A rough estimate is that the entire drug discovery-development process from the initial design idea to the final drug market entry for a drug takes 5-10 years, and it costs about $1.7 billion to successfully carry out the complete process. The idea of a new drug discovery start-up comes from many sources, including current market needs, the emergence of new diseases, academic and clinical research, and more. Once a target has been selected, the pharmaceutical industry or a related academic center goes into early work to identify chemical molecules with suitable characteristics to make the target drug.
The development of new drugs is complex, expensive and risky. Its success is highly dependent on close collaboration and interaction among the many departments within the drug development organization, external researchers and service providers, and ongoing dialogue with regulators, payers, academic experts, clinicians, and patient organizations. Before a drug enters the market, it usually goes through the life cycle below the graph.
Drug Discovery Period >> Drug Development and Registration Period >> Drug Release to Market Drug Marketing and Product Line Expansion
Start Drug Discovery Program >> Combinatorial Chemistry >> Serial Identification of Lead Compounds >> Manufacturing of Additional Compounds >> NCE’s identified
1. New academic research on disease progression encourages scientists to discover new drug products that stop or reverse the effects of disease;
2. Conduct large-scale testing of molecular compounds in a variety of diseases to discover small molecules that may have therapeutic effects against diseases;
3. Existing therapies have additional effects;
4. New technologies, such as those that provide new ways of targeting medical products to specific parts of the body or manipulating genetic material.
At this stage, thousands of compounds could be potential candidates for development for medical treatment. However, after early testing, only a few compounds looked promising and moved on to the next step of research.
Preclinical research >> IND (Investigational New Drug Application) plan established and initiated >> IND submitted >> clinical study initiated >> NDA preparation and submission >> drug launch into the market
During the different stages of a drug's life cycle, drug development is by far the most critical part of the initial and continued success of a drug on the market. Once researchers identify promising compounds, they will conduct experiments to gather information about the following drugs:
❖How drugs are absorbed, distributed, metabolized and excreted (pharmacokinetics studies, pharmacokinetics)
❖Potential benefits and mechanisms of action of drugs (pharmacodynamics studies, pharmacodynamics)
❖Optimal Dosage and Optimal Administration of Drugs
❖drug side effects
❖How drugs affect different groups of people (eg, gender, race, or ethnicity)
❖How the drug interacts with other drugs and treatments
❖Effectiveness of the drug compared to similar drugs
Before testing a drug in humans, researchers must determine whether the drug has the potential to cause serious harm to humans. Preclinical studies are performed on animal models under laboratory conditions.
The two types of preclinical research are:
❖In Vitro Experiments (In Vitro): These experiments are performed in vitro under controlled laboratory conditions in animals.
❖In vivo experiments (In Vivo): These experiments are carried out in animals.
Typically, preclinical studies are not very large. However, these studies must provide detailed information on dose and toxicity levels. After preclinical testing, researchers review and summarize the drug findings and decide whether the drug can be further tested in the population.
The various experiments that are typically performed in this part of the study include:
❖Single-dose toxicity studies Repeat Dose Study Safety Pharmacology Research Genotoxicity studies carcinogenicity studies reproductive toxicity studies
Although preclinical research answers fundamental questions about drug safety, it is not a substitute for research methods of drug-human interactions. "Clinical study" refers to a study or experiment in humans. When developers design a clinical study, they will consider what is being tested in each of the different phases of the clinical study, and then begin the Investigational New Drug (IND) process, which must be done before a clinical study can begin.
After preclinical studies show success, an INDA application will be available to relevant authorities (such as FDA), and if the INDA submission is accepted, the product will be further forwarded to clinical studies (Phase I-IV studies).
Researchers design clinical trials to answer specific research questions related to medical products. These trials follow a specific research plan, called a standard research protocol set by the researchers or drug manufacturers.
Before starting a clinical trial, researchers should review prior information about the drug to formulate research questions and goals. Then decide:
❖who is eligible to participate (selection criteria);
❖how many people will participate in the study;
❖how long the study will last;
❖whether there will be a control group and other methods to limit research bias;
❖how and in what doses the drug is given to the patient;
❖what assessments will be made, when and what data will be collected;
❖How to review and analyze data.
Clinical trials follow a typical research approach from small, early phase I studies to later, large, phase III studies.
Patients: 20 to 100 normal healthy volunteer subjects in a single center, with no benefit to the subjects;Study period: short - days to weeks or months;
Type of study: Open-label (no placebo or comparator), uncontrolled, single-dose or multiple-dose.
Purpose of Phase I experiment:
❖Mechanism of Action (ADME) and PK/PD studies;
❖pharmacological action;
❖Tolerability, side effects and toxicity studies at different doses;
❖Proof of early efficacy;
❖Safety assessment - to determine the most likely potential toxicity and the most effective dose range.
❖The percentage of drugs that make it to the next stage is about 70%.
Patients: Hundreds (100-300) of patients with target disease/condition; Research period: several months to two years;
Purpose of Phase II trial:
❖Dose rage lookup (minimum and maximum effective dose);
❖Therapeutic efficacy for the disease or disorder to be treated;
❖maximum tolerated dose (MTD);
❖Common short-term side effects and risks;
❖Pharmacokinetics.
The percentage of drugs that made it to the next stage was about 33%.
Patients: a few thousand to 3000 patients with the target disease/condition; Research period: 1 to 4 years;
Phase III trial objectives:
❖effectiveness (large scale);
❖relative risk/benefit relationship;
❖Long-term safety information - common side effects, drug interactions, age/ratio/gender differences;
❖Dosage (for product labeling);
❖Safety and efficacy evaluation.
❖25-30% of drugs going to the next stage
Following completion of the Phase III clinical study follow-up, an application may be submitted to the relevant regulatory agency, such as the FDA, for marketing authorization, and after the regulatory agency grants the required approvals, the product will be placed on the market.
Conduct post-market surveillance >> Seek new clinical indications >> Development of new dosage forms and formulations >> Activities to support marketing activities
Phase IV experimental design:
Patients: Hundreds to thousands of patients with the disease/condition;
Purpose of Phase IV trial:
❖Perform uality of Life Tracking (QOL) tracking;
❖conduct pharmacoeconomic studies - whether the drug is more effective than other available treatments;
❖Collect long-term safety information – safety in epidemiological studies and additional surveillance for unexpected or rare adverse reactions;
❖Added product line expansion – new dosage forms and formulations.
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