Drug Development for Myalgic Encephalomyelitis and Chronic Fatigue Syndrome (ME and CFS): Questions and Answers

As evidenced by the hundreds of letters, emails, and testimonies submitted to FDA, Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) is a devastating disease with a serious impact on quality of life. We at FDA are acutely aware of the seriousness of this disease, that no FDA approved treatment option is available, and the community’s strong desire to see rintatolimod injection (Ampligen) approved. The FDA is committed to drug development to treat the symptoms of CFS and remains engaged with the patient and academic communities to foster these efforts. Following are responses to some of your frequently asked questions.
Q: What evidence was used to determine the safety and effectiveness profile of Ampligen?
A: The safety and effectiveness profile of Ampligen was evaluated based on the evidence Hemispherx Biopharma, Inc. (Hemispherx) provided in their New Drug Application (NDA). The documentation required in an NDA is supposed to tell the drug's whole story, including what happened during the clinical tests, what the ingredients of the drug are, the results of the animal studies, how the drug behaves in the body, and how it is manufactured, processed and packaged. How drugs are developed and approved is detailed online at: http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/default.htm.

Q: Has FDA worked with Hemishperx to resolve safety and efficacy questions?
A: Yes. For many years FDA has worked with Hemispherx on Ampligen (see table of Ampligen’s history below). Hemispherx submitted the initial New Drug Application (NDA) for Ampligen for the treatment of CFS in October 2007. The Agency issued a Refusal to File letter in December 2007 because the application was not sufficiently complete to permit review. A large number of deficiencies were cited, the most important and pertinent of which were lack of dose ranging, missing study reports, missing ECG and laboratory data, missing case report forms, discrepancies between the number of patients in the study reports for AMP-502 and AMP-516 and the number of patients in the database, statistical analysis plans inconsistent with the protocols, lack of clinical pharmacology data, and lack of carcinogenicity data.
Hemispherx resubmitted the NDA in March of 2008 and FDA accepted it for review. However, the lack of dose ranging data, inconsistent statistical analysis plans, lack of clinical pharmacology data, and lack of carcinogenicity data were not addressed. The application received a complete response (CR) in November of 2009. Again, the CR letter cited a large number of deficiencies across multiple review disciplines. The primary clinical/statistical deficiency was “Your two main studies (AMP-502 and AMP-516) do not provide adequate evidence of effectiveness or safety.”
In March 2011, the Ampligen application was transferred to the Division of Pulmonary, Allergy, and Rheumatology Products (DPARP) as part of an Agency-wide effort to consolidate ME/CFS applications into one division to allow for a more consistent process for review of products being developed for the treatment of these conditions. In June 2012 the division met with Hemispherix to discuss their development program and their plans for resubmitting the Ampligen NDA, which focused largely on new analyses of the existing clinical trial data. Hemispherx resubmitted the NDA in August 2012.
The Arthritis Advisory Committee (AC) met on December 20, 2012 to provide FDA with objective outside scientific advice about Ampligen and to provide transparency to the CFS community about the issues of safety and efficacy identified with the application. At the meeting, both Hemispherx and FDA reviewers presented data to outside experts in medicine and science, including physicians with expertise in CFS, a CFS patient representative, and an industry representative. The majority of AC members shared FDA’s concerns about the results of the clinical trials being inconsistent, as well as numerous aspects of how the data from them were collected and analyzed. The concerns were so significant that the data could not be relied upon with confidence and was not able to support a conclusion by the AC that an appropriate risk to benefit balance existed to allow marketing. At the end of a full day of discussion about Ampligen, AC members voted 8-5 against the approval of Ampligen for the treatment of patients with CFS because of insufficient safety and efficacy data.
The background information that was reviewed by the AC members to make their decision is available along with the slide presentations and other AC meeting materials at:

The archived webcast of the full meeting is posted online at:

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM332510.pdf (PDF-29KB)

Q: What is the history of Hemispherx’s NDA?
A: History of Hemispherx’s application for Ampligen:

Date	Action
Oct 2007	Hemispherx submits original NDA for use of Ampligen to treat CFS
Dec 2007	FDA refuses to file NDA due to numerous deficiencies including lack of dose ranging, missing study reports, missing ECG and laboratory data, missing case report forms, database discrepancies, statistical analysis plans inconsistent with protocols, lack of clinical pharmacology data, and lack of carcinogenicity data
March 2008	Hemispherx resubmits NDA
Apr 2008	FDA accepts NDA for review
Nov 2009	FDA issues Complete Response to Hemispherx because of clinical, statistical, clinical pharmacology, nonclinical, product quality, and facilities inspection deficiencies FDA asks Hemispherx to conduct at least one additional controlled clinical trial showing a convincing effect in the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) population
March 2011	Ampligen application transferred to DPARP as part of Agency-wide effort to consolidate ME/CFS applications into one division Allow for a more consistent process for review of treatments of CFS
Aug 2012	Hemispherx submits complete response with additional post-hoc analyses of the original clinical trials (additional evaluations of the same original data) Hemispherx submits no additional clinical trials for review
Dec 20, 2012	Arthritis Advisory Committee (AC) meets to discuss Ampligen’s application and history AC members vote 8-5 against approval of Ampligen for the treatment of CFS citing insufficient safety and efficacy data
Feb 04, 2013	Hemispherx announces receipt of a Complete Response letter for Ampligen to treat CFS

Q: Why did Ampligen receive another Complete Response (CR) letter?
A: On February 4, 2013, Hemispherx announced the receipt of a CR letter from the FDA for Ampligen. FDA issues a CR letter to convey that our review of an application is complete and we cannot approve the application in its present form. A CR letter describes all of the specific deficiencies that the Agency has identified in an application, allowing the company an opportunity to correct those clearly defined deficiencies in a re-submission. Because the NDA for Ampligen is not approved, FDA cannot provide information or comment about what was contained in the CR letter unless Hemispherx makes that information public.
Q: What treatment options are currently available to treat ME/CFS?
A: There are currently no FDA approved treatment options for ME/CFS. According to the CDC, managing chronic fatigue syndrome can be as complex as the illness itself. There is no cure, and symptoms can vary over time. Thus, people with CFS should closely monitor their health and let their doctor know of any changes; and doctors should regularly monitor their patients' conditions and change treatment strategies as needed.
Q: Where can I get more information on Ampligen?
A: Please contact Hemispherx for more information.
Q: Does FDA consider ME/CFS to be a serious disease and what is FDA doing to aid those suffering from this disease?
A: Yes. FDA considers ME/CFS to be a serious disease and we are and will continue to be active participants in the search for effective therapies for persons with ME/CFS. The CR letter issued for Ampligen is entirely separate from FDA's support of drug development pathways for CFS.
In support of the ME/CFS community’s needs, FDA is an active member of the Chronic Fatigue Syndrome Advisory Committee, which provides advice and recommendations to the Secretary of Health and Human Services (HHS) on issues related to ME/CFC. In 2012, FDA held a stakeholder teleconference and a November webinar titled “Myalgic Encephalomyelitis and Chronic Fatigue Syndrome: Working Together for Change.” Future plans include an FDA sponsored workshop in spring 2013 focused specifically on ME/CFS drug development.
FDA encourages the pharmaceutical industry to continue to look for new treatments in this area.