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Working in Early Clinical Drug Development


From an early point in my education, I was attracted to the medical sciences. After I completed a degree in medical biology, I spent several years obtaining a Ph.D. in a preclinical setting investigating neuroendocrine responses to stress. Although this research involved animal models, it paralleled many pathologies in humans. I became increasingly interested in human pharmacology, and in the end I decided to move into applied clinical science.

For several years now I have been working at the Netherlands' Centre for Human Drug Research (CHDR). This institute was founded in the 1980s by the present dean of Leiden University, Douwe Breimer, to improve clinical pharmacology and drug development. Because CHDR still has close links to Leiden University and the Leiden University Medical Center, and because it collaborates with many pharmaceutical companies, it provides an ideal environment for performing innovative clinical drug research.

What I enjoy most about clinical research at CHDR is early clinical drug development (traditionally described as phase I and II; see box) involving many compounds with new or more targeted mechanisms of action. Working with such compounds often means that testing these new drugs requires methodological innovation. For instance, how does one evaluate the action of new antithrombotic drugs that only act on specific coagulation factors, whereas current antithrombotic drugs may act on multiple coagulation factors? In this example, new drugs may be just as effective and perhaps even safer without showing efficacy in traditional tests.

How are experimental drugs tested in humans? The process of turning a new compound into a safe, efficient, and marketable medicine is normally lengthy (10 to 12 years), costly (several hundred million dollars), and commercially risky (only one potential drug out of 10,000 will move into and survive extensive testing in the research and development phase). The clinical testing of experimental drugs is normally done in three phases, each successive phase involving a larger number of people.

Phase I studies are primarily concerned with assessing the drug's safety. This initial phase of testing in humans is done in a small number of healthy volunteers (20 to 100). The study is designed to determine what happens to the drug in the human body and to investigate side effects that occur as dosage levels are increased. This initial phase of testing typically takes several months. About 70% of experimental drugs pass this initial phase of testing.

Phase II involves clinical studies on a few hundred volunteer patients to determine the appropriate dose and learn about the activity of the product against the disease. Under certain circumstances, taking into account ethical considerations, type of disease, etc., testing may involve comparison with a placebo treatment. Phase II studies can last from several months to 2 years. Only about one-third of experimental drugs successfully complete both phase I and phase II studies.

Phase III trials test the treatment on several hundred to several thousand voluntary patients, often at many different clinics or hospitals (multicenter trials) and even in different countries (multinational trials). These trials usually compare the new treatment with one already in use. Phase III studies typically last several years. Seventy percent to 90% of drugs that enter phase III studies successfully complete this phase of testing.

Phase IV takes place after marketing authorization. It is to gather data on a product authorized for marketing and used in accordance with approved current medical practice.

For more information, please see the glossary of clinical research terms from CenterWatch Clinical Trials Listing Service.

Because such issues require a certain expertise, we commonly take the lead in setting up study designs that integrate knowledge from experts in the field. In other instances we may only consult on how to clinically develop a drug. Usually, the most stimulating aspect of the work we do is diving into the available preclinical and clinical information to determine which endpoints or biomarkers would be interesting in light of the questions that need to be answered.

Taken together, these aspects turn phase I and II research into scientifically challenging studies (in contrast to more clinically challenging phase III studies; see box). In addition, the projects at CHDR usually are of relatively short duration while covering a broad range of drug classes, thus providing a lot of variation in the work. In practice, much time is required for working out study designs and analyzing and reporting (and publishing) study results, but often these are also the most exciting parts of the research. Personally and in retrospect, I appreciate the dynamics of the rapidly changing topics much more than the narrow focus I experienced during the laboratory experiments for my thesis.

The switch from preclinical pharmacology to clinical drug research also meant a step into a world of many procedures and much administrative work, basically deriving from the international guidelines for good clinical practice (ICH/GCP). Thus, as for many of my colleagues entering the field of clinical pharmacology, the introduction of these qualitatively high standards initially led to some apprehension on my part. In the long run, however, one learns to appreciate a well-organized setting for generating data in an efficient and reliable way. For those who are new to clinical drug development, I would therefore advise you not only to become acquainted with the current GCP guidelines but also to understand how and why they came about.

Although changing responsibilities have shifted my actual work toward financial and personnel management, it is still closely related to current research projects. I think I will enjoy continuing my work in this environment for many more years.

Aernout van Haarst (Ph.D. 1995) is a clinical research scientist at the Centre for Human Drug Research (CHDR) in Leiden, where he has been involved in a broad area of clinical studies. He also consults with pharmaceutical companies and occasionally teaches pharmacology to medical students and nurses