Author: Yolanda Green

Implementation of Consistent Language as Outlined in FDA Draft Guidance on Drug Abuse and Dependence Labeling Will Support Drug Development, Labeling and Prescriber Decision-Making

By Jack Henningfield, Karen Gerlach, Judy Ashworth, Marion Coe, Sid Schnoll

Once finalized, FDA Draft Guidance “Drug Abuse and Dependence Section of Labeling for Human Prescription Drug and Biological Products — Content and Format” will help ensure more consistent language across drug products about abuse, misuse, addiction, dependence, and tolerance. Our experts in the development and evaluation of drugs with abuse potential, and post-marketing risk management for controlled substances submitted comments to the FDA (read more here) about the proposed definitions for abuse, addiction, physical dependence and withdrawal.

To support drug development, and clinical and regulatory strategy, drug developers would benefit from using the proposed definitions from the beginning of drug development to the development of the label.  During development, consistent language will facilitate the collection and characterization of appropriate data in clinical trials and clear communications with FDA when input is needed to guide the development strategy.  Further, consistent use of these definitions in drug labeling will help prescribers communicate the risks to their patients to minimize the occurrence and risk of substance-use related problems and those related to withdrawal and physical dependence.

Our experts’ comments encompassed the following:

 Physical Dependence and Withdrawal. Withdrawal symptoms are hallmark measures for determining physical dependence and are part of the pharmacology of many drugs regardless of whether the drug is considered to carry significant abuse potential. However, withdrawal symptoms by themselves are not sufficient to conclude that the patient is “addicted”, has developed a “dependency” or “or substance use disorder” by criteria of the American Psychiatric Association’s DSM-5 or World Health Organization’s ICD-10  The inappropriate conflating of withdrawal symptoms with “abuse” and “addiction” has led to the misunderstanding of the meaning and relevance of withdrawal. This can impact treatment decisions by healthcare professionals and safe and effective use of prescribed medicines by patients.

For drug developers, assessing the nature of the symptoms of physical dependence should encompass systematic collection and assessment of adverse events Clinical and non-clinical studies should be designed to determine if physical dependence symptoms occur with drug administration (per 2017 Guidance for Industry Assessment of the Abuse Potential of Drugs).

Abuse Potential.  FDA’s 2017 Abuse Potential Guidance describes the data needed for most aspects of the label to address the abuse potential, development of physical dependence, and withdrawal signs and symptoms. This new draft guidance on Drug Abuse and Dependence complements the 2017 Abuse Potential Guidance by proposing the approach by which labeling may include information, data, and study findings relevant to abuse potential.

Labeling on abuse may help differentiate drugs within the same schedule of the Controlled Substances Act This differentiation can be invaluable to health professionals making decisions about which drugs might be most appropriate for a particular patient (Dasgupta, Henningfield, Ertischek and Schnoll, 2011).

Addiction. Addiction is the most commonly used lay term for what is technically termed Substance Use Disorder (SUD) in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) and Dependence in the World Health Organization’s International Classification of Diseases, tenth edition (WHO ICD-10).  In practice, the term addiction is used by the lay public for relatively benign substance use behaviors such as daily caffeine intake, daily consumption of a serving of wine or beer with dinner as well as for life-threatening alcohol, opioid and cocaine patterns of use.

Thus, our experts suggest that FDA make clear that its proposed definition of addiction is not intended to replace SUD, nor does it imply a subset of SUD for diagnostic, therapeutic, or medical disease coding for insurance purposes. Rather ‘addiction’ is a term that is widely used in general communications and warnings, much as other general terms when technical language might be less impactful and less generally understood, e.g., cancer, heart attack, kidney disease, and overdose.

Once finalized, the specific definitions and terminology established by FDA for use in prescription labeling will support harmonized labeling regarding abuse, misuse, addiction, physical dependence, and tolerance. Labeling that conveys more accurate information about these topics is important for patients, prescribers, caregivers and families, as well as pharmaceutical developers. It is also among the many steps needed to more effectively minimize the occurrence and risks of substance use related problems for individual patients and at the societal level.

You can read our comment to the FDA in its entirety here.


Regulatory Case Study: A Strategic Abuse Potential Assessment of Acorda Therapeutics’ INBRIJA™ (levodopa inhalation powder)

By Reggie Fant

In December 2018, the Food and Drug Administration (FDA) approved Acorda Therapeutics’ INBRIJA, the first levodopa inhalation powder for the intermittent treatment of OFF episodes in people with Parkinson’s disease treated with carbidopa/levodopa. As Parkinson’s disease progresses, many people with Parkinson’s fluctuate between ON periods, during which symptoms are controlled and OFF episodes, also known as OFF periods, which are the return of Parkinson’s symptoms that result from low levels of dopamine between doses of treatment.

PinneyAssociates helped Acorda Therapeutics prepare the scientific and public health rationale to support the position that INBRIJA should not be placed into a schedule under the United States Controlled Substances Act (CSA).

Parkinson’s disease is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the brain.  Levodopa, a metabolic precursor of dopamine, increases intracellular dopamine levels in the brain of Parkinson’s patients.

As with all treatments that act on the central nervous system, the FDA required evaluation of abuse potential as per the 2017 Guidance for Industry, Assessment of Abuse Potential of Drugs. For the NDA submission of INBRIJA, Acorda Therapeutics needed an evaluation of the abuse potential of their inhalation powder formulation relative to a marketed oral formulation (none of which are scheduled) to demonstrate that the inhalational route of administration did not increase the likelihood that INBRIJA would be abused or diverted. Scientific evidence was necessary for the FDA to determine that placement into a schedule under the United States (U.S.) Controlled Substances Act was not required.

Our Approach

PinneyAssociates scientists and regulatory experts utilized the full depth and breadth of the available science on the abuse potential of levodopa to address FDA requirements and provided scientific evidence and a public health rationale that INBRIJA should not be placed into a schedule.  This included:

  • A comprehensive review of the pharmacology of levodopa
  • An extensive strategic review of the literature related to nonmedical use, misuse, and abuse of and withdrawal associated with levodopa
  • Assessment of federal survey data about nonmedical use or abuse of levodopa
  • A pharmacokinetics comparison of the inhalation formulation to currently marketed oral formulations of levodopa
  • Independent assessment of clinical trial data including adverse events possibly related to abuse potential or withdrawal, and drug accountability
  • Consideration of the public health impact including likely benefits and risks of the product
  • Development of an abuse potential assessment of the formulation, and a recommendation for no scheduling, which were submitted as part of the NDA
  • Assistance in preparing for the pre-NDA meeting, and review of data analyses in support of interactions with the FDA

Value to Acorda

The abuse potential assessment and scheduling recommendation developed by PinneyAssociates contributed to the FDA’s determination that INBRIJA did not warrant placement into a schedule of the Controlled Substances Act.

Three Takeaways from FDA’s Draft Guidance on Innovative Approaches to Rx-to-OTC Switches

By Bernard G. Simone

In July 2018 the FDA issued a Draft Guidance for Industry on Innovative Approaches for Nonprescription Drug Products.  There are three key takeaways.

  1. First, with this Draft Guidance, the Agency gives Sponsors permission to consider innovative approaches beyond the Drug Facts Label (DFL), when the DFL alone is insufficient to assure safe use in a nonprescription setting. The draft also documents that the Agency believes it has the authority to approve ‘additional labeling’ beyond the DFL if that labeling can be shown to improve outcomes in over-the-counter (OTC) self-selection studies.
  1. Second, while the Draft Guidance discusses “two” innovative approaches, they are difficult to distinguish from each other. (Discussed further below.)  In reality, there appears to be only one innovative change which is that the FDA will now consider approving something incremental to the DFL that a Sponsor proposes for testing in a self-selection study and for use in marketing.
  1. Third, the FDA’s over-riding message is that each Rx-to-OTC switch is unique and the merits of each proposal will depend on the appropriateness for each switch and the circumstances of the particular drug under consideration. Thus, the Draft Guidance invites a case-by-case discussion between the Sponsor and the Agency for using something incremental to the DFL.

Let’s look deeper.  The Agency’s first innovative approach is titled “Labeling in Addition to the DFL for Nonprescription Drug Products”.  Labeling examples provided by the Agency include:

  • Leaflets inside the package (which have long been common in OTC switches)
  • Video display messages
  • Website information
  • Statements or questions on a mobile app

This is where the Agency explicitly says that they “may” approve additional labeling, thus documenting their conclusion that they have the authority to do so.

The second innovative approach, titled: “Nonprescription Drug Products with Additional Conditions for Safe and Effective Use” poses more interesting possibilities.  Examples include:

  • A mobile app self-selection test conducted prior to purchase that affirms a consumer’s appropriateness to use the OTC product
  • Consumer affirmation, again performed prior to purchase, that they have viewed a text or video that describes how to use the product appropriately

If a Sponsor chooses to use an ‘additional condition’, the Agency writes, the Sponsor should consider how to ensure proper implementation of it.  However, the Draft Guidance does not explicitly say that a Sponsor must demonstrate that the consumer will actually use the ‘additional condition’ once it is available to the consumer. Nor does it say that the pre-purchase text or video viewing has to positively influence a consumer’s self-selection decision.

Perhaps these apparent loopholes are subject to the inherent linkage between the two innovations mentioned in the Draft Guidance.  Clearly, any ‘additional condition’ would obviously require content in the form of text or images or both.  Hence, it becomes ‘additional labeling’, which is covered in the first innovative approach.   Further, any ‘additional labeling’, including the explicitly written mobile apps or videos, are subject to FDA approval. Such approvals are based on data, data that demonstrates the labeling leads to self-selection at performance thresholds established with the FDA.  Hence, the two approaches are inextricably linked.

In short, the Draft Guidance can be simplified into three short sentences:

  1. If a Sponsor intends to use more than the DFL to achieve proper self-selection and use, the Agency will consider it as additional labeling subject to approval.
  2. In doing so, the Sponsor should demonstrate that the consumer will use/read the incremental labeling, and that it delivers the agreed performance thresholds.
  3. Sponsors must discuss such initiatives with the FDA because every switch is different.

Developing Psychedelics into Medicines: Potential Opportunities and Pitfalls

By Daniel Wang

Psychedelics, a class of powerful psychoactive substances that alter perception and cognition, have for decades been relegated to the dark corners of illicit recreational substances after many of them were placed in Schedule I of the 1970 Controlled Substances Act (CSA).

However, the Food and Drug Administration (FDA) signaled that the Agency sees therapeutic promise in these substances when it granted Breakthrough Therapy designation to midomafetamine containing 3,4-Methylenedioxymethamphetamine (commonly known as MDMA or ecstasy) in 2017 and a psilocybin therapy for treatment-resistant depression  in 2018.  In doing so, the FDA opened up potential opportunities that have historically been non gratae.

Medicinal use of psychedelics dates back thousands of years, but became more mainstream with the synthesis of lysergic acid diethylamide (LSD) in the 1930s, and its widespread distribution among medical researchers by Sandoz Inc in the 50s and 60s. However, reports of disastrous consequences such as accidents, suicides, murders, and other criminal acts linked to use of LSD, along with the drug’s association with 1970s counterculture, contributed to psychedelics losing favor within the political and medical communities and their subsequent placement into Schedule I of the CSA.

As a Schedule I substance, sales, possession, and research into a drug’s uses are restricted to individuals and institutions who meet strict criteria for licensing imposed by the Drug Enforcement Administration (DEA). Practically speaking, the result is a severe constraint on research into the potential benefits and other effects of these substances.  Yet over the past 20 years, research out of major universities such as the Johns Hopkins University and Imperial College London points towards the potential for psychedelics to treat anxiety, depression, and substance use disorders with effects that last longer and feature fewer side effects than widely accepted mainstream treatments.

Internationally recognized leading clinical and abuse potential experts, PinneyAssociates’ Sid Schnoll, MD, PhD and Jack Henningfield, PhD and RenaSci’s David Heal, PhD, described the unique challenges in developing psychedelics into medicines and how to address them throughout the development process during a complimentary webinar available here >> webinar.

“Understanding the traditional uses of psychedelics and management of their effects can inform current drug development plans,” observed Dr. Schnoll.

“Statements by the Controlled Substances Staff (CSS) of FDA together with the Schedule V classification of Epidiolex suggest that the CSS will approach psychedelics much like any other CNS drug candidate when it comes to controlled drug status and scheduling,” said Dr. Heal. He outlined the steps necessary to assess abuse potential in preclinical trials, including types of studies required, how to evaluate results in the context of psychedelics, and the specific technical challenges when evaluating psychedelics as compared to other drugs of abuse.

Urging drug developers to use evidence obtained during the drug development process to inform postmarketing plans, Dr. Henningfield emphasized that “commitment to a strong Risk Evaluation and Mitigation Strategy (REMS) to address likely abuse-related issues is vital in approval of studies, fundraising, alleviating social and political concerns, and to ensure patient safety.”

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.



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).