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Drugs are one of the most important if not most important aspect of the pharmaceutical world. However, these drugs don’t simply burst onto the scene out of nowhere. There is a long drug discovery process that takes place before the drug is allowed anywhere near the pharmaceutical world. All the drugs that are currently in the pharmaceutical world, they take on average a decade to make.
However, not all drugs make it through, in fact, only 5 out of 5000 preclinical drugs make it into the pharmaceutical world. However, it doesn’t end there, the drugs must be approved by the FDA and on average, only 1 of these 5 drugs are approved by the FDA. The success rate of these drugs are very low, hence why brand name drugs are always so expensive.
Phase 1: Drug discovery
Step 1: Target Validation
The first step is really rough work where the target gene or protein must be chosen. This is the molecule that the drug will primarily target. However, this is not only the thing that is done during this step. The drug developer also must make sure the protein/gene they have selected will actually target the disease that is in concern.
To do this, a rigorous screening process is done to make sure the protein or gene they have identified is the one that interacts with the disease in question. This screening method includes functional genomics or proteomics. In these, they are essentially looking at the functions and interactions of the chosen gene.
Step 2: High Throughput Screening (HTS)
In this step, the scientists are using this screening method to help identify active compounds, genes that are directly linked to the human molecules. They do this to make sure they are dealing with the right molecule from the start.
Step 3: Hit to Lead (H2L)
In this step, the small molecules that hit in the previous step are analyzed and evaluated to find some promising compounds that could be the lead compounds in the drug they are trying to discover.
Step 4: Lead Optimization (HO)
This step and the last step go hand in hand. In this step, the lead compounds that are discovered in the H2L step are then synthesized to help increase the strength and reduce the side effects of the drug. In this step, the lead optimization is tested on animal efficacy models for designing the drug candidate. The animal models that are used are mostly mice and rats. They are used as the testing is primarily done for safety.
Phase 2: Preclinical Research
This is a rather short phase as the scientists have to simply test the safety of the drug on animals before they can move onto clinical trials where they test these drugs on actual humans.
However, it isn’t that simple. There are many different types of preclinical research. The first one is pharmacodynamics, this is research is done to see what the drug will do to the body. The drug that is created won’t just target the 1 main molecule that has been chosen, but it will interact with other molecules throughout the body and this must be done to ensure the side effects aren’t too harsh.
The second type of research is pharmacokinetics, this is what the body will do to the drug once it enters the body. It’s mostly the movement of the drug throughout the body. How long the drug it takes the drug to be excreted. Some of the other things include absorption, bioavailability, distribution and metabolism. These are the main functions that are analyzed and evaluated in this step.
The third type of research is abbreviated into ADME (absorption, distribution, metabolism, excretion). These 4 factors describes the disposition of the drug in an organism, in this case the organism is the human body. This research is done to see the impacts and possibly rule out possible weak drug candidates.
The fourth and last type of research that is done is toxicology testing. This is the safety test that is done. It helps determine the negative impact the drug will have on all the organisms’ biological functions. These tests are done primarily on an animal and the results are converted to understand the risks for human subjects.
Once all the research and tests have been conducted, scientists are then able to come up with a safe amount of dose for the clinical trials on the humans. The main purpose of this phase is to ensure that the drug they have chosen is safe and can be delivered to humans without any severe damage to their core biological functions. One important thing to note is that the FDA has to approve of the drug so lots of testing must be done to prove to the FDA that the drug they are producing has potential.
Making it past this stage is very rare, only 12% of drugs make it past this stage.
Phase 3: Clinical Trials
Step 1: Clinical Trials I
In the first step of the clinical trials for these drugs, the new drug is initially tested on 100 or less healthy patients. This is done to ensure that the drug that they are testing is safe.
However, this phase also includes some carcinogenicity testing on mice. More specifically, they test on a mouse animal model called the Tg rasH2 mouse. It is used to help predict the potential of the drug to cause cancer in the patient. The mouse contains a human copy of a gene in it called the c-Ha-ras oncogene and this helps the scientists to measure the severity of the drug to ensure that the humans don’t contract cancer from the consumption of the drug. This step usually takes around 6 months to complete.
Step 2: Clinical Trials II
In the second phase of clinical trials, the amount of patients increases in size to a group of around 100 to 500. The important thing to note is the patients that are chosen are diagnosed with the disease that the drug is targeting.In this phase, they are testing the effectiveness of the drug. However, that is not the only thing that is tested. They also test for adverse events, side effects and efficacy. Throughout this testing, the ideal dosage and how often each dose is taken is also determined during this phase.
Step 3: Clinical Trials III
In the third phase of clinical trials, the number of patients are once again increased significantly to a size around 1000–5000 patients to generate a large sample of statistical data. Only 12% of drugs make it past this stage as a lot of factors have to be taken into consideration. These factors include safety and efficacy. If the drug does make it past this stage, the data collected is then used to label the prescription in the future.
Phase 4: FDA Review and Approval
Once the drug successfully makes it past the clinical trials, a NDA (new drug application) is then submitted to the FDA so it can reviewed and approved. The document that is submitted is a summary of the clinical trials, it discusses how the trials showed that the drugs safety and efficacy. This document is full of data and all the information that has been noted down from all 3 phases of the clincial trials. This information includes all phases and studies, clinical results, safety precautions and interactions with other medicine.
The purpose of this is to make sure the benefits of the drug outweigh the risks (side-effects) that come along with the consumption of the drug. Some drugs are often giving priority over other drugs. A drug that addresses a disease that no other drug does will be given priority over a drug that is very similar to a drug that has already been in the market. These drugs are fast-tracked as there is a need of those drugs in the market. The review and approval process can take a lot of time, on average 6–10 months.
If the drug does get approved, the labelling process begins. This is the beginning of prescribing information that is in all of the prescription medications.
However, it is very possible the drug fails at this stage as well. There are many reasons for why the FDA would reject ones NDA. There are a total of 3 main reasons why the FDA might reject ones NDA.
- Toxicity: If the toxicity of the drug is too high in human or animal tests then drug may be rejected because of the safety issues surrounding the drug
- Efficacy: If a drug’s efficacy isn’t high enough, the FDA will reject the drug
- Inadequate Drug Performance: If the new drug delivers the desired result but just barely, then the FDA will reject in the hope that a new drug can deliver the desired result to a better degree.
Phase 5: Post-Approval, Research and Monitoring
This last phase never truly comes to an end as the drug reaching the market is not the final stage. The drug is constantly monitored once it enters the pharmaceutical world. There is a lot of data that is obtained from this phase such as serious side effects, interactions with other drugs, alternate uses, and modifications to the amount of dosage.
These 5 phases are needed in order to get a new drug into the pharmaceutical world. This applies to our current pandemic situation in the search for a vaccine to help counter Covid-19. At the moment there are 44 vaccines that are trying to get approved, however these 44 vaccines are split across the many stages we talked about.
In the diagram above, it shows where each vaccine lies. Let’s take a deeper dive into some of the vaccines that are currently being tested for early and limited use.
Vaccine #1: Wuhan Institute of Biological Products
This institution have developed an inactivated virus vaccine. They have ran through all the clinical trials, in the first and second trials, they were able to conclude that the vaccine is able to produce antiboides in the volunteers who have been showing some basic symptoms. Since this, they have went into the third stage and the government eventually gave them approval to inject thousands of people with the experimental vaccines they have during the summer. They have 2 experimental vaccines and recently on Sept. 14th, the U.A.E. gave them approval to use the vaccine on health care workers. There is more to follow if the vaccine does get past this experimental stage.
Vaccine #2: Sinovac
This is a chinese company, Sinovac Biotech and they are testing an inactivated vaccine which is called CoronaVac. In phase 1 and 2 trials, they were able to test more than 700 patients without any severe side effects. They were able to produce an immune response. Since then, they have performed 3rd stage trials and ion Sept. 16th, they were able to do a trail of the vaccine for children. An agreement has been made to supply Indonesia with around 40 million doses by March 2021. The CEO of the company has said that there will be a global distribution of the vaccine in early 2021.
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