Where do the medicines we take from chemicals come from? How do doctors know which medicine is good for which disease? How can drugs actually cure a particular ailment for which they have been prescribed? Do these questions come to your mind every time you buy a medicine?
Come on, let us know today about the development of medicine from the very beginning…
The development of medicine is called Clinical Research and has different Phases. The phases of clinical research are the steps of experiments with a health intervention in an attempt to find sufficient evidence for a process that scientists believe would be useful in medical treatment.
Pharmaceutical study begins its journey from drug design and drug molecule discovery, progressing to animal testing and then human studies to see the efficacy of the drug.
The drug undergoes many trials: preclinical, phase 0, phase I, II, III and IV. Combined trials are also sometimes conducted to reduce development time, such as Phase I/II and II/III.
preclinical study
When the drug molecule is identified, it undergoes many in vitro (test tube or cell culture) and in vivo (animal) experiments. These experiments are performed to find out the preliminary efficacy, toxicity and pharmacokinetics of the different doses of the drug. Many drug molecules are being designed at the same time, and these preclinical studies allow pharmaceutical companies to decide which molecule has the greatest potential in later studies.
Study Design:
Trials are always carried out following a set of steps, called a protocol, developed by researchers to find the specific questions related to the medical product. The information from the previous studies becomes the basis for the researchers to develop the questionnaire and the research objectives:
- Selection of participants
- Number of Attendees
- Study duration
- controlled or not
- How and what dose will be administered
- What and when the data will be collected
- Review and analysis time
Phase 0 study
Also called microdosing trials, 10-15 human subjects are taken and single subtherapeutic doses are given to collect pharmacokinetics (KP) drug data. This allows the company to decide whether or not to proceed with further development of the drug, based on more relevant human data rather than animal data.
Such trials accelerate the development of promising drugs by establishing whether or not the drug works in humans as expected in preclinical studies.
After the company decides to pursue the drug molecule in development, it must submit data from its preliminary studies to the FDA called Investigational New Drug (INDIANA) submission of applications.
Phase I Study
Also called First-in-man studies, as they are the first stage of human testing studies. These are the studies that are designed to determine the maximum dose that can be administered without showing adverse effects.
Contract research organizations (CRO) conduct such studies at clinical trial clinics where medical staff provide full-time care to 2-100 healthy subjects enrolled in the study and collect the data.
These studies determine the safety (pharmacovigilance), tolerability, pharmacokinetics (KP) and pharmacodynamics (database) of the drug. The design of Phase I studies is dose ranging, also called dose escalation studies conducted in controlled clinics called Central Pharmacological Units (CPUs).
Usually healthy subjects are recruited but sometimes patients with terminal illnesses such as cancer and HIV and also those who have already tried and failed to improve existing drugs.
There are two divisions for the Phase I study:
Phase Ia: Single Ascending Dose
Phase Ib: ascending multiple dose
Phase II study
More than 100 diseased subjects are enrolled in a longer study to learn the drug’s benefits along with its safety, which includes genetic testing. These studies are also called “Proof of Concept or Pilot” studies.
This is the phase where drug development may fail due to toxicity or less than expected results.
Two divisions of this phase are:
Phase IIa: Pilot study, to determine clinical efficacy or biological activity.
Phase IIb: Dose-seeking study, to test biological activity with minimal side effects.
A combined trial that determines efficacy and toxicity are Phase I/II trials.
Phase III study
These are pre-registration trials, which means that data from this study is submitted to the regulatory agency via New Drug Application (NDA) for registration. Also called premarket or pivotal trials.
These studies are multicenter, randomized, in a large diseased population (more than 500) with a much longer duration of treatment and a short follow-up period, to determine the long-term safety and efficacy of the drug.
Even if regulatory filing is pending, patients are given the drug in the event that it is a life-saving drug until the drug can be purchased.
‘Label expansion’, meaning that the drug may treat an additional disease, other than the disease for which the drug is already approved, may also be the reason for conducting the Phase III trial.
It is said that for the FDA (United States Food and Drug Administration) and MHRA (UK Medicines and Healthcare Products Regulatory Agency) needs at least two trials of data from successful trials to register the drug.
After these trials, the drug is approved for sale on the market.
Phase IV study
These are post-marketing safety monitoring studies conducted after the drug is registered. Also called late phase or confirmatory trials.
This type of study determines long-term adverse effects in a much larger population over a very long period of time (at least 2 years). If harmful effects are found in this study, the drug is disapproved and the company has to withdraw the drug from the market because it can no longer be sold.
The complete journey of the drug from a molecule to a product for sale on the market takes around 15 to 20 years.