Clinical trials: How do medications reach the patient population?


By Tré LaRosa
NeuLine Health


The process of researching and understanding any disease requires those researching the disease to have a strong grasp of the scientific process. This is why researchers go through extensive academic training followed by apprenticeships in the laboratory or field where they can begin to consolidate their fundamental understanding of the subject combined with the on-the-ground training. Those with doctoral degrees go through this training in a structured manner, but anybody who wishes to understand a subject uses these strategies — the scientific method — to glean a deeper understanding of the topic of choice. This approach, the scientific method, is also the framework by which compounds go from compounds of interest to prescribed medications.

In this blog, we’re going to look at the drug development process from the early lab drug development to ongoing monitoring of safety and efficacy once a drug has been approved by the FDA.

Discovery & Development

The first step of this process is the discovery and development phase where researchers work to identify a compound of therapeutic interest.

Compounds that could eventually become medications are found in a variety of ways. In some cases, researchers discover something previously unknown about a condition and its processes that might reveal a new method of treating a disease. For some diseases, where the etiology (the cause or set of causes for a condition) is still not fully understood, a recently understood aspect of the etiology might open up a new approach to treating or curing a disease.

In other cases, clinicians will learn that another medication might have unintended benefits, thus allowing for an already-approved medication to be repurposed for another condition. The classic example is sildenafil, or Viagra, which was originally designed to be an anti-hypertensive, but has also been approved to treat erectile dysfunction and pulmonary arterial hypertension. The opportunity to repurpose drugs to treat multiple conditions is especially incentivizing since the median cost to develop a drug is $374 million] and the mean amount of years was 8.3 years.

There are also assays used in what’s called high-throughput screening where thousands or millions of compounds can be screened against a large number of diseases to predict potential therapeutic benefit.

Most of the compounds that are evaluated are found to be unlikely to produce therapeutic benefit, but for the compounds found to be promising, researchers will begin evaluating how the compound is absorbed and metabolized, its mechanism of action (how it might work), dose ranges, best method of administration, side effects, toxicity, and more. The compound is also compared to other drugs that might work similarly to evaluate how it compares. From the beginning of the drug development process, researchers are already trying to understand the extensive implications the compound might have in a human population.


Once researchers understand a compound well enough and the evidence suggests it might be more than just promising, the compound reaches what’s called the preclinical phase.

No medication ever reaches the patient population without extensive testing, even after it’s designated as a compound of interest. This requires extensive preclinical testing in cell cultures that act as surrogates for humans — called in vitro research — and animal models — chosen specifically to be the most effective surrogates for humans — where dosing, administration, toxicity, efficacy, and more can be thoroughly evaluated.

The FDA itself emphasizes an important note here: “Before testing a drug in people, researchers must find out whether it has the potential to cause serious harm, also called toxicity.” This point can’t be overstated. This process of evaluating a compound during the preclinical stages is specifically designed to use models, both in cell cultures and animals that act as strong surrogates for humans, to understand both the etiology of a condition and the way a medication affects the models.

For in vitro research, scientists have laboratory models like cell cultures where they can measure the effect a compound has on the cellular response. They perform extensive experiments to ensure reproducibility and accuracy of their data. From there (or sometimes concurrently), research usually moves into animal models, called in vivo research. These animal models are designed to mimic the specific diseases. In the case of mice models, Jackson Laboratory, a global leader in mouse models, notes the reason mice are so effective is because they “can be genetically manipulated to mimic virtually any human disease or condition.”

These models are critical as they help to ensure a range of dosing to better understand potential benefits and the degree by which a compound becomes toxic in mice, which can be extrapolated to predict the level a compound might also be toxic in humans. First-in-human trials are usually dosed at a fraction of the dose which produced toxicity in mice to ensure low doses are the first evaluated in humans.

The FDA also has strict minimum basic requirements for governing study conduct, personnel, facilities, equipment, written protocols, operating procedures, and more. The well-being of the mice is important to researchers.

Phase 1

In clinical trials, it’s of vital importance to ensure that the effects — both positive and negative — seen in the trial participants are due to the compound itself and not other confounding factors. To control for this, participants are usually randomized into two groups: the placebo group and the experimental group. The experimental group receives the compound of interest and the placebo group receives a compound that looks identical to the compound of interest but is actually an inert substance. They are also randomly selected for either group and neither the participant nor the team administering the clinical trial knows which group received which. This is what’s called a randomized, double-blind, placebo-controlled clinical trial and it is the most common type of clinical trial. All participants are closely monitored so they can stop taking the intervention the second they develop any serious adverse effects.

Phase 1 clinical trials, whose primary purpose is evaluating safety and dosage, consist of a small group (20 to 100) healthy volunteers or with the disease. The length of these studies usually last several months and the researchers spend this time gathering information to understand the pharmacology and pharmacokinetics of a given compound. Researchers also use this time to better understand and hone dosing regimes. They usually dose up to understand when compounds begin to cause benefits and side effects.

The FDA reports that approximately 70% of phase 1 clinical trials lead to phase 2.

Phase 2

Phase 2 clinical trials are where we start to get a better understanding of how much a drug might actually help the prospective patients. Side effects are still a key part of phase 2 clinical trials, but their other primary purpose is to evaluate efficacy.

Phase 2 clinical trials usually consist of several hundred people with the disease and last for months to 2 years. This is where there is a large drop-off in the advancement of compounds; the FDA says only about a third of phase 2 clinical trials result in phase 3 trials.

Phase 2 clinical trials themselves aren’t enough to grasp the full scope of benefit and effects for a medication, but they do provide significantly more safety data, as well as a good amount of data to help determine what the most effective outcome measurements, also known as endpoints, will be used in the large-scale, more time-intensive phase 3 clinical trials.

Phase 3

The FDA provides a short, important overview of the importance of phase 3 clinical trials:

“Researchers design Phase 3 studies to demonstrate whether or not a product offers a treatment benefit to a specific population… Phase 3 studies provide most of the safety data. In previous studies, it is possible that less common side effects might have gone undetected. Because these studies are larger and longer in duration, the results are more likely to show long-term or rare side effects.”

Phase 3 clinical trials usually enroll anywhere between 300 to 3,000 volunteers with the disease, and these trials last between 1 and 4 years. It is also important to remember that even though all phases of clinical trials might have people with the disease, there are always experimental and control arms; also, some study designs might allow for multiple compounds to be evaluated independently and concurrently which might result in more experimental arms.

Approximately a fourth to 30% of compounds that conclude a phase 3 trial will advance to FDA drug review upon a New Drug Application (NDA) submission.

FDA Drug Review

Once all the preclinical and clinical trials data are concluded, the developer of the compound then puts together what’s called a New Drug Application (NDA). The purpose is to encapsulate all the data for a given drug and to demonstrate that a drug is safe and effective for its intended use in the population studied. Quite a bit of information is included in the NDA: all of the data from preclinical up until phase 3, all reports on studies, data, and analyses, proposed labeling, safety updates, drug abuse information, patent information, directions for use, and more.

The FDA first must confirm the NDA is complete with all requisite data and information, but once the FDA has confirmed all the data, the FDA review team has six to ten months to review the application. In some cases, a therapeutic might be given a specific status like “breakthrough therapy,” “accelerated approval,” “priority review,” and “fast track.” These designations alter the process for compounds that are more therapeutically relevant and dire for the patient community.

The FDA review team evaluates all the relevant information included, where they then decide whether or not the drug is safe and effective for its target population. It’s at this point the FDA then works with the drug developer to appropriately label the medication during the labeling process.

Phase 4 & Post-Marketing Studies

Once a compound received FDA approval, there are phase 4 clinical trials to ensure compounds are continuously evaluated for safety and efficacy. While the FDA approval process is rigorous, extensive, and time-consuming and is very good at determining the safety and efficacy of drugs, it is impossible to fully determine a medication’s scope of safety and efficacy. For this reason, the FDA monitors adverse effects of patients on medications once medications have been fully FDA-approved. Patients are encouraged to report any and all side effects of medications to their care teams, primary and specific to their chronic conditions. Patients can also report any problems they have with drugs and devices at MedWatch. This reporting mechanism is utilized to continually evaluate any and all medications that patients are taking.


This process of first identifying agents of interest all the way to continually evaluating the effects a medication has in humans is, like all research, an example of the scientific process. In this process, hypotheses are proposed, science experiments are designed, results are analyzed, subsequent experiments are designed to ensure reproducibility to ensure the first experiments weren’t outliers, and on and on. This process, with its many checks and balances, can be deeply frustrating as a researcher since so often experiments produce evidence that the agents of interest are, unfortunately, not that interesting; but science, in its self-correcting and self-calibrating way, does a great job of producing legitimate theories that are either supported or rejected by the overall body of science.

It should also be noted that often many labs or organizations are researching similar subjects which promotes a culture of openness and accuracy as scientists strive to produce good science; the peer-review process also helps to evaluate and ensure good science is being done.

Like all things, this is not perfect; peer-review papers get retracted after new evidence comes to light, but this is incredibly rare. Only about 4 of every 10,000 articles, or 0.04%, are retracted. But not every paper that is retracted is due to deliberate fraud or unethical data fabrication. Sometimes, papers are retracted due to genuine error.

The drug development process, from early identification of interesting agents to the use of medications in large patient populations, requires rigorous scientific and medical investigation. While this process isn’t perfect, it’s very good at producing good, effective, safe medications.

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