data performed by Hemispherx and FDA do not agree on whether this change was significant, and that was a primary point of tension for the advisory committee regarding the effectiveness, or efficacy, of the drug. The FDA”s decision is based on the lack of adequate evidence for effectiveness, according to the company”s press release.
Hemispherx has also conducted small exploratory studies of Ampligen in HIV, renal cell carcinoma, hepatitis B and burn patients. Its clinical program for CFS is the most advanced of the conditions studied. The drug is not approved in any other country or for any other condition.
In 1997, FDA approved a that has allowed individuals to pay for treatment costs associated with the drug while its development continues. The approval allows up to 100 individuals to access the cost recovery program at a time. Of the 164 who have been enrolled over time, 97 have continued on therapy for a year or more. Their experiences taking the drug over many months contribute valuable safety data. Hemispherx did not announce any changes to this program in its Feb. 4, 2013 press release. Its continuation for the benefit of people who have experienced improvement on the drug has been a top concern of many of us in the community.
At the Dec. 20, 2012 meeting of FDA”s Arthritis Advisory Committee convened to review data submitted by Hemispherx and the FDA”s analysis of that data, the committee voted that the drug was shown to be safe by a vote of 8 to 5. However, they did not agree that the data showed the drug to be effective and the final vote on whether FDA should approve it was not supportive. Thirty individuals testified during the 90 minutes dedicated to receiving public comments, providing an emotionally compelling portrait of the great need for better treatment. FDA also received written comments from 750 individuals, a number its representatives called “incredible.”
In the weeks following the decision, patients rallied for approval by collecting electronic signatures on a petition that was delivered by advocate Robert Miller to officials at FDA, the Department of Health and Human Services and Congress. He began a hunger strike on Jan. 29, 2013, as reported by KRNV-4 in Reno. Over the weekend, he appealed to President Obama and Secretary of Health Kathleen Sebelius to request that the National Institutes of Health (NIH) conduct a confirmatory study of Ampligen as a CFS treatment. The Feb. 4, 2013 press release from Hemispherx states, “Hemispherx has asked any hunger strikes be discontinued and that patients join in a collaborative effort between the FDA, Hemispherx, CFS clinicians and patient advocates to find a solution to this significant unmet medical need.” Miller issued his own press release after learning of the decision and company officials also contacted him through Facebook to end the strike. He vows to continue until the federal agencies take “affirmative action.” BioWorld”s Randy Osborne reported on Robert”s strike and an unexpected personal coincidence. Robert ended his strike late on the 11th day after receiving a commitment from HHS officials to take part in an FDA workshop about CFS treatment development being planned for April 2013.
Hemispherx has stated its intention to formally appeal the FDA”s decision. The company is permitted to apply again for marketing approval and the company”s press release suggests that FDA has outlined its expectations for the next application. This is the company”s third attempt to secure FDA”s approval to market the drug. In 2007 the company submitted data based on the same set of studies that formed the basis for the 2012 application. FDA declined the 2007 application in 2009, recommending another phase III blinded study of at least 300 subjects that the company did not undertake.
News coverage of the declined application is expected to be light, compared to announcements for drug approvals of which there are only 35-40 each year. Articles about the Ampligen decision have been posted by Reuters, BusinessWeek, MedPage Today, Medscape, Fierce Biotech, BioWorld, Philadelphia Business Journal, Reno Gazette Journal, RTT News, Minyanville and other investor-related news sites. On Feb. 16, the San Francisco Chronicle ran a front page story highlighting the community”s anguish over the lack of approved treatments for ME/CFS.
An FDA-approved therapy for CFS — even one targeted to a specific subset of patients — will be a huge boost to awareness, understanding and research and development efforts to bring new or repurposed therapies to market. With at least one million CFS patients in the U.S. and no other existing therapies, there is a huge unmet need and large potential market. We share Hemispherx”s optimism that enhanced communications with FDA and new pathways to approval being paved by the agency will rapidly accelerate progress toward safe and effective treatment for all people with CFS.
There will be several opportunities for the CFS community to inform and influence policy at FDA. This spring the FDA will sponsor a meeting of stakeholders across the patient, academic research and industry research landscapes to discuss ways to accelerate CFS drug discovery, development and approval. FDA has stated on several public occasions, including at the Dec. 20, 2012 advisory committee meeting, that CFS meets its criteria as a “serious and/or life-threatening” condition, making drug applicants eligible for various expedited review and approval provisions within the law. The dates and agenda for the spring meeting have not yet been announced. FDA posts its CFS-related announcements and links on this webpage: and we will post updates here on Research1st.
FDA is also exploring new regulatory policies to help foster drug development for areas of “unmet medical need,” of which CFS is certainly one. Written comments from the public are invited until Feb. 28, 2013. More information and a link to the comment docket is available here: http://1.usa.gov/11EYfX9. The CFIDS Association participated remotely in a public hearing on this topic held Feb. 4, 2013 and will submit a detailed statement to support this proposal. This set of activities was recommended by the President”s Council of Advisors on Science and Technology in its Sept. 2012 report, “Propelling Discovery, Development and Evaluation.”
The FDA is also conducting a series of meetings designed to better understand the benefit-risk assessment in conditions for which little is known or understood about effective treatment. CFS was included in the initial list of conditions proposed by the agency and the CFIDS Association participated in a public hearing held Oct. 25, 2012 to support its inclusion in the final list and is actively engaged in the process that will shape how information about benefit-risk is collected from patient and assessed by the agency. Twenty conditions will be selected for this a final list has not yet been announced.
The CFIDS Association of America honors the patients who have participated in the Ampligen studies and the physicians who conducted the clinical trials and cared for people in them, as well as all those who have made their voices heard about the need for better treatments for CFS. There are a growing number of organizations and research initiatives dedicated to advancing CFS treatment research and development. The CFIDS Association of America will be at the forefront of efforts to identify and expand access to safe and effective therapies. Learn about requests we”ve made of various stakeholders in the drug development process and how you can add your voice: http://bit.ly/unmet-need.
The role of patients and nonprofit organizations in the drug development process has never been more vital and we”re actively engaged across a multitude of fronts to derisk and speed up the process so that hope is not tied to a single drug alone. This bears repeating: this FDA decision is disheartening but it should not be viewed as the end. Valuable information was gained that helps bridge gaps. Working together, we can leverage the size and ignite passion of this community to light the path to a world without CFS. The CFIDS Association of America is steadfastly committed to achieving that vision, with you and for you.
Kim McCleary is CEO of the CFIDS Association of America. She has been following the status of Ampligen studies and regulatory approval since joining the Association’s staff in 1991.
This article was last updated on Feb. 20 to add links to newly posted information.