The US Food and Drug Administration (FDA) has released a new set of draft guidelines pertaining to the regulation and sale of opioid medications with the intent of requiring them to be more abuse-resistant, calling on manufacturers to provide it with specific data to promote the safe and proper use of their opioid products.
Leadup to the New Opioid Draft Guidance
The move, long anticipated and foreshadowed by Douglas Throckmorton, deputy director of FDA's Center for Drug Evaluation and Research (CDER), was announced at Elsevier's FDA/CMS Summit in December 2012. At that meeting, he noted that the guidance would be published in January 2013.
In April 2012, Throckmorton explained that FDA was acutely aware of the "epidemic" of abuse of opioid medicines, and was working to reformulate the regulatory framework by which it regulates the products.
Those efforts came in waves last year.
In July 2012, FDA announced the launch of a new class-wide Risk Evaluation and Mitigation Strategies (REMS) policy for opioid products. The new policies would require all sponsors of extended-release (ER) and long-acting (LA) opioid products to make training and educational available to prescribing entities starting in March 2013.
"Misprescribing, misuse, and abuse of extended-release and long-acting opioids are a critical and growing public health challenge," said FDA Commissioner Margaret Hamburg in a statement at the time. "The FDA's goal with this REMS approval is to ensure that health care professionals are educated on how to safely prescribe opioids and that patients know how to safely use these drugs."
Critics meanwhile panned the guidance, calling the move ineffective and potentially misleading.
The agency has also been involved in efforts to promote the use of new abuse-resistant formulations of products. Newer-generation opioid products generally are crush-resistant, making it harder for addicts to get high on smaller amounts of the product. Those changes may have inadvertently caused other problems, such as increased rates of heroin use, according to researchers. In addition, with generic competitors to some crush-resistant products coming to market, FDA is currently grappling with whether it should require all opioid products to be formulated with deterrents to minimize abuse. FDA's new guidance does not address this topic, Throckmorton said in a 9 January conference call with reporters. "What we're going to do about the generics is something that we have not yet determined"
Throckmorton's April 2012 statement also notes that FDA is in the process of working with manufacturers to "Strengthen the science for assessing the abuse potential of new drugs" and "working to speed the development of new medicine with reduced potential for abuse."
FDA's draft guidance, Abuse-Deterrent Opioids-Evaluation and Labeling, hopes to build off Throckmorton's latter goal: speeding development of abuse-deterrent opioids.
It sounds easy enough-just formulate a different version of the drug that's harder to break down-but FDA explains in its guidance that because the science of abuse deterrence "is relatively new," there's no one-size-fits-all approach toward approving the products, requiring a "flexible, adaptive approach" toward both the products and their proposed labeling.
Abuse-deterrent features typically come in one of six forms: physical or chemical barriers, which can prevent a pill from being turned into a powder or extracted using solvents; combinations that reduce the euphoria associated with the use or abuse of a product; aversion techniques that create unpleasant effects at higher doses; delivery systems, such sustained release patches, that prevent excessive dosing at one time; prodrug formulations that require metabolic activity to turn into the active substance; and any combination of the above.
Unlike most product submissions, sponsors of these products will have to take into account not just the intended use of the products but also their likely routes of abuse. However, studies will not be required to examine methods of abuse if they are not relevant or known to that drug type.
However, each abuse-deterrence quality-be it crush-proofing or various routes of administration-will need to be backed up by data to show its safety and efficacy. Companies that successfully complete such testing and clear it with FDA might be allowed at least one indulgence: the ability to market the drug using claims that it is more "abuse-deterrent."
FDA officials noted that "so long as the claim accurately reflects data and doesn't overstep" the trial data, such claims would be allowed, although FDA would subject such claims to scrutiny. They also noted that such labeling is important to inform healthcare providers about the risk-deterrent properties of a particular product, and thus "encourages sponsors to seek approval" for the labeling.
Those labeling claims will fall into one (or more) of four "general tiers of claims available," FDA explained: Tier 1 for products with physicochemical barriers to abuse, Tier 2 for products that block or reduce the effects of abuse when manipulated, Tier 3 for products that "result in a meaningful reduction in abuse, and Tier 4 for products that demonstrate "reduced abuse in the community." These claims will generally-but not absolutely-require data to support their use. Examples of the claims are listed within the guidance.
The guidance also notes that because the science is so new, FDA is looking in particular for outcome measures to show that the abuse-deterrent effects are effective. Unlike other trials, FDA advises sponsors to study the drugs in "opioid experienced abusers who have experience with the particular route of abuse being studied." Their assessment of the drugs should be assessed using both empirical and subjective data, such as their assessment of the drug (likeability), the "high" of the drug and whether they would take the drug again. Sponsors are encouraged to make these assessments using either a unipolar or bipolar scale.
Sponsors might also stand to benefit from conducting post-marketing studies on the abuse potential and actual abuse of their products, FDA wrote. Those studies should include a careful assessment of the populations studied (including at least one high-risk population), outcome measures, a comparator product to control for outside factors (such as background rates of abuse), and sub-analyses of each population studied.
Upcoming Meeting to Address
FDA has also scheduled a meeting in February 2013 to assess the possibility of restricting the on-label prescribing of some opioids to certain indications.
"In particular, members of the public and the regulated community have debated the presence or absence of evidence showing the safety and efficacy of these drugs as pain relievers in the various populations for whom they are prescribed," FDA wrote. Under such a proposed system, a drug might have a specific recommendation for use on its label for a cancer patient, and another for a patient suffering from chronic pain.
The meeting seeks to answer three main questions, as well as a series of sub-questions: Are patients currently diagnosed properly for pain? Do they understand and adhere to the labels of pain-treating products? Are further limits on opioid prescribing necessary?