Could FDA Investigational New Drug Applications Block Supplements Studies?

January 12, 2011

If FDA begins requiring Investigational New Drug (IND) applications as a prerequisite for performing dietary supplement studies on humans, it could stifle research.

If FDA begins requiring Investigational New Drug (IND) applications as a prerequisite for performing dietary supplement studies on humans, it could stifle research. This is the opinion of the Council for Responsible Nutrition (CRN; Washington, DC), which yesterday submitted its comments responding to FDA’s recent draft guidance on the subject.

The draft guidance, titled “Investigational New Drug Applications (INDs)-Determining Whether Human Research Studies Can Be Conducted Without an IND,” was published by FDA in the Federal Register in October. The agency says it released the guidance in response to a high volume of inquiries it has received concerning whether human research studies can or should be conducted without an IND.

“FDA receives frequent inquiries from external constituents, in particular the academic research community (e.g., clinical investigators, Institutional Review Boards (IRBs)) and the pharmaceutical industry, concerning whether various types of human research studies can be conducted without an IND,” FDA stated in the guidance.

The agency is seeking to establish guidance that would explain under which conditions an IND would be required-including which types of studies would be exempt.

Currently, dietary supplements being studied for a structure-function endpoint do not require INDs, while drug studies do require them. However, FDA’s guidance has industry worried that it, too, could become included in the requirement.

CRN: INDs Not Appropriate for Supplements

In its response, CRN applauded the agency’s intent to safeguard against trials potentially harmful to human subjects. However, the association underlined, drugs are different from nutritional ingredients, which in many cases are already being consumed by the public and therefore are generally considered safe and should not be held to drug standards.

“While CRN appreciates that the intent of the IND is to provide the agency with an opportunity to review a study proposal and product for safety to assure that research subjects will not be subjected to unreasonable risk, CRN has concerns that the position reflected in the Draft Guidance may result in unintended consequences for dietary supplement research,” CRN wrote.

“The IND is specifically designed to support companies that have screened a novel molecule for pharmacological activity and acute toxicity potential in animals and wish to test its diagnostic or therapeutic potential in humans,” it continued. “This framework is applicable to the drug-development process, but may not be a suitable framework for research on dietary supplements and food components that are already safety consumed by millions of Americans.”

Moreover, the association argued, the supplements industry already has other “checks and balances” resources to support clinical trial safety and data transparency, including following Consolidated Standards of Reporting Trials (CONSORT) guidelines, using an Institutional Review Board (IRB), convening data- and safety-monitoring boards, and registering trials on ClinicalTrials.gov.

CRN pointed out that a new requirement for INDs could potentially confuse the supplement industry’s research community, which may not be able to easily discern which dietary studies-depending on whether trials are designed to study disease endpoints-would require NDIs. Unlike the drug industry, CRN points out, the supplements research community is primarily comprised of and supported by government grants and academic researchers, who may not understand how a new IND requirement would pertain to supplement studies, causing further confusion.

“These researchers will likely be unaware that the intent of the investigation drives the need for an IND. Furthermore, they may not understand the regulatory distinctions between drugs, supplements, and their intended use, and thus may be unable to appropriately design a study protocol to accurately reflect the intent of the investigation,” the association stated.

Moreover, it argued, researchers may find compiling a complex NDI application onerous. Due to the proprietary manufacturing information required to compile an application and the industry’s limited intellectual property protection, researchers may receive only limited cooperation from dietary supplement manufacturers in compiling an NDI-which could stall the application, and thus, the research process.

“The net effect is that research cannot be conducted, even though in many cases, the investigator and millions of consumers can already purchase the product from a store shelf,” CRN stated. “This example highlights how the Draft Guidance can become an obstacle to gaining a better scientific understanding of potentially health-promoting products already available to consumers.”

Supplement Biomarkers

Whether CRN’s suggestions are taken into account remains to be seen. However, depending on how FDA requires INDs, supplements could fall under this requirement, due to the very fact that there are currently no validated biomarkers to use as surrogate endpoints for conditions such as “health promotion,” “wellness,” or “supporting normal structure and function.” By default, a majority of supplement studies must instead assess disease endpoints such as lowering of blood pressure or serum cholesterol levels. These types of studies could likely necessitate an IND.

“…A search of ClinicalTrials.gov demonstrates the large number of clinical studies examining the therapeutic effects of dietary supplements. By association, this indicates how the Draft Guidance creates a de facto IND requirement for a significant portion of dietary supplement research studies,” CRN wrote.

Setting Research Back

Looking ahead, CRN believes requiring INDs could have long-term consequences by halting the progress of dietary research. It cited comments made by doctors Dan Merenstein of Georgetown University and Patricia Hibberd of Massachusetts General Hospital at a New York Academy of Sciences Symposium, Probiotics: From Bench to Market.

“Both researchers addressed the large number of clinical trials being conducted on probiotics and the fact that the majority of these are conducted outside of the United States to avoid these delays,” CRN relayed.

CRN said the researchers expressed concerned that research in the United States will fall behind the rest of the world due to the challenges and delays associated with submitting NDIs and getting FDA to process what could potentially become an overwhelming number of submissions.

Confusion Lingers

CRN also pointed out that confusion exists in the research community about whether dietary supplements are studied as drugs or foods. It says that the Dietary Supplement Health and Education Act of 1994 (DSHEA) established the National Institutes of Health’s Office of Dietary Supplements (ODS) “to promote scientific study of the benefits of dietary supplements in maintaining health and preventing chronic disease and other health-related conditions.”

“Thus, DSHEA mandates ODS to support and promote the scientific study of dietary supplements as both ‘dietary supplements’ and as ‘drugs,’” CRN said.

However, CRN says, this has sometimes led to confusion, depending on an ingredient’s intended use, about whether a product is being studied as a drug or a supplement.