Unapproved drugs that "present direct challenges" to FDA's new drug approval and OTC drug monograph systems will be high priority for enforcement actions, according to an agency guidance released June 8.

For example, when a company receives approval of an NDA, other companies marketing the same drug without approval will be targeted for enforcement, the agency says in the guidance, "Marketed Unapproved Drugs - Compliance Policy Guide."

Drugs marketed in violation of a final and effective OTC drug monograph fall under this "direct challenge" category as well.

The guidance applies to any drugs required to have FDA approval for marketing, including those covered by the OTC drug review, but excluding licensed biologics and veterinary drugs.

FDA issued the document as part of an initiative to strengthen its efforts against unapproved drugs. The guidance builds on a 2003 draft and reflects comments FDA received on the draft (¹ Also see "FDA Unapproved Drug Draft Compliance Policy Allows One-Year Grace Period" - Pink Sheet, 27 October, 2003., p. 6).

Because FDA is unable to take action immediately against all unapproved drugs on the market, it will focus initially on drugs deemed high priority, under a risk-based approach.

Other priority areas for enforcement of unapproved new drugs include drugs with potential safety risks; drugs that lack efficacy evidence; fraudulent products; drugs that violate the law in other ways, such as GMP violations; and products that are reformulated to evade enforcement actions.

Marketing Exclusivity: An Incentive

The focus on unapproved versions of approved therapies allows FDA to offer incentives to firms that comply with the law.

"Sometimes, a company may obtain approval of an NDA for a product that other companies are marketing without approval," the guidance notes. "We want to encourage this type of voluntary compliance with new drug requirements because it benefits the public health."

In such instances, FDA said it may take enforcement action against remaining unapproved drugs. However, the agency will use its discretion in such cases and would normally allow a grace period of roughly one year before taking enforcement action against others marketing the product.

The variable grace period gives the compliant company a de facto period of market exclusivity in return for being first to obtain approval.

Decisions would be made on a case-by-case basis and could include a substantially shorter grace period depending upon the circumstances, FDA says.

"The shorter the grace period, the more likely it is that the first company to obtain an approval will have a period of de facto market exclusivity before other products obtain approval," the agency explains.

"For example, if FDA provides a one-year grace period before it takes action to remove unapproved competitors from the market, and it takes two years for a second application to be approved, the first approved product could have one year of market exclusivity before the onset of competition," the guidance states.

"FDA hopes that this period of market exclusivity will provide an incentive to firms to be the first to obtain approval to market a previously unapproved drug."

The duration of the grace period would vary based on a number of factors, which FDA outlines in the guidance.

The agency may extend the grace period based on the potential public health effects of immediate removal, in a case where a product is medically necessary or there are concerns that the NDA holder may not be able to meet the public need for a drug, for example.

The agency may shorten the grace period if an applicant seeking approval makes their intention public, the guidance says.

The agency also will factor in the difficulty associated with conducting further study or obtaining approval, the burden on the affected parties of having their products removed, and the agency's available resources.

FDA expects manufacturers of unapproved drugs to comply with the drug approval process and submit NDAs or ANDAs to the agency verifying the safety and efficacy of their products.

During a June 8 press briefing, CDER Director Steven Galson said the agency will work "rationally" to bring such drugs into the approval process.

The agency has used this carrot-and-stick approach in the past in both Rx and OTC drug categories.

The agency ordered single-ingredient extended release guaifenesin products removed from the market following the OTC approval of Adams Labs' Mucinex (² Also see "Rx Extended-Release Guaifenesin Must Exit Market By November, FDA Says" - Pink Sheet, 3 March, 2003., p. 4).

Carbinoxamine

FDA's first action under the new guidance will focus on unapproved prescription products containing the antihistamine carbinoxamine. FDA is requiring that manufacturers of unapproved drugs containing carbinoxamine cease manufacturing within 30 to 90 days. Like many marketed unapproved drugs, carbinoxamine is an older ingredient, initially marketed in the 1950s.

FDA's decision to kick off the effort by focusing on carbinoxamine-containing products is based on a significant safety issue associated with the use of such products in children under the age of two. The agency said it is aware of 21 deaths since 1983 in children under the age of two associated with carbinoxamine-containing products, although "it is not clear that the carbinoxamine caused these deaths."

Numerous drugs containing carbinoxamine either alone or in combination are marketed without FDA approval, according to the agency. Two carbinoxamine products marketed by Atlanta-based Mikart do in fact have ANDA approvals referencing Ortho-McNeil's discontinued Clistin for various allergic symptoms. Those products, approved in 2003, will be allowed to remain on the market.

However, FDA says that many unapproved carbinoxamine products are labeled for the treatment of cough and cold, an unapproved indication, and that many are formulated into drops and syrups labeled for use in children as young as one month, although the product has never been studied in very young children.

The agency will allow makers of unapproved carbinoxamine-containing products carrying a National Drug Code number listed with FDA to continue to manufacture the drug for 30 days if that product is labeled for use in children less than two years of age or marketed as drops for oral administration.

Other carbinoxamine-containing products may continue to be manufactured for 90 days, according to a notice published in the Federal Register June 9.

The guidance specifies that the agency is not required to "and generally does not intend to" give notice that it plans to take enforcement action.

"Any product that is being illegally marketed is subject to FDA enforcement action at any time."

However, FDA specified in the guidance that products subject to an ongoing process such as a DESI proceeding or an OTC monograph proceeding will be allowed to remain on the market while the process is pending.

Under the Drug Efficacy Study Implementation (DESI), which reviewed 3,400 marketed products for efficacy following an act of Congress in 1962, a drug determined to be effective could continue to be marketed provided it was the subject of an application for safety and efficacy. Drugs with NDAs approved for safety before 1962, therefore, required supplements to their original application.

FDA is recommending that patients and health care professionals use the agency's ³ Drugs@FDA website to determine if a drug is approved for marketing.

Unapproved Rx Drugs: A Serious Safety Issue

The agency estimates that several hundred unapproved active ingredients are used in thousands of prescription drugs on the market, but said less then 2% of prescribed drugs are unapproved. Most are older products that for a variety of historical reasons are marketed illegally without FDA approval.

"We consider it a significant and serious drug safety issue that must be addressed," Galson said.

- Christopher Walker

[Editor's note: " ⁴ The Pink Sheet " contributed to this story. For more information call 1-800-332-2181.]

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