James E. Turner, M.D.

In order to participate in testing of new medical treatments, by law, a person must provide informed consent. The term, informed consent implies two requirements. First, the subject must agree to participate in the testing. Secondly, the person must sufficiently understand what he/she is agreeing to so that the decision reflects his values and interests. Informed consent is legally required because during the last Century, several medical experiments in a number of different countries were performed which resulted in deliberate harm to the participants without their knowledge or ability to decline participation. The World Health Organization and the U.S. Congress took the lead in setting standards for the conduct of research on humans, including informed consent, that is binding on all member countries of the United Nations.

To be fully informed of the implications of participation in the study of new medical treatments, it is useful to understand their process of development. That process takes years or decades, and is scientifically rigorous. The goals of testing are to determine if the treatment has any useful effects, and if it is reasonably safe. The treatment is usually first tested on animals for safety. If a disease state exists in animals which is similar to the disease to be treated in humans, then researchers can also assess how effective the treatment is in animals. However, some human diseases have no counterpart in other species, and in those that do, the metabolic pathways may be quite different between species. There are many examples of medications which are very effective in animals and useless in humans. If the treatment appears to be safe in animal testing, then human testing is considered. Once the decision is made to proceed with human testing of a new medicine, a series of experiments, called clinical trials are designed. The first level of testing, called Phase I, is designed to determine if the drug can be safely given to humans. This involves giving the medication to a group of healthy volunteers to see if it makes them sick. The most common serious side effects of medications involve allergic reactions. Damage to the liver, kidneys, lungs, heart and brain may also occur. Changes in the function of these organs are looked for very closely in a welldesigned clinical trial.

The second stage of testing, Phase II studies, are referred to as dose-ranging trials. These studies enroll patients who actually have the disease to be treated. The medication is given in varying dosages, in an effort to find a dosage that appears to improve the condition being treated and has acceptable side effects. In Phase II trials, patients entered early into the study are likely to get low doses of the medication while patients entered later usually get higher doses. Also, in Phase II trials, some patients get placebo (an inactive compound which should have no effect on the condition being treated), or a medication that is already is common use for the condition.

If a dose can be established which appears to be effective and has an acceptable safety record, then Phase III studies are started. Phase I studies typically have a few dozen subjects enrolled. Phase II studies usually enroll 50 – 200 patients. Phase III studies enroll much higher numbers of patients, from several hundred to several thousands. They are conducted at multiple sites around the country and often throughout the world. The purpose is to mimic a broad array of geographic areas and patient types to simulate real world experience. Also, the larger number of patients make the chances better that the results obtained in the trial will be valid.

Phase III trials compare the experimental medication to either placebo or currently accepted standard treatment, usually in a ratio of 1:1. In other words, your chances of getting the experimental medication are 50%. Phase II and Phase III trials are also referred to as double blind trials because neither the medical staff and researcher, nor the patient know whether they are getting the experimental medication or not. This is an attempt to avoid a phenomenon called the "Placebo Effect". Approximately 20% of patients given a placebo will report that they feel better after having the treatment. Since the researcher must report the patients symptoms and whether they improve or worsen, the Placebo Effect can seriously distort the actual effects of the medication being tested. Preventing the research team from knowing which patient is getting which treatment also helps to control another phenomenon called "observer bias". We all want to have safer, more effective medicines. If patients and researchers know who is getting the active compound, they tend to maximize its beneficial effects and minimize side effects. This also distorts the true effectiveness and side effects of the treatment.

Each clinical trial is supervised by a researcher with knowledge and experience in this particular area of physiology or this disease state. In human trials, this researcher must be a physician. At each facility participating in a clinical trial, a physician must be responsible for supervising that particular trial, ensuring that the data gathered from patients at that site is accurate, and communicating with the trial sponsor. That physician is called the Principal Investigator.

In a clinical trial, researchers must gather certain information and describe certain events which are determined when the trial is designed. This information is recorded in a series of forms that are then sent to the sponsoring company or organization (such as the National Institutes of Health). The most important information is sent within a matter of hours or at most a few days from the time it is collected. Serious side effects must be reported to the sponsor within 24 hours of being recognized. The sponsor must then report them, along with their scientistss evaluation of the cause and significance of the event to the Food and Drug Administration within 7 days. Serious side effects must be reported to all Principal Investigators participating in the trial in a timely fashion. (This typically takes 3 – 4 months.) So, the Principal Investigator who is conducting a clinical trial at the site of your participation should be aware of any significant problems which have been observed with this treatment at any site within a few months, at most, of the time of their occurrence. He/she is obligated by the rules of clinical research to inform you of any new side effects or complications of the treatment that have been discovered since you were initially enrolled in the trial, so that you have the opportunity to change your mind about participating in this particular trial.

All clinical trials must also have an independent group of experts not otherwise involved in the clinical trial that periodically reviews (usually monthly or quarterly) the results and safety data available for the patients enrolled to date. This is the only group of individuals who know which patients are getting the experimental compound and which are getting placebo or the comparator drug in the Phase II and III studies. This board of experts has the authority to stop the study at any time if they feel that the study compound has proven effectiveness, no evidence of useful effect, unacceptable side effects, or if it becomes apparent to them that the trial was improperly designed and will not answer the question posed or provide other useful information.

At the local level, each center conducting a clinical trial must have a board of physicians, nurses, pharmacists, and lay members of the local community who review and approve all clinical trials at that hospital, clinic, or office, and who also receive periodic reports of safety issues and outcomes from the clinical trials that they review. For instance, all serious side effects reported to the Principal Investigator at that site must be forwarded to the review organization. This organization, called an Institutional Review Board, ha
s the authority to stop enrollment in a study or investigate its conduct in any way they see fit, at any time at that site.

There are several things that a person should seriously consider before agreeing to participate in a clinical trial. I believe the first and most important concept is to realize and accept the fact that there is no guarantee the patient will benefit from the treatment. If we knew that the treatment was beneficial, it would already be approved for use. The purpose of clinical trials is to determine whether or not this treatment is useful and safe. Principalled researchers only participate in clinical trials that they believe will ultimately benefit patients in some way, so we are all prejudiced in favor of patients enrolling in clinical trials. Some researchers have difficulty concealing their enthusiasm for a new treatment in which they believe, or want very badly to be effective. Remember that if a researcher tells you they believe an experimental treatment will help you, they are being, to at least some degree, intellectually dishonest because we cannot know this. This distinction is blurred considerably in the case of life-threatening or devastating diseases for which there is no good treatment or in cases where traditional treatments have failed. There are times in which I believe it is appropriate to tell a patient that available data appears promising, if the patient requests this information. However this must always be tempered by the realization that "the jury is not yet in" (the Data Safety Monitoring Board).

Secondly, you must trully understand and accept the fact that all clinical trials involve some degree of increased risk for the patient. New medications and treatments have risks and side effects that have not yet been recognized because of the limited experience with the treatment. Some of these events will be identified during the clinical trials, and they may be identified when they happen to you. In order to participate in a clinical trial, you need to be able to contemplate having a catastrophic complication of the treatment and be able to accept the reality that you made the best decision possible with the information you had, and things didnnt work out as planned. This is true of life, and it is certainly true in clinical trials. Unless you honestly feel this way, I would advise against participating. The patient that I most assiduously try to avoid enrolling in clinical trials is the person who wants to enroll because they believe they will receive the experimental treatment (we have no way of knowing or guaranteeing which treatment any individual patient will receive), believes that the treatment will be beneficial to them (we donnt know that either), and is unwilling to accept the reality that fate was not on their side if an unpreventable complication occurs.

The things that I would want to know before agreeing to participate in a clinical trial are the following:

1. What is the purpose of the study? What condition is being treated or studied? (It may not be the condition which concerns you most or even at all.) What is the desired outcome?
2. How many people have received this treatment so far?
3. What serious or very unpleasant side effects have been reported so far and how frequently are they occurring? (Vomiting or severe dizziness may not kill you but it can make you wish you were dead!)
4. How long does the study last? How many times and when do I need to be seen by the researcher?
5. Are any of the tests to be done as part of the trial unpleasant, painful, or dangerous in their own right? If so, they must be fully described and understood.
6. Are there any restrictions on my activities or diet or other medications I may take while enrolled in the trial or during the subsequent period? (Many clinical trials of medications request that women subjects not become pregnant for at least one year after receiving the experimental medication. Some even request that male subjects not sire children during that period. If this will seriously interfere with your family planning, then you may not wish to enroll.)
7. Who are the players in this study at this site? Who is the Principal Investigator? Which physician and clinical coordinator will I be most likely to see and how often will that occur? Who is the study sponsor and why? Who do I call if I have questions and what is the phone number?
8. What is the name of the Institutional Review Board and what is their phone number, in case I have questions or concerns that I would rather have answered by someone not involved with the study?

I believe there are substantial benefits to participating in clinical trials. I think patients enrolled in clinical trials are more likely to receive close scrutiny and fewer errors in the delivery of medical care than people not enrolled because of the requirements of clinical research. I believe that the demands of conducting clinical trials are a good indicator of skill and motivation in hospitals, physicians, and nurses. Participating in clinical research encourages people to remain current in their medical knowledge base, and suggests motivation and interest in their work. Their is, however, a price to be paid in terms of additional laboratory tests and xrays for many trials, the inconvenience of additional visits to the doctor, and increased risk of complications.

People who participate in clinical trials are making a genuine contribution to medical science. Without the generous participation of a large majority of patients when asked, medical knowledge would progress more slowly, and a far larger population of people would be exposed to greater risk because of less experience with new drugs and treatments before they are released for use by the general public. This can create some positive feelings for an individual from an experience that is otherwise mostly negative.

And finally, I think that patients with catastrophic illnesses or diseases where no effective therapy exists may benefit from novel and experimental therapy because, when properly selected, the therapy may provide additional hope, reassures patients and families that extraordinary effort has been expended in searching for an effective treatment, and gives the patient and family the sense that they have contributed something of value to future patients and their death has not been in vain.

About the author:

Dr. Turner received a B.A. degree in Biology and Chemistry from Southern Illinois University at Edwardsville, did graduate studies in Neurosciences at the University of Illinois and then attended Northwestern University School of Medicine where he earned his M.D. He completed residency training in Internal Medicine and a fellowship in Critical Care Medicine at the University of California, Davis Medical Center. Following his fellowship, he served on the faculty of the Medical School at U.C. Davis for seven years. This was followed by an appointment as the Chief Executive Officer of a small, inner-city hospital in the Sacramento area. For the past twelve years, Dr. Turner has been in the private practice of Critical Care Medicine at Sutter Medical Center, Sacramento. He is actively involved in clinical trials with a special interest in the septic process. While at U.C. Davis, Dr. Turner served on the Institutional Review Board for seven years, and is currently an alternate member of the Institutional Review Committee for the Sutter Sacramento area.