Month: January 2018

Behind the Scenes at Closed Sessions of FDA Advisory Committee Meetings for Abuse-Deterrent Opioids

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.

Background

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.

Learnings

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).

Conclusion

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.

References

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.

 

Mobile Health Apps Could Support Novel Rx-to-OTC Switches Suggests New Research from PinneyAssociates

Americans concerned about blood pressure may be more likely to try an OTC blood pressure medicine that had a companion mobile health app, and over 50% of participants in an online survey indicated they would be willing to pay more for the OTC product when it had a companion mHealth app.

“Results of our survey suggest that consumers are eager for mobile apps that will help them manage common diseases, which can help to enable Rx-to-OTC switches of products by supporting appropriate self-selection and actual use,” commented Michael Hufford, PhD.

Dr. Hufford presented the results of this PinneyAssociates survey at the 2017 Consumer Healthcare Products Association (CHPA) Annual Executive Committee (AEC). Using Amazon’s Mechanical Turk, an online crowdsourcing marketplace, PinneyAssociates was able to quickly recruit hundreds of people who were concerned about their high blood pressure and have them complete a brief survey about their interest in, and willingness to pay for, an OTC blood pressure medication with or without a companion health app.

“For Rx-to-OTC switch, the easy switches are behind us,” commented Saul Shiffman, PhD, at the 2017 CHPA Regulatory, Scientific & Quality Conference (RSQ). “Apps are more suitable in the context of complex Rx-to-OTC switches, for managing ongoing use and for products that treat chronic asymptomatic conditions.”

If an app is to be used as part of a switch, testing of the app needs to encompass if the app works as intended relative to the Drug Facts Label (DFL), usability by the intended population, and demonstration of an evidence-based approach. Recently, the FDA has been encouraging sponsors to embrace digital health innovations. (see here and here) As Dr. Gottlieb recently noted in “Fostering Medical Innovation: A plan for Digital Health Devices (June 15, 2017), “To encourage innovation, FDA should carry out its mission to protect and promote the public health through policies that are clear enough for developers to apply them on their own, without having to seek out, on a case-by-case basis, FDA’s position on every individual technological change or iterative software development.”

PinneyAssociates’ presentations at CHPA AEC and RSQ can be found here and here, respectively.

To learn more about our Rx-to-OTC Switch Services, click here.

Rx-to-OTC Switch: Developing a Compelling Science-Based Submission for the FDA

An Rx-to-OTC switch submission depends on well-designed consumer studies that show consumers can follow the Drug Facts label and use a drug safely and effectively in the nonprescription setting.

Our experts can help you:

  • Draft and evaluate OTC Drug Facts Labels, Consumer Information Leaflets, and behavioral support materials
  • Plan and help design the overall development program, including label comprehension studies, self-selection studies, actual use trials and tailored consumer studies

Drs. Janine Pillitteri and Christine Sweeney are two of our behavioral scientists who can help make your Rx-to-OTC switch submission a reality.

Assessment of Abuse Potential in Clinical Trials: The Finalized FDA Guidance

What does the future hold for abuse potential now that FDA has finalized the Guidance on Assessment of Abuse Potential of Drugs? Jack Henningfield, PhD, chaired a workshop at the College on Problems of Drug Dependence (CPDD) to address this topic.

“The science of abuse potential has evolved enormously in recent decades. The FDA’s 2017 Guidance captures this as applied to medicines and other substances. It provides the basis for an orderly and more predictable process for drug development and regulatory decision making.” said Dr. Henningfield. “We urge sponsors to reference the FDA guidance when planning and designing studies and to discuss alternative approaches with the Agency. Phase 3 studies, in particular, often require working within practical constraints and reliance on indirect measures such as spontaneous AE reports that might, but do not necessarily, reflect abuse, dependence or withdrawal.”

Workshop topics included:

  • The process of documenting abuse-related signals from clinical trials, Silvia Calderon, Pharmacologist, Controlled Substances Staff, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
  • Development of a standardized classification system for assessing abuse potential in clinical trials: ACTTION recommended considerations, Shannon Smith, Assistant Professor of Anesthesiology, University of Rochester School of Medicine and Dentistry
  • Development and feasibility of the misuse, abuse, and diversion drug event reporting system (MADDERS®), Nathaniel Katz, CEO, Analgesic Solutions
  • Assessing abuse potential from soup to nuts: Nonclinical and clinical study data that inform label claims and CSA scheduling recommendations, Katherine Bonson, Pharmacologist, Controlled Substances Staff, Center for Drug Evaluation and Research, U.S. Food and Drug Administration

Dr. Henningfield’s presentation can be found here.

To learn more about our abuse potential assessment services, click here.

FDA Workshop on Abuse Deterrent Opioids: Distinguishing Products in Postmarketing Surveillance to Support Category 4 Labeling

Understanding the real-world effectiveness and value of abuse-deterrent opioids depends on surveillance designed to evaluate how these formulations work in the real world, product by product, and distinguishing prescription opioids from illicitly produced street products, such as counterfeit synthetics.

Drs. Sid Schnoll and Jack Henningfield both reinforced this message in a public workshop organized by the FDA in July on “Data and Methods for Evaluating the Impact of Opioid Formulations with Properties Designed to Deter Abuse in the Postmarket Setting: A Scientific Discussion of Present and Future Capabilities”. Dr. Schnoll participated as an invited member of the workshop panel, and Dr. Henningfield presented during the public comment period.

Prescribing and market share of abuse deterrent opioids is very small compared to non-abuse deterrent opioids, largely because of pricing. That makes tracking their impact particularly challenging for surveillance. Abuse-deterrent formulation of opioids constitute one piece of the puzzle to addressing the overall public health goals of preventing and reducing opioid abuse, addiction, and overdose in America. Their effectiveness and value to comprehensive opioid control efforts must be evaluated by measures that are appropriate to what these formulations are designed to do.

“Going forward we need to be careful to distinguish surveillance designed to evaluate how well AD opioids are working to achieve the goals that they are designed to do, product by product, such as reduction of insufflation and injection, rather than stopping the overall abuse of opioids,” said Dr. Schnoll.

Part of the challenge for surveillance is actually relating specific products and substances with abuse and overdose. Most overdose deaths involve the ingestion of several substances yet the headlines often refer to whatever drug happens to be in the media spotlight at the time or confuse illicitly made and distributed synthetics such as fentanyl and analogs with prescription drugs. Similarly, most prescription drug abuse and overdose occurs in people who did not have prescriptions yet are discussed as though they were prescribed pain patients – a population that overall shows very low rates of abuse and overdose.

FDA has yet to describe the requirements for Category 4 labeling, meaning that sponsors have the opportunity to propose study designs. PA experts design and execute postmarketing surveillance for a range of controlled substances, including abuse-deterrent formulations of opioids. Our experts can design prospective or retrospective cohort studies and integrate epidemiology and other data with the cohort study results.