Preclinical Studies in Drug Development
Preclinical studies play a crucial role in the journey toward new drug discovery and development, assessing the safety, efficacy and potential side effects of a target compound or medical intervention before any testing takes place on humans. Such studies help researchers make informed decisions about progressing to clinical trials, paving the way for the development of innovative and effective therapeutics that can improve the lives of patients worldwide.
In the preclinical phase, laboratory-based experiments and tests are typically conducted through in vivo or in vitro testing. These tests must comply with the guidelines dictated by Good Laboratory Practice (GLP) to ensure reliable results. Computer modeling (in silico testing using data, algorithms and previous knowledge to imitate human biology) and artificial organ development (known as organs-on-a-chip systems containing engineered or natural miniature tissues grown inside microfluidic chips) may also be employed.
Preclinical studies are carefully designed to mimic the conditions and variables expected to be encountered in human clinical trials. This includes selecting appropriate models that closely resemble the target patient population and incorporating statistical analyses to ensure robust results. Study design also involves determining the sample size, duration of the study and endpoints to measure a drug’s efficacy and safety.
Toxicity studies are conducted to assess the response to increasing doses of the new compound, while activity or pharmacological effect studies assess its ability to treat the target disease in animals.
Phases of preclinical research
Preclinical research is generally divided into four phases: basic research, drug discovery and candidate nomination, lead optimization and investigational new drug (IND)-enabling studies.
Phase 1
Basic research
Basic research comprises any studies conducted by academic institutions, pharmaceutical companies and biotechnology firms to understand the underlying biology of a disease and how that disease might be treated. This is often where scientists discover drug targets – the biological processes or pathways that play a role in a particular condition, which they will then attempt to modify with drugs to treat the disease.
Once a target is identified, the next step is target validation, in which researchers gather evidence to confirm the therapeutic effects of target modulation. This can involve a range of techniques, such as genetic studies, biochemical assays and animal models.
Phase 2
Drug discovery and candidate nomination
After basic research and target validation are complete, the focus shifts to finding or designing molecules that can interact with the target in a specific and effective manner. In the drug discovery phase, researchers begin testing potential therapeutic compounds, narrowing down the possibilities from a nearly infinite number to one drug candidate for clinical testing. These experiments are often conducted in cellular models of a disease.
The compounds that show promise in these tests are known as hits. In the drug candidate nomination process, various factors are considered when selecting the most promising of these for further development, including potency, selectivity, pharmacokinetics, safety profile and potential for formulation.
Phase 3
Lead optimization
Compounds that appear promising in the in vivo tests are called leads. As researchers learn more about which leads appear to work well, and which ones appear ineffective and/or harmful, they may chemically modify the compound in question to try to improve its performance. Through this stage of study, scientists will also gather information on which doses are the safest and most effective and build a dosing strategy. This third stage of preclinical research is known as lead optimization, referring to the process of arriving at the best possible drug candidate.
Once a lead drug candidate is identified, a typical preclinical development program consists of six major segments:
- Manufacture of drug substance / active pharmaceutical ingredient
- Preformulation and formulation (dosage design)
- Analytical and bioanalytical method development and validation
- Metabolism and pharmacokinetics
- Safety and genetic toxicology and safety pharmacology, including hematology, urine and other analyses
- Good manufacturing practice (GMP) manufacture and documentation of the drug product for use in clinical trials
Development of the dosage formulation
Proper dosing determines medication effectiveness. After researchers identify a promising compound for development, they conduct experiments to gather information on:
- How it is absorbed, distributed, metabolized and excreted (ADME)
- Its potential benefits and mechanisms of action
- Its stability and palatability
- The best way to administer the drug (e.g., orally or via injection)
- Side effects, immune responses or adverse events (toxicity)
- How it affects demographics of people (such as by gender, race or ethnicity)
- Its effectiveness as compared with similar drugs
- How it interacts with other drugs and treatments
The safety assessment of a drug
The safety assessment of a drug monitors both pharmacodynamic (PD) and pharmacokinetic (PK) interactions. PD interactions are where the drug administered can affect the actions of another specified drug without affecting its concentration, such as blood thinners and antibiotics used in tandem. PK interactions are where the drug administered can impact the actions of another specified drug by affecting its concentration or that of its metabolites (any substance produced during digestion or other bodily chemical processes).
Phase 4
Investigational new drug-enabling studies and safety assessments
Leads with the most promising preclinical data may be advanced to a final round of advanced safety testing, known as investigational new drug-enabling, or IND-enabling, studies. At this point, sponsors must also submit information about how the drug will be manufactured and outline their plans for the clinical trial they plan to conduct. The U.S. Food and Drug Administration (FDA) or other regulators will then review the results from these IND-enabling studies along with the plans and evaluate the intervention’s potential risks and benefits before determining if the clinical trial can move forward.
Regulatory guidelines and compliance
Preclinical studies must adhere to strict regulatory guidelines and ethical considerations. Regulatory bodies such as the FDA and the European Medicines Agency (EMA), among others, provide specific guidelines for preclinical study design, conduct and reporting. Compliance with these guidelines is required to obtain regulatory approval to proceed to the next phase of clinical trials.
FAQs
What are the main sources of value of the preclinical stage?
Speed, simplicity, quality and innovation. Preclinical development can reduce costs as well as timelines in drug development.
What is the difference between pharmacodynamics, pharmacokinetics and toxicology?
Pharmacodynamics describes the relationship between the concentration of a drug in the body and its biological effect (i.e., dose response).
Pharmacokinetics describes changes in the compound’s plasma concentrations over time due to its ADME by the body. Pharmacokinetic interactions are where the drug administered can affect the actions of another specified drug by affecting its concentration or that of its metabolites.
Toxicology studies are performed to identify the treatment regimen associated with the least degree of toxicity and thus determine a suitable and safe starting dose for clinical trials. Additionally, these studies can be used to establish biomarkers for monitoring potential adverse events later.
How long does preclinical research typically take?
The duration of preclinical research can vary depending on the complexity of the medical intervention and the specific requirements of regulatory authorities. On average, preclinical research can take several months to a few years. This time is necessary to conduct a series of experiments, gather data, analyze results and ensure the intervention’s safety and efficacy before proceeding to clinical trials. Additionally, factors such as the availability of resources, collaboration with research partners and regulatory processes can influence the overall timeline.
Drive your drug development program forward
Preclinical research is essential to protect human subjects in clinical trials, and positive preclinical results lay the foundation for obtaining regulatory approval and ultimately bringing a new intervention to market.
Partner with a leading, global provider of CRO services that understands the critical role that preclinical research plays in the development of new medical interventions.
The PPD™ clinical research business of Thermo Fisher Scientific is dedicated to delivering accurate, timely and high-quality data to support your drug development programs and to creating detailed preclinical plans with an eye toward the later stages of development. With a clear focus on safety, efficacy and regulatory compliance, we ensure that your preclinical studies are conducted according to the highest standards.