(Applies only to research conducted in the United States)
Sickle cell disease treatment has improved dramatically and the life expectancy of people who have sickle cell disease has been extended due to the research efforts of many people and the willingness of those who have sickle cell disease to participate in this research.
There are many different types of clinical trials and the analysis of the trials can involve complex statistics and protocols, beyond the basics of participation. Research 101 will address the basic information to help you become an informed participant in research.
The Institutional Review Board (IRB)
All studies involving humans have to be reviewed by an Institutional Review Board (IRB). There is an IRB in every hospital or clinic that participates in human research; the IRB is composed of people who know about the ethics of research, laypersons, physicians and others who volunteer to review the research conducted in a hospital or clinic. The IRB is concern is the consent process and whether or not the rights of the subjects are protected, whether the consent process is reasonable, and the consent itself is understandable and complete. There may or may not be members of the IRB who are knowledgeable about the research study itself. They rely on the investigators who conduct the research and any published literature to inform them about the study and the study goals.
There are two general categories of studies: Government funded and Industry funded
Government funded studies are studies that are funded by governmental agencies and institutions that receive support from the government; the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI), and the Health Resources and Services Administration (HRSA) are three of these government bodies that frequently fund research, there are other sources of government funding for research as well. Government funded studies are regulated by a the FDA and other bodies with very strict rules as to who and how subjects are selected and in what studies subjects can participate, for example there are specific rules for the participation of children.
Industry funded studies are those that are funded by a pharmaceutical company, a company that makes medical devices, or a company that has developed a new therapeutic intervention such as a new gene therapy or other biologic product or intervention. Generally, these studies are not obligated to follow the government regulations concerning research, but all have to have IRB approval in order to conduct a study in a hospital or clinic.
If the product or device is seeking approval for use by the Food and Drug Administration (FDA), there must be an investigational new drug or device (IND) authorization from the FDA. The company is then bound by the government regulations concerning research.
Phases of a Research Study in Humans
There are three “Phases” of evaluation of a new drug or procedure.
• Phase I: Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
• Phase II: The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety.
• Phase III: The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, the drug or treatment may be compared it to commonly used treatments, and to collect information that will allow the drug or treatment to be used safely.
• Phase IV: Studies are done after the drug or treatment has been marketed to gather information on the drug's effect in various populations and any side effects associated with long-term use.
The First Phase of Human Research
This is the first phase of human research following the development of a new treatment, device, biological product, or drug that has never been given to, or used on, humans. Prior to a Phase I study, there have usually been animal studies with small animals such as mice or in some cases primates, such a monkeys to show that the drug or biologic material is effective in these animal models and is not so toxic as to be life threatening.
Phase I studies are small studies with a few subjects generating a lot of information. The participants are the first humans to receive the new treatment or drug. In some cases, the subjects are paid to participate in these studies. The goal of a Phase I study is to determine whether the drug or procedure is safe, whether there are side effects that would be serious or life threatening, and at what dose or under what conditions do side effects of the drug or treatment occur.
Phase I studies are not designed to determine whether the drug or treatment is effective. They are safety studies. Although in some studies the effectiveness of the drug, biologic, therapy, or device can be inferred from the outcome of the Phase I study.
Phase I studies can be simple:
Testing one drug on subjects who are healthy and who have not recently been in other studies would be an example. The drug or treatment is given in different doses or under different conditions to evaluate which dose is the most effective and whether or not there are side effects at different doses. There are usually studies of organ function with laboratory testing to be sure there are no adverse effects on the kidney, the muscles, the blood, the chemicals in the blood (metabolic panel), and the endocrine system. The studies and tests are tailored to what would be expected from the drug or treatment. There are some types of outcome measures decided beforehand.
Phase I studies can be complex:
An example would be a new progenitor cell transplant protocol in which drug combinations are new or some of the drugs or processing of the progenitor cells is new, or gene therapy is used as a cancer therapy or to change the progenitor cell in some way. The subjects in this type of study would not be “healthy”; they would have to qualify as having a severe disease that could benefit from such a treatment. Cancer therapies are common Phase I studies.
Some studies do not meet the criteria for a Phase I protocol:
A study such as the STOP Study, which used red cell transfusions to see if they could prevent stroke in children with sickle cell disease, would not need to have a Phase I preliminary study as blood transfusions are standard treatment for people who have had a stroke due to sickle cell disease. In this case, there were several studies leading up to the STOP Study to show that ultrasound (a procedure already approved for evaluating blood flow in the brain) could predict the possibility of stroke in children who had sickle cell disease. Once there was evidence that blood flow in the brain could predict stroke, and blood transfusions were already used to decrease stroke recurrence after a stroke, the study could go forward.
Consent to participate in a study
All studies require informed consent from the subjects. There are rules about who can consent to studies such as children, people who are incarcerated, people who may not be able to understand the implications of being in a study.
In the case of Phase I studies the information for the consent process would be limited as there would be no prior experience with the drug or treatment in humans. For patients with cancer it is understandable that participation in a study that could prolong the subjects life and potentially the lives of others would be worthwhile. Patients with sickle cell disease who are at risk for serious complications such as stroke would also be candidates for Phase I studies that could benefit them and others with the same or similar risk factors.
Government funded studies follow government regulations; which state, among other things, that for studies in children the benefit of a Phase I study should outweigh the risks involved. These requirements would only apply to a government-sponsored study. Otherwise, this requirement may not apply.
More Information Online:
About IRB: http://www.hhs.gov/ohrp/
Additional Resource Information on clinical trials can be found at: http://clinicaltrials.gov/info/resources
Complex, but complete information on the regulations for governmental studies can be found in the
Federal Register: 21 CFR 50.52 (and 45 CFR 46.405), 21 CFR 50 subpart D, and 45 CFR 46 subpart D. These resources can be accessed through government sites or with a search engine on the internet.
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