Holes in the drug market place: How do we overcome these obstacles?

Complex diseases present complex challenges for researchers, clinicians, drug manufacturers, and FDA for a variety of reasons. The impact, however, is felt at the patient level, particularly when there are no FDA-approved treatments. In some cases, such as myalgic encephalomyelitis, commonly known as chronic fatigue syndrome (ME/CFS), the devastating effects of the disease are exacerbated by the huge deficit in the drug application and approval pipeline. This leaves the patient population with little hope.

Dysfunction at multiple levels

ME/CFS is a complex, multisystem disease in which the adverse health consequences are manifold. ME/CFS patients are not homogenous and vary in severity, onset, expression of symptoms, and comorbid conditions. Many of the patients are severely debilitated with little to no function or quality of life. FDA categorizes ME/CFS as a serious condition. Their recent Voice of the Patient report reveals the personal and professional devastation caused by this disease.¹ ME/CFS is characterized by cognitive symptoms such as confusion, disorientation, and the inability to process information. The physical symptoms include unrefreshing sleep, orthostatic intolerance, and gastrointestinal symptoms along with fear, anxiety, and depression. Most notable among symptoms is an overwhelming persistent and relapsing fatigue, as well as “postexertional malaise,” which patients describe as a “collapse” or “crash.” These collapses are a result of cognitive or physical exertion beyond the limited aerobic capacity at that moment and can last for days, weeks, months, or years. The multifaceted nature of this type of chronic illness leaves the question: Where does one start to impact the disease? Drug manufacturers look for a transparent regulatory path, and FDA relies on validated endpoints and biomarkers.

Lack of data and diagnostics

From a research perspective there has been little funding devoted to ME/CFS, which stems from its complexity and past doubt that the disease was real. Research funding continues to lag behind diseases with smaller populations. The National Institutes of Health has committed $116 million to multiple sclerosis with a population of 400,000 and at least 8 approved treatments compared to $5 million for ME/CFS with a population of at least 1 million and no approved treatments.² Although the Centers for Disease Control and Prevention (CDC) was called to investigate the outbreaks of ME/CFS as far back as the mid-1980s, the CDC did not undertake a public awareness campaign until 2006. It was just this month that FDA finally declared it a public health issue. The etiology of ME/CFS is still unknown and there are no diagnostic tests and or widely used biomarkers. Expert clinicians and researchers have identified a number of biomarkers in cytokine levels, viral titers, and VO2 max performance, among others; however, FDA has not yet validated these markers. The disease still lacks credibility and understanding among physicians, causing tremendous underdiagnoses and thus no real market for pharmaceuticals.

No clear regulatory path

With the passage of Prescription Drug User Fee Act V, FDA touts a commitment to bio innovation and treatments for those chronically ill, particularly unmet medical needs. ME/CFS still fails to raise the attention of drug manufacturers. The disease with more than 1 million persons affected by it is too large a group to be categorized as a rare or orphan disease and too small to garner the word “crisis” or “epidemic,” such as does Alzheimer’s disease or obesity. More importantly, the drug manufacturers must see that FDA has opened the door to approving drugs for this disease. To date, ME/CFS has been included in at least 6 different FDA review divisions, illuminating the challenge of such a complex illness given that it can fall into a number of these divisions and still not quite fit the drug profile for that division, thus not fitting into the traditional approval path. Currently ME/CFS has been placed in the rheumatology division, yet it could easily be placed in the antiviral division because many of the patients are often afflicted with underlying viruses. Pharmaceutical manufacturers want to know which division they are betting on.

Expediting review does not equal expedited approval

In the FDA Safety and Innovation Act (FDASIA) of July 2012, Congress and President Barack Obama revised the statutory provisions of Subpart H.³ FDA has published a draft guidance for this provision. In the guidance, FDA expands the use of accelerated approval to expedite patient access to important treatments for serious conditions, provide additional flexibility and clarification concerning the use of endpoints, and make clear that FDA has the authority to consider pharmacologic or other evidence in determining whether an end point [surrogate end point] is reasonably likely to predict the clinical end point. Although these are differing tracks, the expediting really just specifies a timeline that FDA must adhere to throughout the review cycle. It does not have any concrete bearing on advancing final approval or how flexibility is applied during the review process. Furthermore, FDA still has the authority to deny the manufacturer’s application request for one of these designations.

For example, rintatolimod (Ampligen, Hemispherx), the only treatment currently in the pipeline for ME/CFS, was denied fast tracking at least 3 times. In 2012, the drug was reviewed as a new molecular entity, allowing the review cycle to take place within a 6-month timeframe. Even with the large, unmet medical needs and hundreds of patients’ testimony, including confirming its efficacy, rintatolimod was denied approval. One question raised was about the clinical endpoints, which were valid when the drug was in the cardio renal division and now questionably in the rheumatology division.

Overall health improvement versus bull’s eye statistical end point

The critical question becomes whether the standard for evaluating if a drug should be approved is broad enough to encompass chronic complex illnesses, such as ME/CFS. Most drugs are still approved on the strict standard of whether the drug meets the endpoints and standards for safety. Complex diseases, however, require a much higher understanding of the disease in order to apply medical judgment. 

Take the case of the recently approved obesity drugs. Originally denied approval, the stakeholders’ articulated a more global view from which the drugs should be evaluated. By encompassing the breadth of the disease past that of the body mass index (BMI) endpoint, they articulated the day-to-day impact of the disease on the patients’ quality of life. In addition, they demonstrated that a small measure of change can provide health improvement over a number of adverse health concerns.

In these situations, the context of risk versus benefit takes on an entirely different framework and sets the context within the realm of medical judgment and patient care and less inside the strict game of statistical analysis. At last year’s FDA patient-focused drug development workshop on ME/CFS, the lead reviewer of rintatolimod said, “…this was just really amazing, I think, in bringing out the symptoms and making everything so very clear.” This comment leads patients to wonder that if FDA had fully understood the breadth of the disease, the review of this drug months earlier might have had a different outcome for patients who so desperately need a treatment.

Lori Chapo-Kroger, RN, is a former ICU charge nurse. She is now the president and CEO of PANDORA Org, the largest patient advocacy group for ME/CFS and similar neuro-endocrine-immune diseases. She has lived with ME/CFS for the past 11 years.

References

1. The Voice of the Patient. A series of reports from the U.S. Food and Drug Administration’s (FDA’s) patient-focused drug development initiative. Chronic fatigue syndrome and myalgic encephalomyelitis. Public meeting. April 25, 2013. Available at: http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM368806.pdf. Accessed January 7, 2014.

2. National Institutes of Health. Estimates of funding for various research, condition, and disease categories (RCDC). Available at: http://report.nih.gov/PFSummaryTable.aspx. Accessed January 7, 2014.

3. FDA. Accelerated and restricted approvals under Subpart H (drugs) and Subpart E (biologics). Available at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ucm121597.htm. Accessed January 30, 2014.