Drugs are widely used in the treatment of diseases or for the promotion of healthy wellbeing. Hence, a drug discovery program is often driven by clinical needs such as the emergence of a disease that doesn’t appropriate medical intervention protocol.
Though, did you know - it typically takes between 12 to 15 years to discover and introduce a new drug into the market. Additionally, it costs more than two billion US dollars for a new drug to actually reach the pharmacy shelf.
At this point, most of us would probably be asking - why does the process take such a long time and require a huge sum of investments?
In essence, drug development is a complex and rigorous process as we need to ensure the safety and efficacy of all the drugs that are approved for commercialisation. To begin with, there are five critical stages that underpin the drug development process, namely:
1. Early drug discovery and development
3. Clinical trials
4. Review by the FDA
Each stage can be broken down into several phases, and they will all be discussed in greater detail to give you a better understanding of the entire development process.
Figure 1: A summary of the five crucial steps during the drug development process and the approximate timescale for each stage.
Stage 1: Early drug discovery
Target discovery and validation
Most drug targets are genes or proteins whose inhibition or activation results in therapeutic effects in a disease state. Therefore, the purpose is to identify which genes or proteins are more relevant to the disease and also confirm their roles in disease.
A good target should be safe, effective, and accessible to the putative drug molecule. These days, bioinformatics approaches are widely employed in the target identification process through the data mining of the available database. Besides that, pathway analysis, genetic association studies, and phenotypic screening may serve as alternative approaches in the target discovery process. Once a candidate target has been identified, further validation is required before proceeding to the candidate drug discovery step.
A range of target validation techniques are used, both in vitro (i.e. studies performed on cells or molecules outside their normal biological context; in test tubes) and in animal models. This includes signalling pathway analysis, protein interaction analysis, and disease association studies. A multi-validation approach is often applied to increase the confidence of observed outcomes.
Candidate drug discovery
Following target validation, compound screening assays such as high-throughput screening (HTS) and fragment-based drug design are developed to identify molecules that interact with the drug target, which is known as a hit.
Following that, the small molecule hits from the screening assay will be evaluated and optimized to identify the lead compound during the hit to lead (H2L) phase. The lead compounds, which have an activity that is likely to be therapeutically useful, would then move on to the lead optimization phase, in which they are modified and refined to improve their safety and efficacy (while maintaining their desirable properties).
After the final characterization, the lead compound could then eventually become a preclinical drug candidate.
Stage 2: Pre-clinical research
Preclinical studies on animal models are required for adequate safety and efficacy information before moving into clinical trials in humans.
A wide range of doses of the drug is tested both in vitro and in vivo (i.e. studies performed within whole and living organisms). Additionally, in silico assays (i.e. performed on a computer) based on computational simulations are becoming increasingly popular in drug development.
The two major preclinical studies are animal pharmacology studies and toxicology studies. In particular, pharmacology studies reveal the pharmacokinetics (what the body does to the drug) and pharmacodynamics (the effect of the drug on the body) of the candidate drug.
In essence, the drug must have the required pharmacokinetic properties such as absorption, distribution, metabolism, and excretion by the body (these are abbreviated as “ADME”). Pharmacodynamics, on the other hand, reflects the efficacy and toxicity of the drug on the body by recording the body’s response to different doses of the drug. In this scenario, toxicology studies are applied to investigate whether the drug exhibits acute toxicity (short-term), chronic toxicity (long-term), or reproductive toxicity (i.e. potential adverse effects on a person’s reproductivity ability).
In pre-clinical studies, the best method for drug delivery needs to be selected from several routes of administration, such as intravenous injection or oral intake topical delivery (just to name a few). This is really important as there might be physiological barriers in our body that prevent drugs from reaching the target region (e.g. the blood-brain barrier). Therefore, it is essential to choose an appropriate delivery system in order to ensure that the drugs released to the target area have no negative impacts on the healthy tissues and organs.
Bioavailability, which represents the proportion of drug dose that reaches the systemic circulation, is another factor that needs to be considered in preclinical research. It is potentially affected by both pharmacodynamics and administration routes. For instance, an intravenously injected drug is likely to have higher bioavailability than an orally delivered drug since the oral drug needs to be absorbed and metabolized before entering the blood.
The package of collected data from pre-clinical studies would then be submitted for Investigational New Drug (IND) application before the first human exposure. Not to mention, even after IND approval, non-clinical toxicology studies may still be carried out during the clinical phase to evaluate long-term toxicity.
Stage 3: Clinical trials
The candidate drug typically undergoes three phases (four, if you were to count a newly introduced “phase 0”) of clinical trials prior to getting approved by the US Food and Drug Administration (FDA).
Phase 0
In Phase 0, which is also known as human microdose studies, a single sub-therapeutic dose (i.e. a dosage that is too small to achieve therapeutic effects) is given to a small number of subjects - usually around 10 to 15 people - to provide pharmacokinetic data.
Although this is not a mandatory procedure, it allows pharmaceutical companies to decide which of the candidate drugs has the best pharmacokinetic parameters in humans.
Phase I
The primary goal of this phase is to assess the safety and tolerability of the candidate drug. In other words, it allows the detection of the highest dose humans can take without severe side effects. Pharmacokinetics, pharmacodynamics, and administration routes are also monitored in this phase.
Phase I typically takes several months where approximately 70% of the drugs successfully proceed from phase I to phase II. This phase of the clinical trials would usually be performed on 20 to 100 healthy human volunteers. In particular, patients with conditions will only be involved in phase I if the drug causes serious consequences in healthy people.
Phase II
Phase II is carried out in 100 to 250 patients with the target disease to evaluate the efficacy and the optimal dosage of the drug. Safety and side effects are continually monitored as this may be different in patients compared with healthy volunteers tested in phase one.
Meanwhile, phase II is commonly divided into phases IIA and IIB, whereby phase IIA specifically focuses on dosing requirements whereas phase IIB is designed to assess drug efficacy at the prescribed dose.
After several months or years of phase II studies, about 30% of drugs would successfully proceed to phase III studies.
Phase III
The purpose of Phase III trials, which has a longer duration of up to several years, is to monitor the long-term side effects and to compare the efficacy to existing drugs. Phase III involves randomized control trials where patients are randomly assigned into two groups: the experimental group receiving the candidate drug and the control group receiving conventional medication.
In addition to that, phase III trials are typically double-blinded. This means that neither the patient nor the researcher knows which drug was taken. Therefore, this method contributes to the reduction of bias when interpreting the results. Following that, the data from phase I and phase II ought to demonstrate evidence supporting whether or not to continue the development of the drug in larger clinical trials (which consist of up to 3000 patients).
Stage 4: Drug review by the FDA
Every new drug needs to get approval from the FDA before it can be introduced to the market. With that in mind, safety and efficacy data from all stages of preclinical trials and clinical trials need to be collated into a file for a new drug application (NDA), which is then submitted to the relevant regulatory authorities.
Once approved by the FDA, the drug can then be launched on the market. Statistically speaking, approximately 25 to 30% of the drugs in phase III will be approved by the FDA and released into the market. Furthermore, the data of the drug will be compiled into a file and customized for different regions around the world to meet the requirement of local health authorities, which ensures patients all over the globe can access the newly discovered drug.
However, this is not the end of the story!
Stage 5: Post-market surveillance
After the product has been released into the market, drug safety monitoring still continues. This is also known as phase IV trials where additional safety and efficacy data of the drugs are gathered after it is used by a large population with a wide range of medical conditions over a longer period of time.
Basically, drug companies are required to use the FDA Adverse Event Reporting System (FAERS) public dashboard to report post-authorization safety updates and any other additional information at defined intervals as long as the drug remains on the market. This highly interactive web-based tool allows the general public to acquire information about the drug. There is a possibility that the drug would be recalled from the market if potential safety risks are detected.
In fact, it might be worthwhile for you to know that actually - only 70% to 90% of launched drugs manage to stay in the market!
Some final notes
As implied in this article, modern drug discovery is a commercial process that involves complex cooperation between industry, academia, investors, regulatory authorities, marketing, and many other stakeholders.
Despite the great advances already made in technology, drug discovery and development is still an expensive and lengthy process. Additionally, although medicines could help to treat diseases and improve health, they don’t always have positive effects. In other words, all the drugs, both over-the-counter (OTC) and prescription, may have potential side effects. So, the use of drugs is justified when the benefits outweigh its risks. Thus, moving forward, it is crucial that you always follow the directions and speak to your doctor before taking any type of medication.
Author
Helen Luojia Zhang
BSc Biochemistry
Imperial College London