Scott Polisky, Attorney - WorkCompCentral



Rebuttal: Responses to Reasons in California State Fund Letters Denying Reimbursement for TMP Medical Food Products (January 15, 2009)

Prepared by: Scott Polisky, Attorney,

with input from Susan Brienza, Esq, and William Shell, M.D.

1. Erroneously Consider Products to Be Dietary or Food Supplements

Targeted Medical Pharma (TMP) products are medical foods, not dietary or food supplements. Thus, reviewers’ comments regarding supplements are irrelevant and must have no bearing on a decision concerning reimbursement. Dietary supplement is an FDA-regulated category of product, defined in Section 3 of the Dietary Supplement Health and Education Act (DSHEA), as a product to supplement the human diet. Supplements are intended for normal, healthy adults, to support good health.

Medical Foods should not be confused with dietary or food supplements. While both types of product contain nutritional ingredients--such as, minerals and amino acids—they are completely separate categories as defined by Congress, and under FDA regulation, each governed and monitored in a very different way.

First and foremost, by definition, medical foods are specially formulated and intended for the management by a physician of a particular disease, a disease with distinct nutritional requirements. The term Medical Food, as defined in section 5(b) of the Orphan Drug Act [21 U.S.C. sec. 360ee(b)(3)]:

“is a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinct nutritional requirements, based on recognized scientific principles, are established by medical evaluation.” (Emphasis added)

This definition is also presented on FDA’s own web site. (See FDA’s May 2007 Guidance Document, HYPERLINK ""cfsan.~dms/medfguid.html) As opposed to medical foods, dietary supplements are not intended to prevent or treat disease, but rather to help an already healthy individual maintain normal bodily functions, and overall good health and nutritional balance.

As Dr. Robert Moore (Team Leader, Compliance Division of FDA’s Division of Dietary Supplement Programs) has always stressed, dietary supplements are never intended to move an individual from an abnormal to a normal state, but instead are aimed at helping a person in good health maintain that normal state. By contrast, medical foods are specifically formulated to address the nutritional needs of a diseased individual, and under a doctor’s supervision, move that individual from an abnormal to a normal state, or at least to stabilize or “manage” a deficiency or imbalance.

Further, unlike dietary supplements, medical foods:

Are not intended to supplement the human diet, and legally may not be a simple change in the human diet;

Must be developed based on medical evaluation of a particular disease;

Are intended for a particular disease population, not for normal, healthy adults;

Must make a disease claim on the label, indicating that the product is for the dietary management of a particular disease or abnormal condition or for the dietary management of the metabolic imbalances of a particular disease;

May not be sold over-the-counter in retail stores or in any manner; and

Are intended for patients requiring on-going physician supervision and evaluation.

Medical foods cannot be sold directly to patients without physician supervision. Thus, medical foods are properly sold via prescription. The critical differences in the two categories of product, medical foods and dietary supplements, are summarized in the chart attached to this document and to the letter.

In terms of statutory definition and FDA regulation, including claims permitted, medical foods are much closer to prescription drugs than to dietary supplements, with the many similarities shown in the following table.

|Medical Foods |Prescription Drugs |

|Require pre-market safety guarantees: GRAS status of all |Require pre-market safety studies. |

|ingredients used. | |

|Require pre-market “medical evaluation” and determination that |Require pre-market efficacy studies, culminating in human |

|distinctive nutritional requirements of disease are met. |clinical trials. |

|Intended for the dietary management of a disease. |Intended for the prevention, cure, treatment, or mitigation of |

| |a disease. |

|Sold via pharmacies and by Rx only. |Sold via pharmacies and by Rx only. |

|Must be labeled “To be administered under physician |Always administered under physician supervision and used under |

|supervision” and marketed and used as such. |Rx. |

|Often used in hospitals, and not available OTC at retail |Often used in hospitals, and not available OTC at retail |

|establishments. |establishments. |

The FDA has indicated that the term “specific dietary management” is intended to require that medical foods should be “specifically tailored for use as the “nutritional component of the patient’s treatment” and should ameliorate or positively influence clinical manifestations of a specific disease, disease process, or patient outcomes. 61 Federal Register at 60663-64 (Nov. 29, 1996) FDA has expressed the view that medical foods should encompass a narrow category of products intended to address the distinctive nutritional requirements of particular diseases, and thus be part of the medical protocol for those specific diseases. Furthermore, in contrast, to dietary supplements, “medical foods are foods that are an integral component of the clinical management of a patient” and “are not foods simply recommended by a physician as part of an overall diet designed to reduce the risk of a disease or medical condition, to lose or maintain weight, or to ensure the consumption of a healthy diet.”

In 1990, the Life Sciences Research Office of the Federation of American Society for Experimental Biology (LSRO/FASEB) published “Guidelines for the Scientific Review of Enteral Food Products for Special Medical Purposes.” The guidelines defined medical foods as products to be used by patients with “special medically determined nutrient requirements, the dietary management of whom cannot be achieved by the normal modification of the diet alone, by other foods for special dietary uses, or by a combination thereof…”

In addition, under the Nutrition Labeling and Education Act of 1990 (“NLEA”), Congress exempted medical foods from the nutrition labeling, health claim, and nutrient content claim requirements applicable to most other foods. 21 U.S.C. sec. 343(q)(5)(A)(iv); 21 C.F.R. sec. 101.9(j)(8). The definition of a medical food was also incorporated into the FDA’s Final Rule on Mandatory Nutritional Labeling, January 1993. Finally, FDA’s Guidance Document for Field Inspectors (“Compliance Program Guidance Manual 7321.002 – Medical Foods – Import and Domestic) recognizes the separate status of medical foods.

In sum, medical foods are a unique and specialized regulatory category. In every official context: Congressional statute, FDA regulation, FDA compliance Guidelines for field officers, and FDA’s website, medical foods are defined and regulated very differently than dietary supplements. Thus, reviewers’ comments about dietary or food supplements (or “nutraceuticals”) are inapplicable and must have no bearing on a decision concerning reimbursement.

Likewise, statements that TMP medical foods products are merely a “marketing tactic” display a similar misunderstanding of this unique and vital category of product, its role in disease management and the history of reimbursement for the category of product.

Medical foods, strictly regulated by the US Food and Drug Administration, have been reimbursed by Medicare, private insurers, and DWC for many years. Medical Foods are listed in the MediCal Fee Schedule and are registered in the First Data Bank database from which the Medical Fee Schedule is derived. Finally, providing a medical food conveniently packaged with a prescription drug—to be administered according to medical necessity for pain management by the prescribing physician—is just the opposite of any sort of “marketing tactic.” Instead, these two interventions can and do lead to a much lower dose of opiates being required, and for a shorter period of time, again resulting in a better RTW scenario.

2. Erroneously Cite page 7 of OMFS Labor Code 4603.2(b) [Dietary Supplements Not Reimbursable Unless Specific Dietary Deficiency Has Been Established in the Injured Employee as a Result of the Injury or Illness]

Because certain reviewers have confused dietary supplements (or “nutraceuticals”) with medical foods, as detailed in Section 1 above, the oft-repeated citation to page 7 of the OMFS Labor Code makes no sense and has no place in a decision concerning reimbursement.

The metabolic processes associated with pain disorders and inflammatory conditions have already been medically determined to have distinctive nutritional requirements; this is part of the scientific process for the development of individual medical foods. Furthermore, TMP medical foods products have been tested and quality evidence has shown that the medical foods do indeed meet/satisfy the distinctive nutritional requirements of the metabolic processes associated with pain disorders and inflammatory conditions.

3. Erroneously Characterize Products as “Nutraceuticals”

Some reviewers mistakenly characterize TMP medical food products as “nutraceuticals.” The term “nutraceuticals” is not defined by the U.S. Congress or by FDA and has no official or regulatory status. Indeed, the word ‘nutraceuticals’ was coined by some as a marketing term used to justify pharmaceutical or disease claims, and to (illegally) go beyond the dietary supplement category that cannot legitimately make disease claims.

As detailed in depth in Section 1 above, medical foods are not dietary supplements. Unlike dietary supplements, medical foods are a unique category of foods specifically intended for the management of a disease or abnormal condition; and unlike supplements, medical foods may not be purchased directly by consumers but instead must be administered under the supervision of a physician. Thus, reviewers’ comments about “nutraceuticals” are irrelevant and must have no bearing on a decision concerning reimbursement.

4. Erroneously Cite Superseded 1997 Web Site Entry [Specific Requirements for the Safety and Appropriate Use of Medical Foods Have Not Yet Been Established”]

Some reviewers cite an outdated 1997 FDA web site entry, suggesting that requirements for the safety and appropriate use of medical foods have not yet been established. The reviewers have failed to read and consider FDA’s May 2007 guidance document (“Guidance to Industry: Frequently Asked Questions About Medical Foods”), that expressly includes comments on the safety and appropriate use of medical foods and that states simply at the very bottom line: “This document supersedes Medical Foods May 1997.”

Quoting from and referring to an outdated and superseded document has no place and must have no bearing on a decision concerning reimbursement. Significantly, the most current, 14th edition of the ODG guidelines properly cites the FDA’s May 2007 guidance from Center for Food Safety and Nutrition (though with the date of uploading rather than the publication date), as CFSAN 2008.

5. Erroneously State that Medical Foods Do Not Require a Prescription

Some reviewers, oblivious to the law, baldly state that “medical foods do not require a prescription” when in fact they most certainly do as detailed in Section 1 of this letter. There is no way to maintain the statutory requirement of “administered under physician supervision” absent physician prescriptions. Moreover, a short description of medical foods for the layperson, which had been in the FDA’s website until recently, begins: “A medical food is prescription product that . . . “ (emphasis added). Thus, the patently untrue statement that medical foods do not require a prescription has no place and must have no bearing on a decision concerning reimbursement.

6. Erroneously Classifies Product as “Compounded” or as a “Compounded Drug”

A physician’s administration of a medical food plus a drug in the management of a disease in no way can be considered the “compounding” of drugs as defined by FDA. A compounded drug, as defined and regulated by 21 C.F.R. Part 500, involves the mixture of drug components, as prescribed by a physician and tailored to the needs of an individual patient, by a compounding pharmacist. For example, an HRT product for a menopausal woman may consist of specific, tailored amounts of estrogen and progesterone for that woman, as mixed by a compounding pharmacist into 1 pill per day—containing the correct mixture of the 2 hormones.

In the FDA’s website, there is a guidance document on this subject. The FDA’s own answers and explanations show that a compounded drug is very different from a convenience pack containing 1 medical food and 1 prescription drug.

Pharmacy Compounding

1. What is pharmacy compounding?

FDA regards traditional pharmacy compounding as the combining or altering of ingredients by a pharmacist, in response to a licensed practitioner’s prescription, to produce a drug tailored to an individual patient’s special medical needs.  In its simplest form, traditional compounding may involve reformulating a drug, for example, by removing a dye or preservative in response to a patient allergy.  In the case of menopausal hormone therapy, an FDA approved progesterone product contains peanut oil.  Progesterone compounded without peanut oil in response to a prescription for a specific patient who is allergic to this ingredient might allow the patient to safely use the drug.

2. Is combining two or more drugs considered compounding?

FDA would consider the combining of two or more FDA-approved drugs into a single medication, in a manner not described in a drug’s FDA-approved labeling, to be compounding if it is done by a pharmacist in response to a licensed practitioner’s prescription and produces a medication tailored to an individual patient’s special medical needs. 

TMP products are not tailored to particular patients, but rather are used for many patients who all have similar pain due to a work injury. Finally, neither the TMP medical foods nor the convenience package (also including a generic drug) are produced by or processed through a compounding pharmacy. Thus, the erroneous assertion that the TMP products are compounded drugs has no basis in fact or law and must have no bearing on a decision concerning reimbursement.

7. No Mention of Use in ACOEM Guidelines

The revised section of the revised Back Pain Chapter in the most current ACOEM Guidelines, while it does not refer to TMP medical foods products directly (Theramine was properly removed from the Alternative Medicine section), does permit and allow for other inventions, to be judged “on a case by case basis.” As seen in the attached letter from the Executive Director of ACOEM, it is stated: “The further review indicated that the category of medical foods, and the specific medical foods products referenced in the prior draft, did not properly belong in the classification of Alternative Medicine”—which was dominated by discussion of supplement products and “herbal remedies.” Now, under the revised section on alternative medicines, ACOEM categorically states: “it is strongly recommended that patients be treated with therapies proven to be efficacious for these conditions.” And “There are other interventions shown to be efficacious.” Indeed, Theramine and other medical foods have been shown to be efficacious, via the scientific literature (e.g., the over 1,600 papers cited in the Theramine Monograph), and via the scientific method, including clinical trials. (Again, see the attached memorandum on evidence-based medicine.)

Just as the ACOEM Guidelines recommend that pain interventions, such as Theramine, be evaluated on a case-by-case basis, this same standard is recommended for utilization reviews. Utilization management was defined by the Institute of Medicine as “a set of techniques used by or on behalf of purchasers of health benefits to manage health care costs by influencing patient care decision-making through case-by-case assessments of the appropriateness of care prior to its provision.” (Emphasis added.) Similarly, California’s Workers’ Compensation regulations define utilization review as “a system used to manage costs and improve patient care and decision making through case by case assessment of the frequency, duration, level, and appropriateness of medical care and services to determine whether medical treatment is or was reasonably required to cure or relieve the effects of the injury.” (Emphasis added.)

8. No Mention of Use in ODG Guidelines

Remarkably, most of the denial letters refer to an older, outdated edition (the 5th edition, 2006 ) of the ODG guidelines, whereas the current version is the 14th edition, posted on the Internet Jan. 7, 2009. That outdated edition is also cited in the two sample denial letters (see annotated copies attached to the State Fund letter), which are nearly identical. In the newest edition of the ODG guidelines, there is an individual section on Medical Foods, which begins with the statutory definition (from the amendments to the Orphan Drug Act of 1988), and then continues with a summary of the major regulatory points from FDA law:

Recommended as indicated below. Definition: Defined in section 5(b) of the Orphan Drug Act (21 U.s.c.360ee (b) (3)) as “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.” To be considered the product must, at a minimum, meet the following criteria: (1) the product must be a food for oral or tube feeding; (2) the product must be labeled for dietary management of a specific medical disorder, disease, or condition for which there are distinctive nutritional requirements; (3) the product must be used under medical supervision. [Emphasis added.] See Food labeling; Reference Daily Intakes and Daily Reference Values; Mandatory Status of Nutrition Labeling and Nutrition Content Revision proposed rule (56 FR 60366 at 60377, November 27, 1991). Medical foods are exempted from the labeling requirements for health claims and nutrient content claims under the Nutrition Labeling and Education Act of 1990 (see 21 U.S.C. 343 (q) (5) (A) (iv)). Medical foods do not have to be registered with the FDA. (HYPERLINK "" \l "CFSAN"CFSAN, 2008) [sic; 2007].

Also of note in this newest (current) edition of the ODG Guidelines, in the section on Opiates, the recommendation is for the lowest dose that will have a therapeutic effect—which is precisely what the physician can accomplish with the TMP convenience packs.

9. No Scientific Recognition of Role of Amino Acids; Amino Acids Have No Role in Injury Care

The Utility Reviewers ignore significant scientific recognition of the role of amino acids in disease management or injury care. Amino acids are the building blocks of protein. All amino acids are GRAS listed as humans have safely ingested them for thousands of years.

As detailed in the product monograph for Theramine, for example, patients with pain disorders may require an increased amount of certain amino acids that cannot be obtained from normal diet alone. Tryptophan, for example, is an obligatory amino acid. The body cannot make tryptophan and must obtain tryptophan from the diet. Tryptophan is needed to produce serotonin. Serotonin is required to reduce pain. Patients with pain disorders and inflammatory conditions have altered serotonin metabolism. Some patients with pain disorders and inflammatory conditions have a resistance to the use of tryptophan that is similar to the mechanism found in insulin resistance. Patients with pain disorders and inflammatory conditions cannot acquire sufficient trytophan from the diet to alter the perception of pain and the inflammatory process without ingesting a prohibitively large amount of calories, particularly calories from protein. (The role of amino acids is discussed further in Section 10.)

10. No Nutritional Deficiency

Reviewers sometimes state, without any basis in fact, that a patient has no known nutritional deficiency, and often cloak this mistaken assertion in a meaningless citation to page 7 of the California Labor Code on supplements, a law that should have no bearing on a reimbursement decision because it relates to dietary supplements alone and not to the distinct category of medical foods, products that specifically address nutritional deficiencies in patients with diseases. (See discussion in Section 2, above.)

Once again, a critical component of the statutory definition of Medical Foods is that the products are formulated to address the distinctive nutritional requirements of a particular disease or abnormal condition, including a metabolic imbalance. Medical Foods are foods that are specially formulated and processed (as opposed to a naturally occurring foodstuff used in a natural state) for the patient who is seriously ill or who requires the product as a major treatment modality.

FDA scientists have proposed a physiologic definition of distinctive nutritional requirements:

. . . the dietary management of patients with specific diseases, in some instances, the ability to meet nutritional requirements that differ substantially from the needs of healthy persons. For example, in establishing the recommended dietary allowances for general, healthy population, the Food and Nutrition Board of the Institute of Medicine, National Academy of Sciences, recognized that different or distinctive physiologic requirements may exist for certain persons with “special nutritional needs arising from metabolic disorders, chronic diseases, injuries, premature birth, other medical conditions and drug therapies.

Federal Register: November 29, 1996 (Volume 61, Number 231)

Thus, the distinctive nutritional needs associated with a disease reflect the total amount needed by a healthy person to support life or maintain homeostasis, adjusted for the distinctive changes in the nutritional needs of the patient as a result of the effects of the disease process on absorption, metabolism and excretion.” It was also proposed that in patients with certain disease states who respond to nutritional therapies, a physiologic deficiency for the nutrient is assumed to exist. For example, if a patient with chronic pain responds to an arginine formulation by decreasing perceived pain, a deficiency of arginine is assumed to exist. The measurement of the pain response is performed by the use of either a visual analog scale or a Likert numerical scale.

Patients with acute and chronic pain, for instance, are known to have distinctive, characteristic nutritional requirements for 5-hydroxytryptophan, GABA, arginine, Choline, histidine, serine, flavonoids, and certain antioxidants. Patients with acute and chronic pain frequently exhibit reduced plasma levels of arginine, choline, tryptophan, GABA, histidine and serine. These patients have been shown to respond to oral administration of amino acid formulations by alteration of a physiologic variable or improvement of clinical symptoms, for example, reduction of pain. Research has shown that essential amino acid reduced diets result in a fall of circulating essential amino acids. Patients with pain syndromes have activation of the pathways that diverts essential amino acids and increases their turnover rate. Also, a genetic predisposition can lead to increased amino acid requirements in certain pain syndromes.

Arginine is a precursor of the neurotransmitter nitric oxide, which is an important modulator of pain in the central nervous system, and in peripheral neurons. Arginine is a semi-essential amino acid that is produced in small amounts in the liver for use by the liver. Arginine is not produced in other organs, and the utilization of arginine for pain modulation is totally dependent on arginine blood levels. Pain syndromes increase the utilization of nitric acid and arginine. Human diets cannot provide adequate arginine to support the increased turnover rate associated with pain syndromes.

In the body, tryptophan is converted to serotonin. Serotonin is a vital neuromodulator for pain in both the central nervous system and periphery. Tryptophan blood levels determine the production of serotonin. Pain syndromes and depression are associated with reduced circulating tryptophan blood levels, and serotonin production has been shown to be consistently reduced in these syndromes. Trytophan is an essential amino acid that is not produced by the body and is rarely found in adequate quantities in the majority of protein sources in the average diet. Moreover, the average human diet does not provide adequate amounts of tryptophan when there is an increased turnover rate of serotonin related to pain syndromes.

GABA is an important neurotransmitter that inhibits the firing of neurons in both the central nervous system and the peripheral pain producing neurons. GABA is produced from glutamate and glutamine; and both of these neurotransmitters pass through the blood brain barrier. The administration of glutamate and glutamine directly produce GABA in the brain. Pain syndromes increase utilization and turnover of GABA, producing an increased need for this nutrient.

Histidine is an essential amino acid that is found in low concentrations in most protein sources ingested by humans. Histidine is responsible for the production of brain histamine, which facilitates the production of glucocoticoids. Administration of histidine has been shown to produce glucocoticoids that reduce inflammation associated with pain syndromes. Pain and inflammation are closely associated, and administration of histidine has been shown to reduce inflammation. The average human diet produces inadequate amounts of histidine to control inflammation.

Choline is an amino acid that is required to fully potentiate nitric oxide and serotonin synthesis and function. A deficiency in choline leads to reduced function of NMDA receptors, GABA function, and serotonin response. Low fat diets are usually choline deficient. Flavonoids alter inflammation by multiple mechanisms and pathways. Low fat diets and diets deficient in flavonoid rich foods (such as fruits) result in inadequate flavonoid concentrations, impeding anti-inflammatory responses.

In sum, provision of arginine, choline, and flavonoids with antioxidants, in the correct proportions, can restore the production of beneficial neurotransmitter responses involved in and crucial for pain modulation. The evidence of nutritional deficiencies in patients with pain or disease is clear, and there is no doubt as to the role of medical foods in the nutritional management of pain or disease states. For an even fuller explanation, please see the Theramine Monograph, by Dr. William Shell, and attached to this letter.

11. No “Evidence-Based” Support

Evidence-based medicine began in Canada in 1979, and since 1992 become an extensive movement throughout medicine. Scores of evidence-based medicine grading systems have evolved. Many evidence-based medicine systems are prone to political and reimbursement agendas.

The denial letters from State Fund URs do not indicate the nature of the grading system that was utilized within its deliberations. The reviewers appear to have defined their own evidence-based medicine system, which accepts only one form of evidence-- double-blind, randomized clinical controlled studies published in peer-reviewed journals. They are not explicit, however, concerning this choice of evidence-based medicine system. Moreover, they assert indirectly that only this form of evidence can be recommended for a therapeutic regimen and therefore for reimbursement.

The initial evidence-based medicine systems were designed to allow an individual physician to assess an individual published article. This procedure lends itself well to the assessment of cancer trials where there is a hard endpoint such as death, and where the statistics are well understood. The evidence-based medicine system when applied to complex treatment

modalities such as back pain have poorly-defined evidence-based medicine systems, with limitations that are generally well-recognized.

The Food and Drug Administration (FDA) has advocated and advanced evidence-based medicine since its inception—given that the Agency had to define the amount of scientific evidence, quality of evidence, and amount of evidence that it required for approving various new drug classes. Recently, the FDA has published a set of guidance documents to define its precise methodology for evidence-based medicine. TMP has applied and incorporated the FDA schema into its product development and its efficacy documents, e.g., the Monographs on Theramine and GABAdone, which have been sent to you.

This is probably the first time that evidence-based medicine has been applied to the testing for the therapeutic value of medical foods. How we deal with this issue is complex and responsible, based on the most current concepts. We have instituted grading systems based on the FDA scheme, which is summarized as follows (and explained in more detail in the Monographs). Given TMP’s rigorous and conscientious application of an objective procedure, sanctioned and indeed used by the FDA, we believe that TMP’s medical foods and their efficacy are demonstrated by true quality evidence.

An evidence-based rating system is a science-based systematic evaluation of the strength of the evidence behind a statement. In the case of health claims, it would rate the strength of the evidence behind a proposed substance/disease relationship. A large number of evidence-based rating systems are currently in use today by physicians, dietitians and other health professionals. FDA has tentatively chosen to model its evidence-based rating system on that of the Institute for Clinical Systems Improvement (ICSI), as adapted by the American Dietetic Association, with modifications specific to FDA. In making this tentative decision, FDA relied on criteria for evaluating evidence-based rating systems as reviewed and critiqued by the Agency for Healthcare Research and Quality (AHRQ). FDA also found the modifications from the American Dietetic Association to be particularly useful as they considered diet and health relationships, whereas other groups focused on drug and treatment applications.

The FDA has developed a system for evaluating the large body of information that is required to assess the value of therapeutic interventions. (Guidance for Industry, FDA Interim Evidence-Based Ranking System for Scientific Data July 10, 2003 HYPERLINK "") The validation of therapeutic products has been accomplished using this schema advanced by the FDA for assessment of the efficacy of therapies using the concept of Evidence Based Medicine. In the FDA scheme outlined below, the type, quantity, and consistency of evidence is evaluated and graded. The FDA scheme involves several elements:

“Each study would be characterized as a study design type. By categorizing the study, it automatically receives an initial study "rating" based on the type of experimental design, which is independent of the quality of the study. The rating of study design is based on the principle of minimizing bias. Only primary reports of data collection are rated. Reports that synthesize or reflect collections of primary reports are not considered part of the rating system although they may provide useful background information”.

Study Design Type One

Randomized, controlled intervention trials

Study Design Type Two

Prospective observational cohort studies

Study Design Type Three

Nonrandomized intervention trials with concurrent or historical controls

Case-control studies

Study Design Type Four

Cross-sectional studies

Analyses of secondary disease endpoints in intervention trials

Case series

Furthermore, the FDA scheme provides additional criteria, including Quantity and Consistency of Data:

Quantity. Considers the number of studies, the total number of individuals studied and the generalizability of the findings to the target population.

(***) means the number of studies and the number of individuals tested (from all studies of design types one and two that are of high quality (+) combined) are sufficiently large to comfortably generalize to the target population.

(**) means there are a sufficient number of studies and individuals tested from study design type three and higher (i.e., study design types one and two) of at least moderate quality (Ø) but uncertainties remain as to generalizability to the target population.

*) means that the number of studies and the number of individuals tested is insufficient to generalize to the target population.

Consistency. Considers whether studies with both similar and different designs report similar findings.

(***) means a sufficient number of studies of design types one and two that are of high quality (+) have consistent results. Any inconsistencies should be explained satisfactorily.

(**) means there is a moderate consistency across all study levels.

(*) means that the results of studies are inconsistent.

 

Accordingly, the Medical Food Theramine has been validated using physiologic and symptomatic endpoints. These endpoints include documentation of the nutrient requirements, performance of physiologic endpoint trials using a controlled crossover design, and performance of controlled crossover design trials using pain scales with both visual analogue scales and Likert numeric scales. In this way, TMP has used an FDA-developed system to show that Theramine is effective for the dietary management of pain disorders.

12. No “Medical Necessity” or Rationale

Under California Workers Compensation Law, injured workers are entitled to all medical treatment reasonable and necessary to cure and/or relieve them from the effects of their injury. Insurance companies may implement a utilization review program to control costs, but the utilization review program must meet strict guidelines to protect injured workers and their health. Pursuant to Title 8 of the California Code of Regulations, secs. 9792.11-9792.15, Background to Regulatory Proceeding, the major review requirements are set forth as follows:

That process involves a relatively quick, informal ‘dispute’ resolution process whereby: a) treatment decisions are guided by evidenced-based medical guidelines; b) decisions to delay, modify or deny care must be made only by competent medical personnel within the scope of their license and practice; c) specific information explaining the decision including the medical criteria or guidelines used and the clinical reasons regarding medical necessity used must be provided in writing; d) the requesting (treating) physician must be provided the name and phone number of the medical reviewer who made the decision and may contact that medical reviewer to attempt to informally resolve the ‘dispute’ (delay, modification or denial of treatment authorization) . . . [citations omitted; emphasis added].

Notice in c) above that the burden of showing that the treatment was not a medical necessity is on the Utility Reviewer, and that the UR physician is required under the code and the guidelines to provide, in writing, “specific information” “explaining the decision” to deny reimbursement. And part of this explanation must concern the medical necessity: the UR physician must explain why the treatment prescribed was not medically necessary. None of the denial letters as to the TMP products do that. The presumption of the guidelines for review is that the treating M.D.—according to the Hippocratic Oath to cure and relieve patients—is prescribing a treatment that is medical necessary for the injured worker.

The utility reviewers of TMP products have not addressed, nor have they included any analysis whatsoever of evidence-based medicine evidence or the other issues above; instead, in denial after denial they repeat merely blanket statements such as “no medical necessity”. For c) above, there are many definitions of medical necessity. The reviewers have not specified or included a definition or explanation—in violation of the requirements. Here is one definition that is official, well-respected, and useful:

. . . An intervention is medically necessary if, as recommended by the treating physician and determined by the health plan’s medical director or physician designee, it is (all of the following): A health intervention for the purpose of treating a medical condition; the most appropriate supply or level of service, considering potential benefits and harms to the patient; known to be effective in improving health outcomes. For new interventions, effectiveness is determined by scientific evidence. For existing interventions, effectiveness is determined first by scientific evidence, then by professional standards, then by expert opinion; and cost-effective for this condition compared to alternative interventions, including no intervention. [emphasis added].

This definition of medical necessity is quoted in a detailed survey done within HHS, specifically SMHSA’s research on “Medical Necessity in Private Health Plans”; its source is “seminal work” in the health services research community by Singer, Bergthold, Vorhaus, and Enthoven (1999). Of note is that new interventions—such as medical foods—are deemed effective as determined by scientific evidence, which returns us to requirement a) above. Also, the definitions section in Title 8, defines “scientific” as follows: “(k) ‘Scientifically based’ means based on scientific literature, wherein the body of literature is identified through performance of a literature search in Medline, the identified literature is evaluated, and then used as the basis for the guideline [emphasis added].” Again, there are over 1,600 scientific articles used as references in TMP’s Theramine Monograph, articles that have either been ignored or summarily dismissed in the denial letters, and in no way “evaluated” as is required. Instead the reviewers attempt to impose a standard they call “Quality Data” that is neither defined or specific, nor set forth in any law or guideline. Title 8 indicates that the evidence based medicine standard is to be based on a Medline review.

Scott Polisky, Attorney at Law

(A member of the New York and Illinois Bars and of the Washington DC-based Food and Drug Law Institute, specializing in FDA-related matters in all 50 states.)

NY: 450 West 24th Street, Suite 2F, New York NY 10011

IL: 2041 West Division Street, Suite 201, Chicago IL 60622

Cellular Telephone: 917-837-9600

E-Mail: HYPERLINK "mailto:PoliskyLaw@" \o "mailto:PoliskyLaw@" PoliskyLaw@

Attachment: The critical differences in the two FDA-regulated categories of product are summarized in the following chart (revised January 2009).

|Medical Food | | |

| | |Dietary Supplement |

|Defined by Orphan Drug Act & Amendments of| |Defined by Dietary Supplement Health & |

|1988; prior to this, were classified as | |Education Act ("DSHEA") of 1994, as a |

|drugs. | |special sub-category of conventional foods|

| | | |

|Pre-market scientific, medical testing | |No efficacy tests are required pre-market;|

|necessary and required to demonstrate that| |no standard for substantiation is required|

|the product meets and satisfies the | |by FDA (guidance only). Substantiation |

|distinctive nutritional needs of a | |required for structure/function claims, |

|particular patient population. | |but companies may use “borrowed science” |

|Clinical trials on product are the norm. | |from the existing literature, and also |

| | |traditional use. Clinical trials on |

| | |product very rare. |

| | | |

|Requires physician supervision, as part of| |Self-administered by healthy consumers; |

|a patient's medical protocol. “Must be | |may NOT be labeled or promoted as part of |

|administered under physician supervision” | |any medical treatment or protocol. |

|is a required label statement. | | |

| | | |

|Specifically formulated for a particular | |Intended for normal, healthy adults. May |

|diseased population-- after “medical | |NOT be marketed for any prevention, |

|determination” or “medical evaluation.” | |treatment or managing of disease. |

| | | |

|Makes medical claims, that is, to manage a| |Makes “structure/function” claims, to |

|disease, or an abnormal condition or | |support the healthy function of a |

|disorder. Must have on the product label:| |particular body part or process. May NOT |

|“For the nutritional management of X | |make disease claims, even implied, on |

|disease.” | |labels or in advertisements. |

| | | |

|Has a much higher safety standard: All | |Dietary ingredients are exempted from the |

|ingredients must be GRAS (Generally | |GRAS requirement. New supplements, with |

|Recognized as Safe). Arguably, this is a | |new dietary ingredients (NDIs) need only |

|higher standard than the risk/benefit | |be demonstrated as “reasonably expected to|

|analysis used to judge drug safety. | |be safe,” a much lower safety standard. |

| | | |

|Exempt from nutrition labeling because is | |Nutrition labeling required, including |

|neither a conventional food nor a food | |“Supplement Facts” box, the statement of |

|supplement. Must not include DIETARY | |identity DIETARY SUPPLEMENT or HERBAL |

|SUPPLEMENT on the label; would be illegal.| |SUPPLEMENT, and compliance with 21 C.F.R. |

|Is not a supplement to the diet, and may | |sec. 101.9 and sec. 101.36. |

|not be simply a modification of the diet. | | |

| | | |

|Rx: Per FDA guidelines, a prescription | |May not have Rx on the label. Rx or “Rx |

|product. Must be supervised and | |only” on the label renders the product an |

|administered by M.D. May NOT be sold OTC.| |unapproved new drug. May be sold OTC. |

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