Preclinical and Clinical Studies

• Course #9 focuses on pre-clinical and clinical studies.

Preclinical and Clinical Studies

• Involve long, costly, and rigorous processes.
• Studies must meet therapeutic needs while adhering to requirements.
• Require significant scientific rigor and a multidisciplinary approach.
• Subject to evaluation by the Health Products and Food Branch (HPFB) of Health Canada, including the Therapeutic Products Directorate (TPD).

Drug Development Steps

• Begins with fundamental research and discovery of an active principle.
• Preclinical research.
• Optimization of promising compounds.
• Clinical trials (Phases I, II, III).
• Regulatory review and submission of a New Drug Submission (NDS).
• Market release.
• Post-market studies focused on surveillance of the drug (Phase IV).
• Patent application is submitted.
• Clinical trial application.
• Conformity Notice is obtained.

Fundamental Research

• Advances science.
• Conducted in universities, hospitals, research institutes, and companies.
• Supported by government grants.
• Encourages possible alliances.
• Generates new biomedical knowledge.

Target Identification

• Involves empirical therapeutic activity.
• Requires analysis of the action mechanism.
• Involves a process of physio-pathological comprehension.
• Requires the identification of the molecular biology.
• Includes target determination.
• Involves analysis of receptors.
• Includes experimental set-up.
• Requires research in therapeutic indications.
• Allows re-evaluation including synthesis of new products.

Discovery of an Active Principle Includes:

• Selecting a target.
• Confirming a beneficial effect on a pathological state.
• Validating a target's commercial potential.
• Confirming its role in disease pathogenesis.
• Involves research and identification of promising compounds.
• Requires use of previous programs, academic purchases, and natural product banks.
• Developing biological assays and tests.
• Characterizing promising compounds.
• Techniques for high-throughput screening (HTS).

Amyotrophic spinale (SMA) example

• Process is based on the survival rate of neurons.
• Involves evaluation of the survival protein and ISLET cell marking.

Patent Application

• Filed after drug discovery.
• Begins a timeline including preclinical development lasting 3-4 years.
• Followed by clinical development.
• Leads to regulatory approval in approximately 12-14 years.
• Actual patent life typically extends to 20 years.

Optimizing Promising Compounds

• Optimizing requires a good quantitative structure/activity relationship (QSAR).
• The process involves synthesis of analogues, assessment of biological activity by biologists.
• Pharmacologists analyze the functional efficacy and toxicity.

Lipinski's Rule

• States that a drug is poorly absorbed or difficult to penetrate if:
• Its molecular weight is >500 Da.
• It has more than 5 hydrogen bond donors.
• More than 10 hydrogen bond acceptors.
• Log P value is >5.

Example of molecule passing the Lipinski Rule

• Morphine (C17H19O3N).
• Log P of 1.27 meets the criteria.
• Molecular weight of 285 Da meets the criteria.

Pre-Clinical Research

• Conducted to assess the drug.
• Involves in vivo studies using animal models, in vitro studies using cellular models, and in silico studies using computer models.
• Most common number of animals used in 2013: 590245
• Mice were used 64.2% of the time in 2013.
• Rats were used 15.5% of the time in 2013.
• Birds are used 10.9% of the time in 2013.

Physico-chemical Properties Includes:

• Molecule's purity.
• Stability.
• Solubility.
• pKa.
• Log P.
• Impurities.
• Excipients.

Pharmacodynamic Data Involves

• Identifying the drug’s target.
• Understanding its mechanism of action.

Pharmacokinetic Data Includes:

• Target screening.
• Assessing plasma protein binding.
• Assessing nonspecific interactions.
• Studying absorption and distribution.
• Studying passive transport into the systemic circulation (Caco-2 MDCK cells).
• Testing P-gp substrate/transporter assays.
• Assessing absorption through models of the blood-brain, placental/reproductive, epithelial, and corneal barriers.
• PBPK modeling.
• Studying metabolism and excretion.
• Studying CYP metabolism, inhibition/induction, glucuronidation, and nuclear receptor activation.
• Studying the regulation of lipid and cholesterol metabolism.
• Studying aromatase inhibition, metabolite stability, and kidney cells/tissue preparations.
• Pharmaceutical companies increasingly use these approaches.

Fixation to Plasma Proteins

• The drug is added to the chamber with the plasma.
• The free fraction passes through the semi-permeable membrane, reaching equilibrium.

Caco-2 Absorption Model

• A monolayer of Caco-2 cells is placed at the bottom of the first well.
• The drug is added to the first well.
• The drug dosage is measured in the second well.

Toxicological Data

• Used to Evaluate risk versus benefit ratio.
• Tests for acute toxicity, in vitro mutagenesis (Ames test), and chronic toxicity are performed.
• Reproduction functions and studies on fertility/teratogenicity/development are conducted.
• Process can be long and costly.

Clinical Preparation

• Goal is to develop a galenic form (preferably oral).
• Selection of excipients combined.
• Selection of a manufacturing process.
• Apply for clinical trials with Health Canada.

Clinical Studies

• Involve controlled studies to clarify the effects of a drug on a specific disease in a selected, monitored population.
• Conducted according to Good Clinical Practices (GCP).
• Scientifically assesses a drug's efficacy, tolerance, and toxicity.
• Trials must have a comparison principle, asking if the medication better than nothing.
• Trials assess the causal relationship asking if results are associated with the medication.
• Trials assess results asking if results are by chance.
• Clinical trials can be open studies.
• Clinical trials can be single-blind or double-blind.

Phase I Trials

• Are exploratory pharmacology studies.
• Small populations (10-100) of healthy volunteers.
• Evaluates pharmacokinetics, pharmacodynamics, and adverse effects.

Phase II Trials

• Exploratory therapeutic studies.
• Involve larger populations (100-500) of selected patients.
• Determine the dose-effect relationship.

Phase III Trials

• Confirmatory therapeutic studies.
• Conducted on a large scale (>1000 participants).
• Utilize broader usage conditions.
• Demonstrate the drug's efficacy and tolerance.

Submission of a New Drug

• Submission of a New Drug Submission (NDS) to the HPFB.
• May lead to a Notice of Compliance, granting the right to commercialize the drug.
• Sale price submitted to the Patented Medicine Prices Review Board (PMPRB).
• Generic name determined by the World Health Organization (WHO).
• Brand name assigned by the manufacturer.

Phase IV Trials

• Focused on pharmacovigilance.
• Involve long-term monitoring of effects.
• Purpose is to confirm tolerance and report adverse effects.
• Can lead to new therapeutic applications.
• Can expand the indications to additional populations.

Generic Drugs

• Introduced after the original patent expires.
• Demonstrate similarity.
• Focuses on chemical equivalence, bioequivalence, and therapeutic.
• Abridged New Drug for new drugs.

Biotechnological Drugs

• Developed from living organisms.
• Do not undergo traditional genotoxicity.
• Do not undergo traditional carcinogenicity studies.
• Require immunotoxicity and immunogenicity studies.

Natural Health Products

• Involves isolation of a plant extract.
• Requires a market authorization request to Health Canada's Natural and Non-prescription Health Products Directorate (NNHPD).
• Must be suitable for self-administration and be sold without a prescription.