CWWeekly’s semi-monthly company profile feature, Insider Insights, interviews executives of companies and organizations in the clinical trials space. Staff Writer Ronald Rosenberg sat down with Larry Blankstein, senior director of clinical development at Genzyme.

Q: How has finding the basic measure­ments that need to be taken during the early phase of clinical development changed over the past 10 years?

A: The basic approaches have not really changed dramatically yet, but there is a trend toward being more innovative in trial designs. So one can move away from doing the standard phase I, phase II and phase III, and attempt to combine phases. That may mean having some additional assessments or being somewhat creative in the design of the trial, such as adaptive design trials. This potentially could allow one to accelerate the drug development process but, more impor­tantly, make decisions early about whether or not to develop a drug further.

There is more thought about implement­ing these trial designs. The FDA and other regulatory authorities are more open to those kinds of designs, particularly in rare diseases and diseases for which there is an unmet medical need.

Q: Understanding the pharmacodynamic effects of a particular drug early in a clinical trial is a major challenge. What is needed to overcome these difficulties?

A: Most companies, especially the larger ones, are trying to identify early on—even in preclinical studies—a pharmacodynamic marker that would be a good indicator of a drug’s biological activity that may have some relationship to a clinical outcome. I think the trend is to find a biomarker that one can assess in preclinical work that would be relevant to the clinical environment, so that when you enter clinical development you can very early on evaluate whether your drug is having a bio­logic/pharmacodynamic effect before moving to the next stage of development.

You need some level of comfort that you can take this drug forward into a phase II and, eventually, a phase III trial. Many companies now run small proof-of-concept studies to get at that question very quickly and make a go/no-go decision to take a drug forward or not. I think this is becoming a standard to identify a signal early, even in phase I—even in healthy volunteers— looking for a biological/mechanistic effect.

Let’s take an example of a drug that may decrease LDL cholesterol—a marker of an effect on lipid biosynthesis. You can do that in healthy volunteers to see an effect that could provide some indication that your drug is having a desired biologic effect. That is pretty much what people are looking for these days in trying to make decisions early and cor­relate a dose effect with a pharmacodynamic effect. As you increase your dose, it would be ideal to see a corresponding phramacody­namic or biologic effect.

Q: What changes are needed to hold down additional costs and extraneous data to find the right dosage in early stage clinical trials?

A: By performing adaptive trial studies in your target patient population, you can make decisions early about whether or not your drug is safe and effective and at what dose. You may have a trial in which you are looking at three or four different doses if you have a pharmacodynamic marker. You can use it to assess the impact of a dose on that biomarker level and make a go/no-go decision in terms of adding a dose or dropping a dose in a trial design. Using adaptive approaches and biomarkers as an indicator of an effect is one way to make decisions faster and hold down your costs, because you’ll know if it has an effect or not. This is especially true if a clinical effect may not be seen for months or years.

Thus the change in a pharmacodynam­ics biomarker may allow for faster go/no-go decision making and dose selection. It is important to remember that a biomarker is not a substitute for a clinically meaning­ful endpoint, unless that biomarker can be linked to a clinical response that regulators agree to.

Q: As biomarkers play an increasing role in phase I trials, what role does imaging have in completing pharmacokinetic studies?

A: Obviously, when you are working with biomarkers, it is not just plasma biomark­ers that one needs to consider, but also imag­ing biomarkers. A good example is in phase I cancer trials. You know when looking at patients who are fairly well advanced and you are treating them with a drug that imaging is a powerful tool to assess tumor response to treatment and the potential efficacy of your drug. It is a clinical benefit to have tumor reduction, as it has been associated with prolonging the patient’s life. Survival is an excellent clinical endpoint.

Another example is spleen volume in some diseases, in which significant increases can be reduced in response to a drug as as­sessed through imaging. This reduction must be related to a clinically meaningful endpoint that will benefit the patient. Unfortunately, not all biomarkers meet this expectation. You have to show there is some clinical benefit to that change in the biomarker, whether it’s a plasma biomarker or an imaging biomarker. The spleen size decreases as patients are treated with the drug. A key question is: how do you translate that into some clinically meaningful benefit to the patient? That is what regulators are interested in.

So plasma/serum and imaging biomark­ers do play a role in phase I studies. They give you a good indication if your drug is having some biologic effect. Whether it is a reduction in spleen volume or a reduc­tion in plaques in the brain, you can see the changes with imaging.

Q: While vitally important at all stages, how do you uncover pharmacovigilance differences between phase I and phase II of a clinical trial?

A: When we talk about phase I trials, there are two kinds: one is with healthy vol­unteers, and the other is in patients with the disease. With healthy volunteers, you will see a certain safety profile that can give you an indication of some potential safety sig­nals of your drug. However, phase I healthy volunteer studies usually are performed over a two-week exposure period. What you have is a snapshot in a short period of time of what potential adverse events you can observe in a drug in healthy volunteers. Depending on the design of the phase I studies, you may stop before dose-limited toxicities are reached to really identify what potential adverse events you may observe in your patient population.

What a phase I study in healthy vol­unteers provides is an idea of the types of adverse events that you may see with your drug, particularly at higher doses. Hopefully, as you see the beneficial effects of the drug you don’t see serious adverse events in this healthy population. One must still approach a phase II study with some caution, as patients with the disease will have different medical histories than healthy volunteers, as well as different concomitant medications, which could affect the safety profile of the drug, Thus the need for some additional dose-finding studies in the disease population.

In phase I studies in the disease popula­tion, patients could be dosed for six months to a year with your drug. Their exposure is potentially much longer than with healthy volunteers. With a longer treatment period, there is the potential to identify safety signals in this phase I study that may provide greater insight into what you would expect in a phase II trial at different dose levels.

Email comments to Ronald at ronald.rosenberg@centerwatch.com. Follow @RonRCW

This article was reprinted from Volume 19, Issue 08, of CWWeekly, a leading clinical research industry newsletter providing expanded analysis on breaking news, study leads, trial results and more. Subscribe »