Edward Cone, PhD – PinneyAssociates
Chris Miller, MS – 3D Communications
Communicating the public health benefit of abuse-deterrent formulations (ADFs) of opioids at a Food and Drug Administration (FDA) advisory committee (ADCOM) meeting presents complexities for Sponsors of these products. One of the key challenges Sponsors face is knowing what and how to effectively communicate at the closed session, which precedes the open session of all ADCOMs for ADFs. While Sponsors can gain insights on ADCOM preparation for open sessions through publicly-available transcripts and videos, the confidential nature of closed sessions precludes this. The authors have attended most of the closed sessions for ADFs, and in this article, outline steps Sponsors can take to make the closed sessions more effective.
Closed sessions – as their name suggests – are closed to the public. Only the Sponsor, the FDA, and ADCOM members are allowed into the meeting. The FDA states that the purpose of the closed session is “to permit discussion and review of trade secret and/or confidential commercial information.” Importantly, no results can be discussed during the closed session. The topics that are discussed during these closed sessions for ADFs are:
- the details of how the ADF is formulated to deter abuse;
- the methodologies of the Category 1 (i.e., in vitro physical manipulation and chemical extraction) studies; and
- the tools and procedures used to manipulate the ADF and the non-abuse-deterrent comparator for the Category 2 pharmacokinetic and Category 3 human abuse potential studies.
To preserve the confidentiality of the methodologies used in the abuse-deterrent testing, Sponsors prepare a closed session briefing book that provides details on the methodologies. These include: the tools used to physically manipulate the products; solvents used to chemically extract the opioid from the formulation; and other experimental conditions such as temperatures, needle gauge, and pre-treatments with heating and cooling. Each experimental condition is assigned a masked code (e.g., coffee grinder = Tool A) that can then be used in the open session to describe the results of the abuse-deterrent studies.
During the closed session, the Sponsor delivers a short 15- to 25-minute presentation on the same materials described in the closed session briefing document. Following the presentation, ADCOM members may ask the Sponsor questions on proprietary aspects of the formulation and methodologies; the answers can be supported with back-up slides.
All materials should be prepared with the audience in mind. At an ADCOM meeting, most members will not have expertise in the development or evaluation of ADFs, so the Sponsor should provide a rationalization for and description of the choice of experimental conditions that non-experts can understand. The following list details common questions we have encountered, and our recommendations for addressing them:
• No pre-market in vitro study program can be expected to evaluate all possible tools, solvents, and abuse condition manipulations that may be attempted in the real world. Therefore, perhaps the most important point Sponsors can make in the closed session is that the choice of evaluations is meant to be representative, not exhaustive.
• Since large volume extraction studies typically evaluate a wide range of solvents, the ADCOM members should be informed that the solvents are representative of common household and advanced solvents that reflect a range of pH and polarity.
• Although all Category 1 studies of ADFs are expected to conform to the 2015 FDA Guidance, Sponsors should clearly explain how the conditions were selected specifically, with knowledge of the formulation in mind, to challenge the ADF to failure. To that end, ensuring that the ADCOM understands that no ADF is “abuse-proof” has proven to be a helpful concept to set appropriate expectations.
• Since it’s impossible to test every type of manipulation that might be attempted by abusers in the real world, Sponsors must also be prepared to answer why certain manipulations were not evaluated. For example, ADCOM members may know of other tampering methods that were not included in the Sponsor’s Category 1 studies. Sponsors should also be ready to answer questions about physical and chemical manipulation methods that were not included in the studies.
• Another common inquiry during the closed session is why a Sponsor chose a certain condition (e.g., product was ground in a mortar and pestle for two minutes). A common question that may arise is, “Why did you only test the product for two minutes and what would happen if you ground it for five minutes?” Sponsors should be prepared to provide clear rationale for the sufficiency of the conditions studied.
• As mentioned, since most ADCOM members are not experts in opioid abuse behaviors and common methods of tampering, the Sponsor should delineate procedures that are commonly performed by abusers from those that represent extreme laboratory conditions. Due to the constraints of using blinded codes to describe results in the open session, Sponsors should clearly outline the amount of time, effort, knowledge, and advanced laboratory equipment required to perform manipulations that “defeat” the abuse-deterrent properties. In our experience, survey data on the impact of time and difficulty of manipulation on willingness to abuse a product has proven to be useful background information for the ADCOM members (Sellers et al, 2013).
In summary, the keys to a successful closed session at an ADCOM for an ADF is extensive preparation. This includes knowing your audience and making sure your materials are as accessible and as easy to understand as possible. It’s essential that Sponsors provide context for why and how they designed abuse-deterrent studies, so that ADCOM members are able to correctly interpret the results.
Sellers EM, Perrino PJ, Colucci SV, et al. Attractiveness of reformulated OxyContin tablets: assessing comparative preferences and tampering potential. J Psychopharm 2013;27:808-16.
Cone EJ, Giordano J, Weingarten B. An iterative model for in vitro laboratory assessment of tamper deterrent formulations. Drug Alcohol Depend 2013;131:100-5.