Bringing a drug to market is an arduous process that most consumers are oblivious to. The cost to develop a single drug can exceed $2 billion and takes an average of ten years.
The first step in the process is target identification. Once a target has been identified, researchers screen thousands of compounds for their ability to interact with that drug target.
Discovery
The discovery phase is the first stage in the drug development process. It involves scientists identifying and optimizing drug compounds that can elicit an effect on a specific biological target implicated in a disease, in the hopes of treating the condition. This work is conducted in the laboratory using in vitro and animal models.
During the discovery phase, researchers are often eager to learn new scientific findings that may provide potential leads. However, the discovery phase is notoriously long and expensive. By some estimates, it takes up to 5 years and $200 million to winnow down a lead compound from tens of thousands of candidates. The attrition rate is also high, with many molecules failing in later preclinical and clinical studies due to unacceptable toxicity or lack of market attractiveness.
Research during the discovery phase is performed in several ways, including scouring scientific literature and searching available databases for targets relevant to a particular disease. It’s important to note that a molecule will only be considered a “good” candidate for drug development if it has sufficient clinical utility and is a “druggable” target – i.e., it can be effectively altered by a therapeutic agent.
Researchers also carry out a wide variety of studies to confirm that they have identified the appropriate biological target. This is an essential step in the process because it’s important to ensure that the target is relevant to the disease and that it can be successfully modulated by a small molecule or biopharmaceutical.
A key factor in determining success rates during this phase is academic-industrial collaboration. Studies have shown that when scientists collaborate with their counterparts in industry, they achieve higher preclinical and clinical success rates. This is particularly true for targets that are difficult to develop drugs against, such as proteins or RNAs. These higher success rates can be attributed to the fact that scientific knowledge and technological expertise are transferred between teams, which helps improve the quality of the final product. In addition, industrial partners can also help identify and solve technical obstacles that could otherwise halt progress.
Preclinical Testing
During the preclinical testing phase, scientists work to translate research findings into actual drugs. They do this by identifying drug targets and performing so-called in silico — computer – testing on hundreds or sometimes thousands of chemical and biological compounds to determine which have the ability to interact with those targets. The goal is to find “hits” that will treat the target.
If the hits are promising, researchers will take them to the next stage of preclinical development. This phase involves determining whether the compounds have pharmacology (the study of how drugs act on biological systems) and ADME — absorption, distribution, metabolism, and excretion — properties. In addition, they must also ensure that the compound is safe to use in human subjects.
The pharmacology stage also uses human and animal models to test potential drugs for efficacy or how they will act on the target. These tests are typically so-called pharmacodynamic models that measure drug concentrations in the body to identify therapeutic effects. A key part of the pharmacology study is a drug’s bioavailability, which refers to the amount of the compound that enters the bloodstream.
In addition to assessing the target, the pharmacology study will also evaluate how the drug is distributed throughout the body and the interactions with other medications. This information is critical for the next step, which is the development of a pharmaceutical formulation that is both potent and stable.
Once a formula has been developed, it must be produced in large quantities for clinical trials. The preclinical process development group figures out how to make the drug at a high enough level to support human studies and does so while adhering to GMP or good manufacturing practices.
During the preclinical testing phase, it is important that researchers mimic what will happen to patients with the disease who are treated with the new drug. For example, neurodegenerative diseases are progressive, so it is important to test the new drug over a long period of time to see if it can slow or reverse the progression of the disease.
Clinical Trials
Scientists test potential drugs on humans to see if they are safe and effective in treating a disease. During clinical trials, participants may receive an experimental drug or a placebo. If the drug is found to be safe and effective, it will be approved for market use. The FDA requires that clinical trials be conducted on people of different ages, races, and ethnicities to make sure that the results are generalizable to the population.
Getting a new drug to the clinical trials phase takes a lot of work and research. On average, about 1,000 potential treatments are tested in labs before just one makes it to this stage.
During the clinical trials phase, scientists will also study how the body absorbs the drug, its blood levels, and whether it can cause side effects. The drug development team will also need to develop a pill that is easy to swallow and take. The pill must be able to remain stable in a wide range of conditions, including temperature and humidity. In addition, the drug must have a good shelf life and be resistant to degradation from sunlight and chemicals.
Another important aspect of the clinical trial process is making sure that only healthy people participate in the studies. This is done by selecting individuals who meet specific criteria, such as age, sex, medical history, and other health conditions. These criteria are called inclusion and exclusion criteria. Scientists will also try to find ways to predict which patients are likely to respond well or poorly to a particular treatment. This can be done by using new data-rich technologies, sometimes called “-omics.”
During the early phases of the clinical trials phase, researchers will usually conduct several phases, each designed to answer certain questions about the safety and effectiveness of a potential drug or treatment. Each phase will usually include a smaller number of patients to limit the risk to those participating in the trial. Depending on the outcome of these trials, the drug developer will decide to move forward or discontinue its research efforts.
Market Approval
When all testing is complete, and the drug has been deemed safe, the pharmaceutical company can apply to market it. This requires them to submit an extensive documentation package to the approval authority. This dossier contains the results of the preclinical and clinical trials. It also includes the drug’s chemical structure. Once the dossier has been submitted, the official from the drug’s regulatory body will work with the pharma company to refine the drug information, such as how it should be used.
This process is highly regulated by the regulatory bodies, which ensure that only safe drugs with a good risk-benefit ratio are approved for the market. The drug’s effectiveness is taken into account in the ‘benefit/risk’ analysis, as well as the severity of the disease and side effects of the drug itself.
However, despite the recent increase in R&D spending by the pharmaceutical industry, the rate of new drug introductions has not increased. The reason is that the increase in new drug introductions is due to a rise in the number of compounds reaching the clinical trial phase, not because they are improving existing medicines in an innovative way.
In fact, only one in 10 of the compounds that reach the clinical trial phase will be successful. The attrition rate is even higher when it comes to drug candidates that make it to the final clinical stage. This is because the termination of a project at this stage has a significant financial impact on shareholders.
In an effort to streamline the process, some agencies like the EMA have implemented a system called adaptive licensing whereby a drug is first approved for a restricted group of patients (e.g., a specific age range or disease stage) based on strong trends for clinical benefit, with the promise that additional data can be collected and the risk-benefit ratio re-evaluated to broaden its scope. Adaptive licensing, in conjunction with a shift towards more transparent and trustworthy evaluation criteria, can help improve the overall quality of drug development.