During the coming year, FDA intends to accelerate enforcement of regulations pertaining to currently unapproved and unregulated drugs, according to CDER compliance director Deborah Autor. “Working groups are meeting weekly to review priorities, evaluate options, identify avenues for investigation and address other issues that arise,” she said. Autor emphasized, however, that the agency is continuing to encourage voluntary compliance, and is making a serious effort to ensure that the approval process is “accessible,” and as painless as possible. Autor spoke on “The Future of Unapproved Drugs” at the Food and Drug Law Institute’s 5^th Annual Enforcement and Litigation Conference 2/6.

“Many people, including many physicians, are surprised to learn that some drugs on the market have never obtained FDA approval,” Autor said. She explained that this situation is a little-understood legacy of the legislative history of federal drug regulation. “There are three main categories of marketed unapproved drugs,” Autor said, “including so-called DESI (Drug Efficacy Study Implementation) products; prescription ‘wrap-up drugs'; and post-1962 drugs.” She pointed out that for many years federal law did not require that drugs show proof of effectiveness, and did not always require that they be proven safe. Although the Federal Food and Drugs Act of 1906 prohibited the sale of adulterated or misbranded drugs, it did not require drugs to be approved by FDA. In 1938, the Federal Food, Drug and Cosmetic Act required drugs to be approved by FDA for safety only. Between 1938 and 1962, drugs that were considered identical, related, or similar (IRS) to an approved drug were often marketed without independent approval. Many were marketed based on the manufacturers’ belief they were “generally recognized as safe” (GRAS), while others were marketed based on FDA opinions that they were not “new” drugs – all interpretations that were formally revoked in 1968 (21 CFR 310.100).

In 1962, Congress required that new drugs be approved by FDA for effectiveness as well as for safety. The agency was also required to conduct a retrospective evaluation of the effectiveness of drugs that had been approved for safety only between 1938 and 1962. To accomplish this mandate, FDA contracted with the National Academy of Science/National Research Council to provide an initial evaluation of the effectiveness of over 3,400 products approved for safety between 1938 and 1962 (the “DESI” review). FDA evaluated the National Academy/Research Council’s reports and published findings in the Federal Register; findings regarding new drug status and effectiveness are also applied to IRS drugs (21 CFR 310.6).

According to Autor, drugs found in the DESI review to be effective for their labeled indications, as well as drugs considered IRS to them, must still receive FDA approval to continue to be marketed (NDA supplements for drugs with NDAs approved for safety; and NDAs or ANDAs, as appropriate, for IRS drugs). She noted that “DESI-effective” drugs that have not sought or obtained approval are subject to enforcement action. Drugs that have been finally determined to be “DESI ineffective,” and those IRS to them, can no longer be marketed are also subject to enforcement action. “The ‘bottom line’ is that all drugs must have FDA approval, or must comply with a final Over the Counter (OTC) monograph, unless a DESI application or OTC monograph is pending, or unless they are generally recognized as safe.”

FDA estimates that roughly 2% of the 3.6 billion prescriptions filled annually in the U.S. are for unapproved drugs, Autor said. She indicated that these represent a broad range of drugs, some of which have approved versions, while others do not. Some firms are engaged in manufacturing and marketing both approved and unapproved drugs, while others are primarily engaged in marketing unapproved products.

Autor said that a Compliance Policy Guide for FDA’s Unapproved Drugs Initiative, designed to insure that all drugs marketed in the U.S. are approved and compliant, was published last June. She indicated that a “grace period” – whose duration will be at FDA’s discretion – will be extended to most unapproved drugs in order to allow them to come into compliance without interruption to manufacturing and distribution. However, immediate enforcement actions have been taken against products deemed to be real or potential safety risks (Examples: Carbinoxamine, a sedating antihistamine found to pose serious risk for infants and young children; Quinine, labeled for malaria and commonly used off-label for leg cramps, poses serious safety risks, including death. There is only one approved quinine product – made by Mutual Pharmaceutical Co., Inc. – all other unapproved manufacturers must cease operation by 2/13; Syntho/Intermax and Pharmakon Labs, inspections revealed cGMP violations and unapproved drugs).

In addition to taking immediate action against unapproved products that pose safety risks, Autor said enforcement priorities under FDA’s Unapproved Drugs Initiative will include: drugs that lack evidence of effectiveness; fraudulent drugs; unapproved drugs that directly compete with approved drugs, and drugs that are reformulated as a pretext to avoid enforcement.

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