Pre Clinical Phase | Safety data generation | Pharmacovigilance Unit 4 Notes and Lecture

Pre Clinical Phase | Safety data generation | Pharmacovigilance Unit 4 Notes and Lecture

Preclinical studies are performed in in vitro, in vivo, ex vivo, and in silico models to obtain basic information about the safety and biological efficacy of a drug candidate before testing it in a final target population, i.e., humans. Preclinical studies or tests are mainly performed in compliance with GLP/GSP guidelines (good laboratory practice and good scientific practices) to ensure reliability and reproducibility of results.

Regulatory aspects of preclinical studies
Preclinical studies mainly follow a combination of:
• GLP (21CFR, 58) and compliance monitoring;
• OECD principles;
• ICH/M3;
• Common Technical Document/CTD module 4 (article 6 of Regulation (EC) No. 726/2004, and with respect to the Annex I to Directive 2001/83/EC);
• Pharmacopoeial or codex requirements;
• 3R principles;
• Local animal ethical committee guidelines and requirements; and
• ISO regulations

Typical tests for chemical entity and pharma drugs.
• Cell viability assays
 Thymidine incorporation assays
 Cell Titer-Glo cell viability assays
 MTS assay
 ATPlite cell viability assay
 SRB assay
 other specific tests

• Cell proliferation assays
 MTT cell proliferation assay
 cyQuant direct proliferation assay
 BrdU cell proliferation ELISA assay
 Label-free and real time proliferation assay using IncuCyte
 other specific tests

• Cell apoptosis assays
 Caspase-Glo 3/7 activation assay
 Reaction oxygen species (ROS) assay

 Mitochondria membrane potential assay
 Apoptosis analysis by flow cytometry
 other specific tests

• Cell angiogenesis assay
 Matrigel plug assay
 Tube formation assay
 Platelet activation assay
 Co-culture angiogenesis assay
 other specific tests

• Related assays
 Cell migration assay
 Tumor invasion assay
 Chemotaxis assay
 Cellular phosphorylation assay
 Cell cycle assay
 Endotoxin assay
 Genetic stability testing
 Endocrine disruption
 Drug-drug interaction
 Drug efficacy test
 3D angiogenesis assay
 3D invasion assay
 Inflammation assay
 Receptor binding assay
 Enzyme inhibition
 20 messenger analysis
 Plasma stability
 Plasma protein binding assay
 other specific tests
• In vitro permeability and transporter assays
 Caco-2 permeability assay
 MDCK permeability assay
 Parallel artificial membrane permeability assay (PAMPA)
 Transporter assays, e.g., P-glycoprotein (P-gp), BCRP, OCT2
 other specific tests

• Type of toxicity assays
 2D-based hepatotoxicity assay
 3D-based hepatotoxicity assay
 other specific tests

Animal tests
 Local tolerance
 Fertility studies
 Single dose toxicity in animal
 Repeated dose toxicity in animal
 other specific tests

In June 2016, the FDA commissioner proposed building a database that would gather information before clinical trials, meaning from preclinical research (lab animals or cells/cell lines). This proposal of a database for preclinical work received mixed reactions from the scientific community. Currently, if a molecule becomes successful, all the drug development data become trade secret; if it does not, the data are stored in archives, and very rarely published despite their high scientific value. The idea of this database supports learning and sharing from unand successful trials.

Even though the idea is interesting, the scientific community is unsure about the future of it, due to several reasons, such as reliability, funding, legal aspects, government and regulatory scrutiny, etc. https://www. is trying to promote transparency in preclinical research.

The main objective of this database is to

  • increase transparency,
  • avoid duplication of animal studies,
  • reduce bias reporting,
  • increase data sharing on protocols,
  • study  designs, and outcomes, and foster research collaborations.

The UK’s Catapult database 
( provides one-stop information for
ongoing preclinical research activity related to cell, gene, and other advanced therapies.

Elsevier’s PharmaPendium database

( clinical-data) collects data on drug safety, the FDA Adverse Event Reporting System (FAERS),and ADME and drug-drug interactions. This database offers risk-benefit analyses and drug candidate assessments.

Researchers can search FDA and EMA regulatory documents, committee meeting minutes, FAERS, data on pharmacokinetics, efficacy, safety, metabolizing enzymes’ and transporters’ potential drug-drug interactions, and guidance on validation of the best animal model. Other databases include (a French preclinical database) and (the NCI’s Development Therapeutics Program, DTP).


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