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An analysis of safety pharmacology operations across the top 12 pharmaceutical companies
Abstracts
A safety pharmacology strategy for inhaled compounds Silvana Lindgren, Maragreta Some, Aliaksandr Bulhak, Ann-Christin Ericson Safety Pharmacology, Safety Assessment, AstraZeneca R&D, Södertälje, Sweden The ICH S7A guideline defines the safety pharmacology core battery comprising studies on the cardiovascular, central nervous and respiratory systems, as well as suggested follow-up and supplemental studies. The guideline states that the expected clinical route of administration should be used when feasible. However, assessment of effects by more than one route may be appropriate where there are observed or anticipated significant qualitative and quantitative differences in systemic or local exposure. The package of nonclinical studies needed to support administration of an inhaled compound to humans in clinical trials is generally the same as that for other routes of administration. A safety pharmacology strategy for inhaled compounds will be described, using a combination of intravenous and inhaled administration. Experience from 24 compounds tested according to this strategy will be presented. A full regulatory package was completed for nine of these compounds and tested in man with no comments or questions from authorities, hence acceptable to the regulatory authorities.
doi:10.1016/j.vascn.2012.08.141
An analysis of safety pharmacology operations across the top 12 pharmaceutical companies Lorna Ewarta, David Gallacherb, Gary Gintantc, Jean-Michel Guillond, Derek Leishmanf, Nick McMahonh, Paul Levesqueg, Lou Mylecrainei, Willi Suterk, Martin Sandersj, Rob Wallise, Jean Pierre Valentina a
Global Safety Pharmacology, AstraZeneca R&D, Macclesfield, Cheshire, United Kingdom b Janssen, Beerse, Belgium c Abbott, Abbott Park, IL, United States d sanofi-aventis, Vitry-sur, Seine, France e Pfizer, Groton, CT, United States f Eli Lilly, Indianapoli, IN, United States g Bristol Myers Squibb, Yardley, PA h GlaxoSmithKline, Ware, United Kingdom i Bayer HealthCare Pharmaceuticals, Wayne, NJ, United States j Roche, Nutley, NJ, United States k Novartis, Basel, Switzerland What does safety pharmacology (SP) look like in large pharmaceutical companies today? How have they reacted to the increasingly regulated, cost-restrained environment and innovative alliances with academic research centres? A short anonymous survey was conducted, by invitation, to SP representatives of the top 12 pharmaceutical companies, defined by 2009 revenue figures. A series of multiple choice questions was designed to explore the size of SP groups, their accountabilities, the roles and responsibilities of group members, outsourcing policy and publications. A 92% response rate was obtained. Six companies have 10 to 30 full time equivalents in SP, who hold similar roles and responsibilities; although in 9 companies less than 50% are qualified at PhD level or equivalent. Accountabilities were similar across companies and all have accountability for core battery in vivo studies and problem solving activities. Differences in accountability for in vitro safety screening and PK:PD exist. The majority of companies outsource less than 25% of studies, with in vitro profiling being the most commonly outsourced. Publication record was low with 7 companies reporting between 5 and 20
199
publications in a 5 year period (i.e. 1 to 4/year). In conclusion, this short survey has highlighted areas of similarity (e.g. accountabilities) and differences (e.g. number of staff and outsourcing) in the different business models companies employ. Data of this type could now be used to address how the young discipline of SP can be promoted and developed to ensure its impact within the industry. doi:10.1016/j.vascn.2012.08.142
Chronic monitoring of brain tissue oxygen in freely moving rats from a fully implanted telemetry system Simon Malpasa, David Russellb, Emer Garyc, David Budgetta, Andrew Tabernerb a
Telemetry Research Ltd, Auckland, New Zealand Auckland Bioengineering Institute, Auckland, New Zealand c Blue Box Sensors Limited, Dublin, Ireland b
We have developed a fully implantable telemetry system for the continuous and chronic recording of brain tissue oxygen (PO2,BR) in conscious animals. A telemetry system with a sampling rate of 2 kHz was combined with a miniaturized potentiostat to amperometrically detect oxygen concentration with carbon paste electrodes (CPE). Wireless power was employed to inductively recharge the telemeter battery transcutaneously for potential lifetime monitoring. Rats were implanted with the telemeter body in the peritoneal cavity and electrodes stereotaxically implanted into the brain (striatum or brainstem). Whilst animals were living in their home cages the sensitivity to changes in oxygen was validated by repeatedly altering the inspired oxygen (10%, 100%, respectively) or a pharmacological stimulus (carbonic anhydrase inhibitor: acetazolamide 50 mg/kg IP). Basal level of brain tissue PO2 could be monitored for many weeks (N6 weeks) and showed good overall stability, reproducibility and good correlation to common movements such as grooming. During hypoxia, PO2,BR decreased significantly by − 51 ± 2% from baseline whereas it increased by 34 ± 3% during hyperoxia. Immediately following the systemic acetazolamide PO2,BR increased by 38 ± 4%. We propose that this new technology provides a robust method to measure changes in oxygen concentration in a specific area of the brain, allowing conscious and freely moving measurements. The ability to track long term changes with disease progression or drug treatment may be enabled. doi:10.1016/j.vascn.2012.08.143
Dual recordings of left ventricular and arterial pressure in conscious rats via telemetry Simon Malpasa, Ellyce Stehlinb, Sarah-Jane Guildb, David Budgetta, Daniel McCormicka, Dean Rigelc a
Telemetry Research Ltd, Auckland, New Zealand University of Auckland, Auckland, New Zealand c Novartis Institutes for BioMedical Research, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States b
Measurements of cardiac contractility in conscious freely moving animals are uncommon yet could offer considerable opportunity for understanding cardiovascular disease progression and treatment. We have validated a new high fidelity solid state pressure sensor telemetry device for measuring chronic left ventricular pressure (LVP), dP/dt and blood pressure in rats. The pressure sensor catheter tip (2-Fr) was inserted into the left ventricle through the apex of the heart and the telemeter body implanted in the abdomen. Data was
A safety pharmacology strategy for inhaled compounds Silvana Lindgren, Maragreta Some, Aliaksandr Bulhak, Ann-Christin Ericson Safety Pharmacology, Safety Assessment, AstraZeneca R&D, Södertälje, Sweden The ICH S7A guideline defines the safety pharmacology core battery comprising studies on the cardiovascular, central nervous and respiratory systems, as well as suggested follow-up and supplemental studies. The guideline states that the expected clinical route of administration should be used when feasible. However, assessment of effects by more than one route may be appropriate where there are observed or anticipated significant qualitative and quantitative differences in systemic or local exposure. The package of nonclinical studies needed to support administration of an inhaled compound to humans in clinical trials is generally the same as that for other routes of administration. A safety pharmacology strategy for inhaled compounds will be described, using a combination of intravenous and inhaled administration. Experience from 24 compounds tested according to this strategy will be presented. A full regulatory package was completed for nine of these compounds and tested in man with no comments or questions from authorities, hence acceptable to the regulatory authorities.
doi:10.1016/j.vascn.2012.08.141
An analysis of safety pharmacology operations across the top 12 pharmaceutical companies Lorna Ewarta, David Gallacherb, Gary Gintantc, Jean-Michel Guillond, Derek Leishmanf, Nick McMahonh, Paul Levesqueg, Lou Mylecrainei, Willi Suterk, Martin Sandersj, Rob Wallise, Jean Pierre Valentina a
Global Safety Pharmacology, AstraZeneca R&D, Macclesfield, Cheshire, United Kingdom b Janssen, Beerse, Belgium c Abbott, Abbott Park, IL, United States d sanofi-aventis, Vitry-sur, Seine, France e Pfizer, Groton, CT, United States f Eli Lilly, Indianapoli, IN, United States g Bristol Myers Squibb, Yardley, PA h GlaxoSmithKline, Ware, United Kingdom i Bayer HealthCare Pharmaceuticals, Wayne, NJ, United States j Roche, Nutley, NJ, United States k Novartis, Basel, Switzerland What does safety pharmacology (SP) look like in large pharmaceutical companies today? How have they reacted to the increasingly regulated, cost-restrained environment and innovative alliances with academic research centres? A short anonymous survey was conducted, by invitation, to SP representatives of the top 12 pharmaceutical companies, defined by 2009 revenue figures. A series of multiple choice questions was designed to explore the size of SP groups, their accountabilities, the roles and responsibilities of group members, outsourcing policy and publications. A 92% response rate was obtained. Six companies have 10 to 30 full time equivalents in SP, who hold similar roles and responsibilities; although in 9 companies less than 50% are qualified at PhD level or equivalent. Accountabilities were similar across companies and all have accountability for core battery in vivo studies and problem solving activities. Differences in accountability for in vitro safety screening and PK:PD exist. The majority of companies outsource less than 25% of studies, with in vitro profiling being the most commonly outsourced. Publication record was low with 7 companies reporting between 5 and 20
199
publications in a 5 year period (i.e. 1 to 4/year). In conclusion, this short survey has highlighted areas of similarity (e.g. accountabilities) and differences (e.g. number of staff and outsourcing) in the different business models companies employ. Data of this type could now be used to address how the young discipline of SP can be promoted and developed to ensure its impact within the industry. doi:10.1016/j.vascn.2012.08.142
Chronic monitoring of brain tissue oxygen in freely moving rats from a fully implanted telemetry system Simon Malpasa, David Russellb, Emer Garyc, David Budgetta, Andrew Tabernerb a
Telemetry Research Ltd, Auckland, New Zealand Auckland Bioengineering Institute, Auckland, New Zealand c Blue Box Sensors Limited, Dublin, Ireland b
We have developed a fully implantable telemetry system for the continuous and chronic recording of brain tissue oxygen (PO2,BR) in conscious animals. A telemetry system with a sampling rate of 2 kHz was combined with a miniaturized potentiostat to amperometrically detect oxygen concentration with carbon paste electrodes (CPE). Wireless power was employed to inductively recharge the telemeter battery transcutaneously for potential lifetime monitoring. Rats were implanted with the telemeter body in the peritoneal cavity and electrodes stereotaxically implanted into the brain (striatum or brainstem). Whilst animals were living in their home cages the sensitivity to changes in oxygen was validated by repeatedly altering the inspired oxygen (10%, 100%, respectively) or a pharmacological stimulus (carbonic anhydrase inhibitor: acetazolamide 50 mg/kg IP). Basal level of brain tissue PO2 could be monitored for many weeks (N6 weeks) and showed good overall stability, reproducibility and good correlation to common movements such as grooming. During hypoxia, PO2,BR decreased significantly by − 51 ± 2% from baseline whereas it increased by 34 ± 3% during hyperoxia. Immediately following the systemic acetazolamide PO2,BR increased by 38 ± 4%. We propose that this new technology provides a robust method to measure changes in oxygen concentration in a specific area of the brain, allowing conscious and freely moving measurements. The ability to track long term changes with disease progression or drug treatment may be enabled. doi:10.1016/j.vascn.2012.08.143
Dual recordings of left ventricular and arterial pressure in conscious rats via telemetry Simon Malpasa, Ellyce Stehlinb, Sarah-Jane Guildb, David Budgetta, Daniel McCormicka, Dean Rigelc a
Telemetry Research Ltd, Auckland, New Zealand University of Auckland, Auckland, New Zealand c Novartis Institutes for BioMedical Research, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States b
Measurements of cardiac contractility in conscious freely moving animals are uncommon yet could offer considerable opportunity for understanding cardiovascular disease progression and treatment. We have validated a new high fidelity solid state pressure sensor telemetry device for measuring chronic left ventricular pressure (LVP), dP/dt and blood pressure in rats. The pressure sensor catheter tip (2-Fr) was inserted into the left ventricle through the apex of the heart and the telemeter body implanted in the abdomen. Data was