WASHINGTON—FDA guidance governing investigational new drug (IND) applications improperly brings within its scope cosmetics, conventional foods and dietary supplements, creating uncertainty for researchers and companies, and potentially driving up costs, industry lawyers contended in comments filed with the agency.
In September 2013, FDA issued guidance for clinical investigators, sponsors and institutional review boards, helping them to determine when human studies must be conducted under an IND classification. FDA said it reviews INDs to ensure the safety of the subjects and help confirm the scientific evaluation of the drug is adequate to allow for an evaluation of its effectiveness and safety.
But the 20-page document didn't simply touch upon research that is intended to study a pharmaceutical drug's effect on a disease. Some lawyers argued FDA has improperly brought cosmetics, foods and supplements within the guidance's scope.
Not only is the guidance overly broad, it differed substantially from FDA's draft version, depriving the public of the opportunity to comment in violation of the agency's own Good Guidance Practices regulation, according to Wes Siegner, a lawyer with Washington, D.C.-based Hyman, Phelps & McNamara, P.C., in comments filed with FDA.
On Feb. 6, 2014, FDA reopened the docket on its guidance in response to correspondence it received seeking to comment on the cosmetic and food subsections of the guidance.
"The IND process is designed for investigational new drugs and for the drug approval process, and it is not designed for food and supplement research," said Rend Al-Mondhiry, regulatory counsel for the Council for Responsible Nutrition (CRN), a trade organization representing dietary supplement manufacturers and ingredient suppliers.
The preamble to the final regulations for INDs makes it clear that INDs were only intended to be applied to articles that were being researched as drugs and were not intended for foods or supplements, she said.
Neither foods nor dietary supplements are permitted to make claims that such products can treat, mitigate, prevent or cure a disease. But researchers might study the effect of a conventional food or dietary supplement on a disease such as osteoporosis. That is where FDA drew the line in the guidance, requiring an IND, even if the intent is not to promote the product as a treatment for a disease.
In the guidance, FDA notes "a clinical investigation designed to evaluate a dietary supplement's ability to prevent osteoporosis or to treat chronic diarrhea or constipation would need to be conducted under an IND."
In comments filed with FDA, Siegner distinguished a manufacturer's intended use of the product from the scientific objectives of a clinical study. But he said FDA's guidance would subject a food or cosmetic to an IND based on a study's scientific objectives no matter what the manufacturer intended to use the product for.
"The Guidance baldly asserts that an article meeting the statutory definition of a food or cosmetic and intended to be marketed solely and lawfully as such nevertheless can be transformed into a 'new drug' requiring an IND based on a clinical investigation," he wrote. "This is simply not so."
According to CRN, the guidance also would require an IND for research that examined "disease endpoints." For instance, in seeking to analyze the effect of a supplement on the structure or function of the body, such as the ability of a product to support blood pressure levels, researchers may want to study humans with "elevated blood pressure levels" who aren't actually suffering from a disease such as hypertension. Even under this scenario, FDA's guidance would require an IND, Al-Mondhiry wrote in comments filed with FDA.
"Because FDA characterizes this endpoint as a disease endpoint, the study must be conducted under an IND in accordance with the Final Guidance," she stated, "even though the study is intended to support a permissible structure/function claim and not a drug claim."
Supplement firms should not be required to submit an IND if the supplement isn't intended to be marketed as a drug, the studies will be used to substantiate lawful structure/function claims, and the study complies with institutional review board procedures to protect humans who are the subject of a study, Al-Mondhiry said.
The Dietary Supplement Health and Education Act of 1994 (DSHEA) authorizes companies to make claims that a supplement can affect the structure or function of the body.
"Among other consequences, the unnecessary costs of INDs could reduce the use of clinical studies for foods or cosmetics, or drive them abroad," Siegner wrote.
Al-Mondhiry also noted the IND regulations don't provide authority or a role for the agency overseeing conventional foods and supplements—FDA's Center for Food Safety and Applied Nutrition (CFSAN)—to participate in the IND process.
"The guidance doesn't explain how CDER (FDA's Center for Drug Evaluation and Research) would adapt its drug standards to food products," Al-Mondhiry said.
Finally, the guidance—coupled with federal law—raises another quandary for supplement companies that study new dietary ingredients (NDIs) and, pursuant to DSHEA, subsequently submit notifications to FDA 75 days before introducing the product into the market.
If a researcher studying a supplement under an IND publicized his research before an NDI is lawfully marketed, the Federal, Food, Drug & Cosmetic Act prevents that ingredient or product subject to the IND from being marketed, even for lawful purposes such as to promote a structure/function claim like heart health. The guidance, potentially subjecting supplements to more INDs, could discourage supplement firms from pursuing NDI research for fear that the product could not be marketed, stymieing ingredient innovation, Al-Mondhiry said.
"Given the existing uncertainties surrounding the NDI notification process, CRN encourages the agency to further consider how the Final Guidance will affect NDI research and the ability to market NDIs," she wrote in comments filed with FDA. "At a minimum, FDA should clarify under what circumstances, if any, an NDI also being studied under an IND (where the existence of the IND has been made public) may be still allowed to go to market as a dietary supplement, once the NDI review process is complete and the NDI’s safety is established."
Other organizations also have expressed concerns with the guidance, including the Alliance for Natural Health USA (ANH-USA), a membership-based organization that is comprised of health care practitioners, representatives of the food, medical food and dietary supplement industries, and more than 230,000 consumer advocate members.
ANH-USA said FDA should clarify "when an IND is required for human research on foods, including medical foods and dietary supplements." The Consumer Healthcare Products Association (CHPA) also asked for additional clarity, seeking more concrete examples in which the IND regulations would not pertain to supplement studies.
"Because the guidance document should be written for industry personnel of all experience levels, the examples used in the final guidance should be as clear and concise as possible," CHPA stated.
Sebastian Cianci, an FDA spokesman, said the agency has not determined a date for reissuance of the guidance and "is in the process of reviewing the comments."
In reopening the docket, FDA asked parties to submit comments by April 7. But Cianci noted the docket remains open and parties can submit comments anytime.