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 able to have the desired effect on an intended target. These targets vary depending on what the the drug is envisioned to do and the disease it is meant to treat. Only 1 in every 5,000 molecular compounds actually go on to becoming a drug. In this stage, researchers will also study promising compounds’ pharmacokinetic properties including how it is absorbed in the body, how it is distributed within various body systems, and how it is metabolized and excreted out of the body. If results show promise in this stage, the drug compound it will move on to the second step of the drug development process, preclinical trials.

Preclinical trials are tests done in petri dishes and animals to gather more information on the best dose of a drug, how the drug should be formulated (tablets, capsules, injection, etc.) and ensure that it does not cause toxicity to the recipient. If the compound is found to not have toxic effects, the drug company will file an Investigational New Drug application (IND) with the FDA. This application includes information and data that has been collected about this drug up to this point. In addition, it will also contain protocols, or study plans, for future studies. The FDA will review the IND application and notify the drug company within 30 days of an approval or a hold. If the drug company receives an approval from the FDA, they will being step 3 of the drug development process: clinical research.

Clinical research is divided into three stages and is probably the most time consuming and costly stage of the drug development process. The clinical research stage is divided into phase I, phase II, and phase III trials. Each of these phases aim to understand different aspects of the drug in human subjects. Human subjects are accepted or rejected from enrollment into the trial based on pre-specified inclusion and exclusion criteria set forth by the researchers. These pre-specified inclusion and exclusion criteria is established to ensure that the correct patients are being enrolled into these trials. Phase I of the clinical research stage recruits a small number of human subjects that do not have the disease the drug is aimed to treat. These human subjects are asked to take the drug as it was intended for treatment.

The purpose of this phase is to ensure that the human subjects do not experience any harm from the drug. About 30% of drugs that reach phase I of clinical research stage do not make it to phase II and the project is ended. If the drug is deemed to be safe though, it will progress to phase II trials of the clinical research stage. Phase II trials recruit a small number of human subjects, up to several hundred, that do 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 human subjects. This phase can take several years to complete and only 33% of drugs actually progress to phase III. Phase III trials of the clinical research stage aim to enroll a large number of human subjects, in the thousands, with the illness the drug is aimed to treat. The goal of this phase is to study the efficacy and safety of the drug in a large, heterogeneous patient population. It is important to note that if the target disease is a rare disease, these trials may be much smaller in size. For example, the number of human subjects in a phase III trial aimed to study a new blood pressure lowering drug is going to be much higher than a drug developed to treat a rare cancer because there are more people within the general population that suffer from high blood pressure than a certain type of cancer. Therefore, the number of human subjects recruited into 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 beginning stage 4 of the drug development process. The NDA contains detailed information on the drug which includes data from preclinical and clinical research stages. Once the FDA receives this application, a number of experts will gather to review the application and decide whether the drug will be approved or rejected which takes approximately 6-10 months.

The last stage of the drug development process is FDA post-market safety monitoring. By the time a drug gets to the last step, it has already been reviewed, deemed safe and effective, and approved by the FDA for consumer use. In this stage, the drug is now available to providers to prescribe to their patients. The drug has now reached the intended patient population and providers are high encouraged to report any toxicity or adverse effects that could be due to the drug to the FDA. If the FDA detects a pattern in these reports, it can issue a warning to providers and consumers, dictate a change in the drug’s prescribing information, or completely remove a drug from market, all of which have been done within the past decade.

When searching for new drugs targeted to treat certain diseases, researchers are trying to find the best drug compound and formulation that will treat the disease without causing the person additional harm. That is not to say that medications don’t cause adverse effects but the art of medicine is in finding a balance between ensuring positive drug effect while reducing the risk of negative adverse outcomes to the patient.

Elif Özdener, PharmD