http://www.raredr.com/contributor/jennifer-payne/2017/01/medical-food-vah
A Medical Food Affair & VA Health Care


Our Institutional Pride  

VA pride as the nation’s largest, integrated health care system and high performing culture took root more than a century and a half ago with beloved visionary and freedom advocate, President Lincoln.  Our mission and timeless dedication to the provision of safe, quality compassionate care delivers on the promise made by Lincoln in his Second Inaugural address “…to care for him who shall have borne the battle and for his widow and his orphan.1”  

In the backdrop of this famous speech, our country had been ravaged by war, secessionist threats, and slavery. But, the President held steadfast with unwavering commitment to sovereignty, respect, and finding unity and a healing path for directing the course of the nation at the brink of reconstruction. Application of such transformational leadership and values to today’s modern health care system captures the essence of Veterans Health Administration (VHA) and continuously evolving culture of performance improvement. Just as Lincoln persevered in tireless efforts for restoration and transformation of the Union and setting a foundation with progressive legislation, it still takes passionate leaders to make an impact and to strive for what is safe and just;  even when having to “choose the harder right” over the “easier wrong.2
 
Lincoln’s vision for the nation are embodied in the VA Core Values today, defined as Integrity, Commitment, Advocacy, Respect, and Excellence. And, it is our VA Core Characteristics that guide this vision and support the mission for transformational change with fostering a sense of trustworthiness, accessibility, quality, innovation, agility and integration for advancing Veteran’s health. Possessing this strategic vision is as imperative to America in 1865 as it is to setting a blueprint for 21st century excellence today.

However, recent remarks by former VA Secretary Robert A. McDonald remind us that in the provision of Veteran-centric care and adapting to changing needs and changing times, the “VA simply can’t do everything we need to do for our Veterans alone.3” Success also takes the forging of strategic partnerships, empowering Veterans as equal partners, and the recognition for drawing upon unique skills, diverse talents and insights internally and externally with nongovernment expertise for meeting VA priorities in innovative access solutions and optimizing all aspects of Veteran’s health – mind, body and spirit. Failure to do otherwise would be analogous to just plain living in a vacuum.

Bucking the Status Quo on Nutraceutical Nonsense          

While the VA prides itself as being on the forefront of knowledge and discovery – from giving America the first implantable cardiac pacemakers and first successful liver transplants, to artificial limbs, robotics, and leading the precision medicine initiative;3  one area of research that does remain in an existential vacuum and warrants transformational change is the category of FDA regulated medical foods.

The echoes of Lincoln’s promise for healing bonds have been rendered hollow within the brick walls of federal bureaucracy both inside and outside the VA health care system. The FDA’s lack of initiative and unresponsiveness to progressive measures, ownership of problems, and supporting key objectives as a partnering federal  institution to VA have impacted thousands of patients, providers, companies, insurers, policy makers, and researchers  that rely on FDA for guiding therapeutic decision making. Choosing the path for the “easier wrong” has become manifest in a decades-long debate between the US Congress and the FDA over what constitutes a medical food.

Although this topic of discussion is not likely to be laid to rest any time soon and is almost always confused with the overarching non-legal term “nutraceutical,” new impetus is given to the Department of Veterans for addressing medical food game changers emerging on the VHA scene and cutting edge of 21st century microbiome science exploration.
 
For just fiscal year 2016 alone, VA spent $630 million on research4 and the estimated total research resources comes to about $1.8 billion annually3 in meeting a projected population of  over 22 million Veterans. In addition, Robert A. McDonald has praised VA researchers on possessing the “most comprehensive genome data set humanity has created,” which is currently leading the applications of precision medicine for a variety of conditions - such as Gulf War Illness and Post Traumatic Stress Disorder.3

The Gulf War Vets in particular constitute a rare, specialty subpopulation most worthy for translating research into novel therapy. And, already new consumer and ethical demands for elevating medical foods out of what can be coined the “translational valley of death5” have infiltrated VHA framework. The introduction of the first ever probiotic medical food to Veteran-centric  protocol geared at treating symptoms associated with Gulf War Illness is now underway in collaboration with US Department of Defense; business partner, ExeGi Pharma (VisbiomeTM); study sponsor, University of Utah; and VA Office of Research and Development.6 These championing efforts are not only challenging contemporary scientific progress and medical policy recommendations on caring for Gulf War Veterans, but novel use of medical foods bring vision and hope that thinks beyond nutrition.

The mantra of VA registered dietician nutritionists and rare disease advocates is one and the same when it comes to transforming health into meaningful outcomes, “one size does not fit all.” And, when it comes to adding an element of diversity in treatment approach, VA Capitol Health Care Network dietician, Karen Sassaman, offers some food for thought in stating: “We are looking at the whole Veteran and not just one aspect of their food intake. We consider medication, activity, and disease process.7”  

Defining Gulf War Illnesses

Although the VA Research Advisory Committee (RAC) on Gulf War Veterans’ Illnesses concurs with the description offered by National Academy of Medicine (NAM) on Gulf War Illness as “the signature health concern of 1990-1991 Gulf War Veterans,8” the VA does not officially recognize the terms “Gulf War Syndrome ” in denoting this disease process.  Pursuant to the statutory provisions of the Persian Gulf War Syndrome Act and addition of 38 CFR 3.317, VA refers to these illnesses as “Chronic Multi-Symptom Illness” due to their elusive nature. Unexplained multi-symptom illnesses encompass, but are not limited to fibromyalgia, irritable bowel syndrome (IBS) and chronic fatigue syndrome.9  However, one thing for certain is that Chronic Multi-Syndrome Illness is real and as per NAM committee statement, Chronic Multi-Syndrome Illness “is not a psychosomatic illness.8” Historical accounts are offered by Gulf War Veterans in their own words:9

“…In mid-January, my team of about 30 men was directed to begin taking PB (pyridostygmine bromide) …that we had been issued. We were told we had no choice in consenting and we were ordered to take them, and that we would probably experience symptoms similar to mild nerve agent poisoning…I experienced significant side effects, including watery eyes, runny nose, confusion, dizziness, muscle twitching, diarrhea, weight loss, and generally feeling quite ill..”
 
“When I had the honor and privilege of serving with him, Joel was the epitome of what a special operations officer should be – smart, physically and mentally fit, a respected and beloved leader…so it was all the more heartbreaking to learn that he’s now totally debilitated and disabled at home, overcome by chronic, widespread pain that affects so many of us, and more health issues than he can name.”
 
Among the 700,000 thousand men and women deployed to Southwest Asia theater operations during the Persian Gulf War, 25-30% of these servicemen and women ( 175,000) are estimated to be affected.10 In addition, the men and women who served in operation Desert Shield and Desert Storm have been characterized as the most ethnically diverse and older cohort of Veterans “than any deployed force in prior US conflicts in the 20th and 21st century.9 And, with NAM’s Gulf War and Health Volume 10 advice and recommendations for “placing top priority on the identification and development of effective therapeutic interventions and management strategies for Gulf War Illness,8” it goes to follow that such a rare, specialty subpopulation of Veterans is most deserving of alternate approach and rethinking the “brain-body interconnectedness” with the most advanced 21st century scientific applications.8

Visbiome for Gulf War Vets        

The brain and gut interplay has also been the driving force for proposed VA regulatory amendments to 38 CFR 3.317, thereby removing the terms “Irritable Bowel Syndrome” and replacing it with “Functional Gastro-Intestinal Disorders” (FGIDs).11  According to the proposed rules as announced in the Federal Register, FGIDs are “medically unexplained because they are, by definition, disorders that cannot be attributed to observable structural or organic changes and the causes of the disorders are generally not known.11” Examples include IBS and functional dyspepsia, syndromes that vary in both severity and clinical manifestations involving pain and changes in the bowel of recurrent and prolonged nature. 

Because the pathophysiology for GI disturbances and impaired microbiota of the gut include dysregulation of neural pathways9  as opposed to anatomical abnormalities, the statutory criteria as revised in VA regulations are satisfied.11  The development of post-infectious IBS in Gulf War Vets from exposure to enteric pathogens is of special relevance.  Pertinent findings in scientific literature show substantial evidence for deployed Veterans having the following:  a reported 50% higher incidence of acute gastroenteritis; greater risk for IBS diagnosis once exposed to infectious gastroenteritis; and IBS symptoms characterized by heightened activity of cells involved in the immune system’s response pathways for regulating inflammation and infection as opposed to non-deployed Veterans.9   
 
Although the management of global symptoms for IBS span a variety of drug classes such as antispasmodics, selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants  (TCAs),12 expanded research and the development of microbiome science  with probiotic use is becoming an emerging therapeutic reality. 

For example, research methodologies incorporating MEDLINE, EMBASE, and Cochrane Controlled Trials Register in meta-analysis of 24 randomized controlled clinical trials for patients with IBS found beneficial effects and concluded probiotics are effective treatments for improving symptoms.13 Although the optimal species and strains remain to identified,12  the efficacy of medical food, Visbiome (probiotic mixture of ExeGi Pharma)  is of focused study in the treatment of IBS symptoms in Gulf War Veterans. Objectives of a randomized, double-blinded placebo controlled trial aim to improve intestinal symptoms of IBS in Gulf War Veterans with secondary outcomes measures geared at reducing non-intestinal symptoms of IBS and for determining  a correlation with treatment response  to cytokine activity and changes in the gut flora.6  

Visbiome is the therapeutic equivalent to medical food, VSL#3 (VSL Pharmaceuticals) and contains the same probiotic blend of strains that was invented over 25 years ago by recognized fellow of the American College of Gastroenterology (ACG) and distinguished leader in microbiome research and education, Claudio De Simone MD, PhD.   The De Simone formulation has been included in international consensus treatment guidelines14 and is well published among scientific literature. 

In addition, clinical experience supporting use with Visbiome intended for the dietary management of dysbiosis associated with IBS can be found among the Journal of Clinical Gastroenterology, BMC Gastroenterology, Microbial Ecology in Health and Disease,  and American Journal of Gastroenterology.15 

Because  patients with IBS require consumption of higher levels of probiotic bacteria than the general public for maintaining microbial balance and that cannot be met by normal dietary modifications alone, Visbiome is regulated as a medical food and fulfills the statutory requirements defined in [21 USC 360ee(b)(3)], amendment to the Orphan Drug Act. 

Visbiome also addresses the distinct nutritional requirements for patients with ulcerative colitis and hepatic encephalopathy and contains the only probiotic blend recognized by eminent  professionals in the American College of Gastroenterology, German Association of Gastroenterology, British Society of Gastroenterology, European Crohn’s and Colitis Organization, and Cochrane Collaboration as effective in the dietary management of pouchitis.16 

The pipeline portfolio reflects ongoing studies in a variety of other  disease states, such as HIV and collaborative efforts with the National Institute of Allergy and Infectious Diseases (NIAID) on investigating whether probiotic use can restore intestinal function and decrease systemic inflammation in patients taking suppressive antiretroviral therapy.17
 
Can Visbiome deliver for our Gulf War Veterans? Although this remains to be determined, RAC advice related to NAM’s Gulf War and Health Volume 10 reminds us that the most notable limitation of published data – timeliness - can also be a great strength for ExeGi Pharma and the forming of new strategic partnerships in search of innovative access solutions with treatment that is already commercially available for Veterans with rare, unmet needs. 

In a June 28, 2016 letter from Chair, Stephen Hauser of RAC to former Secretary of Veterans Affairs, Robert A. McDonald, it is written: “…published literature does not fully reflect the current state of the field.  New findings are continuously emerging and these require periodic reassessment of underlying concepts of causality and pathophysiology.8”  Hence, the VHA is called to do what the FDA has never done, nor is equipped to do when it comes to the periodic reassessment of medical foods and expanding role in various therapeutic applications. 

This process requires defining substantial evidence for conferring a benefit if transforming health care is the primary goal in accelerating and defining meaningful pathways of significance and value for non-pharmacological treatment.  Leaders and advocates have responsibility to reaffirm the same mission defined by Lincoln - the VA mission of caring - and continuously evaluate and revise policies with the changing of the times in order to be functional and efficiently operative in the 21st century so Veterans get the right treatment – safe, quality and cost effective treatment - in their hands at the right time. 

In the Eye of the Storm    

While expeditious review is an imperative for moving translational research to novel therapy and is most applicable to the ever changing, evolving, heterogeneous industry of medical foods, it is as equally important for National Academy of Science (NAS) and peer advisors to the rest of the nation on matters of public health be fully aware of their decision ramifications on not just VA proposed rulemaking, but regulatory policy in general. 

According to the June 30, 2016 letter to the President of the United States (via the Secretary of Veterans Affairs) from the Commission on Care regarding transforming Veteran’s health care, it is stated that the “most public and glaring deficiency was access problems.18” And, among the single most determinant factors impacting a Veteran’s access and choice is the connotation of service connection and special disability compensation so Veterans can afford treatment. 

VA  statutory authorization for Gulf War Veterans meeting the specified criteria on FGIDs as Chronic Multi-Symptom Illnesses was not enacted until  passage of amendments  to 38 CFR 3.317.  The newly specified adjudication regulations concerning a presumptive service connection went against scientific and medical evidence presented by prior NAS findings regarding the strength of evidence for an identified association between FGIDs and exposure to pathogens which warranted further investigation at the time.11  These new policy revisions clarifying language on FGIDs, the intent behind new proposed VA rulemaking, and both dissemination and implementation of this change really underscore the implications on the primary beneficiary  - the Veteran - and opened the gateway to access treatment.   
 
Regarding the category of medical foods, this same scenario also played out in 1972 for patients with rare, inborn errors of metabolism (IEM) as rare Veterans in the 21st century today struggling with the challenges of Gulf War Illnesses.  Similar to VA decision making, FDA decision making was also much influenced by another national contract initiative with peer academies, the National Academy of Sciences (NAS) and the National Research Council (NRC) in conducting the most comprehensive audit ever into the entire prescription drug market. 

The handling of the 1972 NAS-NRC final report on drugs used in metabolic disorders was most unusual and enacted in response to Congressional mandate with the 1962 Drug Amendments.  NAS influenced FDA with sudden 1972 reclassification of the prescription drug, Lofenalac used in the treatment of rare, IEM, phenylketonuria (PKU) to a food for special dietary use; thereby giving birth to later generations of products now known today as “medical foods.” 

Although medical foods are FDA regulated, medical foods have no official FDA stamp of approval due to no premarket approval requirements as drugs for which randomized, controlled clinical trials are the gold standard for demonstration of safety and efficacy.  Without that FDA seal of approval for medical foods or assurance such periodic reassessment has taken place for optimizing health outcomes based on review of substantial evidence, access is denied. 

This is the story of my life as a patient living with PKU and only pharmacist among 400,000 VHA employees that depends upon medical foods not just for health, but for survival.  To witness a similar repeat of this unfortunate event in VHA over 4 decades later should serve as an admonition.  Similar to rare Veterans for which presumption of service-connectedness was initially denied based upon NAS scientific and medical advisory policy recommendations, it is all of America that lose out when external input does not include the voice of the real expert, the patient.

References

1 President Lincoln, Second Inaugural Address March 4, 1865. The Avalon Project, Lillian Goldman Law Library, Yale 2008. http://avalon.law.yale.edu/19th_century/lincoln2.asp
2 Cadet Prayer, http://www.west-point.org/greimanj/west_point/prayer.htm quoted in Secretary Robert A. McDonald, Code of Support Foundation Holiday Dinner, (speech) December 3, 2016, Arlington VA. https://www.va.gov/opa/speeches/2016/12_03_2016.asp
3 Secretary Robert A. McDonald, Code of Support Foundation Holiday Dinner, (speech) December 3, 2016, Arlington VA. https://www.va.gov/opa/speeches/2016/12_03_2016.asp
4 Veterans Health Administration, Office of the Under Secretary for Health, VHA Vitals (information flyer), March 28, 2016.
5 Robert Ring, Opening Keynote, Global Genes 2016 Rare Patient Advocacy Summit, Huntington Beach, CA, September 24, 2016.
6 Ashok K. Tuteja, VA Office of Research and Development, Probiotic (Visbiome) for Gulf War Illness NCT02011542, service of National Institutes of Health, Clinical Trials.gov, last verified August 2016. https://clinicaltrials.gov/ct2/show/NCT02011542
7 Andre Parker, “Eat Healthy, Feel Great!” VA Capitol Health Care Network, August 14, 2015. http://va.gov/VISN5/features/nutrition.asp
8 Stephen Hauser, University of California San Francisco Department of Neurology, on behalf of  Research Advisory Committee on Gulf War Veterans’ Illnesses, letter to Hon. Robert A. McDonald, Secretary of Veterans Affairs June 28, 2016.
9 Department of Veterans Affairs Employee Education System, Caring for Gulf War I Veterans, Revised October 2010, Released July 2011. 
10 Research Advisory Committee on Gulf War Veterans’ Illnesses, US Department of Veterans Affairs, Gulf War Illness and the Health of Gulf War Veterans: Research Update and Recommendations, 2009-2013, Updated Scientific Findings and Recommendations, Executive Summary, Washington DC., May 2014
11 Department of Veterans Affairs, Presumptive Service Connection for Diseases Associated with Persian Gulf War Service: Functional Gastrointestinal Disorders, Proposed Rule, Federal Register Volume 75, No. 221, November 17, 2010.
12 The Medical Letter, current subscriber, Vol. 58 (1504) September 26, 2016
13 The Medical Letter, current subscriber, Vol. 58 (1504) September 26, 2016 quoted in AC Ford et al. Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis. Am J Gastroenterol 2014; 109:1547
14 ExeGi Pharma - Visbiome™ 2017, https://www.visbiome.com/pages/a-message-from-the-inventor
15 ExeGi Pharma - Visbiome™ Package Insert, recent changes 8/2016
16 ExeGi Pharma - Visbiome™ Package Insert quoted in Kornbluth, et al. Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Committee. Am J Gastroenterol. 2010; Mar;105(3):501-23; Hoffmann JC, et al. Diagnosis and therapy of ulcerative colitis: results of an evidence based consensus conference by the German Society of Digestive and Metabolic Diseases and the competence network on inflammatory bowel disease. Z Gastroenterol. 2004;42:979-983; Mowat C, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2011. May 60(5) 571-607;Biancone L, et al. European evidence-based Consensus on the management of ulcerative colitis: Special situations. J. Crohns Colitis. (2008) 2, 63-92; Holubar SD, et al. Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review). Cochrane Database of Systematic Reviews. 2010, Issue 6. Art. No.: CD001176.DOI:10.1002/14651858.CD001176. pub2.
17 ExeGi Pharma 2016 http://exegipharma.com/pipeline-programs/
18 Commission on Care, letter (enclosed) Final Report of the Commission on Care, June 30, 2016, Washington DC. 
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