Confluence of Symptoms and Treatments at FDA Patient Meetings

The first round of four PDUFA patient-focused meetings concluded with the Sept. 24 meeting on narcolepsy. FDA is beginning to look ahead to the fiscal 2014 meetings – to start with fibromyalgia on December 10. One pattern that is emerging is that three of the first five conditions discussed with patients have overlapping symptoms and treatments.

Chronic fatigue syndrome, narcolepsy and fibromyalgia: three different diseases handled by three different drug review divisions at FDA. Yet they are often described with similar symptoms by patients, they rate highly in drug development challenges within FDA, and they even have overlapping candidate drugs.

Two FDA review divisions from different drug review offices have completed meetings on CFS/myalgic encephalopathy and narcolepsy. A third division will be in charge of fibromyalgia.

• The Pulmonary, Allergy & Rheumatology Products Division (within the Office of Drug Evaluation II) took the lead on CFS/ME at the inaugural patient-focused meeting. (Also see "Patient Feedback Pioneers: Chronic Fatigue Advocates Prepare for First PDUFA V Meeting" - Pink Sheet, 28 Mar, 2013.)
• The Neurology Products Division (ODE I) conducted the most recent meeting on narcolepsy.
• The Anesthesia, Analgesia and Addiction Division (ODE II) will presumably be the lead on fibromyalgia.

The involvement of different divisions reflects FDA’s attempt to bring as many of the specialty review areas as possible into the process of having more direct contact with the patient community. What is intriguing about the choices of diseases on which to meet with patients is the overlap in symptoms and current treatments. (Also see "Getting a Jump on PDUFA V: Fast Start on REMS, Patient Input – And Longer Reviews" - Pink Sheet, 1 Jun, 2012.)

At both the CFS and narcolepsy meetings, for example, patients referred frequently severe night-time sleep disruption and “brain fog” as the type of symptoms that they most want addressed by new treatments.

The CFS meeting has now been summarized by FDA in a report with a Benefit-Risk grid encompassing the viewpoints from the meeting. (See below.) “Brain fog” did not make it onto the grid itself but was highlighted numerous times by FDA in the account of symptoms described by patients. Patients with the two different diseases also deal with daytime sleepiness and exhaustion.

Overlapping Treatments, Different Review Teams

These are clearly conditions that different specialty groups within FDA view as difficult to characterize, underserved, and with clear, very serious impact on daily life routines.

The overlapping symptom information that the agency is receiving suggests that the current distinctions between divisions may be slightly misplaced or too rigid, and that there may be room for cooperation. Any move in that direction would be an unexpected outgrowth of the patient-focused meeting process.

Not surprisingly, given the overlapping symptoms, there is also a confluence of treatments being mentioned at the meetings. That sets the situation where Jazz Pharmaceuticals PLC’s Xyrem (sodium oxybate) is a featured current treatment at the discussions on narcolepsy and likely to be referred to as a failed candidate for fibromyalgia. The product was rejected by two combined FDA advisory committees in August 2010 under a different brandname, Rekinla. (Also see "Jazz Fibromyalgia Candidate Needs More Risk Management, Advisory Panel Tells FDA" - Pink Sheet, 20 Aug, 2010.)

Similarly, list of drugs used by CFS/ME patients from that patient meeting is also heavy in the pain area with fibromyalgia treatments: Cymbalta, Lyrica, Savella. An FDA inventory from the CFS/ME meeting of drugs mentioned by CFS/ME patients is, however, very broad, well beyond the approved fibromyalgia treatments.

An odd twist of the patient-focused meetings is that sponsors probably don’t want the attention that an approved product gets at one of these sessions.

A product is probably in a better position for one of these discussions if it is not a preferred current treatment but is a treatment that is not being used or that FDA is discouraging. FDA has selected the diseases because they are poorly served, which leads to a distinct line of discussion about what patients don’t like about the current products being used.

At the narcolepsy meeting, there were several patients who spoke positively about the impact of Xyrem in phrases like a “wonder drug” or a “miracle drug.” Those comments were generally paired, however, with discussions outside the review division’s purview about the high cost of treatment.

FDA used the praise for Xyrem to try to extract information about what type of symptom improvement would be better than Xyrem. Theresa Mullin (head of the Office of Strategic Planning that plays a key role in the patient meetings) pressed one of the patients who praised Xyrem to explain more carefully just what symptom improvements the drug was producing. The FDA focus is on defining where there should need to be improvements in therapy from current options.

It is awkward for a company with an existing treatment to appear at these patient meetings – where the subtext is the lack of effectiveness of the existing treatments. A Stanford sleep disorder researcher who has worked with Jazz on Xyrem, Jed Black, however, did appear at the narcolepsy open public hearing to emphasize the need to educate physicians to understand the symptoms of narcolepsy.

Trying to balance the discussion with a third-party presentation at the open session of these open meetings is a weak alternative at best for sponsors. It is going to take sponsors awhile to figure out how best to participate in these meetings.

FDA’s “Sample ME-CFS Benefit-Risk Assessment Framework”

Decision Factor	Evidence and Uncertainties	Conclusion and Reasons
Analysis of Condition	− CFS and ME is a chronic multi-system disorder characterized by profound fatigue lasting for six or more months that is not improved by bed rest and that may be worsened by physical or mental activity. The disease may occur with a sudden or gradual onset. − Symptoms often include impaired cognitive functioning, severe fatigue or exhaustion, unrefreshing sleep, chronic pain, tender lymph nodes, sore throat, orthostatic intolerance, and sensory sensitivities. The nature and severity of symptoms vary from person to person. Many patients experience post-exertional malaise or a crash, which may occur without warning and upon even minimal physical or cognitive exertion and is associated with an acute exacerbation of these symptoms. − For most, CFS and ME affects their ability to function in daily activities of work, school, household management, and personal care. Many are bedbound some or all of the time. Many experience loss of careers, decreased quality of family life, social isolation, and feelings of hopelessness. − It is estimated that 1 to 4 million people in the US are afflicted with CFS and ME. − Refer to the Voice of the Patient report for a more detailed narrative.	CFS and ME is a serious disease. It is a highly variable disease and may manifest in different ways from person to person. It severely affects day-to-day functioning, and some patients struggle with the simplest tasks of daily life. CFS and ME has had devastating effects on many patients’ lives.
Current Treatment Options	− There are no FDA-approved therapies for this condition. − Various off-label prescription and non-prescription drug therapies are used by practitioners and patients. Therapies used to treat the underlying disease often include immunomodulators, antivirals, and antibiotics. A wide variety of drug therapies are also used to treat the symptoms of the disease, including analgesics, antidepressants, anti-inflammatories, beta blockers, muscle relaxants, opioids, sedatives, and stimulants. − Non-drug therapies such as pacing, exercise plans, dietary restrictions, vitamins, and supplements are common. − Many patients have experimented with a multitude of complex treatment regimens, with varying degrees of success. − Refer to the Voice of the Patient report for a more detailed narrative.	A significant unmet medical need exists for patients with CFS and ME. Many patients have tried a wide range of drug and non-drug therapies, and for some, none is effective. Patients are desperate for a treatments that target the underlying cause of the disease.