Hugh Davis
It is important that you, as an individual who is considering involvement with clinical trials, understand both the positive and negative ramifications of your involvement.
In a study done for the NIH in 1997, R. Mechanic dubbed a potential negative issue as “the zone of uncertainty.” In the way of background, patients participating in clinical research are guaranteed treatment of any side effects or complications that occur as a result of their direct participation in that trial. This is a necessary element of the consent form. “The zone of uncertainty” occasionally occurs when there is an attempt to determine whether a particular complication is a result of the trial or a natural course of that patient’s pathologic process. For example, if a patient is entered into an angina trial and suffers an exacerbation that requires his or her hospitalization (while beginning to be treated with an experimental drug as opposed to standard therapy), then who is responsible for the cost of that hospitalization: the pharmaceutical company or the patient’s insurance company? It is possible for the patient to be caught in the middle here, and he or she might have to involve an attorney to rectify this situation.
Again this is a rare occurrence.”The zone of uncertainty” issue evolved as a result of managed care. Prior to the current age, insurance companies seldom knew if their patients were involved in clinical trials. Today it is likely a patient being treated outside of the normal paradigm and referral patterns sanctioned by the HMO will be quickly discovered. Clinical trials can be good for your patients, if you keep in mind some important axioms. The first axiom for all clinical investigators must be to do no harm. It is most important that, in your medical opinion, there are no significant dangers to which you would expose your patients unnecessarily. And this, of course, includes any risk involved in stopping that patient’s cur- rent therapy.
Clearly, though, everything is relative. In a life-threatening illness, more risk might still be well within the realm of acceptability.A second axiom is that a patient should never in any way be coerced into a clinical trial. A clinical trial must be presented in a fair and balanced way and the decision to enter must be left to the patient, who needs to be free from both overt and covert influences. As that patient’s physician, you must refrain from allowing your own desires to inadvertently influence the patient. Remember that you are an authority figure, and that frequently, patients will act out of a desire to please you rather than in a way that they perceive as in their own best interests.A third important axiom is that the patient must have a complete under-standing of the risks, benefits and requirements of a clinical trial.
It is important that the consent form {which delineates safety, visit requirements, etc.) be reviewed in detail by the investigator at a level that is compatible with that patient’s language skills and intellect. It is also worth presenting this information to other members of the patient’s family, so that everyone has a clear understanding of the situation. In fact, it has always been my practice to have a patient’s family member witness his or her signature on the consent form.You and your patients may be concerned about patient safety issues.
What are the risks associated with volunteering for a clinical study? There can be risks, but the research process is designed to minimize them.Most investigators become involved in conducting phase II through phase IV trials and rarely do phase I. There will be further discussion about all the trial phases in this on-line course. However, prior to phase I where a drug is tested for the first time in healthy humans, all products undergo extensive animal testing. So, by the time a drug reaches phase II tests, much has been learned about the drug’s toxicity, half-life and potential side effects.
The general intention of each phase of trials is to further expand safety and dosing knowledge. Therefore, an investigator involving himself or herself in phase IIl trials can be assured of much more information regarding these parameters. And, phase II trials are the earliest phase of trials in which practically all clinical investigators will become involved.
As an investigator, you will receive a protocol and a drug manual. The drug manual delineates all the relevant knowledge that has been accumulated about the drug being tested. It includes animal data as well as information on phase I testing and any previous phase I and phase II - III trials done any- where in the world. A copy of this manual, along with the protocol, must be forwarded to your IRB (we will give a definition of IRB / ethic committee later in this course) prior to approval of the trial. It is vital that you, as an investigator, read this manual carefully so you can become familiar with any potential problems or side effects discovered earlier in the drug development process.
Not only does this information impinge upon your decision to take the trial, but it makes you aware of what problems to look for as the trial progresses. Please remember that you must be comfortable with the risks and benefits to your patients in the trial. If you are worried about undue hazards or side effects that seem too severe to justify, then you should not take this trial. It is impossible for an investigator to function effectively under these types of circumstances.
So, always remember that you are the final judge of what is appropriate and what is not.Most clinical trials you become involved with will not be on “first in the class” products, but on “me too” drugs. While this creates less interest for the investigator, it adds a great margin of comfort because a similar product has already been marketed, and the side effect and safety profile will probably be rather similar.It can be argued that patients in clinical trials are actually safer than patients not in clinical trials who are taking the same or similar products. This is because patients in clinical trials are much better monitored than those who are not.
Trials require many more visits to the physician than what is typical in routine practice and also, in general, much more frequent testing than would normally be done. Also, the clinical tests and parameters utilized are frequently at the highest level of technology available. Frequently, because of the thoroughness of the examinations required by clinical trials, serious and silent coexisting disorders are uncovered. During my experience conducting clinical trials, I have uncovered three malignancies only because of the extensive testing required by the protocol.
In two of the cases, the patient’s life was saved.When considering involvement in clinical trials, it is important to step back for a moment and to consider participation from a different perspective. It has been stated that the administration of one million doses of a medication is required before an adequate side effect profile is developed. In most instances, a medication is released on the market after administration of several thousand doses or less.
It is clear from the frequent withdrawal of marketed medications that many people are in danger of suffering potentially serious side effects from many medications that are assumed to be safe because they have received FDA / TPD approval. It is important to remember that every time someone takes a medication, whether it be approved, over the counter, herbal or as part of an experimental protocol, there are potential dangers.
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Hugh Davis is a Senior Instructor , Kriger BioPharmaceutical Training Program http://www.kriger.com/training/ , info@kriger.com
May 20th, 2008 by 
Barry - Admin BioPharmArena
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