New FDA Draft Guidance “Abuse-Deterrent Opioids—Evaluation and Labeling” to Permit Abuse-Deterrent Labeling ClaimsJanuary 10, 2013
By David B. Clissold –
FDA has released a Draft Guidance for Industry, titled “Abuse-Deterrent Opioids—Evaluation and Labeling.” Since at least 2005, Congress has noted the need for FDA guidance governing the development and approval of abuse-deterrent drug products. See e.g., H.R. Rep. No. 109-102 (2005) (here at page 81). Most recently, in the Food and Drug Administration Safety and Innovation Act (“FDASIA”), Congress instructed FDA to promulgate guidance on the development of such products. FDASIA, Pub. L. No. 112-144, 126 Stat. 993, § 1122(c) (2012) (see our FDASIA summary here).
FDA’s draft guidance notes that “[t]he science of abuse deterrence is relatively new, and both the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies are rapidly evolving,” so the agency plans to “take a flexible, adaptive approach to the evaluation and labeling of potentially abuse-deterrent products.” That said, the draft guidance identifies four categories of studies that should be addressed by applicants: Laboratory-based in vitro manipulation and extraction studies (Category 1), pharmacokinetic studies (Category 2), clinical abuse potential studies (Category 3), and postmarketing studies (Category 4). As FDA explained, the first three categories of studies are designed to assess “the potentially abuse-deterrent properties of a product under controlled conditions” whereas the Category 4 postmarketing studies should be designed “to determine whether the marketing of the potentially abuse-deterrent formulation results in a significant decrease in population-based and use-based estimates of abuse compared to estimates of abuse if only formulations without abuse-deterrent properties are marketed.” However, FDA acknowledged that since “data on the actual impact of an abuse-deterrent formulation on drug abuse are limited, the optimal design features of postmarketing epidemiologic studies capable of detecting a change in the occurrence of abuse and abuse-related clinical outcomes (addiction, overdoses, poisonings, and death) as a result of the drug product’s abuse-deterrent formulation have not yet been established.”
The amount of pre-clinical, clinical, and epidemiological data that FDA expects under this draft guidance sets a high bar. However, in an important change with potentially far-reaching implications, the agency is now willing to permit abuse-deterrence information in labeling. The draft guidance explains that four “tiers” of claims are possible: The Product is Formulated with Physicochemical Barriers to Abuse (Tier 1), The Product is Expected to Reduce or Block Effect of the Opioid When the Product is Manipulated (Tier 2), The Product is Expected to Result in a Meaningful Reduction in Abuse (Tier 3), or The Product has Demonstrated Reduced Abuse in the Community (Tier 4). FDA noted that the tiers are generally correlated with the four categories of study data, but cautioned that “in order to provide as complete a picture as possible of a product’s abuse-deterrent properties, FDA generally expects sponsors to provide data from Categories 1, 2, and 3 in order to be eligible for Tier 1, Tier 2, or Tier 3 claims.”
Importantly, the draft guidance does not address the approvability or labeling of generic drugs with abuse-deterrent technology that may be submitted in an abbreviated new drug application (“ANDA”). Must those generic companies have the same “tiered” labeling as the reference listed drug? Must the generic use identical abuse-deterrent technology, or indeed, must the generic be abuse-deterrent at all?
Some of these questions may be addressed in FDA’s pending response to a citizen petition filed on behalf of Purdue Pharma L.P (“Purdue”) (Docket No. FDA-2012-P-0939). In that citizen petition, Purdue explains the development of an “abuse deterrent” reformulation of OxyContin. Among other things, Purdue asks FDA to require any ANDA for reformulated OxyContin to contain comparability data using the in vitro tests performed by Purdue on OxyContin, an in vivo study “comparing the bioavailability of finely crushed generic product [to] finely crushed reformulated OxyContin” and possibly additional in vivo studies. To date, FDA has not permitted Purdue to include abuse-deterrence claims in its labeling for this product, but the draft guidance document may further complicate FDA’s response to Purdue’s request, and have far-reaching implications for generic versions of other drugs with abuse-deterrent formulations. Also pending at FDA are citizen petitions submitted by Endo Pharmaceuticals Inc. (Docket No. FDA-2012-P-0951) and Pfizer Inc. (Docket No. FDA-2012-P-1009) that raise questions about abuse-deterrent versions of OPANA ER (oxymorphone HCI) Extended-release Tablets and Oxecta (oxycodone HCl) Tablets, respectively, vis-à-vis generic competition.
Congress has also entered the fray with the July 2012 introduction of H.R. 6160, the Stop Tampering of Prescription Pills Act of 2012 (“STOPP Act”). The STOPP Act, which is expected to be reintroduced in the 113th Congress, would amend the FDC Act to, among other things, establish new requirements for the approval of brand-name and generic drugs that are otherwise available in a tamper-resistant formulation (see our previous post here). Several Members of Congress have also teamed up to form the Congressional Caucus on Prescription Drug Abuse.
The draft guidance document concludes by highlighting again the “rapidly evolving” technologies involved in this field and the way in which FDA intends to evaluate those technologies. The draft guidance document noted four areas that should be the subject of additional research: (1) Characterization of the quantitative link between changes in the pharmacokinetics of opioids in different formulations and results of a clinical abuse potential study with those same formulations; (2) Characterization of the best assessment methods to employ when analyzing a clinical study of abuse potential; (3) Characterization of the quantitative link between the outcomes from a clinical study of abuse potential comparing formulations and the effect on those same formulations on abuse in the community; and (4) Further understanding of the best study methods to employ to assess the effect of an abuse-deterrent formulation on the rates of abuse in the community.