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Impaired Renal Function Clinical Trials: How to Minimize Risks and Accelerate Timelines
Mira Francis, BPharm, PhD, MBA Director, Medical Science Liaison
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Montreal, Canada Fargo, USA
Overland Park, USA
Three Strategically Located Clinical Units Over 600 beds in North America
Healthy normal volunteer and patient population trials Rapid recruitment and study start-up with a
combined database of over 225,000 volunteers Exceptional retention rates in studies with both
long- and short-term confinement
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AT A GLANCE
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Phase I/II Clinical Conduct
BA/505(b)(2) Clinical Conduct
Bioanalytical Services
Clinical Support Services
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Study Types in Healthy Normal Volunteers and Special Populations
Drug-Drug Interaction Thorough QT Bioavailability/Bioequivalence
(BA/BE) Food Effect Human Abuse Liability and
Substance Abuse
Pharmacokinetics/ Pharmacodynamics Renal/Hepatic Impairment Driving Simulation Cognitive Testing Biosimilars 505(b)(2)
First-in-Human – Single Ascending Dose – Multiple Ascending Dose
Proof-of-Concept (POC) Adaptive Designs Early Cardiac Safety
Assessment
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Therapeutic Areas of Tested Drugs • Abuse Liability • Allergy • Analog Classroom (ADHD) • Anti-histamines • Anti-hypertensive agents • ACE Inhibitors / A-II receptors blockers
(ARBs) • Anti-hypertensive agents • Diuretics • Anti-angina agents • Calcium Channel Blockers / Beta-blockers • Anti-emetic / prokinetics agents • Anti-fungal (systemic) • Anti-malarial Agents • Anti-psychotics • Anti-ulcers / Anti-reflux • Anti-viral • Asthma • Arrhythmia
• BPH (Benign prostate hyperplasia) • Cardiovascular • Central Nervous System (CNS) • Cognitive Testing • Coagulation • Cough / Mucolytic • Depression • Dermatology • Diabetes / Hypoglycemic agents • Epilepsy / Convulsion • Estrogens • Electroencephalography (EEG) • GI • Hematology • Hepatitis • Immunology • Hypolipidemia • Immuno-suppressants
• Inflammatory Disease (Arthritis) • Inflammatory Disease (GI tract) • Metabolic Disorders • Migraine • Obesity • Ophthalmology • Oral Contraceptives • Overactive bladder • Osteoporosis • Parkinson’s disease • Pain Model and inflammation • Potassium salts • Psoriasis / Dermatitis • Psychiatry • Pulmonary • Schizophrenia • Sleep Disorders • Sexual dysfunction • Vaccine
Others on Request
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Protocol Development/Medical Writing
Study Design
Regulatory Affairs
Volunteer Recruitment
PK and PD Analysis
Data Management/Biostatistics
Bioanalytical Services
Comprehensive, Full-Service Offerings
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Strong Partnerships that Complement our Service Offering
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Hospitals Preclinical Services
Cognitive Research
CDISC Standards
Cardiac Safety Altasciences
Human Abuse Liability
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Our strategic alliance with ITR Laboratories provides our clients with a single coordinated team throughout the drug development process, from lead candidate selection to early stage clinical trials. We minimize delays and time lost during the transition from non-clinical to clinical development.
Hospitals Preclinical Services
Cognitive Research
CDISC Standards
Cardiac Safety Altasciences
Human Abuse Liability
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We have partnered with Cognitive Research Corporation (CRC) to provide sponsors with a state-of-the-art driving simulator study solution to test the impaired effects of a wide variety of drugs on driving abilities in both normal and patient populations.
Hospitals Preclinical Services
Cognitive Research
CDISC Standards
Cardiac Safety Altasciences
Human Abuse Liability
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Hospitals Preclinical Services
Cognitive Research
CDISC Standards
Cardiac Safety Altasciences
Human Abuse Liability
Industry leader in the conduct of substance abuse clinical trials through relationships that include Cambridge Cognition (e-VAS) as well as consulting partners for protocol development such as Altreos
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As a CDISC Gold member, we collaborate with global leaders and contribute toward the development and release of new standards.
Hospitals Preclinical Services
Cognitive Research
CDISC Standards
Cardiac Safety Altasciences
Human Abuse Liability
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As a certified member of the Cardiac Safety Research Consortium (CSRC), we participate with industry leaders on key issues that impact cardiovascular safety, including alternative approaches to ICH E14 for the assessment of arrhythmia liability in early drug development.
Hospitals Preclinical Services
Cognitive Research
CDISC Standards
Cardiac Safety Altasciences
Human Abuse Liability
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Our partnerships with local hospitals increase access to patient populations in key therapeutic areas, providing an extended network of clinical research experience.
Hospitals Preclinical Services
Cognitive Research
CDISC Standards
Cardiac Safety Altasciences
Human Abuse Liability
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UNIVERSITY OF MONTREAL HOSPITAL RESEARCH CENTRE (CRCHUM)
Access to an extensive pool of patients Dedicated unit for early stage clinical trials and a
specialized research pharmacy Developed research disciplines Extensive clinical research experience in
therapeutic areas, including: – Neuroscience – Cardiovascular Diseases
Strategic location in downtown Montreal, Quebec
Over 450,000 patients visit CHUM each year 520,000-sq.-ft. research complex, includes:
– Cyclotron – State-of-the-art medical-imaging platform – 75 laboratories – 36 clinical examination rooms – 15 beds for early stage clinical trials – Dedicated research pharmacy – Metabolic Diseases
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HÔPITAL MAISONNEUVE-ROSEMONT (HMR)
Experienced network in key therapeutic areas of research, including Hematology, Nephrology and Metabolic Diseases Clinical research team is comprised of over 60 clinicians Experienced network and patient access in key therapeutic
areas of research including: – Nephrology – Hematology – Metabolic Diseases
Clinical research team of over 60 clinicians and 5,500 employees with over 700,000 patients accessible
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A Case Study Pharmacokinetics in Patients with Impaired Renal Function
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Drug Dosing Adjustment in Patients with Chronic Kidney Disease Recommendation Example
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Drug Dosing Adjustments in Patients with Chronic Kidney Disease, American Family Physician, May 2007, Volume 75, Number 10
FDA Guidance for Industry, Pharmacokinetics in Patients with Impaired Renal Function, March 2010
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Therapeutic Areas
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• Anti-hypertensive agents ACE Inhibitors Beta blockers Diuretics
• Hypoglycemic agents Acarbose Chlorpropamide Glipizide Glyburide Metformin • Statins: Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin
• Anti-infective agents Antifungals Antivirals Carbapenems Cephalosporins Macrolides Penicillins Quinolones Sulfas Tetracyclines
• Other common agents: Allopurinol Esomeprazole Famotidine Gabapentin Lansoprazole Metoclopramide Omeprazole Ranitidine
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Decision tree When a Renal Impairment Study should be conducted?
Recommendation
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FDA Guidance for Industry, Pharmacokinetics in Patients with Impaired Renal Function, March 2010
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OBJECTIVES To assess the impact of different stages of renal function (stages 1 - 4) on the drug PK behavior To assess the drug safety profile in patients with impaired renal function STUDY POPULATION
A total of 32 subjects as follows:
8 subjects with mild renal impairment
8 subjects with moderate renal impairment
8 subjects with severe renal impairment
8 healthy subjects with normal renal function
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FDA Guidance for Industry, Pharmacokinetics in Patients with Impaired Renal Function, March 2010
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Customized Study Plan : CRO – Hospital Collaboration
Study Initiation: CRO
Protocol design and writing Health Canada Submission Communication plan Gantt Chart SIV
Study Operations: CRO-Hospital
IRB submissions Joint patients recruitment and
enrollment
Project Management across sites
Monitoring of Quality and Key Performance Indicators
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Reporting Milestones: CRO
Bioanalysis Data management PK analysis Biostatistics Medical report writing
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Study Design
Study designed in accordance to regulatory guidances Single dose, open-label, non-randomized, parallel study Main Inclusion criteria:
– Adult males or females, of at least 18 years of age – Body mass index (BMI) range of approximately 18.5-42 kg/m2 (inclusive)
Plasma PK sampling: pre-dose, and 0.25, 0.5, 0.75, 1, 1.33, 1.66, 2, 2.5, 3, 4, 6, 9, 12, 16 & 24 hours post-dose
Urine sampling intervals: -2 to 0 h pre-dose, and at 0-2 h, 2-4 h, 4-8 h, 8-12 h and 12-24 h post-dose
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Access to Patients Hospital Phase I unit
Strategic alliance with HMR hospital, an industry leading nephrology site 1300 + patients with impaired renal function impairment, and patients requiring dialysis Easy access to matching healthy control subjects through database of over 120,000
participants, 40,000 active Searchable database to qualify IE criteria for pre-existing conditions, demographics,
medication use, and BMI
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Access to Matching Healthy controls & Mild RI CRO clinics
Healthy subjects are carefully matched to the patients with impaired renal function by age (+/- 10 years) and weight (+/- 20%) to be representative of the patients population to the extent possible
Easy access to matching healthy control subjects through database of over 120,000 participants, 40,000 active
Searchable database to qualify IE criteria for pre-existing conditions, demographics, medication use, and BMI
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Plasma concentration-time profiles
Parent Metabolite
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Timelines
4 months from A to Z; Protocol writing, IRB, CTA, clinic, bioanalysis, DM/Biostatistics, medical reporting
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Study Activities Weeks 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Pre-Study Timelines
IRB Submission
IRB Approval
Clinical Trial Application (CTA) Submission *
No Objection Letter (NOL)
Shipment of Medication
Recruitment
Screening
Weekly Team Meeting
Clinical Dosing
Severe RI dosing
Moderate RI dosing
Mild RI dosing
Control group dosing
Post-study Report
* The CTA submission can be done in parallel with the IRB submission, which offers us the advantage of project initiation with accelerated timelines
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Timeline Impact
The CRO-Hospital model significantly improved study timelines – Parallel enrollment of patients – Centralised project coordination
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Clinical Operations: in Harmony
CRO HOSPITAL IRB submission Principal Investigator * Patients with Mild RI Patients with Moderate RI Patients with Severe RI Control/Matching healthies Project Management
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* Industry leading Principal Investigator Dr. Vincent Pichette, Nephrologist Lead consultant to the FDA for Impaired Renal Function PK Guidance
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CONCLUSIONS
Sponsor benefits from the CRO-Hospital joint expertise on study: – Hospital medical expertise in nephrology; patients access and monitoring – CRO expertise and capabilities in running Phase I clinical trials
Centralized communication Accelerated study timelines “One-stop” for a complete clinical trial
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Thank you!
450 973-6077 (Montreal) 913 696-1601 (Overland Park) 701 551-3737 (Fargo) [email protected]
Contact us at:
altasciences.com