Conferencia “Evaluación del Potencial Abuso de Drogas”

Silvia N. Calderón-Gutkind, Ph.D.

Senior Expert Pharmacologist Controlled Substance Staff, Office of the Center Director, Center for Drug Evaluation and Research, Food and Drug Administration.

 

El abuso y el uso indebido de medicamentos constituyen un problema serio que afecta a la salud pública, reflejándose en un costo social de más de 100,000 muertes por sobredosis en los Estados Unidos en el 2023. Los medicamentos que más frecuentemente se usan fuera del contexto terapéutico y con el propósito de sentir efectos psicoactivos positivos (ej. euforia), son:

1) los analgésicos opioides, 2) los medicamentos usados en el tratamiento de ansiedad y de trastornos del sueño como los tranquilizantes, sedantes, e hipnóticos (ej. benzodiazepinas) y 3) los estimulantes (ej. anfetamina, metilfenidato) que se usan en el tratamiento de trastornos por déficit de atención e hiperactividad.

En este contexto y dentro del marco establecido por la Ley Federal de Alimentos, Drogas y Cosméticos, la Administración de Alimentos y Medicamentos, la Administración de Alimentos y Medicamentos (FDA) reconoce al potencial de abuso de una droga como un riesgo que debe ser evaluado durante el proceso de desarrollo de la droga, y que debe ser comunicado a los profesionales de salud y a los pacientes de manera clara en comunicaciones de seguridad y en el prospecto del medicamento. La Unidad de Sustancias Controladas (CSS) perteneciente al Centro de Evaluación e Investigación de Medicamentos (CDER) de la FDA, es responsable de la evaluación del potencial de abuso de drogas. Esta evaluación provee las bases para efectuar el análisis del riesgo-beneficio de una droga al momento de su aprobación, y también se considera como un factor crítico en las determinaciones de la necesidad del listado de drogas de acuerdo con Ley de Control de Drogas (CSA) de los Estados Unidos.

La evaluación del potencial de abuso de una droga consiste en un análisis sistemático de estudios experimentales de la caracterización de: 1) las propiedades químicas de la droga, 2) la farmacología general y conductual, 3) el perfil farmacocinético y farmacodinámico y 4) los efectos psicoactivos de la droga en humanos. Con respecto a la evaluación clínica del potencial de abuso de una droga, el CSS considera los efectos adversos observados en los estudios clínicos llevados a cabo a través de todas las fases del desarrollo clínico de la droga, y los efectos producidos por la droga en individuos con experiencia en el uso recreacional de drogas.

Estos estudios conocidos como “estudios del potencial de abuso en humanos” (HAP studies) son estudios muy específicos requeridos en los Estados Unidos cuando se observan respuestas positivas en modelos animales conductuales de discriminación y de refuerzo, o cuando se observan efectos psicotrópicos que generalmente se asocian con el uso de drogas de abuso (ej., euforia, alucinaciones, etc.) en estudios clínicos.
La presentación se focalizará en la descripción del proceso y de los modelos experimentales utilizados en la evaluación del potencial de abuso de drogas en el contexto del desarrollo de medicamentos y en el contexto del proceso de control de drogas de acuerdo con la CSA. Se describirá el rol de la FDA en el proceso de control de drogas de uso médico o de drogas psicoactivas ilícitas, al igual que se describirá la información necesaria para justificar una recomendación de control. La presentación también proporcionará una descripción del listado de sustancias controladas de acuerdo con la CSA y de los controles que se aplican sobre la fabricación, la distribución, y la dispensación de medicamentos de acuerdo con su clasificación.

 

Silvia Nora Calderon-Gutkind

Position Title:

  • Senior Expert Pharmacologist Controlled Substance Staff, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA) Silver Spring, MD 20993

 

Education:

  • Ph.D. 1989 Medicinal Chemistry; University of Buenos Aires, Argentina.
  • M.Sc. 1980 Pharmacy; School of Pharmacy and Biochemistry, University of Buenos Aires, Argentina.

 

Employment History:

  • 2000 to Present Expert Regulatory Review Scientist, Controlled Substance Staff, CDER, FDA, Rockville, MD.
  • 1996 to 2000 Senior Staff Fellow, Division of Anesthetic, Critical Care and Addiction Drug Products, CDER, FDA, Rockville, MD.
  • 1992 to 1996 Visiting Associate, Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD. Advisor: Dr. Kenner C. Rice
  • 1991 to 1992 Postdoctoral Fellow, National Institute on Drug Abuse, Addiction Research Center, Drug Development Group, Baltimore, MD. Advisor: Dr. Amy H. Newman
  • 1989 to 1991 Postdoctoral Fellow, National Research Council, Division of Neuropsychiatry, Walter Reed Army Institute of Research, Washington D.C. Advisor: Dr. Amy H. Newman

 

Honors and Awards: Selected awards

  1. Center for Drug Evaluation and Research, Dr. Frances O. Kelsey Drug Safety Excellence Award as a member of Opana ER Safety Review Working Group. For contributions in the assessment of abuse for Opana ER (Oxymorphone Extended-Release) and participation in the March FDA Advisory Committee meeting. September 2018. Silver Spring, MD, USA.
  2. Center for Drug Evaluation and Research, Regulatory Science Award as a member of the Controlled Substance Staff. For active participation in issuing the 2017 revision of the 2010 Guidance for Industry on the Assessment of abuse Potential of Drugs. September 2018. Silver Spring, MD, USA.
  3. Center for Drug Evaluation and Research, Honor Awards Group and Team Recognition as a Silvia N. Calderon-Gutkind member of the FDA’s Opioid Action Plan Implementation Team. For exemplary commitment to enacting FDA’s mission to combat the nation’s opioid epidemic while ensuring patients have access to safe and effective pain management therapies. September 2017. Silver Spring, MD, USA.
  4. Center for Drug Evaluation and Research’s Team Excellence Award as a member of the Opioid Risk Management Team. For outstanding performance contributing to the risk management of opioids including a Methadone Workshop and ALSDAC Advisory Committee on Risk Management of Opiate Analgesics. May 2004. Gaithersburg, MD, USA.
  5. Department of Health and Human Services. Secretary’s Award for Distinguished Service. NIDA/FDA/SAMHSA Buprenorphine Workgroup. June 2003. Washington, DC, USA. ç

 

Ad-hoc Reviewer:

  • Journal Medicinal Chemistry and Journal of Addiction Medicine

 

Membership at Professional Societies:

  1. College on Problems of Drug Dependence, Member Elect (1998 to present)
  2. Interagency Committee on Drug Control (1998 to present)
  3. Interagency Committee on Drug Control. Chairperson 1999
  4. American Chemical Society: Medicinal Chemistry Section (1994 to present)

 

Research Interests:

My research interests include the regulatory and scientific requirements for the development of therapeutics with abuse potential, and the studies of the overlapping scientific principles of opioid therapies and addiction.

 

Contributions to Science:

My career at the Controlled Substances Staff (CSS) in the Center for Drug Evaluation and Research (CDER) has spanned for over 28 years. I summarize many of my contributions to the assessment of drug abuse potential and the field of medicinal chemistry below.

  • Guidance for industry on the assessment of the abuse potential of drugs. The potential that a drug could be abused, meaning that the drug is used and sought after for its capacity to produce positive psychoactive effects, constitutes a safety risk that needs to be evaluated before drug approval. The assessment of the abuse potential of a drug is data-driven, and requires evaluation of the chemical, pharmacological, and pharmacokinetic characteristics of the drug, clinical data (i.e.,human abuse potential studies, clinical trial data relative to abuse), and epidemiological data. The abuse and misuse of novel therapeutic agents, as well as novel opioid formulations, is an area of critical public health importance to CDER and FDA, which has gained attention from the public, legislators, and the press. As a CSS member I have been actively involved in developing the regulatory science that is applied today to the evaluation and prediction of the abuse potential of new drug substances and formulations.
    1. Considerations in assessing the abuse potential of psychedelics during drug development. Calderon, S. N.; Bonson, K. R.; Reissig, C. J.; Lloyd, J. M.; Galati, S.; & Chiapperino, D. Neuropharmacology, 2023, 224, 109352.
    2. A Regulatory Perspective on the Evaluation of Hallucinogen Drugs for Human Use. Calderon, S.N.; Hunt, J.; Klein, M. Neuropharmacology, Special Issue “CNS Psyhedelics” 2018, 142, 135-142.
    3. Trends in Dextromethorphan Cough and Cold Products: 2000-2015 National Poison Data System intentional abuse exposure calls. Karami, S.; Major, J. M.; Calderon, S.; McAninch, J. K. Clin. Toxicol. 2018, 56 (7), 656-663.
    4. Guidance for Industry. Assessment of Abuse Potential of Drugs. Federal Register, 82 (18 January 2017), 5581-5583. Access at: https://www.fda.gov/downloads/drugs/guidances/ucm198650.pdf

 

  •  Guidance for industry to improve the safety of opioid analgesic formulations. The abuse of OxyContin in the early 2000’s was the catalyst for the implementation of strategies to prevent misuse, opioid use disorders, and opioid-related deaths. Drawing on my experience as a pharmacist, as well as my training in chemistry, pharmacology, and clinical methodologies to evaluate abuse potential of drugs, I actively worked with CDER scientists and clinicians to provide guidance for industry to improve the safety of high strength extended-release opioid formulations. These formulations are known as “abuse deterrent formulation” (ADF) opioids. ADF opioids are formulated to have physical, chemical, or pharmacological properties that make it more difficult for individuals to use the formulation by alternative routes (i.e., intranasal and intravenous routes) for purposes of abuse. ADF OxyContin was the first reformulated opioid formulation that came under review by the FDA, and I have been responsible for reviewing this formulation, and other ADF opioids that followed. I continue to be a senior adviser and the lead CSS scientist in this area to help FDA make sound evidence-based regulatory decisions about ADF opioid analgesics.
    1. Concentration-Response Model of Immediate Release Oxycodone Drug Liking by Different Routes of Abuse. Nallani, S.C., Li, W., Calderon, S.N., Fields, E., Roca, R.A., Xu, Y, Zhao, L., Fang, L., Sahajwalla, C.G., Zineh, L. Pain Med. 2022, 23 (7), 1311-1322.
    2. Risk Based In Vitro Performance Assessment of Extended-Release Abuse Deterrent Formulations. Xu, X.; Gupta, A.; Al-Ghabeish, M.; Calderon, S.N.; Khan, M.A. Int. J. Pharm. 2016, 500 (1-2), 255-267.
    3.  Guidance for Industry. Abuse-Deterrent Opioids- Evaluation and Labeling. Federal Register, 80 (2 April 2015), 17765. Access at: https://www.fda.gov/downloads/Drugs/Guidances/UCM334743.pdf

 

  • Evaluation of the abuse potential of novel drugs that come under review by the FDA, and recommendations for scheduling under the Controlled Substances Act (CSA).
    Within CDER, the CSS team is responsible for evaluating all data submitted under a New Drug Application to assess the abuse potential of drugs with central nervous system activity that come under review by the FDA. Based on the evaluation of the abuse potential of a drug, CSS informs regulatory decisions about drug labeling, and drug scheduling under the CSA. I have authored numerous evaluations of the abuse potential of drugs and made numerous drug scheduling recommendations for drugs with recognized medical use and drugs that appeared on the illicit market. I have trained and mentored ten CSS members, who collectively, have been at the center of many important actions to schedule drugs under the CSA, continued their career at the FDA, industry, or currently work as  independent consultants.

 

  • Contributions to FDA/CDER Drug Abuse Advisory Committee Meetings. CDER relies on advisory committees to provide independent advice when a scientific, technical, or policy question arises at any stage of the drug review process and after a product has been approved and marketed. In preparation for these meetings, FDA provides advisors with supporting materials to facilitate discussions and deliberations. As a member of the CDER review team, I have prepared supporting materials and presented at various FDA Advisory Meetings discussing the abuse potential of novel drugs, drug scheduling, and the overall assessment of reformulated opioid formulations. Presentations and supporting materials for these meetings are in the public domain and available at the FDA website.
    1. Psychopharmacology Drugs Advisory Committee Meeting/ Drug Safety and Risk Management Advisory Committee. NDA 211179, AR19, Amphetamine Immediate Release Capsules. October 2020. Virtual Meeting.
    2. Anesthetic and Life Support Drugs Advisory Committee Meeting/ Drug Safety and Risk Management Advisory Committee. NDA 211802, Oxycodegol Tablets. Safety and efficacy, and overall risk-benefit of the product. January 2020. Silver Spring, Maryland, USA.
    3. Anesthetic and Life Support Drugs Advisory Committee Meeting/ Drug Safety and Risk Management Advisory Committee. NDA 213426, Tramadol and Celcoxib Tablets. Safety and efficacy, and overall risk-benefit of the product. January 2020. Silver Spring, Maryland, USA.

 

  • Contributions to the field of medicinal chemistry. As part of my postdoctoral training, I worked on the design and synthesis of anti-convulsant drugs and on the synthesis and enantiomeric resolution of a series of non-peptidic delta opioid ligands. The latter resulted in the synthesis and pharmacological characterization of SNC-80, one of the most selective delta opioid ligands synthesized to date. SNC-80 is currently used as a research tool, contributing to the advancement of our understanding of the effects mediated by delta-opioid receptors including potential for abuse.
    1. Nonpeptidic Delta (δ) Opioid Agonists and Antagonists of the Diarylmethylpeiperazine Class: What have we learned? Calderon, S.N. In Topics in Current Chemistry, Volume 299, H. Nagase, ed., Springer-Verlag, New York, 2011, 121-140.
    2. SNC 80 and Related δ Opioid Agonists. Calderon, S.N. and Coop, A. Current Pharm. Design 2004, 10, 733-742.
    3. Probes for Narcotic Receptor Mediated Phenomena. 19. Synthesis of (+)-4-[(αR)-α((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80): A Highly Selective, Nonpeptide Delta Opioid Receptor Agonist. Calderon, S.N.; Rothman, R.B.; Porreca, F.; Flippen-Anderson, J. L.; McNutt, R.W.; Xu, H; Smith, L.E.; Bilsky, E.J.; Davis, P.; Rice, K. C. J. Med. Chem., 1994, 37, 2125-2128. This paper was reviewed in Chemtracts-Organic Chemistry, 1994, 7, 395-400.

 

Invited Speaker:

  1. Cross Company Abuse Liability Consortium (CCALC), Advances and Challenges in Abuse Potential Evaluation. October 2023. Rockville, Maryland, USA. (Topic: Abuse Potential Assessment. Consideration of Discordant Findings from Nonclinical, Clinical and Epidemiological Data).
  2. College on Problems on Drug Dependence (CPDD) 85th Annual Scientific Meeting. June 2023. Denver, Colorado, USA. (Topic: Xylazine: An adulterant Drug of Concern)
  3. Cross Company Abuse Liability Consortium (CCALC), Advances and Challenges in Abuse Potential Evaluation. April 2018. Bethesda, Maryland, USA. (Topic: Evaluating Human Factors in the Context of Abuse Potential Assessments).
  4. College on Problems of Drug Dependence, 79th Annual Scientific Meeting. Assessment of Abuse Potential in Clinical trials in the Context of the Finalized FDA Guidance Workshop. June 2017. Montreal, Canada. (Topic: The Process of Documenting Abuse- related Signals from Clinical Trials).
  5. Covance Spring Webinar Assessing Abuse Potential of CNS-Active Compounds: Regulatory Environment and Challenges. June 2017. Webinar.