This article submission is in response to recent publication in the Food and Drug Law Journal on medical food best practices1
by principal author, Bruce Burnett and lead of trade association - the Nutrition and Medical Food Coalition (NMFC).
While it is acknowledged the article stems from professional experiences of the author(s) and fall atypical to normal and customary citations under legal conventions, a significant portion appears to have the undertones of nothing more than disgruntled attorneys - the predominant stakeholders of the Food and Drug Law Institute (FDLI).
One has to look no farther than inside the cover page to see the names Hyman, Phelps & McNamara (HPM) listed adjacent to Chair, FDLI and be cautioned to read the fine print in the pages that follow. HPM has a history of screaming foul play at the FDA due to bruised egos on being “deprived meaningful opportunity to change FDA policy2
” and also for threatening law suits in response to what has been perceived as “unconstitutional restrictions2
” by the agency on their clients’ most niche market (diabetes).
While there is no doubt certain lawyers in this prestigious firm (Frank J. Sasinowski, M.S., M.P.H., J.D) have made most notable efforts in rare disease,3
it is paradoxically Hyman, Phelps & McNamara executing some of the most contradictory and damaging behaviors with perversion of federal statute, otherwise known as the federal definition of medical foods (amendment to the Orphan Drug Act).
The proposed industry best practices actually make up a disproportionate part of the article and are comprised mainly in tabular format which lacks substance and a policy design in setting a roadmap for improvement. Most notably, there is no fair inclusion at all for patients with rare disease as principal stakeholder in this dialogue, nor does the true intent of the Orphan Drug Act shine through. When it comes to propelling orphan innovation in the nontraditional drug development setting as such with the category of medical foods, which was engineered specifically for patients with rare, genetic disease, clearly; clarifications and comment are warranted. Moreover, some diversity from an actual orphan and medical foods consumer would allow for more balanced discussion, especially in the backdrop of GAO and pending investigation on possible abuses of the Orphan Drug Act by pharma.4
Debunking Some Myths
In addition, there is need to debunk some myths on this poorly understood and confused category, specifically as it pertains to the treatment of PKU as given in the historical account by Burnett on US regulatory history. I welcome opportunity to share my perspectives.
The proposed best practices in the Food and Drug Law Journal open with description on key attributes for an ideal therapeutic, namely low toxicity and efficacy. Since safety is a given with medical foods generally recognized as safe (GRAS), it is logical to introduce the category as an ideal therapeutic candidate, except efficacy is not proven. Hence, such clinical substantiation is among one the most contentious issues surrounding medical foods since randomized clinical trials (RCTs) are the FDA’s gold standard for defining efficacy in traditional drug development pathways. The author(s) do a nice job identifying the other controversies: lack of FDA approval, awareness/perceptions as huge market uptake barriers, defining distinctive nutritional requirements, and downright confusion.1
I would concur with all these based upon my professional and personal experiences and correspondences with Burnett himself. However, I would add that at the root cause, it is the federal definition on medical foods which is nonworking and falls much short on a setting a distinct and needed critical standard for medical foods as separate from both OTCs and dietary supplements.
In comparison, the industry desires to have the broadest interpretation possible on the federal statute, (21 U.S.C. 360ee(b)(3)). This allows for lucrative reward on medical foods intended for more chronic, prevalent conditions (like diabetes) and larger populations, who, unlike rare disease, already have numerous FDA approved DRUG options that are proven both safe and efficacious and are sealed with the official FDA stamp of approval – the National Drug Code.
What cache lies in the FDA Vault? Was a medical food for diabetes the intent of the FDA in 1972 regulatory decision making? Contrary to Hyman, Phelps, and McNamara’s arguments and back lash on the agency with postulated “blanket prohibition2
” and narrow constraint of federal law, here lies an example of unwavering commitment to PKU and rare in the form of historical proof for FDA having to give an emphatic “no” in reaffirming the agency position - again, and again, in guidance revisions expressing disapproval on medical foods for diabetes:
Robert C. Wetherell, Jr., Associate Commissioner for Legislative Affairs FDA, in reply to Senator Paul S. Sarbanes at the request of FDA Commissioner Kennedy, January 16, 1979:
“When Lofenalac was introduced as a dietary treatment for phenylketonuria in 1958, we classified it AS A NEW DRUG and, therefore, required the manufacturer to submit data on the product through the New Drug Application (NDA) procedures. Since then, THERE HAS BEEN AN INCREASING RELUCTANCE ON THE PART OF MANUFACTURERS TO SUPPLY SIMILAR PRODUCTS DUE TO THE SMALL MARKET INVOLVED, MINIMAL OR NO PROFIT INCENTIVES, PRODUCT LIABILITY, AND THE COST OF THE NDA PROCESS.
In order to ensure the ready availability of these products for the nutritional support of patients WITH GENETIC DISORDERS WE CHANGED OUR POLICY IN 1972 AND RECLASSIFIED THESE PRODUCTS AS FOODS FOR USE SOLELY UNDER MEDICAL SUPERVISION.”
Furthermore, as per the Federal Register vol. 37, No. 175 September 8, 1972: “The following preparation is no longer regarded as a DRUG by the Food and Drug Administration, but as a food for special dietary use coming under the purview of the Administration’s Bureau of Foods: Lofenalac
If that wasn’t an early version of the Orphan Drug Act, I do not what it is.
The excerpt from FDA screams innovation for orphans, and incentive came in the form of bypassing the now more formalized NDA procedures.
Burnett could not have used more offensive misrepresentations on Lofenalac – my lifeline for PKU (diagnosed in 1973) – as a mere “meal replacement therapy1” and catering into Hyman, Phelps & McNamara’s onslaught of real medical foods with such “medical food mumbo jumbo.5”
Medical Foods Can Mean the Difference Between Life and Death
What the proposed best practices omits was that access to Lofenalac dictated the difference between life and death for those touched by PKU. Those who had Lofenalac thrived. And, with continuous therapy, they could have opportunity for living a successful life. Those without this treatment were condemned to a lifetime of institutional care and mental retardation. Permanent disability? Brain death? There is no medical food to date that can confer a proven benefit with significant mental growth in a PKU individual who had already sustained brain damage prior to dietary intervention. PKU is the one and one reason only the category of medical foods exists as well as being the driving force for an early version of the Orphan Drug Act a decade before ever being passed in Congress!
The terms “medical foods” were not legal until the 1988 Amendment to the Orphan Drug Act, which was signed into law under the Republican Reagan administration in 1983. Why? For orphans! There is no mention of this in proposed best practices nor any appropriate reference given to Lofenalac as the first PRESRCIPTION DRUG FDA APPROVED FOR TREATMENT OF PKU. Later generation medical foods still fall purview to the former Bureau of Foods (as did Lofenalac), which has now been renamed the Center for Safety and Applied Nutrition (CFSAN). And, both the CFSAN and Center for Drug Evaluation and Research (CDER, former Bureau of Drugs) are not without the aforementioned controversies eloquently described by Burnett in the article.
I would agree withdrawal of 1996 Advanced Notice of Proposed Rulemaking (ANPR) in 2003 was a tragic move on the part of the agency, and the 2016 finalized guidance falls significantly short of solving anything. Medical foods should be a priority for the agency – and the time to shift attention has never been more critical now than ever. For example, First Databank set off an alarm in assuming its “pseudo- regulatory
” and “possibly illegal role” as per Burnett in today’s Era of Affordable Care Act.1
First Databank, in acting as FDA enforcer where they have no business, caused much damage in the form of significant financial blow to industry stakeholders and patients forced out of treatment options with lost coverage on medical foods in the wake of sudden May 2015 blanket reclassification from Rx to OTC.
This spread of miscommunication by one of the nation’s largest and most respected drug databases for whom insurers (and in my case, Congressional policy makers base therapeutic decisions and reimbursement) impacted me most negatively as end consumer and subscribed member to the Federal Employee Health Benefits program.
I spent months with a pro-bono assistance team from Arnold & Porter, LLP to reverse a historical wrong on losing the first-ever prescription coverage benefit (my one and only access to treatment with medical foods) under BlueCross BlueShield carrier to the Federal Plan. And, what is the irony in all this? I am a pharmacist.
Head Buried in Sand
For the agency to be idle with its head buried in the sand is absolutely unjustifiable given the times and track record of “guidance to nonexistence” as expressed in conversation with Burnett. Even worse, is the continuing operations of a 1970s framework in the 21st
century, and it is much unrealistic to expect the market to be viable any longer (especially for rare disease) when regulatory policy change has been outpaced by a changing science and political environment.
Burnett expressed frustration with such irresponsible governance, which even predates the Orphan Drug Act and the industry having been left to interpret federal statute and self-regulate in the years following its passage. Many subsequent attempts to advise the industry were nothing but utter failures and created more confusion throughout the years, especially following the 1990 Nutrition Labeling and Education Act (1990 Amendments) and the 1994 Dietary Supplement Health and Education Act (DSHEA) which pretty much equated to opening Pandora’s box.
As per the 1993 Federal Register, the 1990 Nutrition Labeling and Education Act incorporated the statutory definition of medical foods and allowed for exemptions on nutritional labeling, health claims and nutrient contents.6
Although the language was still too broad and vague, and necessitated more FDA final rules on implementing the 1990 Amendments, the clarifying criteria for what constitutes a medical food were finally provided.6
Similarly, passage of the DSHEA brought more confusion, with exemptions for unregulated dietary supplements and provision of allowances for structure-function claims as acceptable and no premarket approval requirements and thereby further complicating the distinguishing role and appropriate use of medical foods from nutritional supplements (similarly classified as “foods.”)
And, if the industry thinks it remains challenged by such regulatory burden and communication hazards today (certainly worthy of kick-starting discussion on new rulemaking), imagine the burden of proof on rare disease patients: few in numbers and left to fend on their own without fancy lawyers and big money commanding response to anyone and everyone who would listen about what constitutes a medical food.
Burnett hit the nail on the head in stating the patient’s worse nightmare: “Even if these products have GRAS status or efficacy studies that substantiate label claims, the lack of FDA approval adversely impacts understanding, acceptance, and utilization of MF by the wider medical community.7”
FDA Approval - The Holy Grail
As a pharmacist, I concur this is also a nightmare. It is the FDA stamp of approval which is the single-most precipitating factor triggering prescription drug formulary management and therapeutic decision making. If a firm is granted approval, (which they would seek if profitable), there is more likelihood for patient reimbursement (which translates to access for most folks); but this is not necessarily always a guarantor of coverage.
However, the FDA approval can also open up the adjudication processes within institutions and pharmacies for nonformulary approval pathways and make an exception for getting the appropriate treatment into the patient’s hands and meeting disease-specific needs.
A unique identifier for medical foods as a drug (but without tighter regulation
) under conditions of safe use that assure payers, prescribers, providers, consumers and stakeholders alike the medical food is safe, legitimate, beneficial, substantiated with evidence for claims (not to mention cost effective) would be a step forward in the right direction. This concept is not new to the agency for exploring innovating access solutions and invokes what is known as dual availability.
Furthermore, application of this concept to medical foods challenges current FDA framework with flexibility in design, rethinks the terms “misbranding” as it pertains to pharmaceutical labeling, and is explored further in my 100+ page strategic capstone report calling for adoption of an FDA exceptional labeling standard that is long, long overdue in mitigating the biggest market failure posed to the industry: miscommunication. (See endnote.)
If the industry is still screaming about the division in the agency between the CDER and CFSAN (where the food and drug properties are clearly split just as they were prior to 1972) resulting in “millions of dollars in delay and negotiation costs with IRBs) today,1
imagine the toll on the small, orphan innovators who are more constrained with leveraging high costs on low volume products for patients with legitimate need and rare disease AND WHO HAVE NO OTHER OPTIONS! I will get out my violin for this trade association and would like to welcome them to PKU life in dealing with a chronology of damage that stems from 1972.
It behooves the NMFC to find some common ground with rare disease and level the playing field if there is genuine concern about who is most severely impacted by the alter egos of the US Congress and the FDA on a shared framework and practices surrounding medical foods. It is one thing to propose to Congress giving the CFSAN authority for review or approval pathway as per Burnett. It is another for Congress to actually give FDA the resources and mechanisms to do their job as was called for back in the 1960s with implementation of DESI, the Drug Efficacy Study Implementation project.
Medical Foods Debacle
Nobody will own up to what has been coined the “medical foods debacle8
?” I concur with the coalition and think the CFSAN and CDER need to stop the division and damaging behavior, if this is ongoing internally with the agency – it plays out very bad in policy outside FDA walls. Furthermore, how about engaging the Office of Orphan Products Development on finding responsive regulation? It is unfortunate for the PKU community to have languished for so long in this gray category and be slighted a voice among an expert panel called for by the coalition’s proposed best practices and in revisiting the language of the ANPR. The problems are known, do we really have to keep rehashing them?
In comparison, I could bring unique credentials to the discussion with background in pharmacy, policy and decades of experiences living with PKU as early generation-treated Lofenalacer.
There is no greater resource than the human resource – and I hold the Trump card in serving as primary expert and living, breathing testimony to the benefits of newborn screening and treatment with medical foods for PKU.
Patients Need a Seat at the Table
I think my ideas as discussed in the capstone report (endnote) are most pertinent and synergistic to the suggested industry best practices, especially when it comes to labeling and coding, substantiation of evidence, pharmacovigilance and surveillance, and compliment the kind of academic detailing needed for promoting market viability on all fronts and that can be mutually beneficial for stakeholders. There is no way FDLI as publisher can claim status as “neutral convener and venue for stakeholders to inform innovative public policy, law, and regulation9
” without engaging the patient voice as medical foods primary beneficiary. For FDLI catering to a projected billion dollar plus market manipulation by industry giants (their clients and members) on applicable medical food regulations and statute is shameful and goes against the FDLI mission. But, as a nonprofit, they can do whatever they want as can the NMFC as a for-profit and do what they want with their money. If any change is going to come to the category of medical foods, mark my word - it will begin with PKU and PKU is fearless.
The FDA better make room in the orphanage for the orphans. It has been my experience upholding the spirit of justice for rare is simply not lucrative enough for virtually every lawyer; otherwise I would have one right now to pick up where Arnold & Porter left off and finish the job for PKU victims. If there are any lessons to be had from my personal account (taken from the FDA vault word by word), it is that the cache on medical foods belongs to rare and no money can trump that.
Payne, Jennifer. FDA Regime on Medical Foods for Phenylketonuria: Promoting Market Viability through Retroadaptive Licensing of the National Drug Code to New England College, August 23, 2015 PO 6975 Professor Aaron Cooley Strategic Capstone Report: First-ever proposed policy design that deconstructs traditional regulatory approach through risk benefit assessment and retroactive evaluation of substantial evidence in application of transformative paradigm theory to meet disease-specific needs. Beneficial capabilities surround improved efficiency, access, and provision of timely, accurate information to better mitigate communication hazards, to allow for consistency in policy language through flexible use of the National Drug Code (NDC), and to afford financial incentive to small orphan innovators. https://www.regulations.gov/document?D=FDA-2013-D-0880-0057
1 Burnett BP, Levy RM. Proposed Industry Best Practices in Development and Marketing of Medical Foods for the Management of Chronic Conditions and Diseases while Awaiting Regulation, Food and Drug Law Journal. Vol. 72 No.1, 2017. P 53-77
2 Siegner, Jr, AW. Hyman, Phelps & McNamara,P.C. December 16, 2013 letter to FDA Division of Dockets Management
3. Sasinowski FJ, Hyman, Phelps & McNamara, P.C. http://www.hpm.com/vattorney.cfm?RID=17
4 Tribble SJ, Lupkin S. Three Key Senators Ask GAO To Investigate Possible Abuses of the Orphan Drug Act. March 7, 2017. Kaiser Health News http://khn.org/news/three-key-senators-ask-gao-to-investigate-possible-abuses-of-the-orphan-drug-act/
5 Siegner W, Hyman PM. Medical Food Mumbo Jumbo: Confusing FDA Guidance Documents Will Discourage Medical Food Development. September 18, 2013 FDA Law Blog of Hyman, Phelps & McNamara http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2013/09/medical-food-mumbo-jumbo-confusing-fda-guidance-documents-will-discourage-medical-food-development.html
6 Payne P. Rx: Solving the Satisficing Cost of Medical Food Misbranded, (unpublished) PO 6020 New England College, Professor Callahan August 24, 2014 quoted in FDA, US Department of Health and Human Services, 21 CFR Ch 1 [Docket No. 96-N-0364], Federal Register, vol. 61 No. 231, November 29, 1996, p60663
7 Ibid at 1 quoted in Bruce P. Burnett, Robert M. Levy & Sarah L. Morgan, Medical Foods Come Under Assault in the U.S. NUTRITION INSIGHT, supplement to THE WORLD OF FOOD INGREDIENTS (2016) (summarizing the history of the medical food category, the current state of FDA regulation, and challenges that exist in the managed care industry in the United States)
8 Burnett BP, Levy RM, Morgan SL, Medical Foods Come Under Assault in the U.S. NUTRITION INSIGHT, supplement to THE WORLD OF FOOD INGREDIENTS (2016)