It’s hard to find a more altruistic example of our legislative process at work. Yet fully a generation after the ODA’s passage, companies charged with actually developing the act’s “orphans” are still trying to figure out what kinds of products, exactly, the law encourages them to develop.
This is especially the case with medical foods, which, says Brian Carroll, PhD, scientific and regulatory affairs manager, Primus Pharmaceuticals (Scottsdale, AZ), “have been somewhat poorly defined from a regulatory and FDA point of view. The industry has been working it out in real time.”
And how. One need only read FDA’s latest Draft Guidance for Industry: Frequently Asked Questions About Medical Foods; Second Edition, issued August 2013, to get a taste of the regulatory uncertainty surrounding the sector. An update of past guidances issued in 2007 and 1997, the 2013 document leaves many in industry—and their lawyers—wondering where medical foods fit into the health-and-wellness landscape today.
Looking for a Home
Congress passed the ODA to help patients dealing with health conditions so rare that, absent incentives like temporary market exclusivity or R&D tax credits, pharmaceutical manufacturers would have little to gain in addressing them. “With nobody wanting to take on these particular patient types or rare diseases,” Carroll recalls, “they were looking for a home.”
And because nutrition plays such a critical role in managing many such conditions, Congress extended the law’s “orphan” umbrella to cover not only traditional drugs but medical foods, too, which the statute defined as a food “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.”
There’s a lot to unpack there—and it’s only the start, too. For while “the statute is what Congress gives to FDA,” says Jessica P. O’Connell, special counsel, Covington & Burling LLP (Washington, DC), “FDA then makes rules interpreting it.” In other words, what Congress legislates, FDA implements using rulemaking, guidance, and ground-level regulatory enforcement. And that’s where medical foods get complicated.
A Matter of Interpretation
The reason for this complication is that though the letter of the ODA says one thing, FDA has read it to say…well, not necessarily something different, but something narrower, perhaps.
Specifically, the agency’s 2013 draft guidance on medical foods states that it “considers the statutory definition of medical foods to narrowly constrain the types of products that fit within this category of food.” Thus FDA established the following criteria, found in 21 CFE 101.9(j)(8), to “clarify” the statutory definition:
- A medical food is a “specially formulated and processed product (as opposed to a naturally occurring foodstuff used in its natural state) for the partial or exclusive feeding of a patient by means of oral intake or enteral feeding by tube.”
- It is “intended for the dietary management of a patient who, because of therapeutic or chronic medical needs, has limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foodstuffs or certain nutrients, or who has other special medically determined nutrient requirements, the dietary management of which cannot be achieved by the modification of the normal diet alone.”
- “It provides nutritional support specifically modified for the management of the unique nutrient needs that result from the specific disease or condition, as determined by medical evaluation.”
- It is “intended to be used under medical supervision.”
- And it is “intended only for a patient receiving active and ongoing medical supervision wherein the patient requires medical care on a recurring basis for, among other things, instructions on the use of the medical food.”
And that, ladies and gentlemen, is what FDA calls a “clarification.” Says Laurie C. Dolan, PhD, senior toxicologist, Burdock Group Consultants (Orlando, FL), FDA has “melded the definition of medical food as defined in section 5(b)(3) of the Orphan Drug Act (21 U.S.C. 360ee(b)(3)) with the definition as defined in 21 CFR 101.9(j)(8).”
So you can see why companies are calling their lawyers.
Straight and Narrow
As it happens, Covington & Burling’s O’Connell was an attorney in FDA’s Office of Chief Counsel as the guidance was being drafted, and she participated in the process. To her mind, among the document’s more notable features is its treatment of the ODA’s “distinctive nutritional requirement” language, which she believes FDA has construed “really narrowly” to mean “a need that can’t be met through dietary modification alone,” as noted in bullet 2 above. That narrow reading has led some to question whether it’s “an appropriate interpretation of the statute,” O’Connell adds, and even to charges that FDA is “overstepping its authority.”
Dolan might sympathize with that sentiment. “This new guidance is an attempt by FDA to turn back the clock to before 1972, when medical foods were regulated as drugs,” she says. Taking issue with the document’s “modification of the normal diet alone” language, and with its requirement that medical foods be administered under physician supervision, Dolan claims that it “provides little guidance about the conditions that can be served by medical foods” and “seems to ignore medical-food use for people who cannot swallow or ingest foods normally, but instead stresses the inborn-errors-of-metabolism issue.”
Inborn errors of metabolism (IEMs), as the guidance states, are “inherited biochemical disorders in which a specific enzyme defect interferes with the normal metabolism of protein, fat, or carbohydrate.” Perhaps the best known is phenylketonuria (PKU), in which a deficiency in the enzyme phenylalanine hydroxylase allows toxic levels of phenylalanine to accumulate in the blood and tissues, causing neurological damage and more as a result.
And while the guidance acknowledges medical foods’ centrality in helping phenylketonurics and other IEM patients “obtain adequate levels of essential nutrients which are restricted by modifying the normal diet,” it nevertheless hews to its narrowing of the medical-foods definition, noting that some IEMs can, in fact, be managed entirely via dietary changes—galactosemia being one—and, therefore, don’t require specially formulated and marketed medical foods for their management.
Another good example of FDA’s restricted view, as O’Connell calls it, is the guidance’s stance on diabetes. Both type 1 and type 2 diabetes are metabolic disorders, yet the document makes clear that patients with type 1 diabetes can follow a carbohydrate-counting or -exchange system to match insulin replacement to carbohydrate intake, while those with type 2 “should restrict calories, eat regularly, increase fiber intake, and limit intake of refined carbohydrates and saturated fats” to manage their conditions.
FDA’s conclusion, then: “Diet therapy is the mainstay of diabetes management,” and the agency thus would not generally consider a product marketed for type 1 or 2 diabetes to meet the regulatory criteria for a medical food.
That, however, “is the real dilemma for me,” says Richard L. Eichholz, PhD, partner, bioStrategies Group (Chicago). For despite the fact that rates of type 2 diabetes and related metabolic diseases are approaching epidemic status—with costs to society, the healthcare system, and individual quality of life—“the guidance just said medical foods can’t be used in diabetes or obesity,” Eichholz says.
He can only speculate as to why, but Eichholz figures FDA’s reasoning may rest on a view that type 2 diabetes is “pretty-far removed from an inborn error of metabolism,” he says. Nevertheless, “We still have a huge diabetic problem, and the obesity problem is not going away. So I would honestly say that it makes sense to encourage somebody to develop a medical food for type 2 diabetes and obesity. That’s where I’d like to see this go.”
Off Limits, and On
Alas, he won’t likely see it happen should FDA’s current thinking become legally enforceable fact. So if the medical-food marketplace is off limits to diabetes products—and, by the way, to products targeting pregnancy, scurvy, and pellagra, all of which the guidance also shoots down—what products can we label and market as medical foods?
According to Dolan, “complete nutritional products for tube feeding, or foods specifically designed for people with inborn errors of metabolism” are fair game, such as Phenylade for phenylketonurics and UCD Anamix for urea cycle disorder. Additionally, protein substitutes such as Vitaflo’s PKU gel and TYR gel for tyrosinemia, which “can be mixed with low volumes of water or beverages to form gels to be eaten with a spoon, or with larger volumes of water or beverages to make drinks,” she explains, get the go-ahead.
But as for popular electrolyte replacement beverages like Pedialyte and nutrition drinks like Ensure—both from Abbott Nutrition, an active player in the medical-foods field—it’s unclear where they fit, Dolan says, “as they could be considered supplements, medical foods, or foods for special dietary use, depending on the user.”
Which, again, leaves manufacturers wondering how to proceed. In light of the continuing regulatory uncertainty hanging—the guidance is still in draft form and contains nonbinding recommendations—one suggestion may be: with prudence and caution. After all, Carroll says, the agency “is clearly intent on narrowing the medical-food definition.” And though getting inside the head of the FDA “mega-bureaucracy,” as he calls it, may always be a crapshoot, he suspects the motivation for their narrowing may be resource allocation.
To be fair, whether it’s recalling faulty hip implants or revoking trans fats’ GRAS status, FDA has a lot on its plate; monitoring activity in the medical-foods sector adds yet another task to its docket. So “given the resources FDA has to oversee the category compared to the more traditional categories of pharmaceuticals, foods, and dietary supplements,” Carroll says, “the desire to narrow the category, or at least maintain its current narrowness, makes sense, certainly from their point of view. They probably want to make sure they’re ahead of the wave.”
Riding the Wave
And the wave is cresting. Market research firm Frost & Sullivan predicts the global medical-foods category will reach $13.34 billion by 2018. Already, Nestlé has moved from the consumer space into medical foods with its purchase of several medical-foods makers, and Abbott has made its own shift from pharmaceuticals into medical foods. “And then,” bioStrategies’ Eichholz adds, “you have a whole bunch of startups that started as medical-food companies but got there from different places.”
Ergo the possibility that a slew of products hoping to ride that rising tide will surface. Just consider diabetes. O’Connell wagers that the draft guidance focused so much on the condition “because there was concern that there were a lot of convenience-type products making it easier to eat a low-sugar diet being marketed as medical foods, but that FDA didn’t consider medical foods,” she says. Heading off that flood at the pass “was the only way FDA could communicate its current thinking to industry aside from going through rulemaking, which would have been a lot more time intensive for FDA to do.”
Far less time intensive is issuing warning letters to companies whose products FDA believes violate current medical-foods regulations. And since 2004, O’Connell says, the agency has sent warning letters to a number of companies charging that the products under question address diseases or conditions for which no “distinctive nutritional requirement” exists; since 2009, many letters have zeroed in even further on the charge that the products lack any “distinctive nutritional requirement” that cannot be met through “modification of the normal diet alone.”
“FDA was concerned that they didn’t even know what was out there,” O’Connell says. “And they were concerned that consumers, either seeing the words medical food or seeing a certain disease identified on the label, would assume that the product had undergone some sort of review, or was at least subject to some sort of evidentiary limitations. And that really isn’t the case for that category.”
Indeed, while supplements must follow Nutritional Labeling and Education Act (NLEA) restrictions “on what, where, how, and why food or supplement manufacturers can make health and nutrient-content claims,” O’Connell explains, that same act specifically exempted medical foods from those claim requirements, allowing the products to “explicitly state that they’re for the dietary management of named diseases.” So it’s no surprise, she says, that “companies see the medical-foods category as more appealing: there are fewer labeling requirements than for other products.”
Another possible reason manufacturers are exploring the category might be the financial incentive that comes with marketing medical foods to physicians and healthcare providers charged with supervising their use. As Carroll notes, “The medicines physicians prescribe are subsidized, for the most part. So if you can tap into the subsidy—that is, the insurance reimbursement—that gives you pricing power and enables your margins to be robust and to sustain more development and investment in your business.” Being able to “capture some of this insurance reimbursement,” he says, is the “holy grail” for the medical-foods industry.
All about the Patients
But those who know the sector both inside and out insist: Nobody’s building commercial empires on the back of medical foods alone. Remember, Congress originally wrote the ODA to convince manufacturers to give these products a shot despite their pool of potential consumers being so paltry. Sure, an aging population and an increasingly sophisticated grasp of nutrition’s role in disease management will expand that pool, but “the aggregate of those little niches pales in comparison to the current market size of dietary supplements and functional foods in retail,” Carroll says.
Perhaps that’s why he’s “very optimistic about consumer trends toward healthier alternatives to disease management,” he says. “Medical foods are well positioned to meet a growing need for both traditionally minded and nutrition-focused physicians, their practices, and, most importantly, their patients.”
And bringing these products to market isn’t all about the money anyway. “I have to tell you that the people I’m familiar with in the medical-foods area are highly ethical, highly dedicated, and they don’t generally get in this area just to make a profit,” Eichholz says. “Usually there’s something else that’s driving them. They’re all about the patients.”
Given the direction of FDA’s latest guidance, that’s probably just how the agency likes it. Interestingly, though, Eichholz has noticed a possible unintended consequence of the guidance—namely, that it’s “helped a couple of our clients or would-be clients decide not to be medical foods,” choosing the pharmaceutical route instead. Why? “The bar got a little higher to be a medical food,” he figures, “so if you’re going to raise the bar that much, you might as well go all the way to being a drug.”