ALA+ BioPharma Consulting

Dr. Thomas Hudzik has worked as a pharmacologist, toxicologist, global program leader and advisor in biopharma, binging molecules and cell therapies from bench to clinic to regulatory and marketing strategy. He’s authored numerous peer-reviewed scientific papers, posters and presentations at forums in neuroscience, substance use disorder, toxicology and neurology spaces. He’s co-authored and edited 2 books, one on abuse potential assessment and the other on suicidal ideation and behavior noted in pathologies and as adverse events in clinical studies. In 2022, he founded and is the principal executive of ALA Biopharma Consulting, since providing guidance spanning small biotech to large pharma on assessing abuse potential of new medications, animal models of disease, drug safety and regulatory strategy.

Companies advancing CNS-penetrant therapeutics are often surprised to find the FDA and other regulators will be asking for a consideration of the potential for abuse for their advancing medication. This includes any major metabolites, regardless of indication. This assessment can be a simple as a paper exercise or as complex as dedicated non-clinical and clinical abuse potential assessment studies. If you are unfamiliar with these types of studies or if you need a strategy to implement that will be consistent with your overall clinical and marketing plans, there is a book to provide a detailed overview of the appropriate methods.

However, every new molecular entity is unique and a tailored approach is required at the end of the day, factoring in known clinical exposures, comparative pharmacokinetics, solubility, physicochemical properties, off-target pharmacology, potential controls and comparators, as well as a careful analysis of any noted behavioral effects in preclinical and early clinical studies. Timing of any dedicated abuse potential studies, if needed, should only be conducted when the range of clinical doses are clearly understood. If not needed, a written justification will be required to detail why the work was not conducted.

Regarding the importance of fully understanding the pharmacology of drug and major metabolites, consider the drug tianeptine. This drug, only marketed outside of the US for treatment-resistant depression, was originally touted as tricyclic antidepressant (due to its chemical structure) and selective serotonin reuptake inhibitor. Tianeptine and its major metabolite was only later discovered to be potent mu opioid receptor agonist as its primary mechanism of action. Neither chemical has activity at serotonin transporters, but the opioid properties has made it a prominent drug of abuse globally, including in illicit markets in the US. It is also known to produce severe withdrawal signs, as with heroin. Around a decade after its marketing in the early 1990s, FDA, EMA and ICH guidance documents were published, which outline recommended methods that would have resulting in much greater regulatory control of tianeptine.

The output from dedicated abuse potential assessment studies, together with any abuse-related MedDRA terms and patient narratives allows groups at the FDA, NIH and ultimately DEA to make a drug scheduling decision, which then spans from DEA CI (most restrictive, least potential for medical utility; e.g., heroin or nitazenes, such as etonitazene) to CV (lowest potential for abuse, minimal regulatory oversight; e.g., pregabalin). At the time of NDA submission, the assessment may still be incomplete until post marketing, in which case a Risk Evaluation and Mitigation Strategy may also be required prior to final approval. These are elements are to be considered well in advance of regulatory filings, typically as part of the end-of-Phase II briefing package.

In the US, if non-clinical experiments indicate clear abuse potential, a dedicated study utilizing drug-experienced volunteers is often required to further assist in scheduling decisions. In such clinical studies, pharmacokinetics with respect to participant narratives, visual analog scales for drug effect and measures of drug liking can add helpful, confirmatory data. There is ongoing debate, however, as to what extent drug-experienced adults represent a broader patient population. For example, volunteers are usually more sensitive to detecting drug effects than a general population, and have an often-vast drug experience history with which to compare to study medication. A report of sedative effects in study participants might be reported also as pleasurable, but be noted by patients and an unpleasant nuisance. These disparate observations must be taken into consideration in interpretation of such studies.

Because many larger companies stepped away from CNS drug development in the 2010s, much of the internal and external expertise via academic partnerships has been lost. However, neuroscience indications are currently experiencing a renaissance across the industry, and careful attention to understanding the full spectrum of undesired effects, including abuse potential remains of tantamount importance. Companies should seek out the most experienced consultants to assist with these matters, and having more than one opinion is usually the best way forward.