Phase Zero – Early Stage Clinical Research – The Era of the Human Guinea Pig

Patients with rare diseases and parents of children with rare diseases are under a lot of  pressure to alleviate symptoms, and find new treatments. This makes them particularly vulnerable to what may appear to be  “treatment” approaches that may not provide any benefit to them at all.

The field of research into rare and life threatening diseases is rapidly advancing. Genomics and genetic approaches are being used to advance our understanding of disease. The challenge we face now is that the animal studies and in vitro (test tube) approaches are not really keeping up.  We need the animal studies to be predictive for the human experiences, and many of them are. However, as we seek to evaluate new approaches, the animal studies are limited.  Those that could be more predictive are incredibly expensive, and take a relatively long time to complete.

Often animal studies that are being used are used because they are easy to conduct, not because they are the most appropriate. That is why we can cure cancer in mice but not always in humans.

When faced with conducting an animal study that could cost  close to 1 million USD, and conducting a Phase Zero study in patients or healthy volunteers that may cost  less, naturally some researchers would opt for the Phase Zero studies in human.  FDA believes that too many sponsors of studies are not taking advantage of Phase Zero studies.  This is all well and good for the researchers (and [perhaps the FDA to argue in front of Congress), but perhaps these studies are not being done for a reason. Perhaps patients don’t want to be human guinea pigs.

Phase Zero studies evaluate the new potential drug for its pharmacology, at very low doses, pharmacokinetics (levels in the blood), the proteins that the drug may block in the body, and how the drug binds at certain parts of the body that may be related to the disease. This is all very exciting and may help the researchers to better understand the disease, but just be clear that researchers can only move into the clinical trial phase if patients and healthy volunteers are willing to be subjects in their research. There are many instances where research studies have been designed and money and time expended to set up the clinical trials, without including a single patient.

The problem with the Phase Zero or early Phase 1 clinical trials, is that If we had more predictive animal models, or in vitro approaches, we would not need to conduct these studies. We should be spending more resources on the development of predictive animal and in vitro models to match the advances being made in genomics and genetics.  Everyone talks about the pharmaceutical industry charging high prices for their drugs, but we seem to be overlooking why research is so expensive. Researchers are faced with companies selling animals at exorbitant prices that have to  be used in studies. I heard the other day that one specially designed rat can cost 25,000 USD. Patients need to demand that these exorbitant prices are brought into the realm of reality to serve the needs of patients.

In the Phase Zero studies researchers set out to administer doses which must be so safe (at least in terms of what is known about the drug at that point) that they are termed sub-therapeutic. These very low doses are administered to allow the study of the pharmacology of the drug, i.e. how the drug works in the body.  If the drug does not produce the desired effect, the researchers can go back to the drawing board and place the next drug into more patients or healthy volunteers.

FDA is still requiring researchers to conduct a reasonable amount of work to demonstrate that they know enough about the drug to assure its safety. The reality is that most experienced companies will conduct the appropriate Phase 1 studies rather than try to cut a corner here. Academic institutions may seek to use this approach. I see a real potential for conflict of interest if patients are not being properly informed consented about these studies in institutions, and that there is no potential for benefit. At the same time, there is a potential for risk that has not been characterized to that point.

Here are some questions to ask yourself before going into Phase Zero studies:

  1. What is the Phase of study that I would be going into, or putting my sick child into?
  2. What is the potential risk?
  3. If I am injured what is the process for receiving remedial care and treatment?
  4. Is there any potential for compensation if I am injured?
  5. Will this study prevent me from accessing treatment for my disease?
  6. How much is known about this drug?
  7. Have any other research subjects been administered this drug?
  8. Has anyone been injured in the process of studying this drug to-date?
  9. What were the results of the animal toxicology studies?
  10. What adverse events did the animals experience?
  11. Is this something that I want to do for altruistic reasons, or because I feel the field of knowledge about this disease will be advanced?
  12. Will I have access to the results from this study to know that my effort was worth it?
  13. Will other researchers and patients with the disease be given access to the results of this study?

If you decide that you want to go into this study, ensure that you are clear on what your next step in the process of seeking to advance your health will be after this study.

I cover more on this and related topics in my book, Clinical Trials: What Healthy Volunteers Need to Know. This book is available from Oxford University Press, amazon.com, http://www.barnesandnoble.com, Kindle, and book stores throughout the world.

I would like to hear from you. Have you taken part in a Phase Zero study? What was your experience? Patients with rare diseases would benefit from hearing from you.

Post  your comments in the comments field.

Lorna Speid, Ph.D.

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