Author: Yolanda Green

Q&A with Rachel Beck, Ph.D.: What Do Analytical Chemistry and Forensic Toxicology Contribute to Drug Development and Formulation Evaluation?

Dr. Rachel Beck is an expert in analytical chemistry and forensic toxicology.  In 2018, Dr. Beck joined PinneyAssociates where she is a key contributor to our abuse-deterrent formulation strategy and evaluation team.  She has been qualified as an expert witness in both criminal and civil courts of law and is a fellow of the American Board of Forensic Toxicology.  While on the faculty at the University of Alabama, in the Department of Pathology, she developed a liquid chromatography tandem mass spectrometry (LC-MS/MS) confirmation laboratory for both prescription and pain management drug analytes for the hospital.

 

How does your expertise in analytical chemistry and forensic toxicology support PinneyAssociates’ clients?

My background is especially relevant to testing of abuse deterrent properties and drug development.

Drug development in general depends on good analytical chemistry.  I can help sponsors evaluate metabolic processes and determine the PK profile of a drug.  If the drug is metabolized, companies need to understand the effect of any metabolites.  Further, assessing chemistry laboratory data and discerning potential anomalies depends on understanding the testing protocols.  My experience in developing laboratory workflows and protocols puts me in a position to “read” the data and assess any irregularities. Missing or additional data and tracking data trends are key to discerning and interpreting Sponsor’s data. It may be as simple as a missing data point, or trend data may be accurate and point to a potential problem.

Rigorous abuse deterrent testing depends on accurately simulating drug abuse behaviors.  In my 11+ years in forensic toxicology, I focused on how people prepared drugs for abuse: what methods they applied; what the time course of their efforts was; how much effort drug abusers are willing to put in to maximize the effect of a substance and minimize the time to obtain that effect.  Development of abuse deterrent products depends on a deep understanding of drug abuse behaviors.

 

Your work was key to identifying a new fentanyl analogue (fentalogue) within Jefferson County, Alabama. What does that expertise mean for pharmaceutical developers and manufacturers of controlled substances and other drugs that act on the central nervous system? 

The process of identifying a novel psychoactive substance (NPS) requires an understanding of how to apply laboratory methods and resources.  Also key to the process is perspective into what drugs people are abusing and how they are abusing them.  For developers and manufacturers of compounds and formulations potentially resistant to manipulation and abuse, effective assessment of a drug pipeline requires efficient merging of innovative laboratory methods with insights into real-world abuse of drugs.

 

How has the increase in novel psychoactive substances impacted medical examiners offices? How does your experience in this setting benefit industry?

Statements and reporting that attribute morbidity and mortality to specific substances depend on accurate data.  Good data on drug abuse behaviors and solid drug abuse assessments provide the basis for accurate interpretations.

During the years I worked in forensic toxicology, first at the Alabama Department of Forensic Sciences and then later at the Jefferson County Coroner and Medical Examiner’s (JCCME) Office, we saw both the number and volume of novel psychoactive substances increase, together with recurrent shifts in these substances.  We needed to be able to identify these substances to protect the health of anyone potentially touched by them, including drug abusers, first responders, health care providers treating patients in the emergency department, and even laboratory personnel responsible for managing and testing evidence.

In the face of this public health challenge, I designed and validated a multi-pronged methodological approach in order to identify and report new novel psychoactive substances, which combined known information (i.e., suspect/decedent history and investigator notes), with analytical data (i.e., positive immunoassay screens, spectrum, molecular ion, retention time, etc.), and insights from discussions of illicit drug use on social media. This process not only helped accurately report the drug analytes to the Medical Examiner but ultimately allowed for proper transmission of the data to the Department of Public Health, CDC, and beyond.

Forensic sciences, especially the toxicology and chemistry fields, are charged with determining if a prescription or illicit drug analyte were involved in a particular incident (traffic crash, overdose, etc.). Part of this responsibility is to report findings on drug behaviors to local and state regulatory and public health entities. These data affect new regulation requirements which in turn affect pharmaceutical companies’ processes. Ultimately, to successfully design and receive FDA approval for new drug analytes and formulations, we have to understand current and past use, misuse, abuse, overdose and diversion behaviors.

 

References

Atherton D, Dye D, Robison CA, Beck R. (2019) n-Ethyl Pentylone-Related Deaths in Alabama. J Forensic Sci. 64 (1), pp 304-308.

Beck RC, Kloda S, Whiddon J, Davis GG, Robinson CA. Methodical approach for the identification of novel psychoactive substances. Presented at Society of Forensic Toxicology 2017 Annual Meeting. Boca Raton, FL. (January 2018).

Beck RC, Kloda S, Whiddon J, Dye WD, Robinson CA. Jefferson County fentalogues: A 6 month review. Presented at Society of Forensic Toxicology 2017 Annual Meeting. Boca Raton, FL. (January 2018).

Assessing Abuse Potential of Cannabinoids: Lessons Learned from Past CNS-Active Drug Development

Jack Henningfield, Reginald Fant and Daniel Wang

The confusing and conflicting legal status of cannabis and its active constituents can inhibit product development as companies encounter significant and unique barriers to approval and appropriate scheduling. In a complementary webinar, Jack Henningfield, Ph.D., and Daniel Wang described how the development and regulatory submission of other CNS-active drugs, including the development of the FDA-required abuse potential assessment, provide important precedents and models for cannabinoids.

“Product form and composition are important determinants of scheduling and potential claims. An early assessment can help avoid late stage surprises that add time and cost to development.” – Jack Henningfield

In the case of cannabinoids, an abuse potential assessment, conducted in accordance with the 2017 FDA Guidance on Assessment of Abuse Potential of Drugs, would consider the source of the active ingredients, the content and strength of active ingredients, the route of administration, any subjective effects, and whether the formulation can be manipulated or tampered. These factors can be indicative of the likelihood of diversion and dependence. From a health policy perspective, second hand exposure to the constituents of cannabinoid products would also be important.

The webinar will be available until March 2019 at https://xtalks.com/webinars/cannabinoid-abuse-potential-assessment-the-8-factor-analysis/.

Successful Rx to OTC Switch Depends on Responsiveness to FDA and Other Stakeholder Issues of Concern, Early and Integrated Commercial Planning

Christine Sweeney and George Quesnelle

FDA approval of an Rx-to-OTC switch depend on anticipation of issues likely to be raised by FDA division and nonprescription staff, as well as other policy stakeholders.  Commercial success following approval similarly requires addressing issues even before submission and looking beyond FDA approval.

“Rx-to-OTC switch is not a regulatory check-box exercise, it’s a policy change, supported by argument and data.” – Christine Sweeney

In a two-part webinar (recording available at the links below until February 2019), we discussed the importance of:

  • Thoughtful selection of switch candidates through regulatory and commercial feasibility assessments
  • Early development of FDA strategy, taking into consideration development of a sound Drug Facts Label and other consumer information materials, as well as well-designed consumer studies. These studies include label comprehension, self-selection and, if needed, behavioral (actual use) data to demonstrate the drug can be used safely and effectively in the nonprescription setting
  • Identifying and addressing concerns of FDA and other key stakeholders with science-based, data-driven responses
  • Building a compelling benefit/risk case for the switch
  • Strong leadership and project management linking regulatory, clinical, medical and commercial strategies and workstreams
  • Sound preliminary forecasts requiring consumer behavior insights

“A successful Rx-to-OTC switch process looks beyond FDA approval to encompass the pathway for commercial success.” – George Quesnelle

To access our two-part webinar series on Rx-to-OTC Switch, click here:

Part 1 of 2: Planning for Regulatory Success

Part 2 of 2: Rx-to-OTC Switch: Planning for Commercial Success

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.