Is Two a Crowd?

The recent Bayer incident in which two products had received warning letters from the FDA and were voluntarily withdrawn from market in late October has made it apparent that though these combination products—a drug combined with a dietary supplement—are not common, there may be a lack of understanding of where they stand on the regulatory front.

These products included Bayer Women's, combining aspirin and calcium, and Bayer Heart Advantage, combining aspirin and phytosterols.

Both required a New Drug Application (NDA) not only because the dietary supplement and drug were not approved as a combination, but also because the labels on each implied it could fight or treat a disease.

If a clinical drug and dietary supplement is approved for market on its own, it does not mean that they are automatically approved for market when combined.

"While these combination products are not common, there have been a handful of [them] introduced to the marketplace over the past decade. In two cases, the FDA issued warning letters for these products and they were voluntarily withdrawn by their manufacturers," noted Steve Mister, president and chief executive officer of the Council for Responsible Nutrition (CRN).

In the case of the two products pulled from market that Mister refers to, each required a different dosage in order for consumers to experience the intended benefits.

With contradictory labels "it was difficult for consumers to comply with both the drug labeling and the regimen necessary for the benefits of these particular OTC drug/supplement combinations," Mister added.

When industries meet

Unlike prescription drugs, which are overseen by FDA's Center for Drug Evaluation and Research (CDER), dietary supplements are regulated by the agency's Center for Food Safety and Applied Nutrition (CFSAN).

With dietary supplements managed by CFSAN and drugs regulated by CDER, it appears that products combining the two are without a specified regulatory home. So, what happens when these industries collide as a company moves forward with marketing this type of product?

Products that include both a drug and a dietary supplement, according to government experts, are considered new drugs. Therefore, they must adhere to the procedures of the NDA and gain FDA approval.

The Dietary Supplement Health & Education Act of 1994 (DSHEA) is an amendment to the Federal Food, Drug and Cosmetics (FD&C) Act, which "creates additional requirements for dietary supplements; thus their regulation can be characterized as more rigorous than traditional food, but different than drugs," explained Mister.

Experts from CFSAN and CDER told Applied Clinical Trials that dietary supplements by themselves are only required to submit an investigational new drug (IND) application and are subject to FDA approval when the product is implied for disease treatment, prevention, cure, mitigation, and diagnosis.

Indications for industry

Whether the companies involved in marketing such products have been aware of the regulations is something that cannot be determined. Either way, CFSAN and CDER experts acknowledged that "the existence of unapproved drug products like these reduces incentives for research to prove safety and effectiveness, and it creates inequities in the marketplace where unapproved drugs compete unfairly with approved ones."

Beyond creating discrepancies in the marketplace, making unregulated—and potentially—unsafe products available to the public defeats FDA's purpose to maintain safety.

"The introduction of these kinds of products exposes consumers to potential hazards," explained experts from CDER and CFSAN. "They also significantly challenge the new drug application and over-the-counter drug review processes, which have been established to ensure that drug products are both safe and effective before reaching the marketplace."

Linking Drugs and Dietary Supplements

• Office of Combination Products http://www.fda.gov/oc/combination/

• FDA's Warning Letter to Bayer http://www.fda.gov/bbs/topics/NEWS/2008/NEW01907.html

• CDER Drug and Biologic Approval Reports http://www.fda.gov/cder/rdmt/

• Dietary Supplement Health and Education Act of 1994 http://www.fda.gov/opacom/laws/DSHEA.html