On April 26, 2013, the Food and Drug Administration (FDA) held a public meeting to discuss important and fundamental issues regarding the development of safe and effective drugs for the treatment of patients with chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME). For this meeting and summary report, the terms CFS, ME, and CFS and ME are used interchangeably in describing the conditions.1 This report summarizes the proceedings of this meeting.
The April 26th meeting was part of a larger two-day workshop to explore important issues with respect to the development of safe and effective therapies for CFS and ME. The preceding April 25th (“Day 1”) meeting focused on gathering patients’ experiences and perspectives regarding CFS and ME symptoms, impacts on daily life and treatment approaches currently used.2 The proceedings of the Day 1 meeting are summarized in a separate report.3
More information, including the agenda, transcript, and archived webcast of the April 25 and April 26 meetings, are available on the meeting webpage (http://www.fda.gov/Drugs/NewsEvents/ucm319188.htm).
Overview of CFS and ME
CFS and ME are characterized by profound fatigue, impaired cognitive functioning and other symptoms, and which may be worsened by even minimal physical or mental exertion. Significant symptoms associated with the disease include: impaired memory and mental concentration; exhaustion and weakness; sleep dysfunction including unrefreshing sleep, insomnia and sleep disruptions; chronic pain including muscle and joint pain, head and neck pain, and neuropathy; tender lymph nodes and/or recurrent sore throat; orthostatic intolerance; and sensitivity to light, sound, temperature and other stimuli. Most patients experience recurrent post-exertional malaise (PEM), which is associated with an acute exacerbation of symptoms. PEM can manifest itself in varying ways. It may occur without warning and upon even minimal physical or cognitive exertion. Impaired cognitive functioning and PEM are symptoms that can be particularly severe and disabling.
The exact cause or causes of CFS and ME are unknown. The nature and severity of symptoms vary from person to person, and diagnosis is challenging because there are no specific tests for the disorder. The disease may occur with sudden onset, such as following an infection, or it may occur with gradual onset. Some patients improve spontaneously; however many patients experience a prolonged course of illness with either periods of remission and exacerbation or steady decline.
1The term CFS and ME is used in the singular to refer to a disease or set of diseases. The term is intended to be inclusive and makes no judgment on the cause of different symptom complexes. At the current time, FDA does not endorse a particular definition or name as appropriate for use in clinical trials of drug products for CFS and ME.
2FDA conducted the April 25th (“Day 1”) meeting as part of the FDA’s Patient-Focused Drug Development initiative. For more information, see http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm326192.htm
3The April 25th (“Day 1”) report can be accessed at http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm368342.htm
Currently, there are no approved therapies indicated to treat CFS and ME. Various off-label, non-prescription, and non-drug therapies are used by practitioners and patients, often in combination and with varying degrees of success. Therapies used off-label to treat the underlying disease often include immunomodulators, antivirals and antibiotics. A wide variety of drug therapies are 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, strict control over exercise and activity, dietary restrictions, and vitamins and supplements are common.
A more detailed narrative of patients’ experience with the disease and therapies used to treat the disease are included in the Day 1 “Voice of the Patient” report. CFS and ME is a serious, debilitating disease that can have a devastating impact on the lives of patients and their loved ones. A significant unmet medical need exists to better address either the underlying cause(s) of the disease or its associated symptoms.
The April 26 meeting brought together scientific, industry and regulatory experts, as well as patients, healthcare providers and patient advocates. Discussions focused on several complex issues associated with developing and evaluating treatments for CFS and ME. It also touched upon opportunities for all stakeholders to help facilitate drug development. It focused on the drug development process in general, rather than on the development or use of specific drugs.
The meeting comprised four panels:
- Drug Development: Innovation, Expedited Pathways, Regulatory Considerations
- Symptoms and Treatments: A View from Clinicians and Patients
- CFS and ME Clinical Trial Endpoints and Design
- Roundtable Discussion - Summary and Path Forward
This report provides highlights of the meeting presentations and panel discussions. The transcript contains the full record of the day’s discussion. This report is not intended to be representative of the views and experiences of any specific group of individuals or entities.
Several key themes emerged throughout the meeting presentations and discussion, including the following:
- Participants validated the primary disease symptoms and impacts identified through the Day 1 discussion with patients. They reiterated the devastating toll CFS and ME takes on many patients and their families. They also echoed the need for treatments that can better relieve patients’ symptoms and, ultimately, address the underlying cause(s) of their disease.
- Drug development and innovation in CFS and ME face challenges for a variety of reasons, including the complexity of the disease, lack of known etiologies, and difficulty of diagnosis and clinical trial design. However, other disease areas provide successful examples of strategies, including collaborative research and data sharing, which can help overcome these challenges.
- A variety of groups and individuals play an important role in supporting and advancing drug development in CFS and ME. For example:
- Patients, who can support drug development by participating in patient registries and clinical trials and providing perspective on their disease.
- Advocacy groups, who can coordinate patient registries, support basic science research and natural history data collection, and find avenues for collaboration.
- Researchers and clinicians, who can advance scientific understanding of the disease and develop sound clinical trial methodology, and collaborate in their efforts to conduct research and share data.
- Drug developers, who can recognize the unmet need of patients with CFS and ME, gain a solid understanding of CFS and its symptoms, and utilize the most appropriate outcome assessments in clinical trials.
- FDA, who can utilize a variety of regulatory mechanisms that can facilitate development and evaluation of new therapies for serious diseases, especially in cases of unmet medical need. While these mechanisms can help facilitate drug development, they do not alter the underlying requirements for safety and effectiveness.
- FDA is committed to finding avenues to collaborate with interested parties to foster development for viable treatment options for CFS and ME. FDA is currently working on specific industry guidance for CFS and ME drugs that will provide advice for the pharmaceutical industry to expedite research on the development of treatments for these diseases.
These programs are described in detail in FDA’s Draft Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM358301.pdf
Panel 1: Drug Development: Innovation, Expedited Pathways, Regulatory Considerations
The first panel comprised three presentations focusing on the process of developing and/or repurposing drugs for the treatment of CFS and ME. Panelists explored the topics of drug innovation and “derisking” drug discovery, repositioning currently available drugs, and the available regulatory pathways for expediting drug development. A brief summary of each presentation follows:
Drug Innovation and Derisking Drug Discovery - Bernard Munos, MS, MBA, Founder, InnoThink Center for Research in Biomedical Innovation
Dr. Munos addressed challenges facing drug innovation in CFS and ME and strategies to address these challenges. Specifically, challenges in CFS and ME research are partially due to the heterogeneity of the disease, which makes it difficult to define the disease using traditional means (e.g., causes, endpoints). This, in turn, makes it difficult to advance the science needed to support drug development. However, Dr. Munos emphasized that similar challenges have been faced for other diseases and it is important to learn from successful examples of drug innovation in these contexts. Specifically, drug innovation for CFS and ME requires the development of an “innovation supply chain” that will facilitate research. This is defined by high-quality data, more diverse patient groups, and free access to data. The appropriate tools and technology (e.g., tissue banks, animal models, and biomarkers) should be developed, as well as encouraging a number of partners, including scientists, physicians currently treating CFS and ME, regulators, CFS and ME patients, and funding sources.
Knowledge and Intuition to Reposition Drugs ME/CFS - Suzanne D. Vernon, Ph.D., Scientific Director, the CFIDS Association of America
Dr. Vernon discussed the repositioning of drugs as a potential mechanism to encourage drug development for CFS and ME. She also emphasized the importance of creating a well developed infrastructure in order to encourage scientific innovation by industry and the scientific community. Dr. Vernon highlighted some initiatives that may help foster this infrastructure. She discussed, for example, the SolveCFS BioBank that includes a sample repository and registry of CFS and ME patients in addition to the Clinical Outcomes Search Space (COSS) that taps into existing knowledge (e.g., all CFS-related publications in PubMed) and can be used to identify drugs that have known mechanisms of action that work in specific areas of treatment. Dr. Vernon also described a web-based tool that enables physicians to rate the efficacy of medications used in the treatment of CFS and ME-related symptoms. She further emphasized that the information gathered through recording the results of these treatments may provide a valuable foundation for CFS and ME research.
Regulatory Pathways for Expediting Drug Development - Melissa Robb, Associate Director For Regulatory Affairs, Office of Medical Policy Initiatives, Office of Medical Policy, CDER, FDA
Ms. Robb described regulatory mechanisms that can facilitate and expedite the development and evaluation of new therapies for serious conditions, especially where there is an unmet need. She noted that serious conditions are associated with morbidity that has an impact on day-to-day functioning. Ms. Robb described four programs within FDA that can be used to expedite development and approval of new drug treatments: Fast Track, Breakthrough Therapy, Accelerated Approval, and Priority Review4. While these mechanisms can help facilitate drug development, they do not alter the underlying requirements for safety and effectiveness.
Panel 2: Symptoms and Treatments: A View from Clinicians and Patients
The second panel comprised six CFS and ME clinicians and patients. Two moderators led a discussion on the most significant symptoms of CFS and ME, considerations on clinical trials, decisions about therapies, and drugs or interventions that warrant more exploration.
The first discussion question gathered participants’ impressions regarding the most significant symptoms experienced by patients with CFS and ME, as discussed during the Day 1 meeting. Participants emphasized PEM and neurocognitive symptoms as key symptoms that affect patients. Additionally, other symptoms including pain, flu-like symptoms, disturbed sleep, psychological suffering, gastrointestinal problems, autonomic sensitivities/ orthostatic intolerance, endocrine symptoms, and chemical sensitivities were discussed.
The second discussion question focused on the clinical variables that patients and providers believe would be most relevant for clinical trials and other considerations on their use in clinical trials. Key themes that emerged during the discussion included:
- Recognizing the complexity of measuring fatigue and fatigability, even breaking them down into subcomponents, may ultimately assist with trial design and endpoint selection. For example, a drug may cause some improvement in cognitive fatigue prior to improvement in physical fatigue. With such an improvement, the patient may feel more confident, leading to increased activity and possibly a “crash”. Therefore, separating physical fatigue from cognitive fatigue may be helpful.
- It is important to consider the fluctuating nature of symptoms and symptom severity when designing trials, including how this may affect considerations for when and how often to measure a clinical endpoint.
- There is a relationship between symptoms and function. When designing clinical trials, researchers should consider including measures of both symptoms and function and should consider whether the primary outcome should be a functional assessment.
The third discussion question concerned key factors that patients and clinicians consider when making decisions about therapies to treat the symptoms associated with CFS and ME. Answers included:
- Basing treatment on what the patient is hoping to achieve.
- Addressing the most disabling symptom first.
- Recognizing that patients with CFS and ME have different tolerance to medications than those without the disease.
- Establishing which pain medications have worked in the past.
- Minimizing medications.
- Being mindful of financial and time burdens.
- Ensuring that any practitioner-based treatments (e.g., physical therapy) are provided by professionals knowledgeable about CFS and ME.
- Returning a sense of control to the patient to do self-management.
- Teaching patients pacing, both physical and cognitive.
- Addressing infectious triggers.
- Considering side effects, dependency potential, withdrawal potential, decreased effectiveness over time, long-term effects, teratogenic effects, and interaction of other medications.
The final discussion question asked which drugs or interventions participants were most interested in exploring. Participants indicated interest in: antivirals and immune modulating drugs, symptom management drugs for pain, stimulants for cognition, sleep medications, and drugs for orthostatic intolerance.
Panel 3: CFS and ME Clinical Trial Endpoints and Design
The third panel comprised four technical presentations focusing on different aspects of clinical trial design for the treatment of CFS and ME. Panelists discussed clinical trial design, exercise challenge studies, measures of CFS in a multi-site clinical study, and clinical outcome assessments. A brief summary of each presentation follows:
Clinical Trial Design in CFS - Peter C. Rowe, M.D. Professor of Pediatrics, Johns Hopkins University School of Medicine, Director, Chronic Fatigue Clinic, Johns Hopkins Children's Center
Dr. Rowe noted that, when trying to identify effective therapies, it is important to consider that CFS and ME are heterogeneous, with variable onsets and symptoms for each individual. Among other issues, flare-ups of symptoms can overwhelm the treatment being studied. Possible solutions to this include:
- Providing an initial “run-in program” of specific treatment targeted to help reduce fluctuation of symptoms during the trial period.
- Using a randomized withdrawal design: once patients have responded to a given drug, they are randomly selected to continue or discontinue the drug.
- Using a crossover design for clinical trials in which each person is used as his or her own control.
Dr. Rowe noted that design issues that come up most are the careful selection of groups or subgroups and the decision of which groups of patients to include. Some possible solutions include:
- Enriching study populations to increase the likelihood of enrolling those who could benefit from the study drug.
- Reducing clinical heterogeneity by careful subject selection using clear case definitions and clear eligibility criteria.
- Insisting on clinical evaluation to confirm diagnosis.
Because of the heterogeneity of the disease, much larger studies are needed to detect clinically important yet modest differences between patients.
Exercise Challenge Studies in CFS - Christopher R. Snell, Ph.D., Professor, Health, Exercise and Sports Sciences, University of the Pacific
Dr. Snell discussed exercise testing as a mechanism to assess function in CFS and ME. He noted that exercise testing can provide diagnostic and prognostic information and is a quantifiable measure that could be considered a biomarker. Further, exercise is an effective way to induce stress in order to look for differences between healthy individuals and those with pathology. Dr. Snell explained that humans produce energy through the cardio-respiratory system; therefore, scientists can look at how efficiently it operates before, during, and after exercise and extrapolate results. Dr. Snell described a variety of mechanisms of performing exercise testing. He noted that in his research, single exercise tests could not clearly distinguish between CFS and deconditioning, however two-day exercise testing could distinguish between the two. He noted that objective measures of fatigue in CFS and ME could be functional endpoints in clinical trials.
Measures of CFS in a Multi-Site Clinical Study - Elizabeth R. Unger, Ph.D., M.D., Chief, Chronic Viral Diseases Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention (CDC)
Dr. Unger provided an overview of a CDC study in which clinicians were asked to enroll patients considered to have CFS and ME. The goals were to collect standardized data on the major domains of the illness, and to evaluate how much heterogeneity there is between patients and their practices. Seven clinical centers participated. A wide variety of variables were considered in comparing the study data. Dr. Unger provided summary results of an interim analysis. Preliminary findings/suggestions include:
- For certain symptoms, including concentration/memory problems, one population indicated that there were severe problems but no problem was indicated for another population (supporting a two CFS and ME subtype hypothesis).
- Phenotypic measures may be limited in their ability to distinguish robust subgroups, so it is suggested this study be extended to include other measures.
Dr. Unger noted that additional patients will be enrolled and more data analyses completed. Final datasets will allow comparison of instruments measuring domains of CFS, and will also allow measures to correlate to changes in illness status. Further, this study will be expanded to include healthy controls and ill controls.
Clinical Outcome Assessments to Evaluate Treatment Benefit in Clinical Trials for CFS and ME - Ashley F. Slagle, MS, Ph.D., Oak Ridge Institute for Science and Education (ORISE) Fellow, Study Endpoints and Labeling Development Staff, ONDIO, CDER, FDA (contractor)
Dr. Slagle explained that, from FDA’s regulatory perspective, drug developers must document substantial evidence of treatment benefit from adequate and well-controlled clinical trials. Treatment benefit can be defined as the impact of treatment on how patients feel, function, or survive. The methods to assess a subject’s response must be well-defined and reliable. In CFS and ME, there are no scientifically agreed upon biomarkers to use as assessments. If treatments are approved on the basis of a biomarker that is used as a surrogate endpoint in the accelerated approval process, there is still a need to prove a true treatment benefit in subsequent trials, if that link is not yet fully established, making it critically important to find clinical outcome assessments that can directly tell us how patients are feeling and functioning.
Panel 4: Roundtable Discussion - Summary and Path Forward
The fourth panel included academic, government, and pharmaceutical industry representatives, as well as clinicians and patients, and comprised eight panelists and two moderators. The discussion gathered panelists’ impressions from the preceding panels and their perspectives on possible steps moving forward.
Key take away messages included:
- Panelists believed that continued attention needs to be placed on the following areas:
- The need for better and more accessible data;
- Consideration about how to most appropriately include severely ill, homebound/bedridden patients in studies;
- Encouraging young investigators involvement with CFS and ME;
- Understanding the value of partnerships with academia, the patient community, the pharmaceutical industry, and foundations;
- Understanding that accurate measurements can help ensure that we are being truly representative during the clinical trial process
- Understanding the pain and frustration from patients suffering from CFS and ME.
- There are subsets of patients who may respond differently to different treatments.
- There is unmet need for patients with CFS and ME given the lack of approved therapies. Drug trials in CFS and ME need funding and objective efficacy endpoints.
The discussion then focused on the most important factors in facilitating drug development for CFS and ME.
- There is a need for more data, especially baseline data. Development of data infrastructure and subgrouping to select the best target population is also needed.
- There should be emphasis on creating excellent clinical trial design that can be used in the conduct of clinical trials.
- All federal health agencies must be willing to collaborate in order to determine the appropriate pathway forward to achieving successful clinical trials.
- CFS and ME researchers should be willing to consider novel approaches and new ideas from those in other areas of clinical research who may have techniques, ideas, databases, and information to share.
- Considering the possibilities in repositioning drugs to encourage drug development for CFS and ME
FDA asked panelists what clinical trial design elements are most important to ensure the success of drug development programs for CFS and ME.
- Sample size (larger samples are better).
- Length of trial. Most trials do not show improvement until fourth month, so 10-week trials are too short.
- Conducting clinical trials to assess safety, even in those cases, where drugs are approved to treat other diseases since drug effects may differ for those with CFS and ME.
We asked for feedback from panelists about barriers to conducting CFS and ME research, and possible solutions. Identified barriers included:
- Striving for perfection; improvement is a worthwhile goal.
- The lack of new investigators coming into the field.
- The limited availability of funds or funding.
A question was posed about how to best leverage participants’ experience in order to facilitate drug improvement for CFS and ME. Answers included:
- FDA is willing to work with companies and investigators on drugs for CFS.
- NIH is willing and able to provide technical assistance that will enhance the proposals that are submitted regarding CFS and ME research.
- Members of the pharmaceutical industry can come together with other organizations to look at/understand endpoints for CFS and ME trials.
- Patient organizations are willing to help with recruiting patients for trials.
The final discussion question solicited possible next steps in moving forward with CFS and ME drug development. Suggestions included:
- A small meeting with FDA experts should be held to discuss and determine outcome variables.
- Creation of a guidance document to assist with designing CFS and ME drug development programs.
We are grateful to the patients, academicians, government experts and industry representatives who contributed to this important two-day discussion. We particularly appreciated hearing from the patients who provided important feedback on their symptoms, personal experiences and treatment options. This feedback helped propel all of us towards our mutual goal of moving drug development forward in this area.
Drug development requires multiple partners. In its role, FDA does not conduct the clinical studies needed to approve a drug but instead helps to oversee the drug development process to ensure that these studies meet the regulatory standards for drug approval. FDA works with other stakeholders in drug development, such as pharmaceutical companies, who have expressed interest in developing a drug and advises them about how best to meet the requirements for drug approval. In their role, pharmaceutical companies often develop drugs through use of academia and play an important role in drug development by funding studies and determining study design. Through these types of interactions with other stakeholders, FDA helps assure that we understand the risks associated with drugs, how these risks should be managed, and the anticipated benefits of a drug. These components form the framework of a drug’s risk-benefit profile. In addition to working directly with pharmaceutical companies and other stakeholders, FDA can outline our current thinking on a topic through the use of guidances. FDA is currently working on specific industry guidance for CFS and ME drugs that will provide advice for the pharmaceutical industry in an effort to expedite research on the development of treatments for these diseases. When this guidance is published, we encourage all stakeholder groups to provide comments to us in an effort to encourage appropriate and expedited drug development to treat these diseases.
We recognize that there are no approved therapies to treat CFS and ME and this represents a significant public health concern. A variety of individuals and groups play key roles in the drug development process. We are committed to finding avenues to collaborate with interested parties to foster development for viable treatment options for CFS and ME.