Where do the medicines we take from chemists come from? How do the doctors know which drug is good for which disease? How the medicines really are able to cure a particular ailment they have been prescribed for? Do these questions come to your mind, whenever you buy any medicine?
Come, let us today know about the medicine development from the beginning
The development of medicine is called a Clinical Research and has different Phases. Phases of the clinical research are the steps of experiments with a health intervention in an attempt to find enough evidence for a process which the scientists think would be helpful in medical treatment.
The pharmaceutical study starts its journey from a drug design and drug molecule discovery which further progresses into animal testing and then human studies to see the drug’s effectiveness.
Drug undergoes many trials- Preclinical, Phase 0, Phase I, II, III and IV. Sometimes combined trials also are undertaken to reduce the time of development, like Phase I/II and II/III.
When the drug molecule is identified, it undergoes many in vitro (test tube or cell culture) and in vivo (animal) experiments. These experiments are conducted to know the preliminary efficacy, toxicity, and pharmacokinetics of the various doses of the drug. Many drug molecules are designed at a time and these pre-clinical studies let the pharmaceutical companies decide which molecule has a greater potential in further studies.
Design of the Studies:
Trials are always conducted by following the set of steps, called the protocol, developed by the researchers to find the specific questions related to the medical product. Information from the prior studies become the base for the researchers to develop research questionnaire and objectives:
- Participant selection
- Number of participants
- Duration of the study
- Controlled or not
- How and what dosage will be given
- What and when the data will be collected
- Review and analysis time
Phase 0 Study
It is also called micro-dosing trials, 10-15 human subjects are taken and single sub-therapeutic doses are administered to gather the pharmacokinetic (PK) data of the drug. This enables the company in deciding to go or no go for the further development of the drug, based on more relevant human data instead of animal data.
Such trials exceed the speed of promising drug development by establishing whether or not the drug acts on humans as expected in pre-clinical studies.
After the company decides to take the molecule of the drug forward in development, it will have to submit the data of its preliminary studies to the FDA called Investigation New Drug (IND) application filing.
Phase I Study
Also called First-in-man studies as these are the first stage of human testing studies. These are the studies which are designed to determine the maximum dose that can be administered without showing adverse effects.
Contract Research Organizations (CROs) conduct such studies in the clinical trial clinics where medical staff provides full-time attention to 2-100 healthy subjects enrolled for the study and collects the data.
These studies determine the safety (pharmacovigilance), tolerability, pharmacokinetics (PK)and pharmacodynamics (PD) 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 hired but sometimes terminally ill patients like of cancer and HIV and also those who have already tried and failed to improve on existing medications.
There are two divisions for Phase I study:
Phase Ia: Single ascending dose
Phase Ib: Multiple ascending dose
Phase II Study
More than 100 diseased subjects are enrolled for a longer period study, to know the benefits of the drug along with its safety which includes genetic testing. These studies are also called as “Proof of Concept or Pilot” studies.
This is the phase when the drug’s development can fail due to toxicity or less than expected results.
Two divisions of this phase are:
Phase IIa: Pilot study, to determine the clinical efficacy or the biological activity.
Phase IIb: Dose-finding study, to check the biological activity with minimal side-effects.
A combined trial determining the efficacy as well as toxicity are Phase I/II trials.
Phase III Study
These are pre-registration trials means the data of this study is submitted to the regulatory agency through New Drug Application (NDA) for its registration. Also called Pre-marketing or Pivotal trials.
Such studies are multi-central, randomized, in large diseased population (more than 500) with much longer duration of treatment and short follow up period, to determine the long-term safety and efficacy of the drug.
Even if the regulatory submission is pending, the drug is received by the patients in case it’s a lifesaving drug until the drug can be purchased.
‘Label expansion’ that is drug can treat an additional disease, other than the disease for which the drug is already approved, may also be the reason for running the Phase III trial.
It is said that for FDA (United States Food and Drug Administration) and MHRA (United Kingdom’s Medicines and Health products Regulatory Agency) needs at least two trials of successful trials data to register the drug.
After these trials, the drug is approved for market selling.
Phase IV Study
These are Post Market Safety Monitoring studies done after the drug is registered. Also called Late Phase or Confirmatory trials.
This kind of study determines the long-term adverse effects on the much larger population for a very long duration (at least 2 years). If harmful effects are detected in this study, then the drug is disapproved and the company has to retrieve the drug from the market as it can no longer be sold.
The entire journey of the drug from a molecule to a market selling product takes around 15-20 years.