Drug Safety

• • Drug safety became a thing when the experimental inhibitor of the enzyme fatty acid hydrolase, which breaks down endocannabinoids in the brain caused a person to have severe neurological injuries (brain damage and lesions) that then caused death
  • 90% of clinical drug development projects fail, especially in Phase II, but any that have passed Phase III are usually successful
  • Reasons for failing include safety, efficacy, pharmacodynamics. Pharmacokinetics or strategy - but the main reasons they fail is due to safety and efficacy - this is mainly because toxicity cannot be predicted.
• • The 5Rs
  • Right Target
  • Right Tissue
  • Right Safety
  • Right Patient
  • Right Commercial Potential
• • Drug Discovery Process ( ~23 Years and ~ $250 billion)
  • Drug Discovery (7-10 years) : Target Identification --> Lead Discovery --> Lead Optimisation --> Preclinical Testing --->
  • Clinical Trials (6-12 years): Phase I --> Phase II --> Phase III --->
  • Approval for Production (1-2 years): FDA/EMA Review and Approval --> Post-Approval
• • Stage 1
  • Research Development
  • Target Identification
  • Compound Screening
  • Lead Identification
  • Stage 2
  • Preclinical Studies
  • In Vitro Studies
  • In Vivo Studies
  • Required Standards
  • Stage 3
  • Clinical Trials
  • Phase I Trials
  • Phase II Trials
  • Phase III Trials
  • Stage 4
  • Review and Approval
  • Evaluation
  • Approval and Manufacture
  • Post-Release Monitoring
• • Where Safety Fits:
  • Investigative in vivo/ in vitro safety toxicology
  • Pharmacokinetics, pharmacology and toxicology
  • Phase I, II and III
  • Pharmaco-epidemiological observational studies
• • or small molecules, PROTACS, oligo-nucleotides, biologics and cell/gene therapies the key investigative toxicology in drug development include:
  • Supporting the assessment of the target and the competitive landscape
  • The use of safety profiling and target organ models to guide candidate design and selection
  • To de-risk preclinical in vivo findings and address human relevance
  • To support the identification of the mechanisms underlying clinical events
  • It is a case of imagining the worst and work forwards with the risks instead of hoping for the best
• • In silico
  • Start with a literature review - target functions, pathways, cross-species or genetic modification
  • Basically a simulation that involves: quantitative structure, AI, target modelling and target-ligand docking simulation, PK and PD modelling and AI generated ADME parameters.
• • In vitro
  • Used for secondary pharmacology profiling  so that undesirable off-target activity can be identified
  • Secondary pharmacology studies evaluate the drugs effects against a broad range of molecular targets that can have side effects
  • There are various protocols for screening that include binding, functional or enzymatic assays, which give information on potency, efficacy and type of interaction which makes it cost-effective and efficient for safety screening so hazards can be identified and eliminated early on
• In Vitro

  • Secondary pharmacology profiling can be used to lead optimisation of the drug, can be used to select drug candidates, and can be used to aid in mechanistic understanding of in vivo effects.
  • Can predict and understand organ specific drug toxicities to varying levels of confidence, simple cell cultures can be used to test to the robustness.
  • After simple cell cultures are used you can move on to organoids or micro physiological systems (MPS) or organ explants and slices.
  • With MPS you can connect this to organ models with just a single chip.
• In Vitro

  • Can give high-content imaging of cells using multiplexed dyes to generate morphological profiling data.
  • The organs on a chip can have 18 organ tissues on 1 chip and can detect metabolism and toxicity.
  • In terms of confidence: MPS > 3D systems and organoids > Stem Cells > Primary Cells > Cell lines
• • In vivo
  • There are ICH Guidelines that have to be followed
  • Use silico data and factors including pharmacological relevance, modality and PK and PD profiles and responses need to be considered but so does animal welfare
  • Histopathology samples can be coupled with mass spectrometry imaging to allow for spatial analysis
  • MRI, PET, CT and single photon emission tomography can be used for in vivo imaging to assess biological events in real time.
• In Vivo

  • Non-specific biomarkers are better suited for pre-clinical general toxicology and clinical monitoring,
  • Current game changers for novel assay and technology - high contrast imaging, modelling and simulation and genomics
  • Future game changers - organs on chips, gene editing, metabolomics and system toxicology
• in vivo

  • Looking at exploratory effects, safety, efficacy, compare them to known treatments and what are the long term effects
  • Clinical trials must follow established standards for the rights, safety and well-being of the participants. Standards include:
  • International Conference on Harmonisation Good Clinical Practice
  • International Ethical Guidelines for Biomedical Research Involving Human Subjects issued by the council for International Organisations of Medical Sciences
  • Declaration of Helsinki
• • Sponsors:
  • are held accountable to comply and there is rigorous safety monitoring and evaluations for all stages throughout the trial
  • Clinical trial sponsors are responsible for developing protocols and must contain information on all aspects of the trial as well as informed consent forms as well as case report forms that are designed to be data collection tools
• • Subjects
  • Healthy and agree to participate with signed informed consent forms
  • Encouraged to follow protocol but can withdraw at any time
  • Phase I volunteers are compensated for time and willingness
  • Later phases are for patients with the disease of interest so pay is unlikely
• • Investigators
  • Qualified and experience
  • Educate participants
  • Adhere to protocol treatment plan
  • Observe, manage, evaluate and document
  • They are held accountable and are responsible for the conduct of the trial
• • Ethics Committee
  • Protect the rights and welfare of the subjects
  • Review all clinical trials protocols
  • Review ongoing research to ensure continued diligence
• • Data Monitoring Committee
  • Review data on a regular basis
  • Review efficacy of data
  • Not all trials require DMC and are most common for double blind randomised studies
  • Regulatory Authorities
  • FDA or EMA
  • Issues guidance for safety reporting requirements
• Pharmacovigilance

  • Process and science of monitoring the safety of medicines and taking action to reduce the risks and increase the benefits of medicines
  • Framework provides a system for monitoring the safety of medicines that are on the market. By prevention, detection and assessment of the adverse reactions to medicine
  • Act to protect public health
  • Audit the outcomes of and key processes involved