Most people have used prescription drugs at some point in their lives whether it was antibiotics for an infection or analgesics for aches or pains. According to the Center for Disease Control and Prevention (CDC), between the years 2011-2014, approximately 50% of Americans stated that they have used prescription medications within the last 30 days. Among the most frequently prescribed medications are antidepressants and cholesterol-lowering drugs. With the integration of prescription drugs into our daily lives, one cannot help but wonder how these drugs end up on our pharmacy shelves.

The drug development process in America is 10-year, 2.6-billion-dollar venture. Just to clarify and shine light on the complexity of this process, these figures are estimates per drug and not an overall cost of all drugs available on market. The development of a drug goes through various stages of laboratory, animal and human research before it is brought to the Food and Drug Administration (FDA) for review. The FDA divides the drug development process into 5 stages: discovery and development, preclinical research, clinical research, FDA review, and FDA post-market safety monitoring.

In the discovery and development stage, medicinal chemists work with numerous molecules to assess whether the molecule is capable of having the desired effect on an intended target. These targets vary depending on what the drug is envisioned to do and the disease it is meant to treat. Only 1 in every 5,000 molecular compounds actually advances to becoming a drug. During this stage, researchers also study the pharmacokinetic properties of promising compounds, including how they are absorbed in the body, how they are distributed within various body systems, and how they are metabolized and excreted from the body. If the results show promise at this stage, the drug compound will move on to the second step of the drug development process: preclinical trials.

Preclinical trials are tests conducted in petri dishes and on animals to gather more information about the optimal drug dosage, how the drug should be formulated (tablets, capsules, injections, etc.), and to ensure that it does not cause toxicity in recipients. If the compound is found to be non-toxic, the drug company will file an Investigational New Drug application (IND) with the FDA. This application includes the information and data collected about the drug up to this point. Additionally, it will contain protocols or study plans for future research. The FDA will review the IND application and notify the drug company within 30 days of either approval or a hold. If the FDA grants approval, the drug company will proceed to step 3 of the drug development process: clinical research.

Clinical research is divided into three stages and is arguably the most time-consuming and costly phase of the drug development process. The clinical research stage consists of phase I, phase II, and phase III trials, each aimed at understanding different aspects of the drug in human subjects. Human subjects are accepted or rejected for enrollment in the trial based on pre-specified inclusion and exclusion criteria established by the researchers. These criteria are set to ensure that the correct patients are being enrolled in these trials.

Phase I of the clinical research stage recruits a small number of human subjects who do not have the disease that the drug is intended to treat. These subjects are asked to take the drug as it was designed for treatment. The purpose of this phase is to ensure that human subjects do not experience any harm from the drug. Approximately 30% of drugs that reach phase I of the clinical research stage do not advance to phase II, and the project is terminated. If the drug is deemed safe, it will then progress to phase II trials within the clinical research stage.

Phase II trials involve recruiting a small number of human subjects, typically up to several hundred, who have the disease the drug is intended to treat. The aim of this phase is to study the efficacy and safety of the drug in these subjects. This phase can take several years to complete, and only 33% of drugs actually progress to phase III.

Phase III trials within the clinical research stage aim to enroll a large number of human subjects, often in the thousands, who have the illness the drug is intended to treat. The goal of this phase is to study the efficacy and safety of the drug in a large and diverse patient population. It is important to note that if the target disease is rare, these trials may be much smaller in size. For example, the number of human subjects in a phase III trial aimed at studying a new blood pressure-lowering drug will be much higher than in a trial for a drug developed to treat a rare cancer because high blood pressure is more common in the general population than certain types of cancer. Therefore, the number of human subjects recruited for these clinical trials may vary. Approximately only 30% of drugs studied in phase III trials actually progress to the next stage of the drug development process.

If phase III trial results are positive, the drug company that has developed the drug will file a New Drug Application (NDA) with the FDA, thereby initiating stage 4 of the drug development process. The NDA contains detailed information about the drug, including data from the preclinical and clinical research stages. Once the FDA receives this application, a panel of experts will convene to review the application and make a decision regarding the drug’s approval or rejection, a process that typically takes approximately 6-10 months.

The last stage of the drug development process is FDA post-market safety monitoring. By the time a drug reaches this stage, it has already undergone thorough review, been deemed safe and effective, and received FDA approval for consumer use. In this stage, the drug becomes available for healthcare providers to prescribe to their patients. The drug has now reached the intended patient population, and providers are strongly encouraged to report any instances of toxicity or adverse effects that may be attributed to the drug to the FDA. If the FDA identifies a pattern in these reports, it can issue warnings to providers and consumers, modify the drug’s prescribing information, or even withdraw the drug from the market. All of these actions have been taken within the past decade.

When searching for new drugs to treat specific diseases, researchers aim to find the best drug compound and formulation that can treat the disease without causing additional harm to the individual. This is not to say that medications do not have adverse effects, but the art of medicine lies in striking a balance between achieving the desired therapeutic effects while minimizing the risk of negative outcomes for the patient.

Elif Özdener, PharmD