Impaired Renal Function Clinical Trials: How to Minimize Risks and Accelerate Timelines

Mira Francis, BPharm, PhD, MBA Director, Medical Science Liaison

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

AT A GLANCE

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Phase I/II Clinical Conduct

BA/505(b)(2) Clinical Conduct

Bioanalytical Services

Clinical Support Services

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

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

Protocol Development/Medical Writing

Study Design

Regulatory Affairs

Volunteer Recruitment

PK and PD Analysis

Data Management/Biostatistics

Bioanalytical Services

Comprehensive, Full-Service Offerings

Strong Partnerships that Complement our Service Offering

Hospitals Preclinical Services

Cognitive Research

CDISC Standards

Cardiac Safety Altasciences

Human Abuse Liability

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

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

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

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

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

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

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

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

A Case Study Pharmacokinetics in Patients with Impaired Renal Function

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

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

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

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

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

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

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

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) contact@altasciences.com

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