Understanding the Process and Importance of Clinical Research

By: Mardi Gomberg-Maitland, MD, MSc

Professor of Medicine, VCU School of Medicine
Director of RV Failure, HFpEF, and Cardio-Oncology Programs
Co-Director of the Pulmonary Vascular Disease Program
Inova Heart and Vascular Institute
3300 Gallows Road
Falls Church, VA 22042

The goal of a clinical trial is to develop safe and effective therapies efficiently. Early in development, investigators need to learn about the pros and cons of the drug in order to prepare for upcoming phases and determine if the drug is a worth pursuing. With an orphan disease such as PAH, participation in early clinical trials and during the later pivotal studies is important as without patient participation new therapies can not be approved.

Preclinical Phase

Prior to initiation of clinical trials in humans, it is essential to assess both the safety, pharmacology and biologic properties of the drug in preclinical models of the disease. Scientists use animal models: rats, mice, dogs, etc. to learn about the mechanisms of disease to help target potential new therapies. Although many times these trials do not always guarantee that the mechanism will be similar in people, they are an essential step in the drug development process. After an understanding of the pharmacology and safety are well assessed in these models one precedes to a phase I trial.

Phase I Trials

Phase I trials are small trials done to test the safety in people, usually in normal healthy volunteers. It is also important to determine safety and dosing in PAH subjects as this may differ considerably. Often PAH patients respond differently and it is important to assess safety of the new drug in addition to medications that patients are all ready receiving. This is essential for phase II.

Phase II Trials

Evidence that the drug helps patients and a better understanding of final large scale clinical trial is the goal of a phase II trial. The design is dependent on quality and adequacy of the preceding phase I trial and typically a range of doses is tested. For PAH studies, previous trials have used improvement on the six minute walk but current trials are utilizing heart catheterization pressures and function of the heart (blood flow), time to clinical worsening (hospitalizations, worsening exercise capacity, survival). Phase II trials if tremendously successfully can lead to approval but usually will result in a Phase III trial to confirm results.

Phase III Trials

Phase III trials establish both if the drug helps patients. This trial is usually a trial compares the study medication to a placebo (a pill that does not work). The trial may be larger, longer, and include a more diverse group of patients compared with a phase II design.


If a new therapy that appears safe and important in PAH in animal models, the timeline for the next 3 phases is not trivial. Unless the medication is a true blockbuster, curing the disease, or demonstrating remarkable improvements, each phase has the potential to fail based on safety or lack of efficacy. Each phase will be limited by patient study enrollment and organizational trial design. Single center phase I trials of 10 patients can take over a year to enroll. Phase II which is typically multicenter averages 1-2 years dependent on the enrollment criteria and sites chosen for participation. Most Phase III trials enroll over several years before the data is tabulated. This is added to the time needed to submit the findings to the FDA for approval. The overall process can take anywhere from 4-10 years.

Participation in clinical trials is most important in an orphan disease. Without this the field can only advance on the scientific level but patients won’t ever get to use new therapeutics.