Federal regulators have at long last finalized a policy which establishes voluntary guidelines by which manufacturers of opioid-based painkillers can prove that their products are resistant to misuse and abuse by patients.
The abuse of opioid painkillers in the US is a major problem. There were an estimated 16,235 opioid-related overdose deaths in the US in 2013, and recent studies have found that nearly a quarter of all patients on opioids misuse the drugs and 10% become addicted.
To combat this trend, the US Food and Drug Administration (FDA) has been working for several years to encourage drugmakers to develop abuse-resistant versions of their opioids.
In January 2013, FDA released a draft guidance document, Abuse-Deterrent Opioids-Evaluation and Labeling, intended to make it easier to bring abuse-deterrent products to market. As regulators explained in the guidance document, making a drug deterrent to abuse is important, but isn't as easy as it sounds.
For starters, there's no one-size-fits-all approach to abuse deterrence. Instead, 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 as sustained release patches, that prevent excessive dosing at one time;
- prodrug formulations that require metabolic activity to turn into the active substance
- combinations of one or more approaches, such as a prodrug with physical barriers
The main problem lies in the labeling of a product as "abuse-deterrent." Companies are not permitted to simply assume a product with features intended to deter abuse will actually accomplish its goal. Instead, they must prove those claims to regulators through testing.
The labeling of a product as "abuse-deterrent" is no small matter. If FDA finds that a product is deterrent to abuse, it may be eligible for a new period of marketing exclusivity (three years for most new chemical drugs).
More than two years after first releasing its draft guidance on opioid deterrence labeling, FDA is now out with the final version of that guidance document, Abuse-Deterrent Opioids—Evaluation and Labeling.
As with the original document, FDA's guidance is focused on telling companies how they can show to regulators that their opioid drug is deterrent to abuse. The word "deter" is important within the guidance, because FDA concedes that few, if any, drug characteristics will be able to fully prevent abuse. Instead, the goal is to make the abuse of an opioid difficult so as to deter the majority of intended abuse.
"Because FDA expects that the market will foster iterative improvements in products with abuse-deterrent properties, no absolute magnitude of effect can be set for establishing abuse-deterrent characteristics," FDA explains in the guidance. "As a result, FDA intends to consider the totality of the evidence when reviewing the results of studies evaluating the abuse-deterrent properties of a product."
As a part of that review process, FDA says it will consider comparisons between products to evaluate abuse-deterrence.
FDA's guidance contains extensive advice on the studies companies will need to conduct to prove their product is deterrent to abuse. Such studies should first and foremost be "scientifically rigorous," FDA explained, and keep in mind the contexts of likely abuse.
For example, FDA said, a drug predominantly abused through oral routes might not benefit from a change which makes it more difficult to abuse through a nasal route.
The guidance goes on to call for companies to conduct various "categories" of study:
- Category 1: Laboratory-based in vitro manipulation and extraction studies
- Category 2: Pharmacokinetic studies
- Category 3: Clinical abuse potential studies
- Category 4: Postmarket data analysis of actual abuse
The guidance devotes extensive advice on the conduct of each category of study.
For example, category 1 studies should involve the use of a comparator, and should assess a product's susceptibility to crushing, cutting, grating, grinding, dissolution and extraction. "Studies should be designed with knowledge of the physicochemical properties of the product and the methods available to abusers to manipulate the product and should be conducted on the to-be-marketed formulation," FDA recommended.
Category 3 studies, meanwhile, should assess the potential for a product's abuse among "opioid-experienced, recreational drug users who have experience with the particular route of abuse being studied." Studies will assess whether the drug was able to be abused, with a primary endpoint known as "Visual Analogue Scales (VAS)"—a measure of the effects experienced by the attempted drug abuser.
"The VAS should be the primary measure for drug liking because it appears to correlate most directly with potential for abuse," FDA explained. "Other measures of particular interest include assessment of likelihood to take the drug again and assessment of overall drug liking."
Finally, FDA's guidance notes that, "Including information about a product’s abuse-deterrent properties in labeling is important to inform health care professionals, the patient community, and the public about a product’s abuse potential."
FDA advises that labeling should reflect evidence supported by data, as well as outstanding possibilities. For example, a drug may have been found to be resistant to abuse by injection routes. Even still, FDA cautions that companies should not label their products as being immune to abuse. Labels should "include a caveat that abuse is still possible," such as through an alternate route of administration, FDA suggested.
Labeling should also "reflect the predictive quality of premarket studies" unless postmarket data is available, FDA said. Comparisons may be made between different opioids with different abuse features so long as those comparisons are supported by data, FDA said. This might permit companies with more advanced abuse-deterrence features to gain a marketing edge.
Companies should also describe in their label the studies (the Category studies) used to substantiate the product's abuse-deterrence claims, FDA said. Several examples are provided within the guidance.
FDA also said it "expects sponsors to update their formulations to take advantage of technological improvements and further expects to allow labeling statements related to abuse deterrence commensurate with those advances."
The guidance does not require that an opioid drug be shown to be deterrent to abuse as a condition of marketing approval.
In a call with press officials, FDA officials also said a similar guidance on generic opioids and abuse-deterrent qualities was being worked on and would become available "soon."
Abuse-Deterrent Opioids—Evaluation and Labeling (FR)
FDA Press Announcement
Regulatory Focus story on FDA's draft guidance