Karl Cremer, PharmD and AnnKatrin Petersen, MD, MS
January 25, 2012
Chances are that you have clicked on this link because you may be interested in participating or learning more about clinical trials – also known as clinical research. We hope that the information assembled will provide you with a good understanding about clinical trials and what it might mean for you.
Clinical Research doesn’t really start with a clinical trial; its foundation has been laid long before.
Basic Research: Like all research, it starts somewhere in someone’s mind, usually a scientist. People who think and observe without pre-formed judgments are at the center of all renewal. The observations are linked by thought and sometimes, after long and arduous work, lead to new ideas and inventions like the discovery of atorvastatin (a molecule that blocks the synthesis of cholesterol in the liver, thus lowering blood cholesterol). As high blood cholesterol is a common problem for many people because it increases the risk of cardiovascular disease, the discovery of this molecule by a chemist working for Parke-Davis, Ann Arbor, Michigan in 1985 meant a great advance for millions of people.
Atorvastatin, marketed by Pfizer as a calcium salt under the trade name Lipitor.
Just recently, on November 30, 2011, this amazing drug came off patent, which means that there is now a generic atorvastatin on the market.
Once a basic observation is described, like the HMG-CoA pathway in the liver that is responsible for the synthesis of cholesterol, hundreds of experiments are run and rerun to obtain in-depth understanding of the initial observation/s. This basic research is done in institutions that you might have heard of, e.g. National Institutes of Health (NIH), National Cancer Institute, MD Anderson Cancer Center, The Salk Institute of Biological Sciences, The Scripps Research Institute, Pharmaceutical and Biotechnology companies and Universities around the globe.
Pre-clinical Research: Once basic research has found sufficient evidence to demonstrate the mechanisms that cause a disease, such as in the atorvastatin example, the search for a new treatment can be initiated. Presently, many treatments are targeting very specific molecules to either ‘block’ or ‘inhibit’ their activation, or on the contrary to enhance or increase their activity. Other treatments may help replace important substances in your body like the replacement of thyroid hormone for patients who suffer from hypothyroidism; or they may help deliver drugs to the right place where they should be active, avoiding unnecessary exposure to the entire body.
The research of these new treatments continues to be done in laboratories, test tubes, and eventually in animal models. Before any new drug can be given to a human being in a clinical trial, it has to undergo extensive testing of all aspects of potential toxicity (e.g. cardiac toxicity, cellular toxicity, resistance development, hypersensitivity). These tests are mandatory by the Food and Drug Administration (FDA). The efficacy aspect of a new molecule will also be studied in cell cultures or animal models (e.g. the activity of antibiotics is tested in culture against bacteria). These in-vitro and in-vivo tests allow the scientists and doctors to make a reasonable, data-driven assessment on how the drug will work in the human body and what the potential benefits and risks are.
Another example of an important new treatment that was developed in the past decade is Herceptin, a (monoclonal antibody) drug that blocks the activation of a transmembrane protein called Her2. To view a video on Herceptin, click here.
Clinical Research: So once a clinical trial begin, years of work, even decades of time, have been invested to develop a new medication (aka ‘investigational agent’, or ‘compound’). The new medication that you might receive to treat your disease has been studied in many different experiments to understand the behavior of the compound under different conditions and in different settings.
At this point the FDA and the Ministries of Health (MoH) will decide if it is sufficiently safe and beneficial to test the new compound in humans. While there might be differences between the practices in different countries, most follow similar guidelines and regulations in assessing the worthiness of a new drug or device. These guidelines are called the ICH-GCP guidelines that stand for International Conference on Harmonisation of Technical Requirements – Good Clinical Practice. View the guidelines here.
One critical consideration is the assessment of your (the patient’s) potential benefits compared to the potential risk factors that have to weigh in favor of the benefits. If the FDA allows, an Investigational New Drug Application (INDA) to move forward, Clinical Development of this new product can finally begin.
What are Clinical Trials?
A clinical trial is a research study that evaluates the performance of a medical product (medication, therapy, medical device, diagnostic test, etc.) in normal volunteers (people that are healthy) or patients (people with a medical condition or disease).
In a clinical trial, health care practitioners (e.g., doctors, nurses, etc.) use a specific set of procedures that are based on science (i.e., protocol) to evaluate the medical product. For example, you may be given a new drug to treat diabetes and the doctor may then interview you, and perform diagnostic tests to determine if the drug controls your blood sugar as it is supposed to.
Clinical Development is structured in three research phases that occur sequentially but depending on the circumstances may also occur in parallel. There is also a fourth phase that applies to drugs that have already received market approval.
Four Phases of Clinical Research
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Clinical Development Phases
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Definition
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Benefit
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Risk
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| Phase I |
Usually enroll healthy normal volunteers. These studies evaluate the safety, dose and treatment pattern of a new medication. |
Free medical care and compensation for participation contribute to identify the safety and tolerability profile of a drug at different dosing levels. |
Being a subject in one of the first-in-men studies always carries risk because the safety profile has only been tested in animals and in in-vitro models. As every living system is different, especially between species, initial exposure to a new medication has to happen very gradual – very low dose to higher doses. |
| Phase II |
These clinical trials are conducted in patients with a particular medical condition or disease that a new medication is intended to treat. The studies are designed to evaluate safety, the effectiveness of the product, and to explore different doses. The initial Phase II studies frequently include a lot of blood work and other tests to assess pharmacological parameters, such as drug metabolism and distribution. |
Since clinical trials evaluate medicinal products to improve medical care, your participation in a clinical trial will benefit people with disease, including yourself. You have access to potentially better treatments for your disease than those that are available to you on the market. You also benefit from free state-of-the- art medical care. If people do not participate in clinical trials, it will be virtually impossible to improve medical care. Your participation makes a difference! |
Phase II studies explore the investigational drug, either for the first time in patients or in a new indication, with a new dose, new formulation, or in a new drug combination. Because it is the first time that the drug is administered in a new setting, there are more unknowns about efficacy and safety. The risk factors are normally balanced out by tighter surveillance, such as more doctor visits, more blood tests etc. |
| Phase III |
These clinical trials are usually very large studies involving many patients and are designed to prove the safety and effectiveness of a new medication. Traditionally, the FDA requires 2 Placebo-controlled Phase III studies to prove that the drug is safe and efficacious. |
At this stage of drug development, a lot of clinical information about safety and efficacy is available, thus increasing the potential benefits and decreasing the potential risks. You also benefit from free state-of-the-art medical care.This is the final decisive stage of development that will determine if the FDA/MoH will approve the drug and how it will be prescribed by health care professionals. |
At this stage, most risk factors should have been described and the treating physician will know how to recognize, prevent, or treat these adverse events. However, every person is different, and with every person, there remains a potential of new adverse event findings. The more patients exposed to the drug, the less likely unknown safety events will be found. |
| Phase IV (post-approval) |
Smaller-sized studies mostly intended to assess additional properties of a drug; these studies are not required by the FDA. |
Free medical care and treatment. |
Further reduced safety risks because more is known about the drug. |
Types of Clinical Trials
The type of clinical trial will vary depending on:
- The type of medical product (medication, therapy, medical device, diagnostic test, etc.)
- The stage of product development (e.g., product that is already marketed, new product, etc.)
- Trial sponsor (e.g., government, private company, university, etc.)
- Some clinical trials are in normal volunteers (people that are healthy) and some are in patients (people with a medical condition or disease)
Clinical Trials for Medical Devices
In contrast to the development of a new medication, the clinical trials used to develop a new medical device or diagnostic test are generally of shorter duration and include fewer patients. However, the precautions and monitoring to protect patient safety and the care that you receive, is the same.
Overview of a Typical Clinical Trial
First, the clinical trial is reviewed and approved by an independent Institutional Review Board (IRB) or Ethics Committee (EC). The IRB/EC is a group of people, who make sure that the clinical trial, and the health care practitioners, who conduct the clinical trial, protect patient rights and safety at all times during the study.
Second, a doctor or nurse explains the study to you. It is important that you understand the risks, benefits, and your rights as a subject in the trial. If you agree to participate in the clinical trial, you sign an “informed consent form,” which indicates that you agree to participate in the study.
Important – Steps one and two are designed to protect people who participate in clinical trials. One should never participate in a clinical trial if you do not understand the risks and benefits of the medical product and your rights as a participant.
Third, you participate in the clinical trial, which usually consists of the following:
- Sign the informed consent form before any trial procedures are performed
- Screening procedures to make sure that you are eligible for the study and to establish a baseline
- Use the medical product (e.g., take a medication, be treated by a medical device, undergo a diagnostic test, etc.). This could range from a 1-2 minute diagnostic test or you could receive a new medication for months to years depending on the type of clinical trial.
- The healthcare practitioners monitor and measure your response to the medical product (e.g., they measure your blood pressure to see if the antihypertensive drug lowered your blood pressure).
- After you stop using the medical product, a follow-up visit is performed to make sure that you are not experiencing any side effects after receiving the medical product.
Comparing Typical Medical Care to Clinical Trials
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Typical Medical Care
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Clinical Trial
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| “Medical care is costly and I still have co-pays.” |
Medical care is free and you may even be paid to participate in a clinical trial. |
| “Scheduling appointments is a nightmare and I have to wait so long to see the doctor.” |
Medical visits are scheduled when you enroll in a clinical trial and you do not have to wait to see the doctor because he/she wants to see you. |
| “I saw the doctor, but I still do not feel well.” |
Clinical trial participants are monitored closely, and often, so you may receive better medical care. |
| “I’ve seen so many doctors and they still do not know what is wrong with me.” |
While there are no guarantees, the doctors and nurses who conduct clinical trials are generally more knowledgeable and know more about the latest and best therapies. The screening tests are designed to confirm the medical condition that you have. |
| “I’ve tried every medication and nothing seems to work.” |
Many clinical trials evaluate new and improved medical products, so you may be able to find a product that finally works. |
| “They ran three different blood tests and no one called me with the results.” |
The health care practitioners that conduct a clinical trial must monitor you closely, they will share the results with you, you have a legal right to see the results of the study, and the increased level of observation may result in better health care. |
| “Are my headaches caused by my new medication? I cannot reach my doctor to ask him.” |
Medications cause side effects. The doctor or nurse will tell you about them, monitor you frequently, and treat any new side effects or change your medication, if necessary. You will be monitored more closely in a clinical trial. |
| “I do not know my legal rights.” |
The doctor or nurse will explain your legal rights before you enroll in the study. They are obligated by law to make sure that you understand your legal rights. In addition, you may contact the Institutional Review Board (your advocate) to answer any questions that you might have about the trial and your rights. |
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