Clinical Trials

A clinical trial is a research study to answer specific questions about vaccines or new therapies or new ways of using known treatments.

Clinical Trials also called medical research and research studies] are used to determine whether new drugs or treatments are both safe and effective. Carefully conducted clinical trials are the fastest and safest way to find treatments that work.

Leads for clinical trials usually come from researchers. Once researchers test new therapies or procedures in the laboratory [animal studies] and get promising results, they begin planning Phase I clinical trials [in humans].

New therapies are tested on people only after laboratory and animal studies show promising results. Clinical Trials make it possible to apply the latest scientific and technological advances to patient care.

When a new medical treatment is studied for the first time in humans, it is not known exactly how it will work. With any new treatment, there are possible risks as well as benefits.

Clinical trials help physicians discover the answers to the following questions

1. Is the treatment safe and effective?

2. Is the treatment potentially better than the treatments currently available?

3. What are the side effects of the treatment?

4. Does the treatment have any possible risks?

5. How well does the treatment work?

Phases of a Clinical Trial

Clinical Trials are conducted in Phases, each designed to find out specific information. Each new phase of a clinical trial builds on information from previous stages.

Clinical Trials of experimental drugs proceed through Four phases.

Phase I. In Phase I clinical trials, researchers tests a new drug or treatment in a small group of people [20-80] for the first time to evaluate its

· Safety

· Determine a safe dosage range

· Identify side effects

Phase II. In Phase II clinical trial, the study drug or treatment is given to a larger group of people [100-300] to see if it is EFFECTIVE. And to further evaluate its Safety.

Phase III. In Phase III studies, the study drug or treatment is given to large groups of people [1000-3000] to confirm its

· Effectiveness

· Monitor side effects

· Compare it to commonly used treatments

· Collect information that will allow the drug or treatment to be used safely.

Phase IV. Phase IV studies are done after the drug or treatment has been marketed. These studies continue testing the study drug or treatment to collect information about their effect in various populations and any side effect associated with its long term use.

The clinical trial participants are willing volunteers. There are several advantages as well as potential side effects from participating in a clinical trial.

Types of Clinical Trials

Some clinical trials are Blinded, Placebo controlled. The blinding can be single, double or triple blinding.

Informed Consent

Prior to getting involved in a clinical trial, informed consent is to be obtained from the volunteers. Informed consent means that as a patient, he is given all the available information so that he can understand what is involved in a specific clinical trial.

The researchers conducting the clinical trial will explain the treatment schedules, including its possible benefits and risks. The informed consent process is ongoing till the end of the trial.

Every clinical trial is designed to meet a specific set of research criteria. Clinical trials are often expensive and time consuming. But, the results are often scientifically sound and rewarding.

Research Ethics and Stem Cells

Stem cells show potential for many different areas of health and medical research, and studying them can help us understand how they transform into the dazzling array of specialized cells that make us what we are. Some of the most serious medical conditions, such as cancer and birth defects, are caused by problems that occur somewhere in this process. A better understanding of normal cell development will allow us to understand and perhaps correct the errors that cause these medical conditions.

Research on one kind of stem cell—human embryonic stem cells—has generated much interest and public debate. Pluripotent stem cells (cells that can develop into many different cell types of the body) are isolated from human embryos that are a few days old. Pluripotent stem cell lines have also been developed from fetal tissue (older than 8 weeks of development).

As science and technology continue to advance, so do ethical viewpoints surrounding these developments. It is important to educate and explore the issues, scientifically and ethically. The NIH maintains a Department of Clinical Bioethics, and the NIH bioethics special interest group offers a list of online resources about the ethics of stem cell research.

Stem Cells and Diseases

The Promise of Stem Cells

Studying stem cells will help us understand how they transform into the dazzling array of specialized cells that make us what we are. Some of the most serious medical conditions, such as cancer and birth defects, are due to problems that occur somewhere in this process. A better understanding of normal cell development will allow us to understand and perhaps correct the errors that cause these medical conditions.

Another potential application of stem cells is making cells and tissues for medical therapies. Today, donated organs and tissues are often used to replace those that are diseased or destroyed. Unfortunately, the number of people needing a transplant far exceeds the number of organs available for transplantation. Pluripotent stem cells offer the possibility of a renewable source of replacement cells and tissues to treat a myriad of diseases, conditions, and disabilities including Parkinson's and Alzheimer's diseases, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis and rheumatoid arthritis.

Have human embryonic stem cells successfully treated any human diseases?

Scientists have been able to do experiments with human embryonic stem cells (hESC) only since 1998, when a group led by Dr. James Thomson at the University of Wisconsin developed a technique to isolate and grow the cells. Moreover, Federal funds to support hESC research have been available since only August 9, 2001, when President Bush announced his decision on Federal funding for hESC research. Because many academic researchers rely on Federal funds to support their laboratories, they are just beginning to learn how to grow and use the cells. Thus, although hESC are thought to offer potential cures and therapies for many devastating diseases, research using them is still in its early stages.

Adult stem cells, such as blood-forming stem cells in bone marrow (called hematopoietic stem cells, or HSCs), are currently the only type of stem cell commonly used to treat human diseases. Doctors have been transferring HSCs in bone marrow transplants for over 40 years. More advanced techniques of collecting, or "harvesting," HSCs are now used in order to treat leukemia, lymphoma and several inherited blood disorders.

The clinical potential of adult stem cells has also been demonstrated in the treatment of other human diseases that include diabetes and advanced kidney cancer. However, these newer uses have involved studies with a very limited number of patients.

Similarities and Differences between Embryonic and Adult stem cells

Human embryonic and adult stem cells each have advantages and disadvantages regarding potential use for cell-based regenerative therapies. Of course, adult and embryonic stem cells differ in the number and type of differentiated cells types they can become. Embryonic stem cells can become all cell types of the body because they are pluripotent. Adult stem cells are generally limited to differentiating into different cell types of their tissue of origin. However, some evidence suggests that adult stem cell plasticity may exist, increasing the number of cell types a given adult stem cell can become.

Large numbers of embryonic stem cells can be relatively easily grown in culture, while adult stem cells are rare in mature tissues and methods for expanding their numbers in cell culture have not yet been worked out. This is an important distinction, as large numbers of cells are needed for stem cell replacement therapies.

A potential advantage of using stem cells from an adult is that the patient's own cells could be expanded in culture and then reintroduced into the patient. The use of the patient's own adult stem cells would mean that the cells would not be rejected by the immune system. This represents a significant advantage as immune rejection is a difficult problem that can only be circumvented with immunosuppressive drugs.

Embryonic stem cells from a donor introduced into a patient could cause transplant rejection. However, whether the recipient would reject donor embryonic stem cells has not been determined in human experiments.

IV. What are adult stem cells?

An adult stem cell is an undifferentiated cell found among differentiated cells in a tissue or organ, can renew itself, and can differentiate to yield the major specialized cell types of the tissue or organ. The primary roles of adult stem cells in a living organism are to maintain and repair the tissue in which they are found. Some scientists now use the term somatic stem cell instead of adult stem cell. Unlike embryonic stem cells, which are defined by their origin (the inner cell mass of the blastocyst), the origin of adult stem cells in mature tissues is unknown.

Research on adult stem cells has recently generated a great deal of excitement. Scientists have found adult stem cells in many more tissues than they once thought possible. This finding has led scientists to ask whether adult stem cells could be used for transplants. In fact, adult blood forming stem cells from bone marrow have been used in transplants for 30 years. Certain kinds of adult stem cells seem to have the ability to differentiate into a number of different cell types, given the right conditions. If this differentiation of adult stem cells can be controlled in the laboratory, these cells may become the basis of therapies for many serious common diseases.

The history of research on adult stem cells began about 40 years ago. In the 1960s, researchers discovered that the bone marrow contains at least two kinds of stem cells. One population, called hematopoietic stem cells, forms all the types of blood cells in the body. A second population, called bone marrow stromal cells, was discovered a few years later. Stromal cells are a mixed cell population that generates bone, cartilage, fat, and fibrous connective tissue.

Also in the 1960s, scientists who were studying rats discovered two regions of the brain that contained dividing cells, which become nerve cells. Despite these reports, most scientists believed that new nerve cells could not be generated in the adult brain. It was not until the 1990s that scientists agreed that the adult brain does contain stem cells that are able to generate the brain's three major cell types—astrocytes and oligodendrocytes, which are non-neuronal cells, and neurons, or nerve cells.

A. Where are adult stem cells found and what do they normally do?

adult stem cells have been identified in many organs and tissues. One important point to understand about adult stem cells is that there are a very small number of stem cells in each tissue. Stem cells are thought to reside in a specific area of each tissue where they may remain quiescent (non-dividing) for many years until they are activated by disease or tissue injury. The adult tissues reported to contain stem cells include brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, skin and liver.

Scientists in many laboratories are trying to find ways to grow adult stem cells in cell culture and manipulate them to generate specific cell types so they can be used to treat injury or disease. Some examples of potential treatments include replacing the dopamine-producing cells in the brains of Parkinson's patients, developing insulin-producing cells for type I diabetes and repairing damaged heart muscle following a heart attack with cardiac muscle cells.

B. What tests are used for identifying adult stem cells?

Scientists do not agree on the criteria that should be used to identify and test adult stem cells. However, they often use one or more of the following three methods: (1) labeling the cells in a living tissue with molecular markers and then determining the specialized cell types they generate; (2) removing the cells from a living animal, labeling them in cell culture, and transplanting them back into another animal to determine whether the cells repopulate their tissue of origin; and (3) isolating the cells, growing them in cell culture, and manipulating them, often by adding growth factors or introducing new genes, to determine what differentiated cells types they can become.

Also, a single adult stem cell should be able to generate a line of genetically identical cells—known as a clone—which then gives rise to all the appropriate differentiated cell types of the tissue. Scientists tend to show either that a stem cell can give rise to a clone of cells in cell culture, or that a purified population of candidate stem cells can repopulate the tissue after transplant into an animal. Recently, by infecting adult stem cells with a virus that gives a unique identifier to each individual cell, scientists have been able to demonstrate that individual adult stem cell clones have the ability to repopulate injured tissues in a living anim

What are embryonic stem cells?

A. What stages of early embryonic development are important for generating embryonic stem cells?

Embryonic stem cells, as their name suggests, are derived from embryos. Specifically, embryonic stem cells are derived from embryos that develop from eggs that have been fertilized in vitro—in an in vitro fertilization clinic—and then donated for research purposes with informed consent of the donors. They are not derived from eggs fertilized in a woman's body. The embryos from which human embryonic stem cells are derived are typically four or five days old and are a hollow microscopic ball of cells called the blastocyst. The blastocyst includes three structures: the trophoblast, which is the layer of cells that surrounds the blastocyst; the blastocoel, which is the hollow cavity inside the blastocyst; and the inner cell mass, which is a group of approximately 30 cells at one end of the blastocoel.

B. How are embryonic stem cells grown in the laboratory?

Growing cells in the laboratory is known as cell culture. Human embryonic stem cells are isolated by transferring the inner cell mass into a plastic laboratory culture dish that contains a nutrient broth known as culture medium. The cells divide and spread over the surface of the dish. The inner surface of the culture dish is typically coated with mouse embryonic skin cells that have been treated so they will not divide. This coating layer of cells is called a feeder layer. The reason for having the mouse cells in the bottom of the culture dish is to give the inner cell mass cells a sticky surface to which they can attach. Also, the feeder cells release nutrients into the culture medium. Recently, scientists have begun to devise ways of growing embryonic stem cells without the mouse feeder cells. This is a significant scientific advancement because of the risk that viruses or other macromolecules in the mouse cells may be transmitted to the human cells.

Over the course of several days, the cells of the inner cell mass proliferate and begin to crowd the culture dish. When this occurs, they are removed gently and plated into several fresh culture dishes. The process of replating the cells is repeated many times and for many months, and is called subculturing. Each cycle of subculturing the cells is referred to as a passage. After six months or more, the original 30 cells of the inner cell mass yield millions of embryonic stem cells. Embryonic stem cells that have proliferated in cell culture for six or more months without differentiating, are pluripotent, and appear genetically normal are referred to as an embryonic stem cell line.

Once cell lines are established, or even before that stage, batches of them can be frozen and shipped to other laboratories for further culture and experimentation.

C. What laboratory tests are used to identify embryonic stem cells?

At various points during the process of generating embryonic stem cell lines, scientists test the cells to see whether they exhibit the fundamental properties that make them embryonic stem cells. This process is called characterization.

As yet, scientists who study human embryonic stem cells have not agreed on a standard battery of tests that measure the cells' fundamental properties. Also, scientists acknowledge that many of the tests they do use may not be good indicators of the cells' most important biological properties and functions. Nevertheless, laboratories that grow human embryonic stem cell lines use several kinds of tests. These tests include:

• growing and subculturing the stem cells for many months. This ensures that the cells are capable of long-term self-renewal. Scientists inspect the cultures through a microscope to see that the cells look healthy and remain undifferentiated.
• using specific techniques to determine the presence of surface markers that are found only on undifferentiated cells. Another important test is for the presence of a protein called Oct-4, which undifferentiated cells typically make. Oct-4 is a transcription factor, meaning that it helps turn genes on and off at the right time, which is an important part of the processes of cell differentiation and embryonic development.
• examining the chromosomes under a microscope. This is a method to assess whether the chromosomes are damaged or if the number of chromosomes has changed. It does not detect genetic mutations in the cells.
• determining whether the cells can be subcultured after freezing, thawing, and replating.
• testing whether the human embryonic stem cells are pluripotent by 1) allowing the cells to differentiate spontaneously in cell culture; 2) manipulating the cells so they will differentiate to form specific cell types; or 3) injecting the cells into an immunosuppressed mouse to test for the formation of a benign tumor called a teratoma. Teratomas typically contain a mixture of many differentiated or partly differentiated cell types—an indication that the embryonic stem cells are capable of differentiating into multiple cell types.

What are the unique properties of all stem cells?

Stem cells differ from other kinds of cells in the body. All stem cells—regardless of their source—have three general properties: they are capable of dividing and renewing themselves for long periods; they are unspecialized; and they can give rise to specialized cell types.

Scientists are trying to understand two fundamental properties of stem cells that relate to their long-term self-renewal:

1. why can embryonic stem cells proliferate for a year or more in the laboratory without differentiating, but most adult stem cells cannot; and
2. what are the factors in living organisms that normally regulate stem cell proliferation and self-renewal?

Discovering the answers to these questions may make it possible to understand how cell proliferation is regulated during normal embryonic development or during the abnormal cell division that leads to cancer. Importantly, such information would enable scientists to grow embryonic and adult stem cells more efficiently in the laboratory.

Stem cells are unspecialized. One of the fundamental properties of a stem cell is that it does not have any tissue-specific structures that allow it to perform specialized functions. A stem cell cannot work with its neighbors to pump blood through the body (like a heart muscle cell); it cannot carry molecules of oxygen through the bloodstream (like a red blood cell); and it cannot fire electrochemical signals to other cells that allow the body to move or speak (like a nerve cell). However, unspecialized stem cells can give rise to specialized cells, including heart muscle cells, blood cells, or nerve cells.

Stem cells are capable of dividing and renewing themselves for long periods. Unlike muscle cells, blood cells, or nerve cells—which do not normally replicate themselves—stem cells may replicate many times. When cells replicate themselves many times over it is called proliferation. A starting population of stem cells that proliferates for many months in the laboratory can yield millions of cells. If the resulting cells continue to be unspecialized, like the parent stem cells, the cells are said to be capable of long-term self-renewal.

The specific factors and conditions that allow stem cells to remain unspecialized are of great interest to scientists. It has taken scientists many years of trial and error to learn to grow stem cells in the laboratory without them spontaneously differentiating into specific cell types. For example, it took 20 years to learn how to grow human embryonic stem cells in the laboratory following the development of conditions for growing mouse stem cells. Therefore, an important area of research is understanding the signals in a mature organism that cause a stem cell population to proliferate and remain unspecialized until the cells are needed for repair of a specific tissue. Such information is critical for scientists to be able to grow large numbers of unspecialized stem cells in the laboratory for further experimentation.

Stem cells can give rise to specialized cells. When unspecialized stem cells give rise to specialized cells, the process is called differentiation. Scientists are just beginning to understand the signals inside and outside cells that trigger stem cell differentiation. The internal signals are controlled by a cell's genes, which are interspersed across long strands of DNA, and carry coded instructions for all the structures and functions of a cell. The external signals for cell differentiation include chemicals secreted by other cells, physical contact with neighboring cells, and certain molecules in the microenvironment.

Therefore, many questions about stem cell differentiation remain. For example, are the internal and external signals for cell differentiation similar for all kinds of stem cells? Can specific sets of signals be identified that promote differentiation into specific cell types? Addressing these questions is critical because the answers may lead scientists to find new ways of controlling stem cell differentiation in the laboratory, thereby growing cells or tissues that can be used for specific purposes including cell-based therapies.

Adult stem cells typically generate the cell types of the tissue in which they reside. A blood-forming adult stem cell in the bone marrow, for example, normally gives rise to the many types of blood cells such as red blood cells, white blood cells and platelets. Until recently, it had been thought that a blood-forming cell in the bone marrow—which is called a hematopoietic stem cell—could not give rise to the cells of a very different tissue, such as nerve cells in the brain. However, a number of experiments over the last several years have raised the possibility that stem cells from one tissue may be able to give rise to cell types of a completely different tissue, a phenomenon known as plasticity. Examples of such plasticity include blood cells becoming neurons, liver cells that can be made to produce insulin, and hematopoietic stem cells that can develop into heart muscle. Therefore, exploring the possibility of using adult stem cells for cell-based therapies has become a very active area of investigation by researchers.

Future!!

Stem Cells for the Future Treatment
of Parkinson's Disease

Parkinson's disease (PD) is a very common neurodegenerative disorder that affects more than 2% of the population over 65 years of age. PD is caused by a progressive degeneration and loss of dopamine (DA)-producing neurons, which leads to tremor, rigidity, and hypokinesia (abnormally decreased mobility). It is thought that PD may be the first disease to be amenable to treatment using stem cell transplantation. Factors that support this notion include the knowledge of the specific cell type (DA neurons) needed to relieve the symptoms of the disease. In addition, several laboratories have been successful in developing methods to induce embryonic stem cells to differentiate into cells with many of the functions of DA neurons.

In a recent study, scientists directed mouse embryonic stem cells to differentiate into DA neurons by introducing the gene Nurr1. When transplanted into the brains of a rat model of PD, these stem cell-derived DA neurons reinnervated the brains of the rat Parkinson model, released dopamine and improved motor function.

Regarding human stem cell therapy, scientists are developing a number of strategies for producing dopamine neurons from human stem cells in the laboratory for transplantation into humans with Parkinson's disease. The successful generation of an unlimited supply of dopamine neurons could make neurotransplantation widely available for Parkinson's patients at some point in the future.

What are stem cells and why are they important?

Stem cells have two important characteristics that distinguish them from other types of cells. First, they are unspecialized cells that renew themselves for long periods through cell division. The second is that under certain physiologic or experimental conditions, they can be induced to become cells with special functions such as the beating cells of the heart muscle or the insulin-producing cells of the pancreas.

Scientists primarily work with two kinds of stem cells from animals and humans: embryonic stem cells and adult stem cells, which have different functions and characteristics that will be explained in this document. Scientists discovered ways to obtain or derive stem cells from early mouse embryos more than 20 years ago. Many years of detailed study of the biology of mouse stem cells led to the discovery, in 1998, of how to isolate stem cells from human embryos and grow the cells in the laboratory. These are called human embryonic stem cells. The embryos used in these studies were created for infertility purposes through in vitro fertilization procedures and when they were no longer needed for that purpose, they were donated for research with the informed consent of the donor.

Stem cells are important for living organisms for many reasons. In the 3- to 5-day-old embryo, called a blastocyst, stem cells in developing tissues give rise to the multiple specialized cell types that make up the heart, lung, skin, and other tissues. In some adult tissues, such as bone marrow, muscle, and brain, discrete populations of adult stem cells generate replacements for cells that are lost through normal wear and tear, injury, or disease.

It has been hypothesized by scientists that stem cells may, at some point in the future, become the basis for treating diseases such as Parkinson's disease, diabetes, and heart disease.

Scientists want to study stem cells in the laboratory so they can learn about their essential properties and what makes them different from specialized cell types. As scientists learn more about stem cells, it may become possible to use the cells not just in cell-based therapies, but also for screening new drugs and toxins and understanding birth defects. However, as mentioned above, human embryonic stem cells have only been studied since 1998. Therefore, in order to develop such treatments scientists are intensively studying the fundamental properties of stem cells, which include:

1. determining precisely how stem cells remain unspecialized and self renewing for many years; and
2. identifying the signals that cause stem cells to become specialized cells.

I. Introduction

Research on stem cells is advancing knowledge about how an organism develops from a single cell and how healthy cells replace damaged cells in adult organisms. This promising area of science is also leading scientists to investigate the possibility of cell-based therapies to treat disease, which is often referred to as regenerative or reparative medicine.

Stem cells are one of the most fascinating areas of biology today. But like many expanding fields of scientific inquiry, research on stem cells raises scientific questions as rapidly as it generates new discoveries.

The NIH developed this primer to help readers understand the answers to questions such as: What are stem cells? What different types of stem cells are there and where do they come from? What is the potential for new medical treatments using stem cells? What research is needed to make such treatments a reality?

Stem Cell Basics

Stem cells have the remarkable potential to develop into many different cell types in the body. Serving as a sort of repair system for the body, they can theoretically divide without limit to replenish other cells as long as the person or animal is still alive. When a stem cell divides, each new cell has the potential to either remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell.

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