The process starting from identification/creation of a new molecule befitting a therapeutic target until its introduction into clinical use is broadly referred to as drug development.
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Under the wider umbrella of drug development come several streams and disciplines, mainly constituting the domains of drug discovery, clinical development, and pharmaceutical manufacturing.
Generally speaking, drug discovery is the first big milestone in this resource-intensive marathon that lasts around a decade.
Once a promising molecule is discovered/synthesized, the next set of steps leads to the establishment of its practical utility, generally referred to as the clinical development phase, and may include a step to obtain regulatory approval before the drug goes into production.
Drug discovery and clinical development
Chemical entities that fit into the dynamics of a disease mechanism, and have the potential to alter it favorably, are identified during the drug discovery phase.
The history of some blockbuster drugs shows that they were discovered by serendipity. However, the researchers cannot rely on luck when they are looking at challenging therapeutic landscapes. Hence, a systematic approach is utilized.
As with any other innovation, necessity is the driving force for this process. Diseases with either high burdens, less curability rate, high mortality rate, or poor quality of life pose a high unmet medical need.
Such diseases are the prime targets for the new drug discovery process. Whether a pharmaceutical company would be willing to invest in the development of a molecule or not, is also driven by the cost-effectiveness analyses considering practical costs and profitability in real-life situations.
Scientists study the physiological pathways of the disease in question and then try to discover or synthesize a molecule whose mechanism of action is to intervene in the disease pathway, and thereby cure the disease.
This reverse-engineering process encompasses an array of scientific streams such as microbiology, pharmacology, medicinal chemistry, human physiology, and computer-aided drug design.
From a library of identified potential molecules, a high-throughput screening process narrows it down to a select set of few promising leads.
Criteria such as selectivity, potency, tolerability, adverse effects are mainly taken into account during the screening process.
The lead molecules go through a series of in vitro assays, followed by testing in the animal models, commonly referred to as preclinical research. It includes single- and multiple-dose studies, acute and chronic toxicity studies, reproductive and genetic toxicity studies, and carcinogenicity studies.
Once a drug has shown some promise in the preclinical setting, the first-in-human study is carried out, which serves as the pilot trial of the clinical phase. Clinical trials are classified into phases.
Phase 1 or human pharmacology trials are usually monotherapy studies, either single-dose or repeat-dose studies of escalating doses to identify a maximum tolerable dose (MTD) and recommended Phase 2 dose (RP2D) in humans.
Once the safety in humans is tested sufficiently, Phase 2 or therapeutic exploratory trials focus on the clinical efficacy of the drug in a small-scale setting, usually at multiple study centers. Besides, safety is also evaluated in a larger group of patients during these trials.
The next stage is Phase 3 or therapeutic confirmatory trials, which are conducted in a large group or population across multiple study centers often spread across countries or continents. These trials employ complex study designs, including additional subgroup analyses.
They aim to take into consideration geographical and ethnic variations as well, which are not studied in the preceding phases of clinical research due to a limited number of patients.
Each clinical trial is a systematic evaluation with predefined objectives, methods to measure the desired response, data collection, analysis, and interpretation techniques.
In a pharmaceutical company setting, it is a collaborative effort of departments such as clinical science, clinical monitoring, data management, biostatistics, medical writing, pharmacovigilance, and regulatory affairs. In addition to preclinical and clinical testing, the drug substance also has to pass through several other studies, for example, stability testing.
Once a drug candidate emerges through all these trials, and is proven safe and efficacious for treating the disease in the given regulatory framework, it can be approved by the respective regulatory authorities for marketing.
Drug developers also need to abide by the regulatory requirements post-marketing such as continuing the collection and monitoring of safety data in the widespread population.
Out of a few thousand molecules at the start of the drug development process, only a handful enters the clinical phase. The success ratio of getting approved for marketing is usually less than 0.1% in this intense course of the process.
A separate set of requirements apply for large-scale production of the approved drug for marketing. It encompasses active pharmaceutical ingredient (API) manufacturing, finished drug product manufacturing, and series of in-process and post-production quality testing.
API manufacturing is an isolation/extraction process for naturally derived molecules or a chemical process for synthetic drug molecules. Finished drug product manufacturing involves the production of a dosage form by mixing an API with excipients to form a product fit for intake by a patient.
Unlike the manufacturing of small batches of a drug product for preclinical/clinical testing, large-scale production is affected by several factors such as demand of the drug, scale-up challenges, supply chain management, storage conditions, transportation, and batch to batch consistency.
The drug manufacturing process includes a wide group of operations. For instance, a typical tablet manufacturing process involves steps like size reduction, mixing, sifting, powder filling, tablet compression, coating, packaging, and labeling.
Depending on the type of formulation under production, the unit operations vary. Formulation development is, therefore, a unique discipline often dealing with innovative ways of enhancing the bioavailability of drugs and reducing their side effects by employing different routes of administration and novel drug delivery systems.
During the drug manufacturing process, a series of in-process quality control tests need to be carried out, to make necessary adjustments during the process itself.
A Production Manager of a tablet manufacturing assembly would perform simple tests such as moisture content, hardness, disintegration, and dissolution tests to ensure that the tablets being manufactured are of adequate quality and meet the applicable requirements.
Similarly, post-manufacture quality control tests are also performed for each batch of the drug product before they are released for marketing
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