Background
The drug development and discovery process entails a sophisticated and protracted collaboration between pharmaceutical companies and academic institutions, aimed at translating novel compounds from initial discovery to eventual clinical application. This multifaceted process encompasses various intricate phases and demands rigorous scientific investigation. Key components of the drug discovery process encompass candidate identification, synthesis, characterization, validation, optimization, screening, and thorough analysis of therapeutic efficacy. Subsequently, compounds demonstrating significance in these studies proceed to initiate the drug development process, advancing towards early-stage clinical trials. This arduous journey of new drug development necessitates traversing several distinct stages, ensuring the drug's safety, effectiveness, and compliance with all regulatory requirements. Explore with our Bioinformatics Analysis for Drug Discovery and Development for services.
We shall embark upon an in-depth exploration of each stage and its associated phases within the drug development landscape, fostering an enriched understanding of the overall process. The stages of drug development can be encapsulated as follows:
Fig. 1. Schematic representation of the drug discovery process. (Duelen R, et al, 2019)
Step 1: Early Drug Discovery and Development
The inception of the drug development process heralds the drug discovery phase. This phase encompasses a diverse array of pathways, ranging from repurposing existing molecules and creating variants of known compounds to identifying molecules that selectively target specific biochemical pathways or scouting for untapped compounds in the realm of nature. Once potential compounds have been identified, they undergo an intensive drug design process meticulously crafted to optimize their intrinsic properties and therapeutic potential.
The early drug discovery process unfolds through a series of distinct phases that contribute to the identification and optimization of potential drug candidates.
Target Identification and Validation
The foremost stage in early drug discovery entails the identification and validation of viable targets. This intricate process involves discerning specific genes, proteins, or molecular targets intricately linked to particular diseases or conditions. The ultimate aim is to pinpoint targets that hold pivotal roles in disease pathology and can be modulated by drugs to yield desired therapeutic effects.
Researchers harness an assortment of cutting-edge techniques and tools to identify and validate these targets. Such methodologies encompass disease association studies, genomic analysis, functional genomics, proteomics, and molecular interaction studies. By unraveling the underlying mechanisms and pathways implicated in disease, researchers can successfully identify potential targets primed for therapeutic intervention.
High Throughput Screening
High-throughput screening (HTS) and high-content screening (HCS) occupy a pivotal position within the early drug discovery process. These methodologies leverage advanced technologies, automation, and robotics to rapidly screen expansive libraries of compounds, genes, or antibodies. The objective is to identify entities that effectively interact with the target of interest and demonstrate the desired biological activity.
Hit-to-Lead Optimization
Once hits, or initial promising compounds, are identified, they undergo hit-to-lead optimization. This phase involves a meticulous process of refining and enhancing the hits to bolster their potency, selectivity, and drug-like properties. The ultimate goal is to transform a hit into a lead compound boasting the potential to evolve into a viable drug candidate.
In this crucial phase, medicinal chemists assume a pivotal role by synthesizing analogs of the hits and systematically modifying their chemical structures to augment their activity and properties. An iterative cycle encompassing synthesis, testing, and conformational relationship (SAR) analysis guides the optimization process.
The optimization of lead compounds primarily focuses on augmenting potency, efficacy, pharmacokinetic properties, metabolic stability, and oral bioavailability. The overarching objective is to cultivate lead compounds showcasing the desired attributes, poised for further development into potential drug candidates.
Preclinical Evaluation
Following the optimization of lead compounds, they undergo preclinical evaluation. This pivotal phase necessitates comprehensive testing of the lead compound through a myriad of in vitro and in vivo models, facilitating the assessment of its efficacy, safety, pharmacokinetic profile, and toxicological characteristics.
Fig. 2. Overview of drug discovery screening assays. (Hughes JP, et al, 2011)
Step 2: Preclinical Studies
After the initial discovery phase, compounds that show promise in preclinical testing move on to extensive preclinical studies. These studies are conducted in animals and serve as an important bridge between laboratory studies and human trials. Preclinical studies assess the compound's toxicity, pharmacokinetics and potential for disease relief. Explore with our Bioinformatics Analysis for Preclinical Research for services.
In Vitro Studies
In vitro studies involve experiments using isolated cell or tissue cultures to assess the effects of lead compounds at the cellular and molecular levels. These studies help researchers understand the compound's mechanism of action, potency and selectivity. Various assays are used to assess the interaction of the compound with the intended target, its effect on disease-related pathways and the potential for off-target effects.
Pharmacokinetic Studies
Pharmacokinetic studies focus on understanding how lead compounds are absorbed, distributed, metabolized, and eliminated by the body. These studies provide information on the bioavailability, half-life, clearance and tissue distribution of compounds.
Researchers use techniques such as in vitro drug metabolism and pharmacokinetic assays and animal models to study the pharmacokinetic properties of compounds.
Pharmacodynamic Studies
Pharmacodynamic studies are designed to elucidate the effects of compounds on their targets and their biological activity in vivo. These studies assess the ability of a compound to modulate the intended target and its effect on relevant biomarkers or disease-related processes.
By measuring the potency, efficacy and dose-response relationships of compounds, researchers can gain insight into their therapeutic potential. Pharmacodynamic studies help to determine the optimal dose range and provide preliminary evidence of a compound's effectiveness.
Acute and Repeated Dose Toxicity Studies
Toxicology studies are conducted to assess the safety profile and potential side effects of the compound. Acute toxicity studies typically assess the toxicity of a compound after a single dose in an animal model to determine any immediate adverse effects.
Repeat dose toxicity studies involve administering the compound to animals over a longer period of time to assess cumulative toxicity, potential organ toxicity and long-term effects.
Other Preclinical Evaluations
Depending on the intended therapeutic application and potential risks of the compound, additional preclinical evaluations may be performed. These evaluations may include genotoxicity studies to assess the potential for the compound to cause DNA damage, carcinogenicity studies to assess its potential to induce cancer, and reproductive toxicity studies to understand its effects on fertility and embryonic development.
The Investigational New Drug Process (IND)
Drug developers must file an Investigational New Drug application to FDA before commencement clinical research. In the IND application, developers must include:
- Preclinical and toxicity study data
- Drug manufacturing information
- Clinical research protocols for studies to be conducted
- Previous clinical research data (if any)
- Information about the investigator/ developer
Step 3: Clinical Studies
After preclinical studies are completed, researchers move on to clinical drug development, a critical stage in the drug development and discovery process. These studies involve the use of the investigational drug in human subjects to assess its safety, efficacy, dosing and potential side effects. Explore with our Bioinformatics Analysis for Clinical Research for services.
Before clinical trials begin, investigators review prior information about the drug to develop research questions and objectives. Then, they decide:
- Criteria for participant selection.
- The number of participants in the study.
- The duration of the study.
- Dose and dosage form route of administration.
- Parameter evaluation.
- Data collection and analysis.
Phase I Clinical Studies: Safety and Dosage
Phase I studies are the first step in testing study drugs in humans. These studies focus primarily on assessing the safety, dose range, and potential side effects of the drug. They are usually conducted in a small number of healthy volunteers or sometimes in patients with the target disease.
The primary goals of Phase I clinical studies are to:
- Determine the pharmacokinetics (absorption, distribution, metabolism and excretion), pharmacodynamics (how the drug affects the body) of the drug
- Determine the maximum tolerated dose (MTD) or optimal dose range Conduct further testing
- Determine any potential adverse reactions or side effects associated with the drug.
Phase 2 Clinical Studies: Efficacy and Side Effects
Phase 2 studies involve a large number of patients with the specific disease or condition for which the investigational drug is being developed. These studies are designed to collect additional data on the safety and efficacy of the drug and to determine the appropriate dose and dosing regimen.
In Phase 2 clinical studies, investigators investigate the effectiveness of a drug in treating a target disease or condition. They may evaluate various endpoints, such as improvement in symptoms, reduction in disease progression or favorable changes in biomarkers. These studies also provide additional information about the side effects and potential risks of the drug.
Phase 3 Clinical Studies: Efficacy and Adverse Drug Reactions Monitoring
Phase 3 studies are the last and largest phase of clinical research before regulatory approval is sought. They involve large numbers of patients and are usually conducted in multiple centers or countries. The primary goal of a Phase 3 study is to further evaluate the efficacy and safety of the drug in different patient populations.
Fig. 3. : Phases of clinical trials. (Deore A B, et al, 2019)
Step 4: New Drug Application and Post-Marketing Studies (Phase IV studies)
Upon the successful completion of the Phase 3 clinical trial, signifying a significant milestone in the drug development process, the pharmaceutical company proceeds to embark upon the intricate journey of preparing and submitting a meticulous New Drug Application (NDA) to the esteemed regulatory body, the Food and Drug Administration (FDA). This pivotal document serves as a comprehensive dossier, encompassing a vast array of imperative data pertaining to the pharmaceutical compound under scrutiny.
The NDA serves as a reservoir of vital information, incorporating critical updates on the compound's safety profile, proposed labeling, exclusive proprietary data, and comprehensive instructions elucidating its intended usage. It behooves the FDA's diligent review team to meticulously scrutinize this intricate compilation, often spanning thousands of pages, with utmost care and scientific acuity. Their evaluative efforts are primarily focused on assessing the compound's overall efficacy, its potential impact on public health, and ensuring its continued adherence to stringent safety standards.
As a testament to their commitment to robust decision-making, the FDA may additionally convene an independent advisory committee, comprising esteemed experts from diverse scientific disciplines, to obtain invaluable insights, expert advice, and pertinent public comments pertaining to the compound in question. This advisory committee plays a pivotal role in augmenting the FDA's knowledge base and ensuring a comprehensive and well-rounded assessment of the compound's merits.
If the FDA deems the submitted NDA to be in alignment with their rigorous regulatory standards and upon a comprehensive evaluation affirming the compound's safety, efficacy, and potential benefits, the regulatory body grants its coveted approval. Subsequently, the pharmaceutical company gains the privilege to embark upon marketing and commercialization endeavors, making the drug available to the public for the FDA-approved indication.
However, the FDA recognizes the inherent limitations of pre-approval clinical trials and acknowledges the necessity of monitoring real-world outcomes to comprehensively assess the compound's long-term safety and efficacy. To address this imperative concern, the FDA may mandate the undertaking of post-marketing studies, commonly referred to as Phase IV studies. These studies are designed to meticulously monitor the real-world utilization of the approved drug, collecting additional data on its performance, safety profile, and long-term effects in diverse patient populations.
Through the rigorous implementation of these post-marketing studies, the FDA endeavors to bolster the existing body of scientific evidence, ensuring continuous surveillance of the drug's real-world performance. This proactive approach further enables the regulatory body to promptly identify and respond to any unforeseen adverse events, while simultaneously fostering a climate of ongoing pharmacovigilance.
In essence, the successful completion of the Phase 3 trial propels the pharmaceutical company towards the momentous task of submitting an all-encompassing New Drug Application to the FDA. Subsequently, through a comprehensive evaluation process, which may include expert advisory committee deliberations, the FDA meticulously determines the drug's suitability for approval. Upon gaining regulatory approval, the pharmaceutical company embarks upon marketing efforts while recognizing the ongoing need for post-marketing studies to enhance our understanding of the drug's real-world performance and ensure the continued safeguarding of public health.
References
- Duelen R, Corvelyn M, Tortorella I, et al. Medicinal biotechnology for disease modeling, clinical therapy, and drug discovery and development[J]. Introduction to Biotech Entrepreneurship: From Idea to Business: A European Perspective, 2019: 89-128.
- Deore A B, Dhumane J R, Wagh R, et al. The stages of drug discovery and development process[J]. Asian Journal of Pharmaceutical Research and Development, 2019, 7(6): 62-67.
- Hughes JP, Rees S, Kalindjian SB, Philpott KL. Principles of early drug discovery. Br J Pharmacol. 2011 Mar;162(6):1239-49.
