David Gauvin - Academia.edu (original) (raw)

Papers by David Gauvin

Research paper thumbnail of The Functional Observation Battery: Utility in Safety Assessment of New Molecular Entities

Research paper thumbnail of Use of inulin and PAH for renal drug safety evaluations in conscious dogs

Journal of Pharmacological and Toxicological Methods, 2016

Then, unbound fraction (fu) values at low and high concentrations (100-fold differences) in CMM w... more Then, unbound fraction (fu) values at low and high concentrations (100-fold differences) in CMM were calculated. When saturation of binding at the high concentration was observed, an additional experiment was done at a middle concentration. Most of compounds showed similar fu values at low and high concentrations. On the other hand, several compounds such as Mibefradil, Thioridazine, Bepridil, Prenylamine, Tolterodine, Haloperidol, and Dronedarone showed more than 2-fold higher fu values at high concentrations than those at low ones. Tamoxifene and Amiodarone showed very low fu values (less than 0.01) which indicated very strong protein binding. Further analysis of the relationships between the fu values in CMM and human plasma was conducted. Good correlation in rank order with non-linier correlation was obtained. These results indicated that the actual unbound concentrations in CMM will be very useful to consider and interpret the relationship to unbound plasma concentrations which caused CV events in human.

Research paper thumbnail of GLP-compliant preclinical assessment of the reinforcing properties of NCEs in the NHP

Journal of Pharmacological and Toxicological Methods, 2010

Research paper thumbnail of Free Radical Production during Ethanol Intoxication, Dependence, and Withdrawal

Alcoholism: Clinical and Experimental Research, 1997

Research paper thumbnail of Do rat strain differences in ethanol consumption reflect differences in ethanol sensitivity or the preparedness to learn?

Alcohol, 1993

Do rat strain d~fferences in ethanol consumption reflect d~fferences in ethanol sensitivity or th... more Do rat strain d~fferences in ethanol consumption reflect d~fferences in ethanol sensitivity or the preparedness to learn? ALCOHOL 10(1) 37-43, 1993.-Three strains of rats (Wistar, Sprague-Dawley, Long-Evans; n = 10/strain) were trained to drink various concentrations of ethanol (ETOH) in the rats' home cage in daily 30-min drinking sessions using a modified "Samson" sucrose-fading procedure. Wistar and Sprague-Dawley rats were similar in their voluntary intake of a wide range of ETOH concentrations and both of these strains drank considerably more ETOH than the Long-Evans strain. For comparison purposes only, pharmacological pretreatment tests were later conducted with the Sprague-Dawley strain of rats using a maintenance concentration of 20070 w/v ETOH. Low-dose ETOH pretreatments increased (125 °7o of control), and high-dose ETOH pretreatments decreased the subsequent voluntary consumption of ETOH. Low-dose nicotine pretreatments increased ETOH consumption to 148070 of control intake, and high doses of nicotine decreased ETOH consumption. Both opiate antagonists, naloxone and naltrexone, produced dose-dependent decreases in ETOH consumption. The dopamine antagonist, haloperidol, produced dose-and time-dependent increases in voluntary ETOH consumption. The strain differences in voluntary ETOH consumption described in the present study differ from those previously described by other labs. We suggest that this strain-dependent disparity between laboratories, with respect to ETOH consumption/preference tasks, may reflect genetic differences in the preparedness to condition (learn) voluntary ETOH consumption rather than genetic differences in ETOH's reward/reinforcement attributes. Ethanol Sucrose-fading technique Ethanol self-administration THE experimental analysis of CNS sensitivity and the role it may play in the regulation of alcohol consumption in rats and mice have been inconclusive (3,4). Recently Elmer et al. (5) ' Requests for reprints should be addressed to David V. Gauvin, Ph.D.

Research paper thumbnail of Identification of NOEL and NOAEL in functional safety (pharmacology) studies: A survey of a contract research organization master schedule

Journal of Pharmacological and Toxicological Methods, 2018

periods at approximately 20 minute post dose. Originally, the data analysis design called for 15 ... more periods at approximately 20 minute post dose. Originally, the data analysis design called for 15 min data bins to be used for the duration of the study. Initial post in-life observations of the 15 minute trend graph showed an observed effect that appeared to start at approximately 1 hour post dose. This was further obscured by a 30 minute blood collection which resulted in an increased heart rate and blood pressure while the sample was being obtained. In order to view the data set in more detail, we re-analyzed using 1 min data bins. At this point we were able to accurately correlate the data with what we had observed during the in-life portion of the study where the observed effect start time occurred around 20 minute post dose.

Research paper thumbnail of Rx: Observe, Do not Treat When is it Appropriate not to Treat?

Pharmaceutical Regulatory Affairs: Open Access, 2017

Development of a protocol for a nonclinical safety study to evaluate the safety profile of an inv... more Development of a protocol for a nonclinical safety study to evaluate the safety profile of an investigational therapeutic, whether it is a toxicology or safety pharmacology study, must not be conducted in haste. The evaluation of this novel therapeutics relies on the integrated strategy developed by the scientific team, which may include the pharmaceutical company and the services of a contract research organization. All nonclinical study protocols involving the use of live animals require the inclusion of the Institutional Animal Care and Use Committee (IACUC) and staff veterinarians during the review of the study protocol. The team, as a whole, must endure a frank, honest, and open discussion regarding study design and animal welfare issues. All available information regarding the test material should be shared with all parties in a manner and time that allows for constructive protocol and treatment strategy development. The intent of nonclinical safety assessments is driven by both administrative guidelines from drug regulatory agencies and statutory (legal) controls of federal laws. In working with test articles, particularly for small molecules, the probability of unexpected findings is relatively high. The research team must maintain the highest standards of animal care throughout this process which is complicated by the fact that when animal health and welfare issues occur they must be remedied fast, efficiently, and transparently. We review the pitfalls of safety assessment strategies and offer some industry standard resolutions that may help to make the road to market a little easier. The paper is written based on small molecule development, but many of the points would also apply to biopharmaceuticals as well.

Research paper thumbnail of Defining “Quality” With Respect to Study Conduct, Science, and Contract Research Organizations

Journal of Pharmaceutical and Pharmacological Sciences

Quality is a common point of discussion in the preclinical evaluation process of new drug candida... more Quality is a common point of discussion in the preclinical evaluation process of new drug candidates, however this can be a very subjective topic. While there is no universally accepted definition of "Quality", under the US Food & Drug Administration's Good Laboratory Practice Guidelines it is most often used to describe study performance, scientific validity, reliability and rigor, and last but not least-documentation. It can be a challenge for the CRO industry to fully appreciate the practical constraints of operating in a typical preclinical research setting as it relates to quality and quality management systems. This overview highlights some of the basic issues defining "Quality" with respect to GLP-compliant research generated as part of the drug development process.

Research paper thumbnail of The Lexicon of Drug Abuse

Journal of Drug Abuse

In the turmoil of the 1960s the Committee further revised their name to the "WHO Expert Committee... more In the turmoil of the 1960s the Committee further revised their name to the "WHO Expert Committee on Dependence-Producing Drugs". At its 13 th meeting in 1964 [3] it was voted to abandon the terms, "drug addiction" and "habituation" in favor of "drug

Research paper thumbnail of Further Support for the AVMA-Approved Rodent Euthanasia Protocol

Animal Research and Veterinary Science

nature of rodents, the series of events that occur at the end of most every study plan using rode... more nature of rodents, the series of events that occur at the end of most every study plan using rodents will viewed as humane and ethical.

Research paper thumbnail of Marijuana Toxicity: Heavy Metal Exposure Through State-Sponsored Access to “la Fee Verte”

Pharmaceutical Regulatory Affairs: Open Access, 2018

Federally unregulated, Marijuana Growth Organizations (MGOs) have now provided a path to exposure... more Federally unregulated, Marijuana Growth Organizations (MGOs) have now provided a path to exposures to the neurotoxicity of heavy metals. The lack of US Food and Drug Administration (FDA) and US Environmental Protection Agency (EPA) testing and oversight of the MGOs now threatens the public health. Agribusiness and botany experts proclaim the value of cannabis as a perfect rotating plant for phytoremediation programs to help scavenge heavy metals from soils prior to seeding the land for food product. Cannabis has a high affinity for soil contaminants without affecting its own heartiness. However, "legal" marijuana plots have burgeoned in the "Emerald Triangle" of Northern California, Oregon and Washington. According to the FDA's toxicology program, the largest sources of heavy metals (HMs) are the environments surrounding abandoned or active mines. The history of gold, platinum, coal, and copper mining in these grow areas now threatens the end-user; the plants ability to "scrub the earth" of these highly toxic HMs provides main stream smoke contamination to the consumer. Published reports of cannabis users showing hearing loss and neurological changes to temporal lobe structures involved in audition as well as learning and memory. The apoptotic cascade of cytotoxic events initiated by heavy metals is linked to the progression of Alzheimer's and Parkinson's disease, as well as hearing loss related to brain stem and temporal lobe neurotoxicity.

Research paper thumbnail of A Plant is NOT Medicine: Plant vs. Constituent Element

Pharmaceutical Regulatory Affairs: Open Access, 2017

Research paper thumbnail of GLPs, Human Error, and Deviations: When Are Quality and Integrity Compromised?

Pharmaceutical Regulatory Affairs: Open Access

The Good Laboratory Practice guidelines (GLPs) of the US Food and Drug Administration are primari... more The Good Laboratory Practice guidelines (GLPs) of the US Food and Drug Administration are primarily a process of bookkeeping to ensure that agreed procedures have been followed and procedural documentation is true and accurate. It is the goal of the GLPs to ensure that any study can be recreated through the accurate and detailed description contained within the audited final study report. The GLPs require the designation of a Study Director (SD) for each nonclinical safety study. Under the administrative policy, a SD represents "the single fixed point of responsibility for overall conduct of each study" (21 CFR52 (172) 33770). The SD is charged with the technical conduct of the study including interpretation, analysis, documentation, and reporting of the results. As such, when an error or deviation is made on a study it is the SD, alone, that must ensure accurate and detailed description of the error, and initiation appropriate 'due diligence' to ensure that similar events on the study are minimized, and that the final report contains a clear and concise listing of all errors and guideline deviations, as well as a fair assessment of their potential impact on the overall quality and integrity of the data. Deviations happen on studies conducted in the best of laboratories, this review details a process of remediation that must take place to ensure that the study integrity is intact and need for repetition of the study is minimized.

Research paper thumbnail of Hair Loss in Laboratory Bred Macaques: An Idiopathic Disorder of Major Consequence

Archives on Veterinary Science and Technology

In spite of the idiopathic nature of hair loss in non-human primates, the presentation of monkeys... more In spite of the idiopathic nature of hair loss in non-human primates, the presentation of monkeys with hair loss has become a concern during site visits by Sponsors and federal regulatory authorities. This review attempts to define, describe, and somewhat defend the clinical findings of alopecia in colony-maintained nonhuman primates in research institutions and to allay any fears of maltreatment or neglect if the hairless monkey is found in the colony. Self-directed behaviors to the point of self-injury are common features of both nonhuman primates and humans. The etiology of alopecia in free-range and laboratory-maintained monkeys, as well as the human patient involves multiple factors, many of which are not in the direct control of behavioral management or therapy. Proper and complete documentation of initial observations, progression and recurrence, as well as active therapeutic interventions can go a long way to protect the laboratory from experiencing a "teaching moment" during regulatory agency inspections.

Research paper thumbnail of Conducting Preclinical Abuse Liability Screening in Only One Sex: Making a Case for “Reasonable Exclusion”

Pharmaceutical Regulatory Affairs: Open Access

The Animal Welfare Act (AWA; 1990) requires the reduction in use of purpose bred animal subjects ... more The Animal Welfare Act (AWA; 1990) requires the reduction in use of purpose bred animal subjects in bona fide research conducted in drug development. The National Institutes of Health (NIH) Revitalization Act of 1993 also requires its Director to reduce the number of animals used in government funded research as well as promoting those specific study protocols that provide valid and reliable data using only one gender. The consensus between the pharmaceutical industry and FDA was that a valid and reliable set of abuse liability studies did NOT require the inclusion of both male and female subjects. In recent pre-study protocol reviews, FDA has required the inclusion of both males and female animals in all three core abuse liability assays, basically doubling the total number of animals used on a single study design. NIH/FDA policy does allow for exceptions to the new rule. We provide evidence to establish a defence of a more balanced approach to these study designs that complies with the AWA and the NIH Revitalization Act by reducing the use of laboratory animals in preclinical research and to align the study designs with current goals of the International Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).

Research paper thumbnail of Comparisons of 3 plethysmography techniques for rodent pulmonary function assessment using ponemah waveforms analysis

Journal of Pharmacological and Toxicological Methods, 2010

Research paper thumbnail of Ototoxicity: The Radical Drum Beat and Rhythm of Cochlear Hair Cell Life and Death

International Journal of Toxicology

The function and structure of the auditory information processing system establishes a unique sen... more The function and structure of the auditory information processing system establishes a unique sensory environment for the “perfect storm.” The battle between life and death pits the cascade of an apoptotic storm, programmed cell death cascades, against simple cell death (necrosis) pathways. Live or die, the free radical biology of oxygen and hydroxylation, and the destruction of transition metal migration through the mechanical gate sensory processes of the hair cell lead to direct access to the cytoplasm, cytoplasmic reticulum, and mitochondria of the inner workings of the hair cells. These lead to subsequent interactions with nuclear DNA resulting in permanent hearing loss. The yin and yang of pharmaceutical product development is to document what kills, why it kills, and how do we mitigate it. This review highlights the processes of cell death within the cochlea.

Research paper thumbnail of A reply to Henningfield, Fant & Wang (2018): regulatory action to control kratom is long overdue

Research paper thumbnail of Defining “Best Practices” For Critical Endpoints In Preclinical Screening of New Chemical Entities For Ototoxicity Liability

Otolaryngology - Open Journal

Introduction: Ototoxicity has been defined as the tendency of certain therapeutic agents and othe... more Introduction: Ototoxicity has been defined as the tendency of certain therapeutic agents and other chemical substances to cause functional impairments and cellular degeneration of the tissues of the inner ear resulting in hearing loss. Objectives: This review is intended to provide details of a standardized preclinical assessment for ototoxicity under the current US FDA guidance documents that represents "industry best practices" for new drug application review of all new chemical entities being developed for human use. Methods: A literature review was conducted to assimilate study strategies that represent "Industry Best Practices" for the conduct of preclinical ototoxicity evaluation for submission to regulatory drug approval agencies. Conclusion: We have proposed a systems-approach and protocol criteria for the valid and reliable assessment of auditory function that can be easily included as a screening tool for ototoxicity within the Tiered Structure of preclinical assays required for approval of any chemical entity targeted for human use.

Research paper thumbnail of The Drug Discrimination Procedure: A Microanalysis of the Qualitative Properties of Quantal Responses

The Psychological Record

APA PsycNET Our Apologies! - The following features are not available with your current Browser c... more APA PsycNET Our Apologies! - The following features are not available with your current Browser configuration. - alerts user that their session is about to expire - display, print, save, export, and email selected records - get My ...

Research paper thumbnail of The Functional Observation Battery: Utility in Safety Assessment of New Molecular Entities

Research paper thumbnail of Use of inulin and PAH for renal drug safety evaluations in conscious dogs

Journal of Pharmacological and Toxicological Methods, 2016

Then, unbound fraction (fu) values at low and high concentrations (100-fold differences) in CMM w... more Then, unbound fraction (fu) values at low and high concentrations (100-fold differences) in CMM were calculated. When saturation of binding at the high concentration was observed, an additional experiment was done at a middle concentration. Most of compounds showed similar fu values at low and high concentrations. On the other hand, several compounds such as Mibefradil, Thioridazine, Bepridil, Prenylamine, Tolterodine, Haloperidol, and Dronedarone showed more than 2-fold higher fu values at high concentrations than those at low ones. Tamoxifene and Amiodarone showed very low fu values (less than 0.01) which indicated very strong protein binding. Further analysis of the relationships between the fu values in CMM and human plasma was conducted. Good correlation in rank order with non-linier correlation was obtained. These results indicated that the actual unbound concentrations in CMM will be very useful to consider and interpret the relationship to unbound plasma concentrations which caused CV events in human.

Research paper thumbnail of GLP-compliant preclinical assessment of the reinforcing properties of NCEs in the NHP

Journal of Pharmacological and Toxicological Methods, 2010

Research paper thumbnail of Free Radical Production during Ethanol Intoxication, Dependence, and Withdrawal

Alcoholism: Clinical and Experimental Research, 1997

Research paper thumbnail of Do rat strain differences in ethanol consumption reflect differences in ethanol sensitivity or the preparedness to learn?

Alcohol, 1993

Do rat strain d~fferences in ethanol consumption reflect d~fferences in ethanol sensitivity or th... more Do rat strain d~fferences in ethanol consumption reflect d~fferences in ethanol sensitivity or the preparedness to learn? ALCOHOL 10(1) 37-43, 1993.-Three strains of rats (Wistar, Sprague-Dawley, Long-Evans; n = 10/strain) were trained to drink various concentrations of ethanol (ETOH) in the rats' home cage in daily 30-min drinking sessions using a modified "Samson" sucrose-fading procedure. Wistar and Sprague-Dawley rats were similar in their voluntary intake of a wide range of ETOH concentrations and both of these strains drank considerably more ETOH than the Long-Evans strain. For comparison purposes only, pharmacological pretreatment tests were later conducted with the Sprague-Dawley strain of rats using a maintenance concentration of 20070 w/v ETOH. Low-dose ETOH pretreatments increased (125 °7o of control), and high-dose ETOH pretreatments decreased the subsequent voluntary consumption of ETOH. Low-dose nicotine pretreatments increased ETOH consumption to 148070 of control intake, and high doses of nicotine decreased ETOH consumption. Both opiate antagonists, naloxone and naltrexone, produced dose-dependent decreases in ETOH consumption. The dopamine antagonist, haloperidol, produced dose-and time-dependent increases in voluntary ETOH consumption. The strain differences in voluntary ETOH consumption described in the present study differ from those previously described by other labs. We suggest that this strain-dependent disparity between laboratories, with respect to ETOH consumption/preference tasks, may reflect genetic differences in the preparedness to condition (learn) voluntary ETOH consumption rather than genetic differences in ETOH's reward/reinforcement attributes. Ethanol Sucrose-fading technique Ethanol self-administration THE experimental analysis of CNS sensitivity and the role it may play in the regulation of alcohol consumption in rats and mice have been inconclusive (3,4). Recently Elmer et al. (5) ' Requests for reprints should be addressed to David V. Gauvin, Ph.D.

Research paper thumbnail of Identification of NOEL and NOAEL in functional safety (pharmacology) studies: A survey of a contract research organization master schedule

Journal of Pharmacological and Toxicological Methods, 2018

periods at approximately 20 minute post dose. Originally, the data analysis design called for 15 ... more periods at approximately 20 minute post dose. Originally, the data analysis design called for 15 min data bins to be used for the duration of the study. Initial post in-life observations of the 15 minute trend graph showed an observed effect that appeared to start at approximately 1 hour post dose. This was further obscured by a 30 minute blood collection which resulted in an increased heart rate and blood pressure while the sample was being obtained. In order to view the data set in more detail, we re-analyzed using 1 min data bins. At this point we were able to accurately correlate the data with what we had observed during the in-life portion of the study where the observed effect start time occurred around 20 minute post dose.

Research paper thumbnail of Rx: Observe, Do not Treat When is it Appropriate not to Treat?

Pharmaceutical Regulatory Affairs: Open Access, 2017

Development of a protocol for a nonclinical safety study to evaluate the safety profile of an inv... more Development of a protocol for a nonclinical safety study to evaluate the safety profile of an investigational therapeutic, whether it is a toxicology or safety pharmacology study, must not be conducted in haste. The evaluation of this novel therapeutics relies on the integrated strategy developed by the scientific team, which may include the pharmaceutical company and the services of a contract research organization. All nonclinical study protocols involving the use of live animals require the inclusion of the Institutional Animal Care and Use Committee (IACUC) and staff veterinarians during the review of the study protocol. The team, as a whole, must endure a frank, honest, and open discussion regarding study design and animal welfare issues. All available information regarding the test material should be shared with all parties in a manner and time that allows for constructive protocol and treatment strategy development. The intent of nonclinical safety assessments is driven by both administrative guidelines from drug regulatory agencies and statutory (legal) controls of federal laws. In working with test articles, particularly for small molecules, the probability of unexpected findings is relatively high. The research team must maintain the highest standards of animal care throughout this process which is complicated by the fact that when animal health and welfare issues occur they must be remedied fast, efficiently, and transparently. We review the pitfalls of safety assessment strategies and offer some industry standard resolutions that may help to make the road to market a little easier. The paper is written based on small molecule development, but many of the points would also apply to biopharmaceuticals as well.

Research paper thumbnail of Defining “Quality” With Respect to Study Conduct, Science, and Contract Research Organizations

Journal of Pharmaceutical and Pharmacological Sciences

Quality is a common point of discussion in the preclinical evaluation process of new drug candida... more Quality is a common point of discussion in the preclinical evaluation process of new drug candidates, however this can be a very subjective topic. While there is no universally accepted definition of "Quality", under the US Food & Drug Administration's Good Laboratory Practice Guidelines it is most often used to describe study performance, scientific validity, reliability and rigor, and last but not least-documentation. It can be a challenge for the CRO industry to fully appreciate the practical constraints of operating in a typical preclinical research setting as it relates to quality and quality management systems. This overview highlights some of the basic issues defining "Quality" with respect to GLP-compliant research generated as part of the drug development process.

Research paper thumbnail of The Lexicon of Drug Abuse

Journal of Drug Abuse

In the turmoil of the 1960s the Committee further revised their name to the "WHO Expert Committee... more In the turmoil of the 1960s the Committee further revised their name to the "WHO Expert Committee on Dependence-Producing Drugs". At its 13 th meeting in 1964 [3] it was voted to abandon the terms, "drug addiction" and "habituation" in favor of "drug

Research paper thumbnail of Further Support for the AVMA-Approved Rodent Euthanasia Protocol

Animal Research and Veterinary Science

nature of rodents, the series of events that occur at the end of most every study plan using rode... more nature of rodents, the series of events that occur at the end of most every study plan using rodents will viewed as humane and ethical.

Research paper thumbnail of Marijuana Toxicity: Heavy Metal Exposure Through State-Sponsored Access to “la Fee Verte”

Pharmaceutical Regulatory Affairs: Open Access, 2018

Federally unregulated, Marijuana Growth Organizations (MGOs) have now provided a path to exposure... more Federally unregulated, Marijuana Growth Organizations (MGOs) have now provided a path to exposures to the neurotoxicity of heavy metals. The lack of US Food and Drug Administration (FDA) and US Environmental Protection Agency (EPA) testing and oversight of the MGOs now threatens the public health. Agribusiness and botany experts proclaim the value of cannabis as a perfect rotating plant for phytoremediation programs to help scavenge heavy metals from soils prior to seeding the land for food product. Cannabis has a high affinity for soil contaminants without affecting its own heartiness. However, "legal" marijuana plots have burgeoned in the "Emerald Triangle" of Northern California, Oregon and Washington. According to the FDA's toxicology program, the largest sources of heavy metals (HMs) are the environments surrounding abandoned or active mines. The history of gold, platinum, coal, and copper mining in these grow areas now threatens the end-user; the plants ability to "scrub the earth" of these highly toxic HMs provides main stream smoke contamination to the consumer. Published reports of cannabis users showing hearing loss and neurological changes to temporal lobe structures involved in audition as well as learning and memory. The apoptotic cascade of cytotoxic events initiated by heavy metals is linked to the progression of Alzheimer's and Parkinson's disease, as well as hearing loss related to brain stem and temporal lobe neurotoxicity.

Research paper thumbnail of A Plant is NOT Medicine: Plant vs. Constituent Element

Pharmaceutical Regulatory Affairs: Open Access, 2017

Research paper thumbnail of GLPs, Human Error, and Deviations: When Are Quality and Integrity Compromised?

Pharmaceutical Regulatory Affairs: Open Access

The Good Laboratory Practice guidelines (GLPs) of the US Food and Drug Administration are primari... more The Good Laboratory Practice guidelines (GLPs) of the US Food and Drug Administration are primarily a process of bookkeeping to ensure that agreed procedures have been followed and procedural documentation is true and accurate. It is the goal of the GLPs to ensure that any study can be recreated through the accurate and detailed description contained within the audited final study report. The GLPs require the designation of a Study Director (SD) for each nonclinical safety study. Under the administrative policy, a SD represents "the single fixed point of responsibility for overall conduct of each study" (21 CFR52 (172) 33770). The SD is charged with the technical conduct of the study including interpretation, analysis, documentation, and reporting of the results. As such, when an error or deviation is made on a study it is the SD, alone, that must ensure accurate and detailed description of the error, and initiation appropriate 'due diligence' to ensure that similar events on the study are minimized, and that the final report contains a clear and concise listing of all errors and guideline deviations, as well as a fair assessment of their potential impact on the overall quality and integrity of the data. Deviations happen on studies conducted in the best of laboratories, this review details a process of remediation that must take place to ensure that the study integrity is intact and need for repetition of the study is minimized.

Research paper thumbnail of Hair Loss in Laboratory Bred Macaques: An Idiopathic Disorder of Major Consequence

Archives on Veterinary Science and Technology

In spite of the idiopathic nature of hair loss in non-human primates, the presentation of monkeys... more In spite of the idiopathic nature of hair loss in non-human primates, the presentation of monkeys with hair loss has become a concern during site visits by Sponsors and federal regulatory authorities. This review attempts to define, describe, and somewhat defend the clinical findings of alopecia in colony-maintained nonhuman primates in research institutions and to allay any fears of maltreatment or neglect if the hairless monkey is found in the colony. Self-directed behaviors to the point of self-injury are common features of both nonhuman primates and humans. The etiology of alopecia in free-range and laboratory-maintained monkeys, as well as the human patient involves multiple factors, many of which are not in the direct control of behavioral management or therapy. Proper and complete documentation of initial observations, progression and recurrence, as well as active therapeutic interventions can go a long way to protect the laboratory from experiencing a "teaching moment" during regulatory agency inspections.

Research paper thumbnail of Conducting Preclinical Abuse Liability Screening in Only One Sex: Making a Case for “Reasonable Exclusion”

Pharmaceutical Regulatory Affairs: Open Access

The Animal Welfare Act (AWA; 1990) requires the reduction in use of purpose bred animal subjects ... more The Animal Welfare Act (AWA; 1990) requires the reduction in use of purpose bred animal subjects in bona fide research conducted in drug development. The National Institutes of Health (NIH) Revitalization Act of 1993 also requires its Director to reduce the number of animals used in government funded research as well as promoting those specific study protocols that provide valid and reliable data using only one gender. The consensus between the pharmaceutical industry and FDA was that a valid and reliable set of abuse liability studies did NOT require the inclusion of both male and female subjects. In recent pre-study protocol reviews, FDA has required the inclusion of both males and female animals in all three core abuse liability assays, basically doubling the total number of animals used on a single study design. NIH/FDA policy does allow for exceptions to the new rule. We provide evidence to establish a defence of a more balanced approach to these study designs that complies with the AWA and the NIH Revitalization Act by reducing the use of laboratory animals in preclinical research and to align the study designs with current goals of the International Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).

Research paper thumbnail of Comparisons of 3 plethysmography techniques for rodent pulmonary function assessment using ponemah waveforms analysis

Journal of Pharmacological and Toxicological Methods, 2010

Research paper thumbnail of Ototoxicity: The Radical Drum Beat and Rhythm of Cochlear Hair Cell Life and Death

International Journal of Toxicology

The function and structure of the auditory information processing system establishes a unique sen... more The function and structure of the auditory information processing system establishes a unique sensory environment for the “perfect storm.” The battle between life and death pits the cascade of an apoptotic storm, programmed cell death cascades, against simple cell death (necrosis) pathways. Live or die, the free radical biology of oxygen and hydroxylation, and the destruction of transition metal migration through the mechanical gate sensory processes of the hair cell lead to direct access to the cytoplasm, cytoplasmic reticulum, and mitochondria of the inner workings of the hair cells. These lead to subsequent interactions with nuclear DNA resulting in permanent hearing loss. The yin and yang of pharmaceutical product development is to document what kills, why it kills, and how do we mitigate it. This review highlights the processes of cell death within the cochlea.

Research paper thumbnail of A reply to Henningfield, Fant & Wang (2018): regulatory action to control kratom is long overdue

Research paper thumbnail of Defining “Best Practices” For Critical Endpoints In Preclinical Screening of New Chemical Entities For Ototoxicity Liability

Otolaryngology - Open Journal

Introduction: Ototoxicity has been defined as the tendency of certain therapeutic agents and othe... more Introduction: Ototoxicity has been defined as the tendency of certain therapeutic agents and other chemical substances to cause functional impairments and cellular degeneration of the tissues of the inner ear resulting in hearing loss. Objectives: This review is intended to provide details of a standardized preclinical assessment for ototoxicity under the current US FDA guidance documents that represents "industry best practices" for new drug application review of all new chemical entities being developed for human use. Methods: A literature review was conducted to assimilate study strategies that represent "Industry Best Practices" for the conduct of preclinical ototoxicity evaluation for submission to regulatory drug approval agencies. Conclusion: We have proposed a systems-approach and protocol criteria for the valid and reliable assessment of auditory function that can be easily included as a screening tool for ototoxicity within the Tiered Structure of preclinical assays required for approval of any chemical entity targeted for human use.

Research paper thumbnail of The Drug Discrimination Procedure: A Microanalysis of the Qualitative Properties of Quantal Responses

The Psychological Record

APA PsycNET Our Apologies! - The following features are not available with your current Browser c... more APA PsycNET Our Apologies! - The following features are not available with your current Browser configuration. - alerts user that their session is about to expire - display, print, save, export, and email selected records - get My ...