When you take a Paracetamol or an antibiotic, or any other medicine prescribed by your doctor or the one that you have bought over the counter, have you ever wondered about how that particular drug rightly cures the disease or condition which you consume it for?
Be it a small over-the-counter drug like Paracetamol or something as big as a #covid19 vaccine, all drugs and even medical devices like the pacemaker, catheter, or a surgical suture have to go through a process that ensures the safety and efficacy of the drug. This process easily costs hundreds of millions of dollars to the company and it can take a decade to get the drug approved and reach the market for human consumption.
There are different phases/stages in this drug approval process and each phase has an important submission that is required by the regulatory body. These regulations have been put forth based on the learnings from several medical disasters in the past like the Thalidomide tragedy, the Tuskeegee study, etc.
There are 4 Phases in a Clinical Trial Process (Phase 1 - Phase 4). Prior to all these phases, the beginning point of any drug lies at the discovery stage. More than 1000 prospective molecules enter the research and throughout the drug development process, several of these get filtered out on the basis of safety, efficacy, and target identification. In the end, only one receives the approval and reaches the market.
A series of experiments are conducted in animals and cell lines in the laboratory to study the preliminary effectiveness, toxicity, pharmacokinetics, and safety information. It is the so-called move from bench to bedside. Varying doses are tested in vitro and in vivo. In silico profiling is also performed using computer models for drug-target interactions. These studies pave the way for the first-in-human trials (FIH).
The First-in-human (FIH) trials also called human microdose studies, have single sub-therapeutic doses given to 10 to 15 subjects and yield pharmacokinetic data or help with imaging specific targets without introducing pharmacological effects. Pharmaceutical companies perform Phase 0 studies to decide which of their drug candidates has the best pharmacokinetic parameters in humans.
These studies are usually carried out on small samples of subjects. The idea here is to determine the safety of the drug in a small and usually healthy volunteer study population. The study also helps in determining how much drug is measured in the blood after administration, how the drug works in the body, and the side effects associated with increased dosage. These studies are oftentimes very fast-moving projects because they are quick to enroll patients and the results are needed rapidly. This can be challenging for the statistical programmer, and there is little time to spare when the time frame of a phase 1 study can be weeks or months at most.
This phase explores and defines the efficacy of a drug. Phase 2 studies have larger (100–200 patients) study populations with the disease or condition of interest and are aimed at narrowing the dose range for the new medication. Safety is monitored at this stage as well, and phase 2 trials are generally conducted in the target study population. Phase 2 studies can often take a bit longer to complete because the trial timeline may be longer, with more assessments, and with more patients than phase 1 trials.
These are large-scale clinical trials on populations that number in the hundreds to thousands of patients. These are critical trials that the drugmaker runs to show that its new drug is both safe and efficacious in the target study population. If the phase 3 trials are successful, they will form the keystone elements of a New Drug Application (NDA). NDA is submitted to the FDA (or analogous applications may be submitted to other regulatory agencies outside the US) for consideration for marketing approval. This type of clinical trial can take several months or years to complete.
The post-marketing trials are usually conducted to monitor the long-term safety of a new drug after the drug is already available to consumers. Phase 4 trials can run for years, and they tend to have a lessened sense of urgency than you would see from the earlier phase trials. The drugmaker has many tools to conduct Phase 4 and the ultimate goal is to assess the safety and efficacy of a drug in a large population in an uncontrolled environment.
The overall process of drug development and approval in a typical pharmaceutical company can be seen in the below flow diagram.
The process of discovery, development, clinical research, manufacturing, and marketing of the drugs are guided by several regulations imposed by the drug approval organizations in the respective countries. These include the ICH Guidelines, 21 CFR Part 11, GxP, etc. Conformance to these guidelines is mandatory for the drug approval process and would be audited periodically by the regulatory agency.
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'SAS® Programming in the Pharmaceutical Industry', by Jack Shostak.