Markgraf / Hudzik / Compton Nonclinical Assessment of Abuse Potential for New Pharmaceuticals

1. Auflage 2015
ISBN: 978-0-12-420216-0
Verlag: Academic Press
Format: EPUB
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 320 Seiten, Format (B × H): 191 mm x 235 mm

Nonclinical Assessment of Abuse Potential for New Pharmaceuticals offers a complete reference on the current international regulatory guidelines and details best practice methodology for the three standard animal models used to evaluate abuse potential: physical dependence, self-administration and drug discrimination. This book also includes chapters on alternative models and examples of when you should use these alternatives. Case histories are provided at the end of the book to show how the data generated from the animal models play a pivitol role in the submission package for a new drug.  By incorporating all of this information into one book, Nonclinical Assessment of Abuse Potential for New Pharmaceuticals is your single resource for everything you need to know to understand and implement the assessment of abuse liability.


- Provides a consolidated overview of the complex regulatory landscape
- Offers best practice methodology for conducting animal studies, including selection of doses and positive control agents that will help you improve your own abuse potential studies
- Includes real-life examples to illustrate how nonclinical data fit into the submission strategy

Zielgruppe

Scientists in the pharmaceutical industry who conduct nonclinical studies (in Discovery and Nonclinical Safety departments); professionals who use the data in decision-making (Management, Regulatory and Project Managers); academics conducting research in these areas and clinicians in the pharmaceutical industry; Health Authority regulators

Autoren/Hrsg.

Markgraf, Carrie

Hudzik, Thomas

Compton, David

Fachgebiete

• Naturwissenschaften Chemie Chemie Allgemein Pharmazeutische Chemie, Medizinische Chemie
• Medizin | Veterinärmedizin Medizin | Public Health | Pharmazie | Zahnmedizin Pharmazie

Inhaltsverzeichnis

Foreword Preface
- Principles of Assessing Nonclinical Abuse Potential 
- Neurochemistry of Drug Abuse
- Regulatory Landscape for Abuse Liability 
- Rodent Self-Administration Model
- Primate Self-Administration Model
- Physical Dependence Studies
- Drug Discrimination Model
- Conditioned Place Preference
- Intra-cranial Self Stimulation
- Clinical Evaluation of Abuse Potential for New Pharmaceuticals
- Critical Decision Points in Abuse Potential Evaluation

Leseproben

Foreword
The epidemic of drug abuse has been studied and written about extensively for the past few decades. According to the Centers for Disease Control and Prevention (CDC)1, drug overdose death rates in the United States more than tripled from 1990 to 2008. Overdose deaths involving opioid analgesics increased and exceeded deaths involving heroin and cocaine combined. The CDC analyzed rates of fatal overdoses, nonmedical use, sales, and treatment admissions for opioid analgesics. In 2008, drug overdoses in the United States caused 36,450 deaths. Opioids were involved in 14,800 deaths (73.8%) of the 20,044 prescription drug overdose deaths. Most abuse involves polypharmacy whereby abuse involves the use of opioids in combination with other central nervous system-active drugs for enhanced effects or for otherwise altering the pharmacologic effect. During 1999–2008, overdose death rates, sales, and substance abuse treatment admissions related to opioids all increased substantially. Other statistics describe the issue with details about regions of the country that are particularly affected by the current national drug abuse problem. Each manner in which data on abuse is presented makes the problem seem closer to all of us and more and more personal. Individual stories are routinely reported in newspapers about seemingly average people, including young people, who are affected by the availability of prescription and nonprescription drugs with abuse potential. In some cases, they are being treated with a medicine and begin abusing it, and then they take it for recreational purposes and become dependent. Such use may lead to addiction and overdose and, in the worst cases, death. The abuse potential of a new drug needs to be assessed in controlled nonclinical and clinical studies before it is approved for marketing. The general public wants to know about the drugs that they take and they want to be informed about their risks and likelihood for abuse before they become a problem. Drug developers and regulators need to acquire this information as early as possible. Many types of prescription drugs are abused (opioids, sedatives, hypnotics, stimulants, and hallucinogens) and abuse in the US is primarily in the form of polypharmacy. These drug classes comprise most substances that are listed in the schedules of the Controlled Substances Act (CSA)2. A single drug for abuse appears to be an infrequent event, though confirmatory and specific data describing an abuse incident is not often available. In 2011, the Drug Abuse Warning Network (DAWN)3 ceased to collect data related to actual drug abuse encounters reported in hospital emergency departments and medical examiners. A compilation of DAWN reports once provided annual national statistics on abuse, often of specific drug products and the combinations of drugs that are abused. Since 2011, a greater reliance on this type of information has fallen to a variety of surveys and other sources of data, including poison control center reports to identify drug abuse problems. Oftentimes, abuse and diversion data are not systematically acquired and the reliability of such data is questioned. These sorts of data also cannot be trended from year to year, so they do not allow us to interpret with accuracy the meaning of any observed annual changes in patterns of use, extent of drug use, and new drug abuse fads. Determining whether things are getting better or whether regulatory efforts are successful is difficult if one relies on such data. We are limited in our ability to know whether new approaches have been successful and where future efforts should be applied when successes are based on data that are not systematically collected. Anticipated problems and needed risk management can be predicted by the assessment of the drug’s abuse potential. Rigorous scientific studies and a logical approach to conducting studies on the abuse potential of drugs are needed prior to approval and marketing. Drug regulators can make a risk benefit calculation of the drug and ensure that appropriate risk management strategies are in place to address anticipated problems. Several years ago, I was told by a pharmaceutical industry representative that the abuse potential assessment of a drug is arcane—a mysterious and obscure process known only to a few. To him and many others, assessing the abuse potential of a drug seemed to rely more on anecdotal reports of abuse than on scientific data and analysis. One inherent problem with the assessment of abuse potential was that it relied on a random consensus of nonclinical and clinical interdisciplinary scientific data from a variety of studies. The sort of studies and the Food and Drug Administration (FDA) standards and expectations from these studies were not widely known. The investment of capital (intellectual and otherwise) into conducting these studies and developing an abuse potential assessment and integrating it into the entire drug development process was largely unheard of. Such efforts needed to be justified and directed such that not only were meaningful scientific results produced but that the appropriate studies were performed at the appropriate times and on a fair playing field for all companies. Companies were limited in their ability to perform a successful program in this area prior to the FDA publication of the draft Guidance for Industry: Assessment of Abuse Potential of Drugs4 in January 2010. The Guidance provided a framework for assessing abuse potential. In addition to describing the types of studies and data that are needed, the Guidance laid out a stepwise scientific approach, offering a logical sequence and timeline for performing certain studies before others, whereby later studies could build on results from earlier studies as new information about the new drug is obtained. Today, the assessment of abuse potential is a part of the FDA’s Twenty-First Century Drug Review Process in the Center for Drug Evaluation and Research (FDA/CDER). For drugs with abuse potential, expert regulatory reviewers participate in all milestone meetings and prepare reviews of the studies with recommendations prior to approval. The assessment of the abuse potential of a drug—whether new or well-known and already on the market—is part of the evaluation of the overall safety profile of a drug. The safety profile evaluation for a drug relates to the medical use of a drug and is primarily applicable to patient populations. In this context, the risk benefit determination for the drug can be made, since all drugs offer risks and potential therapeutic benefits. A unique feature of a drug’s abuse potential is that the “abuse” of a drug affects a wider population of individuals than patients. Different populations are affected (or at risk) and studies in different populations often show a range of effects to the drug. For this reason, the pivotal human abuse potential study is carried out in experienced or recreational drug abusers, rather than drug-naïve healthy subjects or patient populations who are prescribed a drug for intended therapeutic purposes. When a company submits a new drug application (NDA) to the FDA for review and approval, if the drug has a potential for abuse, the company must submit in the NDA an analysis of studies and other information related to the potential abuse and dependence liability of the drug and propose scheduling under the CSA, if appropriate, and drug product labeling that is supported by study data. The company project management should ensure that the drug development process addresses all pertinent nonclinical and clinical study data related to biochemistry, pharmacology, animal behavior and dependence, pharmacokinetics, chemistry, and drug formulation. An adverse events profile that includes events such as euphoria and hallucinations that are related to abuse potential are relevant. The nonclinical data informs us early in development of the likely mechanism of action of the drug and is highly predictive of how the drug should be studied further in humans. The early safety pharmacology and in vitro binding studies are useful in informing us about the drug’s possible central nervous system activity and similarity to other known drugs of abuse. We gain from these studies an understanding of the relationship of the drug’s pharmacology to neurotransmitters that may be associated with the mechanism of action leading to abuse. Importantly, the nonclinical studies are useful in the design of other behaviorally related animal studies (such as the drug discrimination and self-administration paradigms) in the selection of appropriate positive controls and doses. Importantly, the nonclinical study results assist in designing human abuse potential studies and provide assurance of safety in the conduct of clinical studies so that the necessary safeguards are in place at the start of the clinical studies. A thorough knowledge of the nonclinical data of the new drug assists in interpreting adverse events related to abuse that are reported in Phase 3 of development and postmarketing as well. This book presents numerous contributions on the nonclinical assessment of abuse potential for new pharmaceuticals by expert scientists from industry, academia, and government. It contains a wide range of information on scientific laboratory studies that are used in acquiring data on drug abuse for new drugs. Finally, the book contains vital information beneficial to pharmaceutical companies, researchers, policymakers, and all others who are engaged in areas of drug development and drug abuse issues. Michael Klein, PhD5,     Director Controlled Substance...

Über Autor(innen)

Hudzik, Thomas
Dr. Hudzik received his BA in experimental psychology from Rutgers College, and his MS and PhD from the University of New Orleans in Biological Psychology and Pharmacology in 1990. His Master's and Dissertation work focused upon how drug-drug interactions could elucidate mechanism of action of novel opioids. He had a highly productive fellowship at the University of Arkansas for Medical Sciences, where, under the guidance of Drs. McMillan and Wenger, he developed novel behavioral assays that addressed how drugs disrupt temporal perception, which was also useful in detecting antidepressant activity and neurotoxicity. Additionally, Dr Hudzik's postdoctoral work also addressed how drugs of abuse could interfere with working memory across multiple species such as primate, pigeon, rat and mouse. After his fellowship, he began his 22-year career in the pharmaceutical industry at Fisons Pharmaceuticals in Rochester, NY, which was later acquired by Astra AB, Sweden, then ultimately became AstraZeneca. He has worked to model and to identify novel targets on such diverse disease areas as substance use disorder, appetite suppression, epilepsy, stroke, neuroprotection, Alzheimer's, Parkinson's, anxiety, depression, schizophrenia, and bipolar disorder. During this time, he led research teams which delivered four candidate drugs into clinical development. He accepted a position at Abbott Labs in 2010 (now AbbVie), to develop an abuse liability strategy for the company, and leads a cross-functional team that addresses CNS safety concerns within projects. Dr Hudzik has authored more than 60 original research papers, and edited and contributed to 2 books. He is a member of the College on Problems of Drug Dependence, the List Committee of the World Anti-Doping agency, the Society for Neuroscience, the Behavioral Pharmacology Society, a reviewer of manuscripts for numerous journals, and is a very active participant in inter-company consortia supporting prediction of risk associated with abuse liability of novel drugs or the potential for psychiatric complications such as suicidal behavior, as well as two directed at discovery of early biomarkers for neurotoxicity. He enjoys teaching, and has served as an instructor for undergraduates, medical and nursing students, as well as presents on neuroscience topics to grammar school children. When not writing for science, Dr. Hudzik also enjoys writing fiction and poetry, running marathons, and brewing beer - usually not at the same time.

Markgraf, Carrie
Carrie is a native of Williamstown, MA. She received her BA from Middlebury College in Biology and Psychology, with an Honor's Thesis investigating the role of the hippocampus in learned taste aversion. She received her MD, PhD from the University of Vermont, where her dissertation assessed the role of the central nucleus of the amygdala in cardiac arrhythmias. After graduation from UVM, she completed two post-doctoral fellowships at the University of Miami, FL: one in Psychology, where she also taught undergraduate classes in Introductory and advanced topics in psychology, and one in Neurology. It was during the post-doctoral fellowship in Neurology under Dr. Myron Ginsberg that she became involved in animal models of acute neurologic injury, creating some of the early behavioral outcome measures for assessing neurologic function in these models. Work in these models lead to a position at Marion Merrell Dow in Cincinnati OH, in the CNS Discovery group and after that to a position as Assistant Professor of Neurosurgery at the University of Texas-Houston Medical School. After nearly 10 years in the field of treatment of acute neurologic injury, Carrie started a new chapter of her career at Schering Plough as a Principal Scientist, then Senior Principal Scientist, setting up the company's first CNS Safety Pharmacology lab, gaining skills in GLP regulations and serving in the roles of Study Director and Study Monitor for Safety Pharmacology and Toxicology studies. She also represented the department on Project Teams on various neuroscience programs. Now at Merck, as Senior Principal Scientist, Carrie is in Discovery Sciences Support and represents the department on Project Teams in varied therapeutic areas and serves on an internal group that assists programs with abuse liability issues.
Carrie has been a member the Society for Neuroscience since 1983, and has been a full member of SOT (Society of Toxicology) since 2001. She has also been a member of the Safety Pharmacology Society (SPS) since 2001, where she has served on a number of Committees, including the Program Committee and holding the position of Chair of the Academic Outreach Committee. She is currently serving on the Board of Directors of SPS as Secretary. At the annual meetings of these societies, Carrie has presented scientific posters, given symposia presentations and organized and served as the chair of symposia on drug abuse/liability. In 2010 she was Merck's. representative to a PhRMA group responsible for industry's response to the draft FDA guidance on Assessment of Abuse Potential of Drugs. Carrie has been a member of the CCALC (Cross-Company Abuse Liability Consortium) since its inception in 2006 and has served as Co-Lead of the PAL (Preclinical Abuse Liability) sub-group of CCALC since that time. She was a member of the CCALC organizing committees for the 2008 and 2015 FDA-Industry Dialogue sessions on abuse potential issues, and is also on the By-Laws committee to establish CCALC as a scientific non-profit organization.
Carrie was a founding member of the non-profit New Jersey Brain Bee Association (NJBBA), a group dedicated to neuroscience educational outreach to area schools. The NJBBA also hosted an annual local competition in neuroscience for high school students. She continues her interest in educational outreach by speaking annually with student groups interested in careers in the pharmaceutical industry at Rutgers University and at Weill Cornell Medical School.