Questions and Answers on the Unapproved Drug Compliance Policy Guide (CPG)

FDA is issuing draft guidance designed to make sure that all drugs marketed in the U.S. have been shown to be safe and effective. For a variety of historical reasons, some drugs, mostly older products, continue to be marketed illegally in the United States. This guidance clearly articulates FDA’s expectation that manufacturers of products requiring FDA approval show that their products are safe and effective. The draft guidance reflects the agency's desire to address this issue with policies that are predictable, reasonable, and supportive of the public health. The agency's approach encourages companies to comply with the drug approval process, but it also seeks to minimize disruption to the marketplace. The draft guidance explains that FDA will continue to give priority to enforcement actions involving unapproved drugs (1) with potential safety risks, (2) that lack evidence of effectiveness, and (3) that constitute health fraud. It also explains how the agency intends to address those situations in which a firm obtains FDA approval to sell a drug that other firms have long been selling without FDA approval.

A patient or prescriber may believe that a drug is safe or effective because of individual experience, but we have found that such subjective experiences can be misleading and insufficient to establish safety and effectiveness. Instead, we rely on carefully designed clinical trials that weigh the risks and benefits of taking a drug compared with the risks and benefits of taking a placebo or another accepted therapy. In many cases, we find that the original hypothesis that a drug is safe and effective is not correct. Carefully designed clinical trials have repeatedly demonstrated that the safety and effectiveness of drugs cannot be adequately established from anecdotal evidence or consumer or prescriber preferences. Our evidence-based system of drug approval provides great public health benefits to American consumers and health professionals because patients are able to rely on the medications that they take and avoid ineffective therapies or those for which the risks do not outweigh the benefits. They may also save money that they might otherwise spend on ineffective therapies or unsafe medicines. To support our evidence-based system of medicine, FDA must continue to take appropriate and judicious regulatory action against unapproved drugs. Such enforcement actions maintain the necessary incentives to develop and submit to FDA scientific evidence demonstrating the safety and effectiveness of marketed drug products as required by the Act and help preserve the integrity of the new drug approval system.

FDA is issuing this draft guidance for reasons directly related to its mission of protecting and advancing the public health. This guidance clarifies what companies should do to obtain approval for their products, so that the products they market are proven to be safe and effective. The guidance is also designed to emphasize that illegally marketed drugs must obtain FDA approval. Moreover, FDA is explaining how it will exercise its "enforcement discretion" with respect to different types of illegally marketed drugs.

Yes, FDA is inviting comments for 60 days and will closely consider them before finalizing the guidance.

We believe the document is needed now because it has been almost 20 years since FDA last articulated its policies in this area, and because the law, regulations, and policies in this area are very complex. We believe that the complexity in this area of the law and policy, coupled with FDA's limited resources for enforcement in this area, has served to decrease some of the incentives needed to conduct the research needed to submit applications to FDA to prove drugs safe and effective. We believe that providing greater clarity and transparency will improve the public health and result in greater availability of drugs that have been proven to be both safe, effective, and of the highest quality.

The document does not represent a significant shift in FDA's approach. It is intended to explain existing and longstanding agency policies that may not have been explicitly articulated previously. As always, FDA will continue to give the highest priority to drugs with potential safety risks, drugs that lack evidence of effectiveness, and health fraud drugs.

The document discusses a scenario where a company has obtained an NDA for a product that other companies are marketing without approval and discusses how the agency might provide a "grace period" of enforcement discretion to phase out the marketing of the unapproved products. The draft guidance document states that FDA normally intends to allow a grace period of roughly one year before the agency begins enforcement actions. The guidance also identifies factors that could affect the length of the grace period.

A large number of drugs were being marketed before Congress made successive changes to the law that required drugs to be subject to FDA approval. Resource limitations have prevented FDA from determining the regulatory status of many drugs that may require approval and have prevented enforcement actions against many of the unapproved drugs that have been determined to require approval. As always, FDA focuses its limited resources where they will do the most good, giving highest priority to drugs with potential safety risks, drugs that lack evidence of effectiveness, and health fraud drugs. In some cases, FDA action requiring application approvals must be very gradual to avoid shortages of medically necessary products, like levothyroxine.

No, FDA inaction would not change the legal status of a drug product.

Manufacturers who sell illegally marketed unapproved drugs do so at the risk that FDA could take regulatory action at any time. An unapproved drug may come to the agency's attention for a variety of reasons that are discussed in the draft guidance document. The absence of "known" safety problems is not enough to meet the legally required standard of proving safety and effectiveness.

These are drugs that were approved solely on the basis of their safety prior to 1962. Thereafter, Congress required drugs to be shown to be effective as well. FDA initiated a Drug Efficacy Study Implementation (DESI) to evaluate the effectiveness of those drugs that had been previously approved on safety grounds alone. These drugs, and those identical, related, and similar to them, may continue to be marketed until the administrative proceedings evaluating their effectiveness have been concluded, at which point continued marketing is only permitted if an NDA is approved for such drugs. The vast majority of the DESI proceedings have been concluded, but a few are still pending.

No. DESI drugs are generally not the same as drugs marketed prior to 1938. DESI drugs include those that were the subject of pre-1962 FDA approvals and those drugs that are identical, related, and similar to them. These drugs are required to obtain approved applications after the DESI administrative proceedings have been concluded.

An OTC monograph is a regulation that establishes the conditions (including claims, labeling, and active ingredients) under which a drug product for over-the-counter (OTC, or non-prescription) use may be recognized as generally recognized as safe and effective and not misbranded. Products marketed in accordance with final monographs do not require FDA-approved marketing applications.

Levothyroxine sodium products were considered to be medically necessary products. Over 15 million Americans were taking these products when FDA determined that they were new drugs and required applications. The safety and effectiveness of these products had been well-established in the medical literature, but FDA had concerns about the quality of marketed products because of manufacturing issues. Patients can be at risk when the drug they are taking is not being manufactured properly or consistently from batch to batch. On the other hand, the public health consequences of immediately removing these products from the market would have far outweighed the risks of leaving them on the market for a reasonable period to allow companies to develop reliable formulations and obtain approval for them. There are now 8 manufacturers of approved levothyroxine sodium products on the market, and patients with thyroid deficiency now have much greater assurance the quality of the drugs they must take throughout their lives.

No. FDA may take action against unapproved new drugs without first publishing its intentions in the Federal Register. However, FDA will continue to be mindful of the effects of its action on consumers and health professionals and set its priorities according to their public health impact.

FDA is examining whether any class or classes of prescription drugs might be regulated under a monograph system in lieu of requiring individual applications. The Agency will be preparing a report to Congress, in the coming months, that considers the feasibility and cost of such a system. Although FDA has considered and declined this approach on several past occasions, the agency will consider whether new, relevant factors affect our analysis as we re-visit the question.

In deciding whether, and in what manner, to take enforcement action against an unapproved drug, FDA will consider, among other factors, whether there is also an approved drug available to serve consumers who need the drug. Allowing continued marketing of unapproved drugs that compete against approved counterparts challenges the integrity of the drug approval system that is designed to avoid the risks associated with potentially unsafe and ineffective drugs. Allowing continued marketing of these drugs also undermines the incentives needed to conduct the scientific studies to determine the safety and effectiveness of drugs, which benefits the public health.

FDA will continue to be mindful of the effects of any regulatory action on consumers and health professionals. The highest priority for enforcement action will continue to be drugs with potential safety risks, drugs that lack evidence of effectiveness, and health fraud drugs. Before pursuing regulatory action, FDA will consider the effects on the public health of such action, including whether the product is medically necessary and, if so, the ability of legally marketed products to meet patient needs.

The highest priority for enforcement action will continue to be drugs with potential safety risks, drugs that lack evidence of effectiveness, and health fraud drugs. FDA will proceed on a case-by-case basis with these priorities in mind, without adversely affecting public health, imposing any undue burdens on consumers, or unnecessarily disrupting the market.

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Date created: October 17, 2003

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