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European Biopharmaceutical Review

Behind the Screens

In early stage drug discovery, overcoming the ongoing challenge for finding the appropriate allocation of R&D resources in an economic environment of declining budgets and tighter resource allocation is imperative for an effective process.

A key challenge in the pharmaceutical industry is to fulfil the principal objective of the drug discovery and development process by creating safe and effective drugs. Late stage candidate failure is a huge burden on pharmaceutical companies in terms of research as well as having high cost implications. As a result, it is necessary for companies to implement efficient early stage screening to filter out potential molecules.

Ideally, it takes 10 to 15 years on average and $1.2 billion to $1.3 billion to develop a new drug. For every 5,000 to 10,000 compounds that enter the drug development process, about five molecules receive approval to enter the clinical trials stage and only one gets approved by regulatory agencies.Many drugs that have passed the early stage development phase still fail during clinical trials.Drug failure at this stage is primarily attributed to poor pharmacological response (around 41 per cent), lack of biological activity (around 31 per cent) and drug toxicities (around 22 per cent). Sophisticated testing strategies have to be put in practice in order to streamline the drug development process and to prevent incurring huge losses due to drug failure in late stages.Thus, early stage drug development is a crucial phase in the drug development process.

Early Stage Discovery

Thousands of molecules are discovered every year through high-throughput screening, which often begins with identification of the target. Potential drugs are then assessed for interaction with the target. After assessment, lead compounds are further screened for their activity and their properties are improved to be developed into safe and effective medicines (see Figure 1).

The early stage studies include:
  • Toxicity and immunotoxicity studies
  • Mutagenecity and genotoxicity tests
  • Safety pharmacology and pharmacokinetic (PK) studies
  • Absorption, distribution, metabolism and excretion (ADME) examinations
  • Development of physicochemical and biological assays and tests
  • Pharmaceutical development
  • Various stability studies
  • Design of the drug manufacturing process to be adopted
The preclinical stage of development experiences the highest attrition rates, with only 0.1 per cent of molecules screened during drug discovery entering the Phase 1 clinical trial.Thus, a well designed preclinical pharmacology and toxicology study is critical for the longterm effectiveness of the drug development process.

Key Technologies

Early stage drug discovery studies make use of systems or models such as in vitro, in vivo and in silico models, highthroughput laboratory experimentation, advanced biotechnology tools and techniques, and bioinformatics tools. Absorption, distribution, metabolism and excretion and toxicity (ADMET) studies are conducted initially to investigate and correlate the test compound’s absorption, distribution, metabolism, excretion and toxicology profile in preclinical systems with humans.

Major tools and technologies employed in the preclinical ADME testing include in vitro enzyme linked immunosorbent assay (ELISA) based testing and mass spectrometry. Chromatographic instruments such as liquid chromatography (LC), high performance liquid chromatography (HPLC) and rapid resolution liquid chromatography (RRLC) are also used for separation and purification of the chemical entities (test compounds). For gene therapy related preclinical studies, genotyping and polymerase chain reaction (PCR) based analyses are performed. Major technologies used in preclinical efficacy and toxicology studies are listed in Figure 2.

Technology Trends

Developments in comparative genetics provide relevant information, particularly with regard to the role of human-specific genes and the suitability of animal models for drug development.The field of preclinical imaging systems is coming up with new technologies with improved penetration, efficiency and spatial resolution.The application of nanotechnology, advanced bioinformatics tools and expert systems has also found greater importance in preclinical research. Some of the recent technological developments in this field include:

Modern technological development in preclinical studies has seen integration between molecular imaging techniques and biomarkers. Imaging techniques in preclinical research help to visualise and track the changes (at the organ, tissue, cell or molecular level) in research animals.Many different technological developments are taking place in imaging systems, such as optical/fluorescence imaging,positron emission tomography (PET), magnetic resonance imaging (MRI), X-ray computed tomography (CT), single photon emission computed tomography (SPECT), ultrasound and microwave.These imaging techniques are very sensitive, providing accurate and real-time visual data with high spatial resolution and offering extensive application in preclinical cancer research.

Nanotechnology-based tools and techniques are currently rapidly emerging in the fields of preclinical imaging and diagnostics. Nano-constructs such as dendrimers, liposomes, nanoshells, nanotubes, emulsions and fluorophores can be used in preclinical diagnostics related to the targeted therapy.

QuantumDot Fluorescence
QuantumDot Fluorescence is an emerging nanotechnological application which makes use of semiconductor nanocrystals, known as Quantum dots (Qdots), that fluoresce when excited by a light source, emitting bright colours that can identify and track properties and processes in various biological applications.

Combidex (ferumoxtran-10) is another nanotechnological application, which consists of iron oxide nanoparticles for use in conjunction with MRI to aid in the differentiation of cancerous from noncancerous lymph nodes. Combidex is used extensively in cancer research (prostrate and breast cancer).

Nanofluidic Systems
Nanofluidic systems represent nanoscale cell culture systems to enable the analytical separations and determinations of biomolecules, such as proteins and DNA.These are potential systems which can be integrated into microfluidic systems to develop lab-on-a chip devices (gene chips) for polymerase chain reaction (PCR) and related techniques, and they help in developing in vitro assays.

Nanoarrays are the miniaturised version of microarrays, fabricated using lithographic techniques such as electronbeam lithography, ion-beam lithography and nanoimprint lithography. These nanoarray systems can be used in bioaffinity tests for proteins, nucleic acids and receptor-ligand pairs.

Nanoscaffolds are nano-polymeric structures, which play an important role in organ regeneration as they act as templates for cell proliferation, differentiation and tissue growth. Therefore nanoscaffolds have found greater application in ex vivo preclinical research, which involves artificial tissues or organs.

Mobility Spectrometry
This can be used in conjunction with nanoelectrospray mass spectrometry, which expands the sensitivity and selectivity of nano liquid chromatography mass spectrometry (LCMS) in global and targeted proteomics approaches.This particular technology plays an important role in biomarkerrelated preclinical research for monitoring disease progression and drug efficacy. Topography and recognition imaging (TREC), coupled to atomic force microscopy (AFM) and nanoflow liquid chromatography (nano-LC) are some of the recent technological developments in preclinical research.

Application in Preclinical Studies
Some of the new approaches to conducting preclinical studies are discussed below:

Genomics, Proteomics and Metabolomics
Recent advancements in genomics, proteomics and metabolomics with highthroughput screening techniques provide critical computational data required to design, develop and screen lead compounds for efficacy and safety.Genomics help researchers to identify new targets for the drug molecule using a genome sequencing database. Complementary DNA (cDNA), RNA interference (RNAi) and SNP libraries are used here. Applications of genomics have proved useful in fundamental research regarding drug activity.

This is an approach that involves measuring total cellular protein and determining the post-translational modification and fate of proteins. The most applicable techniques involve spotting cell lysates onto arrayed antibody wells to search for potential biomarkers and to profile molecular pathways.

This is the study and profiling of smallmolecule metabolites of specific cellular processes. Analytical techniques such as gas chromatography (GC), high performance liquid chromatography (HPLC), capillary electrophoresis (CE) (separation techniques), mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy (detection techniques) are used here. Major applications of metabolomics in preclinical research include:
  • Toxicology studies for metabolic profiling of urine or blood plasma samples, which can be used to detect the physiological changes caused by the toxic content of a chemical
  • Functional genomics, where metabolomics can be used as a tool for determining the phenotype caused by a genetic manipulation, such as gene deletion or insertion. These phenotypic changes may represent any genetic disorder
Toxicogenomics is a systems biology approach applied to preclinical research. It is a study of the response of a genome to hazardous substances, using genomics, proteomics and metabolomics technologies in combination with bioinformatics and conventional toxicology.Geneexpression microarrays, molecular-based screening technologies – including HTS and HCS – and computer-based expert systems/softwares support toxicogenomics studies by providing a cost-effective approach for prioritisation or hazard identification of large numbers of chemicals in a short period of time.

Surgical Models
Some preclinical CROs develop customised surgical models in a range of animals for dosing and PK studies.This involves both acute and chronic surgical models for use in any drug metabolism, pharmacology or safety study for enhanced understanding of drug or chemical compound.

Transgenic Animal Models
A transgenic animal is one that carries a foreign gene that has been inserted into its genome. It can also be a situation where certain genes are either deleted or modulated.These models are also known as induced animal or disease models, where the expression of an inserted foreign gene would induce a disease condition in the research animal.

Simulation Models
This is a computerbased modelling approach that simulates the in vivoor ex vivo conditions in the form of virtual patients or organs. The main objective of this preclinical approach is to determine the human equivalent dose (HED), based on the extrapolation of safety doses in animals. PK/PD modelling and simulation can be integrated for obtaining proper relationships between dosage and response.

Several large pharmaceutical companies, including Pfizer, GlaxoSmithKline, Lilly and Novartis, along with many CROs that offer preclinical services, have been implementing these integrated simulation models.These models are progressive in nature and typically involve research projects that are unspecified at the time of establishment and data collection.They provide common access to researchers for ethically approved research purposes and contain biospecimens which are linked with phenotypic and genotypic data. Biobanks have established governance procedures that protect participants’ interests.These procedures include the requirement that all people or institutes who request access to biospecimens and relevant data be reviewed by a human research ethics committee, which ensures ethical standards are maintained.

Early Stage Drug Discovery in Disease Segments
The majority of the molecules in the early stages of discovery are being developed for cancer indications. Molecules under development for breast cancer account for 23 per cent of the total early stage molecules under development for cancer, followed by prostate cancer (20 per cent) and colon cancer (15 per cent).The other therapeutic areas are CNS disorders that accounted for 14 per cent of early stage drugs under development, followed by immunological disorders (13 per cent) and metabolic disorders (10 per cent) (see Figure 3).


Drug discovery and development has changed extensively over the years. Though there has been significant advancement in the development of drugs, these changes are proving to be insufficient to meet market needs and the needs of modern medicine. Scientists are continuously striving to transform the efficiency of target developments in early stage drug discovery in order to make drug discovery and development a comparatively economical process. Thus it is necessary for the companies to implement robust early stage screening in order to screen potential molecules that are robust and affordable to minimise the possibility of late stage failures

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Sandhya Vellore is an Analyst in the Healthcare practice at GBI Research and has authored numerous drug discovery and development technology market reports on request and of interest to various biopharmaceutical companies. Sandhya has examined and presented a variety of topics pertaining to pharmaceutical and healthcare markets. She has worked in close collaboration with industry experts and has rich experience in identifying client strategic needs and providing research support. Prior to joining GBI Research, Sandhya was an Analyst with Thomson Reuters. She has a Master’s degree in Integrative Bioscience from the University of Oxford.
Sandhya Vellore
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